{"paper_id":"46fb0d40-6139-4f11-b6f4-302df030d583","body_text":"Characterization and interactions between piperine and ezetimibe in their Anti-hyperlipidemic efficacy using Biopharmaceutics and Pharmacokinetics | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Characterization and interactions between piperine and ezetimibe in their Anti-hyperlipidemic efficacy using Biopharmaceutics and Pharmacokinetics Kavitha Marati, Sujatha Palatheeya, Ananda Kumar Chettupalli, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5194363/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jan, 2025 Read the published version in BMC Pharmacology and Toxicology → Version 1 posted 4 You are reading this latest preprint version Abstract Background The antihyperlipidemic action of Ezetimibe (EZ) is influenced by its secondary metabolite, piperine. Independent risk factors for cardiovascular illnesses, including atherosclerosis, include hyperlipidaemia. Preventing cardiovascular events and death in patients requires the use of antihyperlipidemic medications. We set out to find a way to make the BCS II lipid-lowering medication EZ more water-soluble. EZ is now very poorly soluble. Increasing the bioavailability of other medications is possible using piperine, a bioenhancer, without changing their base properties or improving their effectiveness. Method At dosages of 10 and 5–20 mg/kg b.w., the antihyperlipidemic efficacy of EZ with piperine was evaluated in vivo. Hyperlipidaemia in rats was tested using rats induced with propylthiouracil and rats administered Triton X-100. Propylthiouracil with piperine, 400 mg/kg body weight, should be administered together. Notably, there were notable increases in the blood concentrations of all three types of cholesterol (lipid levels, LDL, total cholesterol, and very low-density lipoprotein ) (p < 0.01). It resulted in HDL production (p < 0.01). One intraperitoneal Triton X-100 dosage increased lipids. Results Lower levels of high-density lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), and very low-density lipoprotein (VLDL) were significantly reduced by EZ at 100 mg/kg b.w. and piperine at 200 mg/kg b.w., respectively (p < 0.01 and p < 0.05). Liver histology studies provided further evidence supporting the present findings. Areas of concentrated periportal lymphocytes and hepatocytes formed a cord pattern in rats with hyperlipidaemia. It seemed like the hepatocytes, periportal area, and centrilobular part of the liver were all normal in the group who had the treatment. An analysis of the EZ plasma drug concentration with time was carried out in a research. The medication's most effective concentration (Cmax) was determined to be within 4 hours after delivery, and The quantified concentration of the active medication was detectable in the bloodstream for 24 hours. Conclusion The antioxidant and antihyperlipidemic properties of EZ when combined with piperine are particularly noteworthy. This suggests that EZ may have further applications in the treatment of hyperlipidaemia and atherosclerosis as a result of its capacity to increase the drug's oral absorption and availability. Piperine Ezitamibe Propylthiouracil Triton X-100 Bioavailability and anti-hyperlipidemic properties Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Introduction Approximately 2.6 million people die every year from hypercholesterolaemia (hyperlipidaemia), a condition defined by unusually high plasma cholesterol levels. This condition accounts for 4.5% of all fatalities worldwide. Atherosclerosis is characterised by increased levels of plasma triglycerides (> 200 mg/dL), reduced levels of HDL (< 40 mg/dL).) and increased LDL levels (> 190 mg/dL) [ 1 ]. Prolonged elevated cholesterol levels might increase the likelihood of developing certain cardiovascular illnesses. Typical anti-hyperlipidemic medications used to treat such risk factors include fibrates, bile acid-binding resins, and statins. Unfortunately, there is a long list of undesirable side effects linked to these medications, including problems with the oesophagus, aches and pains in the muscles and joints, and elevated liver enzyme activity. The optimisation of lipid-lowering treatment (especially in severe hypercholesterolaemia), side effects, statin tolerance, hereditary diseases, drug resistance, noncompliance, and other therapeutic issues continue. To decrease cholesterol while minimising the adverse effects of conventional lipid-lowering medications, novel, safe, and effective therapeutic agents are needed [ 2 ]. A new strategy has emerged that involves the combination of nonstatin medicines with low-intensity statins rather than high-intensity statins [ 3 ]. This technique improves statin tolerance and prevents dropout. Hyperlipidaemia—high serum and plasma lipid levels—is the main cause of mortality and disability globally. High levels of cholesterol and lipids in the blood are linked to most arterial, cerebrovascular, and cardiac illnesses [ 4 ]. Previous studies predicted a shocking 25–30% rise in worldwide mortality by 2020; yet, 30 percent fewer cardiovascular problems and deaths might be prevented with just a 10% drop in cholesterol levels [ 5 ]. Ezetimibe (EZ), the newest successful hypercholesterolaemia treatment after statins, lowers cholesterol [ 6 ]. EZ can be used alone or with statins to treat primary hypercholesterolaemia and decrease cholesterol. Tolerance and safety are its best qualities. Blocking the function of the Niemann-Pick C1-like 1 protein in the tiny intestine prevents cholesterol absorption but not fat-soluble vitamin or mineral absorption [ 7 ]. Due to its lower pharmacokinetic interactions with cytochrome P450-metabolized drugs, EZ is less likely to injure muscles [ 8 ]. EZ belongs to BCS Class II because to its low solubility in water and strong tissue permeability [ 9 ]. This very lipophilic molecule has subject-to-subject variability and a log p-value of 4.5 with oral bioavailability of 35–60%. Its rapid efflux via p-glycoprotein (P-Gp) and low dissolving rate and water solubility (0.00846 mg/mL) are the reasons behind its uncertain bioavailability [ 10 ]. The oral bioavailability of poorly soluble medications has been enhanced by the development of many approaches throughout the years. Accordingly, there are several advantages to these treatments and hardly any disadvantages [ 11 ]. They argues that their key benefits are to reduce the unpredictability of oral medicinal molecules, increase oral bioavailability, and reduce favourable dietary effects [ 12 ]. The metabolic processes including shikimate, acetate-malonate, and acetate-mevalonate provide the bulk of the hallucinogenic compounds included in herbal medicines. Alkaloids, peptides, polysaccharides (like gums and mucilages), resins, essential oils, phenolic glycosides (like flavonoids, cyanogens, and glucosinolates), terpenoids (such sesquiterpenes, steroids, carotenoids, and saponins), and volatile oils are all components found in plants. Complexity worsens the negative interactions that can occur between therapeutic drugs [ 13 ]. Given the limited understanding and investigation of botanical-drug interactions, more research into herbal medicine is essential to analyze specific plant constituents and elucidate their interactions with food and pharmaceuticals. Thus, it is crucial to study botanicals for therapeutic uses and promote their responsible and safe use, considering their impact, effectiveness, and ways of operation. As a result, a big problem with using both herbs and conventional medications is herb-drug interaction (HDI) [ 14 ]. The HDI of popular herbal remedies and extracts, alone and in conjunction with medicines, is being extensively studied [ 15 ]. Ayurveda and other Indian medicine prioritise natural bio-enhancers. These substances increase bioavailability and biological activity of active drugs, even at moderate dosages. Bio-enhancers lower dose and frequency while minimising toxicity and adverse pharmacological effects. Bio-enhancers increase the bioavailability and effectiveness of active medications, regardless of their pharmacological qualities. Bio-enhancers improve oral absorption, metabolism, and drug molecule conversion [ 16 ]. Long pepper (Piper longum L.) and white pepper (Piper nigrum L.) both have high piperine content [ 17 ]. Pepper has long been valued for its therapeutic, preservative, aromatic, and spicy properties, despite its PIP-related pungency [ 18 ]. According to recent studies, PIP has anti-inflammatory, immunomodulatory, anti-cancer, antispasmodic, anti-secretory, and anti-hyperlipidemic properties [ 19 ]. In pharmacokinetic investigations, PIP inhibits enzymes such as aryl hydroxylase, O-deethylase, cytochrome P450, UDP-glucuronosyl transferase, sulfotransferase, and CYP3A4 [ 20 ]. Piperine increases the bioavailability of rosuvastatin, peurarin, and docetaxel by blocking the actions of CYP3A4 and P-glycoprotein [ 21 ]. The supposed antihyperlipidemic potential of piperine is the reason why it is used in some herbal cardiotonic preparations [ 22 ]. These include Ridayarishta, Mahamrityunjaya rasa, Heart plus, Cardana, etc. Multiple studies have looked at how piperine affects the metabolism and absorption of different drugs. Besides anti-inflammatory and hepatoprotective effects, piperine is an effective antioxidant. Furthermore, it has been found to improve the absorption of pharmaceuticals like curcumin and simvastatin, while preserving their efficacy [ 23 ]. Therefore, we evaluated piperine's efficacy in increasing EZ bioavailability in this study without compromising hepatic function. Materials and Methods The sample of ezetimibe was provided by Sava Healthcare Ltd of Pune, India. Sava Healthcare Ltd of Pune, India, supplied the diclofenac sodium utilised as an internal standard, while Sigma Aldrich Chem.Co. of Mumbai, India, offered 97% pure piperine. Sigma-Aldrich in India supplied the medications, chemicals, and biochemical test kits for the research. All solvents and compounds were analytical-grade for HPLC. Analytical techniques used water filtered using a 0.25-µm membrane and double-distilled. Experimental animals The research utilized Sprague-Dawley rats. The National Institute of Nutrition, a public health, nutrition, and translational research entity in Hyderabad, India, under the Indian Council of Medical Research purchased 190–230 g male rats from an animal source. The seller's paperwork showed healthy, active rats. We set up our lab for 23°C and 12:12 light:dark. The mice were kept in polypropylene cages and given an unrestricted supply of water in addition to a pellet diet [ 24 ]. This study's use of animals was authorised by the Institutional Animal Ethics Committee (IAEC). The use of animals in toxicology was conducted in accordance with the standards established for animal care and procedures (Society of Toxicology USP 1989). Jeeva Life Sciences' Institutional IAEC, located in Uppal, Hyderabad, India (approval number: CPCSEA/IAEC/JLS/28/08/24/002). All procedures were carried out in accordance with CPCSEA guidelines. Classifying and preprocessing Two groups of five rats each were randomly allocated to the experiment after acclimatisation period of one week. Control animals on a regular diet were in Group 1. With regular pellet feed, Group 2 animals received a 10% fat, 2% cholesterol diet for 30 days. Documenting body weights before and after exams confirmed hypercholesterolaemia start. Therapeutic intervention and pharmacological delivery Therapeutic intervention and pharmacological delivery Four-week trial pharmaceutical interventions: Group 1 (Normal) was the normal saline control; group 2 (HFD) (high fat diet) was the disease control and received no pharmacological intervention; Group 3 (EZ) got EZ alone at 10 mg/kg/day as the medication control, Nevertheless, piperine (5 mg/kg/day) was administered alone to group 4 (PIP). At a dosage of 10 mg/kg/day for EZ and 5 mg/kg/day for piperine, Group 5 (EZ-PIP-5) was treated. Unit 6 (EZ-PIP-10) For oral treatment, maize oil was used. Group 1 and Group 2 received maize oil during the study. After 4 weeks, rats were slaughtered by cervical dislocation under ether anaesthesia after body weights were recorded [ 25 ]. Propylthiouracil induced hyperlipidemia Mice received 10 mg/kg orally and 0.01% intravenously of propylthiouracil (PTU) for 7 days to develop hyperlipidaemia. Subjects took the experimental drug orally on day eight [ 26 ]. Seven groups of six rats were randomly assigned. A control was normal saline for Group I patients. After receiving PTU (10 mg/kg body weight) for 1–8 days, Class II rats with severe lipidemia were administered 400 mg/kg of cholesterol on day 8. For Group III, the regimen consists of ten days of sterol (400 mg/kg body weight) administered after eight days of PTU (10 mg/kg body weight) or EZ (10 mg/kg body weight) alone. The fourth group begins PTU (10 mg/kg body weight) for 1–8 days in addition to 400 mg/kg cholesterol, 10 mg/kg EZ, and 5 mg/kg piperine on day 8. Participants in Group V are administered 10 mg/kg body weight of PTU on days 1 through 8. On eighth day they get 400 mg/kg cholesterol, EZ, and piperine. Group VI: Give 10 mg of PTU per kilogramme of body weight for 8 days, starting on day 1. On day 8, provide 400 mg/kg cholesterol. Give 10 mg EZ per kilogramme on day 8. Give 20 mg piperine per kilogramme on day eight. For Group VII's hyperlipidemic rats, the recommended dosage was 10 mg/kg of body weight of Simvastatin given on the same day as 400 mg/kg of cholesterol and PTU given for 1 to 8 days. The results shown cholesterol testing kit results on the seventh day. Hyperlipidemic rat model caused by Triton Each of the seven groups of rats consisted of six rats. Regular saline was given to the control group in Group I. One example of a Category II therapy is intravenous administration of Triton X-100 at a dose of 100 mg/kg. Triton X-100 (100 mg/kg body weight intraperitoneally) or EZ (10 mg/kg) were administered to the subjects in the third group. The fourth category of medications includes EZ (10 mg/kg), Triton X-100 (100 mg/kg intraperitoneally), Piperine (5 mg/kg), and Triton X-100. Triton X-100 (100 mg/kg intraperitoneally), EZ (10 mg/kg), and Piperine (10 mg/kg) make up the trio that comprises the sixth regimen. Step 6: Introduce the mixture intraperitoneally by mixing 100 mg/kg Triton X-100 with 10 mg/kg EZ and 20 mg/kg Piperine. Both Triton X-100 (100 mg/kg intraperitoneally) and Simvastatin (10 mg/kg) are part of Group VII [ 27 ]. In the results part cholesterol measurement kit results show lipid levels. Assessment of serum lipid metrics The abdominal aorta blood was drawn and coagulated at room temperature. Serum was extracted after 10 minutes of 3000 rpm centrifugation. In order to analyse lipid markers such as overall cholesterol (TC), triglyceride levels (TG), HDL, LDL, which is and VLDL, the samples were stored at 4°C [ 28 ]. Assessment of hepatic lipid and functional parameters Painstakingly, 0.5 g of rat livers were extracted and combined with 0.15 g of body mass per 1 mL of phosphate-buffered saline (PBS, pH 7.2). Centrifuging the mixture at 3000 rpm for 10 minutes separated the solids, and then the liquid phase was recovered and kept at 4°C., liver enzyme tests, we measured hepatic lipids and serum glutamate, SGOT, SGPT, and ALP. Enzyme assay kits were used [ 29 ]. Biochemical and histopathological studies Standard diagnostic kits were used to assess the concentrations of total lipids, total triglycerides, low-density lipoprotein, high-density lipoprotein, serum alanine aminotransferase, and total protein. We euthanised the animals and took their livers after blood collection during the experiment [ 30 ]. Before being embedded in paraffin for histological examination, the liver tissue specimens underwent washing in phosphate-buffered saline (PBS), fixation in 10% neutral buffered formalin, dehydration in rising alcohol grades, and storage. H&E dyes were applied to paraffin-preserved ultrathin slices (5 µm thickness) after microtomy. Using an Olympus E-330 imaging equipment and a BX51 light microscope from Tokyo, Japan, the slices were examined. Five slides each liver showed hepatotoxicity and liver damage. Molecular docking studies The ligand's proper orientation in protein active sites was determined using a molecular docking research, which also helped to decrease false positives. The ligands utilised in this investigation were docked to the active regions of proteins using AutoDock, an advanced molecular docking tool [ 31 , 32 ]. Human lanosterol 14alpha-demethylase (3LD6) and These X-ray crystal structures of C-Reactive Protein (1B09) were sourced from the Protein Data Bank ( http://www.rcsb.org/pdb ). To make the protein crystal structures dockable, we added hydrogen atoms, ordered the bonds, and removed any ions, water, or ligands. We used Marvin Sketch 5.11.4 to make the ligands, which include ezetimibe, piperine, and a conjugate of the two. MTT Cytotoxicity Assay To ascertain the cytotoxic effects of EZ, Piperine, and Group-VII, vero cells from Akkar Bitech Pune served as a control group. To evaluate the cytotoxic activity of the compounds following just minor modifications, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was employed [ 33 ]. We seeded 96-well plates with 3×10^5 cells/mL and incubated them at 37°C for one day after adding 100 µL of cells to each well, ensuring a density of 5% CO2. Each test sample's cells were treated in triplicate at different concentrations (0.39, 0.78, 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 µg/mL). Twenty microlitres of a 5 mg/mL MTT stock solution was added to each well after 72 hours, after the cell monolayers had been washed three times with sterile PBS. After incubating at 37°C for 4 hours, the wells were medium-free.To dissolve azan crystals, 200 µL of acidified isopropanol was used in each well. A 0.073-milliliter solution of 0.04% hydrochloric acid in 100% isopropanol produced isopropanol. The formazan solutions' 570 nm absorbance was measured with a multiwell plate reader. Formula for calculating live cell percentage. An online software estimated this [ 34 ]. Optical density (OD) determines the medication concentration that inhibits 50% of cellular growth. % viability = \\(\\:\\frac{\\text{M}\\text{e}\\text{a}\\text{n}\\:\\text{O}\\text{D}\\:\\text{T}\\text{r}\\text{e}\\text{a}\\text{t}\\text{e}\\text{d}\\:}{\\text{M}\\text{e}\\text{a}\\text{n}\\:\\text{O}\\text{D}\\:\\text{C}\\text{o}\\text{n}\\text{t}\\text{r}\\text{o}\\text{l}}\\) Estimation of EZ concentration in plasma Configuration of HPLC System HPLC reversed phase measured plasma pharmacological concentrations. The LC-10 AT-VP system from Shimadzu HPLC systems (Japan) employed an LC-20AT pump and SPD-10A UV detector. In the setup, the Phenomenex C18 analytical column (4.6 mm x 250 mm) was loaded with 5 µm particles. A Rheodyne 7725-I auto-injector was used to inject a 25 µL plasma sample. The combination of distilled water, acetonitrile, and 0.4% w/v phosphoric acid was filtered through a 0.25-µm membrane in the proportions 1953:47. In this investigation, 22.0°C and 1.2 mL/min were used. Up to 232.5 nm UV detection is effective [ 35 ]. Deproteination and plasma preparation On the last day of the study, the drugs were given using the above method. Samples of blood were taken from the retro-orbital plexus at 30, 1, 2, 4, 12, 16, and 24 hours after ether anaesthesia. Next, mix 1 mL of blood with 50 εL of the freshly prepared 0.02% sodium EDTA solution in a centrifuge tube [ 36 ]. Samples remained at -20°C until required. After 10 minutes of centrifugation at 3000 rpm, the material was blended with equal acetonitrile. Using cellulose acetate filter sheets, the organic layer was removed before being put into HPLC apparatus to measure EZ [ 37 ]. Comparative statistics We utilized GraphPad Prism 5.04 on Windows 10 to analyze the data. The data were taken from each iteration of the experimental process and presented as the mean standard deviation. Using Dunnett's test both in a one-way as well as a two-way variance analysis (ANOVA), we determined if there were significance levels. We considered P < 0.001 and P < 0.05 to be statistically significant. Results Impact of concurrent treatment of EZ and piperine weight increase Fluctuations on body weight The findings demonstrated that hyperlipidemia was effectively induced during 30 days, as the HFD group gained a significantly higher weight of 171.3 g compared to group-I (53.6 ± 6.94 g). The rat weights in the EZ group were around 65.29 ± 4.13g, which was considerably lower than in group-I. A similar outcome was accomplished by PIP.Weights were normalised and did not differ from group-I when EZ was given with 5 mg/kg piperine. Table 1 and Fig. 1 show that when the dosage of piperine was increased to 10 mg/kg and 20 mg/kg, respectively, a significant decrease in weight of -12.32 ± 4.65g and − 7.13 ± 2.35g was seen, in comparison to the initial weights. Table 1 EZ & piperine affect rat weight gain. Group Initial Weight (g) Final Weight (g) Weight Gain (g) Liver Weight (g) Relative to Initial body (g/ 100g) Relative to Final body (g/ 100g) I 215.34 ± 8.65 268.94 ± 13.54 53.6 ± 6.94 5.63 ± 1.35 2.25 ± 0.12 2.89 ± 0.95 II 214.39 ± 10.25 385.69 ± 10.69 171.3 ± 6.28 10.24 ± 0.26 5.34 ± 0.36 6.34 ± 1.84 III 206.85 ± 17.94 272.14 ± 16.35 65.29 ± 4.13 7.35 ± 0.38 3.61 ± 0.52 4.12 ± 1.62 IV 226.75 ± 18.53 302.64 ± 17.62 75.89 ± 3.64 6.94 ± 0.95 3.57 ± 0.48 4.36 ± 1.53 V 195.26 ± 11.42 259.86 ± 15.02 64.6 ± 0.95 5.96 ± 0.76 3.18 ± 0.31 3.85 ± 1.25 VI 204.53 ± 10.36 216.85 ± 16.94 -12.32 ± 4.65 4.32 ± 0.58 2.97 ± 0.29 3.62 ± 1.37 VII 210.46 ± 8.96 217.59 ± 15.23 -7.13 ± 2.35 5.13 ± 0.34 2.53 ± 0.12 3.45 ± 1.82 The standard deviation of rat weight with a 6-sample size is shown. An one-way ANOVA was performed to assess the data, and Dunnett's test determined statistical significance. A notable difference was highlighted by *P < 0.001 in comparison to group-I. aLoss of weight is indicated by negative readings. A significant change is shown by bP < 0.001, when comparing the liver weight to the original body weight. An increase in dietary carbohydrates and lipids has been linked to obesity [ 36 ]. A few studies have indicated that various HFD strains cause obesity in rats and mice [ 37 ]. It is true that certain rat strains, such A/J and C57BL, can become overweight being fed high-fat. Whenever given the exact same HFD, SWR rats showed no signs of becoming overweight. Hepatic weight variations Every rat's liver was weighed, and its weight was later determined by dividing the difference between its starting and ending weights by 100 grammes. The first group showed notable increases in liver weight (10.24 ± 0.26g) compared to the starting body weight and 5.34 ± 0.36g compared to the end weight.Group I's livers put on extra pounds and deposited more cholesterol and fat as a result. The other groups' relative liver weights were within the normal range and did not change substantially from their starting and ending body weights, as seen in Fig. 2 . Impact of concurrent treatment of EZ and piperine on lipid metrics Lipid profile of serum The high-fat diet raised serum lipid levels in rats. In contrast to normal rats, the HDF rats had a considerably higher TG content in their serum, reaching 246.31 ± 2.54mmol/L. Using piperine as a sole treatment did not appreciably reduce the high TG, and the value stayed at 182.43 ± 1.95mmol/L. In the EZ group, there was no discernible drop in TG levels. Table 2 Effect of EZ and piperine serum lipid profile on High fat diet method Group TG (mmol/L) TC (mmol/L) LDL (mmol/L) HDL (mmol/L) VLDL (mmol/L) I 96.35 ± 1.23 224.31 ± 2.13 112.43 ± 0.95 85.32 ± 0.95 21.34 ± 0.23 II 246.31 ± 2.54 312.64 ± 2.64 275.43 ± 1.34 20.46 ± 0.86 56.22 ± 0.15 III 221.37 ± 2.34 286.34 ± 2.95 95.64 ± 0.68 30.42 ± 0.75 43.48 ± 0.18 IV 197.26 ± 1.29 259.85 ± 2.48 84.12 ± 0.47 26.95 ± 0.64 37.47 ± 0.17 V 182.43 ± 1.95 226.45 ± 2.06 76.49 ± 0.59 35.42 ± 0.35 31.56 ± 0.16 VI 167.94 ± 1.37 203.54 ± 2.03 70.26 ± 0.65 46.35 ± 0.22 26.85 ± 0.09 VII 152.34 ± 1.29 186.95 ± 1.95 61.42 ± 0.28 51.23 ± 0.15 21.46 ± 0.11 We have established that atherosclerosis and myocardial infarction can result from elevated blood cholesterol and low-density lipoprotein levels. There is evidence that elevated serum triglycerides (TGs) contribute to the worsening of atherosclerosis [ 38 ]. Drugs that reduce oxygen Many studies show that TG, LDL, and cholesterol prevent heart disease [ 39 ]. The antiatherogenic phenols gallic acid and linoleic acid in green tea extracts lower blood triglycerides and cholesterol and increase energy expenditure, fat oxidation, and stools [ 40 ]. Nevertheless, the TG levels dropped to 182.43 ± 1.95, 167.94 ± 1.37, and 152.34 ± 1.29 mmol/L when piperine was administered with EZ at 5, 10, and 20 mg/kg, respectively. There were also noticeable shifts in the TC concentrations. The HDF group's TC level was 312.64 ± 2.64 mmol/L, which was lower than the usual group. The simultaneous treatment of EZ and piperine at 10 and 20 mg/kg reduced TC levels significantly. Table 2 – 4 shows that HDL levels increased following EZ treatment and simultaneously with piperine at all doses. Therefore, the efficacy of piperine therapy was enhanced when administered in conjunction with EZ. The lipid-lowering action of EZ was therefore significantly enhanced by the co-administration of piperine (Fig. 3 , Fig. 4 and Fig. 5 ). Table 3 Anti-hyperlipidemic activity for EZ heads on Propylthiouracil induced hyperlipidemic rats Group TG (mmol/L) TC (mmol/L) LDL (mmol/L) HDL (mmol/L) VLDL (mmol/L) I 95.64 ± 2.63 172.54 ± 2.69 93.46 ± 1.95 83.26 ± 2.39 18.34 ± 0.65 II 236.45 ± 2.84 269.85 ± 3.45 215.64 ± 2.64 20.43 ± 1.36 52.34 ± 0.42 III 139.85 ± 1.95 213.46 ± 2.75 149.68 ± 2.13 36.59 ± 2.31 31.24 ± 0.31 IV 126.95 ± 2.64 195.86 ± 1.03 123.46 ± 1.06 40.24 ± 0.64 26.59 ± 0.25 V 118.25 ± 2.13 169.84 ± 1.26 112.43 ± 1.05 52.36 ± 0.98 24.53 ± 0.13 VI 109.64 ± 1.34 156.34 ± 1.05 106.58 ± 1.27 59.84 ± 0.46 20.64 ± 0.32 VII 101.23 ± 1.26 142.35 ± 1.34 82.34 ± 1.05 67.21 ± 0.52 18.64 ± 0.16 Mean ± SEM (n = 6) values are shown. After ANOVA, The statistical analysis was conducted using Dunnett's test. We compared the outcomes to those of the control group, the hyperlipidemic control, and the standard (a = p ⋤ 0.01, b = p ≤ 0.05), with p-values ranging from 0.01 to 0.05 for the control group and 0.05 for hyperlipidemic control. Abnormal lipid profiles are a common pathogenic outcome of diabetes, found in 40% of diabetics. Diabetes causes hyperglycaemia, hypercholesterolaemia, and hypertriglyceridemia due to organ dysfunction in the heart, arteries, kidneys, eyes, and neurones [ 41 ]. In hyperlipidaemia, oxidative stress, lipid peroxidation, and reactive oxygen species (ROS) may only develop in a state of excess total cholesterol, or TC, and high-density lipoprotein cholesterol (LDL). Moreover, DNA and mitochondrial membrane oxidation are the primary contributors to significant cellular damage resulting from elevated ROS levels [ 42 – 44 ]. Studies have shown that OS is essential for the development and progression of several human disorders, such as CVI, CVD, and DM [ 45 – 47 ]. Accordingly, natural flavonoids like piperine have demonstrated strong antioxidant capabilities, which can halt or slow the progression of diseased states caused by harmful situations. More than that, persistent hyperlipidaemia raises the odds of developing advanced heart diseases such atherosclerosis [ 48 , 49 ]. Figure 5 shows the results of routine blood tests for total cholesterol (TC), total lipids (TG), low-density lipoprotein (LDL-C), and very low-density lipoprotein (VLDL-C) in rats that were put on a high-fat diet (HFD) to determine the effects of hyperlipidaemia. Table 4 Anti-hyperlipidemic activity for EZ heads on Triton induced hyperlipidemic rat’s Group TG (mmol/L) TC (mmol/L) LDL (mmol/L) HDL (mmol/L) VLDL (mmol/L) I 92.36 ± 1.95 165.94 ± 1.26 80.36 ± 2.34 68.53 ± 1.26 20.64 ± 0.24 II 223.47 ± 0.63 259.36 ± 1.34 201.26 ± 1.36 12.34 ± 0.35 52.31 ± 0.41 III 130.64 ± 0.85 195.84 ± 0.95 152.34 ± 2.59 39.64 ± 0.94 33.64 ± 0.31 IV 124.13 ± 1.04 185.74 ± 0.86 146.29 ± 3.12 46.24 ± 0.56 28.95 ± 0.26 V 115.64 ± 1.34 179.43 ± 0.36 124.75 ± 2.61 52.31 ± 0.67 26.49 ± 0.35 VI 106.95 ± 1.26 165.34 ± 0.62 109.46 ± 2.05 56.98 ± 0.83 20.64 ± 0.24 VII 101.42 ± 0.95 156.22 ± 0.52 98.54 ± 1.34 63.51 ± 0.46 19.35 ± 0.21 These results are provided as Mean ± SEM with a sample size of 6. We then utilised Dunnett's test for statistical analysis. Comparisons were made with the control group, hyperlipidemic control, and benchmarks. The significance levels were There are two outcomes: A and B, both with p-values less than or equal to 0.05. Rats as controls and atorvastatin-treated rats were compared to the EZ and piperin treatments. In rats given 5, 10, or 20 mg piperin, total cholesterol fell similarly to atorvastatin (10 mg). With 10 mg EZ, total cholesterol dropped significantly. Supporting these findings is the observation that rats without hyperlipidaemia had lower levels of TG, HDL, LDL, and VLDL. When rats were given ezetimibe and piperine together, the high-fat diet had less of an impact on them. Due to HFD, there was a significant rise in blood total cholesterol, triglycerides, LDL, and VLDL and a significant fall in HDL (p 0.01). After EZ was given, total cholesterol, triglycerides, LDL, and VLDL levels significantly decreased (bp < 0.01). EZ therapy also significantly raised HDL values. Examining lipid profile parameters changes caused by cholesterol intake and persistent high-fat diet consumption has helped determine the effects of pathophysiological alterations on blood homeostasis and EZ-piperin. We created hyperlipidaemia in rats by feeding them saturated fat and injecting propylthiouracil and triton X-100 orally. The injection of cholesterol raises plasma cholesterol levels. Triton X-100 and Propylthiouracil raised lipid levels and boosted duodenal cell cholesterol absorption into the bloodstream. Hyperlipidaemia was explored by measuring TC, TG, LDL, and HDL after a high-fat meal, Propylthiouracil, and Triton X-100 treatment developed it. Unsurprisingly, the control group's cholesterol levels were significantly lower than those of the high-fat diet group. Total cholesterol levels are higher in hyperlipidaemia, according to the data. The results show that EZ-Piperine significantly decreased total cholesterol when compared to the group on a high-fat diet. The HFD group had greater total and low-density lipoprotein levels when contrasted with the negativity control group. Unlike the high-fat diet groups treated with Propylthiouracil and Triton X-100, EZ-piperine significantly reduced TG and LDL levels in this research. Curiously, as compared to animals treated with EZ alone, mice given EZ-piperine (20 mg) exhibited remarkable improvements in HDL, triglyceride, and cholesterol levels. Hepatic lipid profile Table 5 shows blood lipid levels matched liver tissue homogenate lipid characteristics (TC and TG). however, piperine had a larger action when compared to EZ alone. Lipids in the liver were unaffected by EZ's ability to reduce blood lipid levels. Nevertheless, when compared to the individual medications, the combined effects of EZ and piperine were far more effective. For both TGs and TCs, the outcomes were comparable. Hepatic function test HFF rats' high lipid content in hepatic tissues may cause oxidative damage and large elevations in SGOT, SGPT, and ALP (Table 5 ). Both EZ and piperine significantly lowered these increases. The groups given medication or piperine alone had enzyme levels within the normal range despite a significant drop, indicating improved liver function. Taking both drugs together boosted liver function. Curiously, piperine dose-dependently increased hepatic activity, even at 10 mg/kg (Fig. 6 , Fig. 7 and Fig. 8 ). After being administered different dosages of EZ and piperine, rats that were treated with propylthiouracil (TRITON X-100), given a high-fat diet (HFD), or received no treatment whatsoever had their liver enzyme activity and total protein levels measured (Table 6 and Table 7 ). The enzymatic activities of liver function (SGOT, SGPT, and ALP) were found to be elevated in rats that were subjected to a high-fat diet (HFD), administered propylthiouracil (PT), or caused hyperlipidaemia, according to the results. Results were similar across dosages in the combination EZ and piperine groups., and in the groups treated with either compound alone, demonstrating substantial and normalising effects. At doses two times greater than the level of HFD, Propylthiouracil, and Triton X-100 (10 mg), EZ and piperine (at 10 and 20 mg) were just as effective as HFD, Propylthiouracil, and Triton X-100. In addition, both the 10 mg and 20 mg doses of EZ and piperine had a notable impact; however, the ideal dosage for hyperlipidaemia was found to be 20 mg. Interestingly, SGPT and ALP activities responded better to EZ with piperine's lowering effect than to EZ alone or combinations below 20 mg. After p.o. therapy with group VII (10 and 20 mg/kg), SGOT and SGPT levels significantly lowered (cp < 0.01). After treatment with EZ and piperine, ALP enzyme activity considerably lowered (dp < 0.05). EZ and piperine restored total protein levels in HDF-induced hyperlipidemic rats. Taking atorvastatin helped reduce hyperlipidemia-related levels of total protein, the SGOT, SGPT, and ALP in rats that were given a high-fat diet. Table 5 Hepatic lipid profile effects of EZ and piperine using High fat diet method Group TG (µmol/L) TC (µmol/L) SGOT (U/mmol) SGPT (U/mmol) ALP (U/mmol) I 25.63 ± 0.25 12.67 ± 0.12 26.35 ± 1.02 28.96 ± 1.02 5.23 ± 0.35 II 48.95 ± 0.36 40.29 ± 0.24 75.64 ± 1.32 a 85.43 ± 1.32 a 12.64 ± 0.64 b III 38.76 ± 0.42 24.67 ± 0.35 35.64 ± 1.42 c 40.25 ± 1.24 a 4.52 ± 0.85 d IV 31.24 ± 0.51 23.94 ± 0.13 30.42 ± 1.26 c 35.62 ± 1.52 c 5.24 ± 0.05 V 20.56 ± 0.36 15.86 ± 0.21 34.62 ± 1.08 32.69 ± 1.36 3.94 ± 0.04 VI 17.34 ± 0.25 12.43 ± 0.26 30.68 ± 1.27 30.64 ± 1.25 3.16 ± 0.36 VII 12.95 ± 0.22 6.26 ± 0.25 26.95 ± 1.35 c 26.49 ± 1.34 c 2.94 ± 0.57 c Table 6 Hepatic lipid profile effects of EZ and piperine using PIU method Group TG (µmol/L) TC (µmol/L) SGOT (U/mmol) SGPT (U/mmol) ALP (U/mmol) I 28.63 ± 0.26 15.63 ± 0.95 28.73 ± 0.12 30.59 ± 0.94 7.53 ± 0.21 II 46.95 ± 0.41 38.95 ± 0.86 79.41 ± 0.69 90.53 ± 0.57 15.94 ± 0.36 III 40.31 ± 0.35 26.74 ± 0.76 40.67 ± 0.45 45.76 ± 0.64 5.36 ± 0.51 IV 35.64 ± 0.11 20.48 ± 0.58 35.69 ± 0.21 40.11 ± 0.25 6.89 ± 0.42 V 25.94 ± 0.26 18.95 ± 0.64 35.42 ± 0.37 36.93 ± 0.31 4.97 ± 0.31 VI 19.46 ± 0.31 15.34 ± 0.31 26.49 ± 0.15 35.46 ± 0.12 4.02 ± 0.25 VII 15.42 ± 0.19 10.26 ± 0.11 20.87 ± 0.41 22.13 ± 0.42 3.16 ± 0.61 Table 7 Hepatic lipid profile effects of EZ and piperine using Triton X-100 induce method Group TG (µmol/L) TC (µmol/L) SGOT (U/mmol) SGPT (U/mmol) ALP (U/mmol) I 28.93 ± 0.39 15.94 ± 0.13 29.46 ± 0.95 32.46 ± 0.25 8.26 ± 0.26 II 52.36 ± 0.12 45.89 ± 0.14 82.41 ± 0.62 a 92.46 ± 0.85 a 16.49 ± 0.74 b III 43.12 ± 0.24 32.64 ± 0.21 40.56 ± 0.43 b 45.79 ± 0.76 b 6.24 ± 0.69 c IV 35.94 ± 0.21 36.94 ± 0.22 37.16 ± 0.15 c 41.36 ± 0.43 c 5.94 ± 0.28 b V 26.43 ± 0.31 20.79 ± 0.13 35.46 ± 0.18 a 35.94 ± 0.05 a 4.75 ± 0.36 a VI 20.69 ± 0.26 18.46 ± 0.15 32.46 ± 0.32 a 31.49 ± 0.04 a 3.94 ± 0.51 b VII 14.79 ± 0.27 9.76 ± 0.16 28.49 ± 0.26 c 27.41 ± 0.01 c 3.24 ± 0.34 c When there are six samples, the results are shown as the mean plus or minus the standard error of the mean. Statistical significance is determined when ap < 0.01 and bp < 0.05, in comparison to the normal control group. If cp < 0.01 and dp < 0.05, then there is statistical significance when compared to the HFD control group. Histopathological Examination Figure 9 shows that hepatic tissue samples from rats with HFD-induced hyperlipidaemia were more disorganised, had fatty alterations, and condensed nuclei than those from rats without HFD, It showed a well-structured liver with a central vein, bile duct, and cord-shaped hepatocytes.. Hepatocytes treated with EZ showed an improvement in cellular histoarchitectural shape, although the histopathology profile was unique from that of rats treated with piperine, which had condensed nuclei (Table 8 ). NAFLD prevalence ranges from 10–35%. contingent upon the demographic surveys and diagnostic methodologies employed. However, out of all chronic liver illnesses, the United States has the highest prevalence rate at 75% [ 50 ]. Theoretically, by influencing metabolic and lipid profiles, high-fat diets (HFDs) may exacerbate non-alcoholic fatty liver disease (NAFLD) [ 51 – 53 ]. Biochemical and histological results showed hepatic mutilation in 90-day high-fat diet (HFD) rats. When treated with EZ and piperine, enzyme activity decreased temporarily, demonstrating that the two drugs protected against hyperlipidaemia. Piperine and cobmination EZ shown to have considerable antihyperlipidemic and hepatoprotective properties, as indicated by the reduced incidence of high-fat diet-induced NAFLD. Cardiovascular disease can cause hyperlipidaemia, which is characterised by minimal and extremely low density lipoprotein cholesterol as well as high total cholesterol. WHO estimates that 40% of the global population suffers from hyperlipidaemia. This is concerning because high cholesterol is considered the leading cause of death (Organisation, 2019). Approximately 23.6% of adult Africans have dyslipidaemia, according to meta-analyses [ 54 ], whereas 31% of Asians are at high risk for hyperlipidaemia, according to other reports [ 55 ]. Fatty liver and myopathy are two of the several disorders that are more common in people with hyperlipidaemia. The impact of group VII on hepatic cells and skeletal muscle structure was investigated in this investigation. Histology confirms biochemical results in this research. Under the light microscope, liver tissue sections taken from the negative control group revealed a typical histological layout of the surrounding hepatocytes (A) and central vein (CV). In the positive control group, the liver portion had a few inflammatory cells, diffuse fatty change surrounding hepatocytes, a clogged cardiovascular system, enlarged sinusoids, and bile duct dilatation (B). Fewer fat vacuoles in hepatocytes, dilated sinusoids, minor congestion around the portal region, and modest bile duct dilatation (C) were seen in the liver tissues of animals treated with EZ solution. In contrast, animals given EZ and piperine exhibited a return to normal hepatic cord organisation around the portal vein and sinusoids. Pattern of hepatocytes known as mild cord. Mild haemorrhage and dilatation of the sinusoidal space. The Kupffer cells are operating normally (D). There was modest dilatation of the sinusoidal gaps and haemorrhage in the extrahepatic area (E), but the hepatocytes and periportal and centrilobular regions seemed normal. Periportal liver sinusoidal space dilatation was modest. (F), but otherwise the hepatocytes and periportal and centrilobular regions seemed normal. Hepatocyte cord pattern in a normal state. A few number of lymphocytes are present around the portal of entry. It seemed like the sinusoids and Kupffer cells were OK. A few number of lymphocytes are present around the portal of entry. G: No signs of fibrosis. Table 8 Effect of EZ-piperine alone and combination on histopathological changes Groups Vacuolization of Hepatocytes Enlargement Sinusoids Kupffer-Cell Infiltration Vascular Congestion I - - + - II +++ ++ +++ +++ III ++ ++ + + IV ++ ++ ++ ++ V + + - + VI + + - + VII - + - - ( ):Nil;(+):mild;(++):Moderate;(+++):Severe. Molecular interaction studies Two distinct receptors, human C-reactive protein (PDB ID: 1B09) and human lanosterol 14-alpha-demethylase (PDB ID: 3LD6), were analysed using molecular docking simulations to see how our formulations interacted with them. In order to better understand how our formulation interacts with these proteinsWe performed molecular docking experiments. To further our comprehension of the interaction between our formulation and these proteins, we performed molecular docking tests. The molecular docking results demonstrate that all of the compounds had lower binding energies relative to the gold standard medication Atorvastatin (-9.2 Kcal/mole) when applied to the human C-reactive protein receptor. Ezetimibe has two hydrogen bonds with amino acid residues Lys114 and Glu88 and a dock score of -8.4 Kcal/mole when taken alone. In contrast, our phytochemical piperic acid has a dock score of just − 6.6 Kcal/mole, suggesting that it does not interact significantly with the receptor on its own. Thr41, Ala92, Thr90, and Tyr73 are the amino acids with which piperic acid forms hydrogen bonds (Table 9 & Table 10 ). Ezetimibe and piperic acid, when formed into a conjugate, demonstrated promising outcomes. The conjugate docked with a binding score of -7.9 Kcal/mole, and it formed hydrogen bonds with Arg116 and Ser44 (Fig. 10 & Fig. 11 ). Accordingly, it appears that piperic acid will have a more favourable effect when combined with Ezetimibe rather than when used alone. In both cases, the hydrogen connection between piperic acid and Ser44 remains intact. However, when compared to being used alone, the way Ezetimibe interacts in conjugate formulation is completely different. Table 9 Molecular docking studies Interaction with 1B09 S. No Name of the compound Dock Score (kcal/mol) Interaction Type Amino acid involved Interaction with structural feature Distance (Ǻ) 1. Ezetimibe -8.4 H-bond H-bond π-π π-π π-π Lys114 Glu88 Val111 Val111 Val86, Val94 F O of OH Azatidine phenyl Phenyl 4.44 4.35 5.39 4.95 5.27, 6.45 2. Piperic acid -6.6 H-bond H-bond H-bond H-bond π-σ Thr41 Ala92 Tyr73 Thr90 Val86 O of C = O O of OH O of benzodioxol O of benzodioxol Phenyl 3.74 3.23 5.37 4.56 4.85 3. Ezetimibe and piperic acid conjugate -7.9 H-bond H-bond π-π Arg116 Ser44 Tyr73 O of COO F Phenyl 5.75 3.78 6.92 4. Atorvastatin -9.2 H-bond H-bond π-π Unfavourable doner-doner Phe42 Pro42 Tyr31 Arg82 OH of COOH OH of COOH phenyl OH of COOH 5.66 5.09 5.52 5.12 Table 10 Molecular docking studies Interaction with 3LD6 S. No Name of the compound Dock Score (kcal/mol) Interaction Type Amino acid involved Interaction with structural feature Distance (Ǻ) 1. Ezetimibe -10.6 π-π π-π π-π PHE34 TYR31 TRP39 Phenyl Phenyl Phenyl 6.23 4.56 4.44 2. Piperic acid -7.2 H-bond π-π Unfavourable doner-doner His89 Phe34 Ile79 O of COOH Phenyl O of COOH 3.47 5.19 3.60 3. Ezetimibe and piperic acid conjugate -11.5 H-bond π-π π-π π-π π-sulphur ARG82 Phe34 Tyr 31 Trp39 Met81 Flurine Phenyl and fluro-benzene Phenyl Phenyl Phenyl 5.53 6.06 6.74 4.10 6.30 4. Atorvastatin -8.7 H-bond H-bond π-π halogeb Asn61 Thr76 Phe66 Glu128, ASP140 F O of COOH Pyrrole F F 5.42 4.09 6.27 5.02 5.54 Molecular docking studies on the human C-reactive protein receptor revealed that, with the exception of piperic acid, all substances exhibited lower binding energies than the gold standard medication atorvastatin (-8.7 Kcal/mole). With three π-π bonds with amino acid residues Phe34, Tyr31, and Trp39, the medication Ezetimibe alone has a dock score of -10.6 Kcal/mole. However, with a dock score of just − 7.2 Kcal/mole, our phytochemical piperic acid has not demonstrated significant interaction with that receptor on its own. Piperic acid forms hydrogen bonds with the amino acid His89. Ezetimibe and piperic acid, when formed into a conjugate, demonstrated promising outcomes. Conjugate binding dock scores were − 11.5 Kcal/mole, and hydrogen bond interactions were observed with Arg82 and Phe34. Phe34, Tyr31, and Trp39 are amino acid residues that form π-π bonds with this compound. MTT Cytotoxicity Assay To confirm their safety, we evaluated EZ's cytotoxic effects using the MTT test., an optimised combination of EZ and pipierine, and piperine on normal Vero cells after 72 hours of treatment. In a manner that depends on the drug decreased the number of viable Vero cells compared to the control, with an IC50 value of 36.54 µg/mL (refer to Fig. 12 for details). Compared to the optimal combination of EZ and piperine, the medication suppressed cells more effectively at 259 µg/mL. According to experiments on typical Vero cells, EZ plus piperine was significantly safer than EZ alone [ 56 ]. The optimal outcomes from the pharmacological studies regarding in vitro characterization and cell survival were derived from an enhanced combination of EZ and piperine. Consequently, pharmacological research was undertaken on the optimized combination of EZ and piperine to elucidate the effect of the EZ solution on reducing cholesterol levels. Pharmacokinetic studies Enhancement of plasma concentration of EZ Table 11 presents the estimated plasma concentrations of EZ at different intervals post-injection. The concentration of EZ reached a maximum of 24.36 ± 1.36 µg/mL after 2 hours, then declining to half its value after 4 hours, EZ T1/2 and Cmax values match prior reports. Within 4.36 hours of administration, the highest plasma concentration of 159.86 ± 0.54 µg/mL was achieved after co-delivery of EZ and piperine at dosages of 10 + 20 mg, which was 100% more than the peak value when EZ was given alone. For twenty-four hours, the target plasma concentration was maintained. Piperine at 30 mg/kg did not change concentration. Thus, piperine and EZ enhanced the drug's plasma levels and slowed its elimination, confirming its improved action [ 57 ]. Figure 13 shows the evolution of the EZ plasma concentration following its concurrent treatment with piperine and with the passage of time (Fig. 13 ). Table 11 Pharmacokinetic studies of pure EZ solution and combination of EZ and Piperine solution Pharmacokinetic Parameters EZ solution Piperine solution EZ and piperine solution Intercept 1.278799 1.560009 1.820917 Slope -0.03723 -0.01811 -0.02158 Co (mcg/mL) 19.00198 36.30855 66.20892 K (hr-1) 0.085744 0.041701 0.049706 Dose (mg) 10 10 10 Dose (mcg) 10000 10000 10000 Vd (mL) 526.261 275.4172 151.037 Vd (L) 0.526261 0.275417 0.151037 t1/2 (hr) 8.082205 16.61823 13.94199 Cl (L/hr) 45.12369 11.48523 7.507444 AUC-o-t (mcg.hr/mL) 4.875494 9.202138 16.67723 AUC 1-t (mcg.hr/mL) 202.0825 573.825 1053.75 AUC 1-inf(mcg.hr/mL) 29.03996 323.2522 391.5022 AUC total (mcg.hr/mL) 235.998 906.2793 1461.929 Cmax (mcg.hr/mL) 24.36 61.25 159.86 Tmax (mL/min) 1.95 3.25 4.36 Discussion The majority of the small chemicals approved for use in medicine this decade have originated in nature. Some have speculated that the drug development process may be enhanced by shifting focus from finding new chemical entities to combining existing drugs. Increased dose, inadequate absorption, insufficient bioavailability, and patient noncompliance are further pharmacological drawbacks. Black pepper includes around 5 to 9 percent piperine, which is an active chemical component. It was recognised as a safe spice by the FDA, which categorised it as a herb. It would appear that the safe dosage of piperine, 15–20 mg per person per day, split, far above the human LD50 dose. Piperine can enhance the effectiveness of xenobiotics and decrease the dose frequency. The adverse effects and toxicity of the medication can be alleviated by co-administering piperine, which improves bioavailability at the site of action and reduces the required dosage. Lipid-rich plaque builds up in the coronary arteries and other major arteries, causing atherosclerosis. In vulnerable persons, a high-fat diet raises cholesterol and obesity risk. There is a correlation between cardiovascular disorders, particularly coronary artery disease, and an increased prevalence of hyperlipidaemia [ 15 ]. To raise the likelihood of ischaemic heart disease, blood lipid levels, overall cholesterol levels, and triglycerides must all be below average. according to several studies Cholesterol feeding is routinely employed to increase blood and tissue cholesterol levels in animal models utilized for investigating metabolic disorders associated with hypercholesterolemia. Hesperetin and piperine, two active compounds derived from plants, show tremendous potential as potential treatments and preventatives for several diseases. The neuroprotective properties of both drugs, such as antioxidant, anti-inflammatory, and hazardous protein aggregation inhibition, have been demonstrated in several studies. These chemicals have limited therapeutic use due to low bioavailability and insufficient solubility. Consequently, the pharmacological effects are not up to par since the blood concentrations are too low. We are attempting to develop amorphous systems as a solution to these issues. The scientists took into account the compounds' beneficial effect on enhancing bioavailability when they developed the dispersions. Conclusion Taking EZ with piperine at the same time can increase its efficacy by a factor of several, according to this study. EZ is already an excellent medicine for hyperlipidaemia. In vivo activity experiments showed piperine was a bio-enhancer at 20 mg/kg. Piperine improved EZ absorption and bioavailability without liver damage. The objective is to create effective formulations that target the molecular mechanisms that cause this activity, so that dosing is less frequent and the dosage remains adequate. It is important to understand how EZ and piperine interact with each other to ensure their safe and effective co-administration. Abbreviations EZ Ezetimibe LDL Lower levels of high-density lipoprotein TC total cholesterol TG triglycerides VLDL very low-density lipoprotein HDI herb-drug interaction IAEC Institutional Animal Ethics Committee PTU propylthiouracil HFD high-fat diet NAFLD non-alcoholic fatty liver disease CV central vein. Declarations I hereby declare that this submission is entirely my own work, in my own words, and that all sources used in researching it are fully acknowledged and all quotations properly identified. Ethics approval The use of animals in toxicology was conducted in accordance with the standards established for animal care and procedures (Society of Toxicology USP 1989). Jeeva Life Sciences' Institutional Animal Ethics Committee (IAEC), located in Uppal, Hyderabad, India (approval number: CPCSEA/IAEC/JLS/28/08/24/002). All procedures were carried out in accordance with CPCSEA guidelines. Consent to Participate Not applicable Consent for publication All the authors have read and agreed to the final copy of the finding as contained in the manuscript. Availability of data and materials The datasets/information used for this study is available on reasonable request. Funding The author(s) received no specific funding for this work. Authors' contributions Conceptualization: K.M. and S.P. Formal analysis and investigation: K.M. and S.P. Writing - original draft preparation: S.P.N.B. and A.K.C. Writing - review and editing: S.P.N.B., K.M., A.K.C. and S.P. Critically revised: A.K.C. and S.P. Funding acquisition: None Resources: S.P.N.B. Supervision: K.M. All authors read and approved the final manuscript. Acknowledgements The authors thank to University college of pharmaceutical sciences, Palamuru University for supporting this research work. 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Simple and Sensitive HPLC Method for Determination of Gemfibrozil in Human Plasma with Fluorescence Detection. J Liq Chromatogr Relat Technol. 2006;29:403–14. Bray GA, Fisler J, York DA. Neuroendocrine control of the development of obesity: understanding gained from studies of experimental animal models. Front Neuroendocr. 1990;11:128–81. Fresco P, Borges F, Marques MPM, Diniz C. The anticancer properties of dietary polyphenols and its relation with apoptosis. Curr Pharm Des. 2010;16:114–34. Langer T, Hoffmann RD. Virtual screening: an effective tool for lead structure discovery? Curr Pharm Des. 2001;7:509–27. Frostegård J. Systemic lupus erythematosus and cardiovascular disease. Lupus. 2008;17:364–7. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326:1423. Firdous SM, Hazra S, Gopinath SCB, El-Desouky GE, Aboul-Soud MAM. Antihyperlipidemic potential of diosmin in Swiss Albino mice with high-fat diet induced hyperlipidemia. Saudi J Biol Sci. 2021;28:109–15. Bhargava A, Raghuram GV, Pathak N, Varshney S, Jatawa SK, Jain D, et al. Occult hepatitis C virus elicits mitochondrial oxidative stress in lymphocytes and triggers PI3-kinase-mediated DNA damage response. Free Radic Biol Med. 2011;51:1806–14. Lu J, Ho DWC, Cao J. A unified synchronization criterion for impulsive dynamical networks. Automatica. 2010;46:1215–21. Yazdanparast R, Bahramikia S, Ardestani A. Nasturtium officinale reduces oxidative stress and enhances antioxidant capacity in hypercholesterolaemic rats. Chem Biol Interact. 2008;172:176–84. Feldo M, Woźniak M, Wójciak-Kosior M, Sowa I, Kot-Waśik A, Aszyk J, et al. Influence of Diosmin Treatment on the Level of Oxidative Stress Markers in Patients with Chronic Venous Insufficiency. Oxid Med Cell Longev. 2018;2018:2561705. Mahmoud AM, Hernández Bautista RJ, Sandhu MA, Hussein OE. Beneficial Effects of Citrus Flavonoids on Cardiovascular and Metabolic Health. Oxid Med Cell Longev. 2019;2019:5484138. Mahmoud JSR, Staten R, Hall LA, Lennie TA. The relationship among young adult college students’ depression, anxiety, stress, demographics, life satisfaction, and coping styles. Issues Ment Health Nurs. 2012;33:149–56. Martins IJ, Redgrave TG. Obesity and post-prandial lipid metabolism. Feast or famine? J Nutr Biochem. 2004;15:130–41. Mbikay M. Therapeutic Potential of Moringa oleifera Leaves in Chronic Hyperglycemia and Dyslipidemia: A Review. Front Pharmacol. 2012;3:24. El-Sheekh MM, Daboor SM, Swelim MA, Mohamed S. Production and characterization of antimicrobial active substance from Spirulina platensis. Iran J Microbiol. 2014;6:112–9. Altunkaynak A, Özger M, Çakmakci M. Water Consumption Prediction of Istanbul City by Using Fuzzy Logic Approach. Water Resour Manage. 2005;19:641–54. Conková E, Laciaková A, Pástorová B, Seidel H, Kovác G. The effect of zearalenone on some enzymatic parameters in rabbits. Toxicol Lett. 2001;121:145–9. Kameshwara KK, Sandoval-Hernandez A, Shields R, Dhanda KR. A false promise? Decentralization in education systems across the globe. Int J Educational Res. 2020;104:101669. Noubiap JJ, Bigna JJ, Nansseu JR, Nyaga UF, Balti EV, Echouffo-Tcheugui JB, et al. Prevalence of dyslipidaemia among adults in Africa: a systematic review and meta-analysis. Lancet Glob Health. 2018;6:e998–1007. Wu P-H, Aroush DR-B, Asnacios A, Chen W-C, Dokukin ME, Doss BL, et al. A comparison of methods to assess cell mechanical properties. Nat Methods. 2018;15:491–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Jan, 2025 Read the published version in BMC Pharmacology and Toxicology → Version 1 posted Editorial decision: Revision requested 07 Oct, 2024 Editor assigned by journal 03 Oct, 2024 Submission checks completed at journal 03 Oct, 2024 First submitted to journal 02 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-5194363\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":363988379,\"identity\":\"86cb0dc4-5fd4-4131-998b-785cad64b4d1\",\"order_by\":0,\"name\":\"Kavitha Marati\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University college of pharmaceutical sciences, Palamuru University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kavitha\",\"middleName\":\"\",\"lastName\":\"Marati\",\"suffix\":\"\"},{\"id\":363988383,\"identity\":\"69fca48a-2bbb-4b34-9f38-47a7f481ac42\",\"order_by\":1,\"name\":\"Sujatha Palatheeya\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University college of pharmaceutical sciences, Palamuru University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sujatha\",\"middleName\":\"\",\"lastName\":\"Palatheeya\",\"suffix\":\"\"},{\"id\":363988385,\"identity\":\"aa07256b-c9fe-4c30-97a8-3ebc109a04fd\",\"order_by\":2,\"name\":\"Ananda Kumar Chettupalli\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Galgotias University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ananda\",\"middleName\":\"Kumar\",\"lastName\":\"Chettupalli\",\"suffix\":\"\"},{\"id\":363988386,\"identity\":\"64b9ce89-a454-480c-94ff-f0d42e582df8\",\"order_by\":3,\"name\":\"Sarad Pawar Naik Bukke\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYDCCA2CSGcL5cECCRC2MM0jWwsxzgAgdfLePP/xcUWOdxz8j+dlnmzMWiQ3shx8w8/zCrUXyXI6x5Jlj6cUSN9KMZ+fckEhs4EkzYObtw63F4AwPg2QD2+HEhtsJxsw5H4BaGHIYmHl78Glhf/yz4d/hxPm30z8zW4C08L8hpIXBTLKx7XDihts5xswMIIdJAG3h+YHHL2d4zCwb+9KLDe+/KWbsOSNh3CbxzODg3AbcWviADrvZ8M06T+7M8c0MP47VyfbzJz988OYPbi0wkABnsQHxAcY2UrRAABG2jIJRMApGwYgBAI0UVhgzbaM9AAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Kampala International University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Sarad\",\"middleName\":\"Pawar Naik\",\"lastName\":\"Bukke\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-10-02 17:38:16\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-5194363/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-5194363/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s40360-025-00836-z\",\"type\":\"published\",\"date\":\"2025-01-14T15:58:02+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":69886578,\"identity\":\"0aa99080-c6bb-427c-aec7-d226e637b9a7\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:52:58\",\"extension\":\"jpeg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":359192,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eWeight fluctuations in rats subjected to treatment drug and piperine with different concentrations\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/e8ffae58d3ca0f9f84d44eea.jpeg\"},{\"id\":69885912,\"identity\":\"0bb1caac-3705-4457-8d31-9ce146dcc354\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":307109,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFluctuations in hepatic mass in relation to body mass in rats\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage2.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/49b15fc8f9e5bffd1f3cbd7d.jpeg\"},{\"id\":69888084,\"identity\":\"73a84830-fdb3-4ca0-8bd3-9778beebf682\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 10:00:58\",\"extension\":\"jpeg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":98976,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eEffect of EZ and piperine serum lipid profile on High fat diet method\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage3.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/3f61a667bd203ac146bcc6fb.jpeg\"},{\"id\":69885919,\"identity\":\"b0a403f5-1da6-4efa-be04-0456e470be16\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":443961,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHyperlipidaemia treatment is effective of EZ in Propylthiouracil-induced hyperlipidemic rats\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage4.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/b3a079fd5a246c27814dc78f.jpeg\"},{\"id\":69886579,\"identity\":\"e933aa6e-e6b0-42bb-b478-58e80a449ff1\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:52:58\",\"extension\":\"jpeg\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":470980,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eAnti-hyperlipidemic activity for EZ heads on Triton induced hyperlipidemic rats\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage5.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/d000164e23f2e45d30b5d15d.jpeg\"},{\"id\":69885916,\"identity\":\"87575a6c-c1c0-400d-8256-dc232745f07b\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":404161,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHepatic lipid profile effects of EZ and piperine using PIU method\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage6.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/9c908e4471061f1a51ae8aa7.jpeg\"},{\"id\":69886575,\"identity\":\"7f7fdbb2-b064-4979-8ae9-7eba3d0523db\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:52:58\",\"extension\":\"jpeg\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":400736,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHepatic: lipid profile effects of EZ and piperine using PIU method\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage7.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/e7cc87500af64aeef637928a.jpeg\"},{\"id\":69888085,\"identity\":\"c644234c-5bab-4520-92a4-fbe47eb8a450\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 10:00:58\",\"extension\":\"jpeg\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":414624,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHepatic lipid profile effects of EZ and piperine using Triton X-100 induce method\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage8.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/f265115ba6bade81af289828.jpeg\"},{\"id\":69885922,\"identity\":\"4e35f3eb-6dcf-452d-8657-6f76637db6c8\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":9,\"title\":\"Figure 9\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":532337,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHisopatholocal examination of HFD method Group-I to Group-VII\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage9.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/61a34b86e75841bd0f3ea1b2.jpeg\"},{\"id\":69885918,\"identity\":\"2887bb81-af90-43d5-9379-a2a3a6aeabc7\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":10,\"title\":\"Figure 10\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":395270,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eA\\u0026amp;B are E\\u0026amp;F, B\\u0026amp;C, and Docking models of ezetimibe and piperic acid with 1B09 protein A model for the docking of the 1B09 protein with ezetimibe and piperic acid.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage10.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/cbd5af77d149eae7635a9ada.jpeg\"},{\"id\":69885914,\"identity\":\"914db212-d0b3-4970-9e9d-dd139d6dbe1e\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":11,\"title\":\"Figure 11\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":371175,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eA \\u0026amp; B are The docking models of ezetimibe and piperic acid conjugate with 3LD6 protein are shown in E \\u0026amp; F, alongside the docking models of piperic acid and 3LD6 protein in B \\u0026amp; C.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage11.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/218e4e7c18e834e50a05426e.jpeg\"},{\"id\":69885924,\"identity\":\"7b5961a1-f99c-45e1-add4-f66be783e980\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 09:44:58\",\"extension\":\"jpeg\",\"order_by\":12,\"title\":\"Figure 12\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":419970,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDrug's effect on normal Vero cells, as opposed to untreated cells, as well as the optimised combination of EZ and pipierine, and piperine\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage12.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/3a7a8c8d74566bb198d4f696.jpeg\"},{\"id\":69888086,\"identity\":\"bf82fff2-8564-4a21-8b91-63a944194f89\",\"added_by\":\"auto\",\"created_at\":\"2024-11-26 10:00:58\",\"extension\":\"jpeg\",\"order_by\":13,\"title\":\"Figure 13\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":313278,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eConcentrations of EZ solution, piperine, and the optimised EZ/piperine solution in the blood changing over time.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage13.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/22a84fbf32079a02a074ad3e.jpeg\"},{\"id\":74284712,\"identity\":\"444021e8-3801-4b44-bf91-86aa06500267\",\"added_by\":\"auto\",\"created_at\":\"2025-01-20 16:11:27\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":6687176,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5194363/v1/d154b4b2-e1a3-41c7-86c4-1f109d83de42.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Characterization and interactions between piperine and ezetimibe in their Anti-hyperlipidemic efficacy using Biopharmaceutics and Pharmacokinetics\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eApproximately 2.6\\u0026nbsp;million people die every year from hypercholesterolaemia (hyperlipidaemia), a condition defined by unusually high plasma cholesterol levels. This condition accounts for 4.5% of all fatalities worldwide. Atherosclerosis is characterised by increased levels of plasma triglycerides (\\u0026gt;\\u0026thinsp;200 mg/dL), reduced levels of HDL (\\u0026lt;\\u0026thinsp;40 mg/dL).) and increased LDL levels (\\u0026gt;\\u0026thinsp;190 mg/dL) [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Prolonged elevated cholesterol levels might increase the likelihood of developing certain cardiovascular illnesses. Typical anti-hyperlipidemic medications used to treat such risk factors include fibrates, bile acid-binding resins, and statins. Unfortunately, there is a long list of undesirable side effects linked to these medications, including problems with the oesophagus, aches and pains in the muscles and joints, and elevated liver enzyme activity. The optimisation of lipid-lowering treatment (especially in severe hypercholesterolaemia), side effects, statin tolerance, hereditary diseases, drug resistance, noncompliance, and other therapeutic issues continue. To decrease cholesterol while minimising the adverse effects of conventional lipid-lowering medications, novel, safe, and effective therapeutic agents are needed [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. A new strategy has emerged that involves the combination of nonstatin medicines with low-intensity statins rather than high-intensity statins [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. This technique improves statin tolerance and prevents dropout. Hyperlipidaemia\\u0026mdash;high serum and plasma lipid levels\\u0026mdash;is the main cause of mortality and disability globally. High levels of cholesterol and lipids in the blood are linked to most arterial, cerebrovascular, and cardiac illnesses [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. Previous studies predicted a shocking 25\\u0026ndash;30% rise in worldwide mortality by 2020; yet, 30 percent fewer cardiovascular problems and deaths might be prevented with just a 10% drop in cholesterol levels [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eEzetimibe (EZ), the newest successful hypercholesterolaemia treatment after statins, lowers cholesterol [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. EZ can be used alone or with statins to treat primary hypercholesterolaemia and decrease cholesterol. Tolerance and safety are its best qualities. Blocking the function of the Niemann-Pick C1-like 1 protein in the tiny intestine prevents cholesterol absorption but not fat-soluble vitamin or mineral absorption [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. Due to its lower pharmacokinetic interactions with cytochrome P450-metabolized drugs, EZ is less likely to injure muscles [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eEZ belongs to BCS Class II because to its low solubility in water and strong tissue permeability [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. This very lipophilic molecule has subject-to-subject variability and a log p-value of 4.5 with oral bioavailability of 35\\u0026ndash;60%. Its rapid efflux via p-glycoprotein (P-Gp) and low dissolving rate and water solubility (0.00846 mg/mL) are the reasons behind its uncertain bioavailability [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. The oral bioavailability of poorly soluble medications has been enhanced by the development of many approaches throughout the years. Accordingly, there are several advantages to these treatments and hardly any disadvantages [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. They argues that their key benefits are to reduce the unpredictability of oral medicinal molecules, increase oral bioavailability, and reduce favourable dietary effects [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe metabolic processes including shikimate, acetate-malonate, and acetate-mevalonate provide the bulk of the hallucinogenic compounds included in herbal medicines. Alkaloids, peptides, polysaccharides (like gums and mucilages), resins, essential oils, phenolic glycosides (like flavonoids, cyanogens, and glucosinolates), terpenoids (such sesquiterpenes, steroids, carotenoids, and saponins), and volatile oils are all components found in plants. Complexity worsens the negative interactions that can occur between therapeutic drugs [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. Given the limited understanding and investigation of botanical-drug interactions, more research into herbal medicine is essential to analyze specific plant constituents and elucidate their interactions with food and pharmaceuticals. Thus, it is crucial to study botanicals for therapeutic uses and promote their responsible and safe use, considering their impact, effectiveness, and ways of operation. As a result, a big problem with using both herbs and conventional medications is herb-drug interaction (HDI) [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. The HDI of popular herbal remedies and extracts, alone and in conjunction with medicines, is being extensively studied [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eAyurveda and other Indian medicine prioritise natural bio-enhancers. These substances increase bioavailability and biological activity of active drugs, even at moderate dosages. Bio-enhancers lower dose and frequency while minimising toxicity and adverse pharmacological effects. Bio-enhancers increase the bioavailability and effectiveness of active medications, regardless of their pharmacological qualities. Bio-enhancers improve oral absorption, metabolism, and drug molecule conversion [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Long pepper (Piper longum L.) and white pepper (Piper nigrum L.) both have high piperine content [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]. Pepper has long been valued for its therapeutic, preservative, aromatic, and spicy properties, despite its PIP-related pungency [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. According to recent studies, PIP has anti-inflammatory, immunomodulatory, anti-cancer, antispasmodic, anti-secretory, and anti-hyperlipidemic properties [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. In pharmacokinetic investigations, PIP inhibits enzymes such as aryl hydroxylase, O-deethylase, cytochrome P450, UDP-glucuronosyl transferase, sulfotransferase, and CYP3A4 [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. Piperine increases the bioavailability of rosuvastatin, peurarin, and docetaxel by blocking the actions of CYP3A4 and P-glycoprotein [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. The supposed antihyperlipidemic potential of piperine is the reason why it is used in some herbal cardiotonic preparations [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. These include Ridayarishta, Mahamrityunjaya rasa, Heart plus, Cardana, etc.\\u003c/p\\u003e \\u003cp\\u003eMultiple studies have looked at how piperine affects the metabolism and absorption of different drugs. Besides anti-inflammatory and hepatoprotective effects, piperine is an effective antioxidant. Furthermore, it has been found to improve the absorption of pharmaceuticals like curcumin and simvastatin, while preserving their efficacy [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Therefore, we evaluated piperine's efficacy in increasing EZ bioavailability in this study without compromising hepatic function.\\u003c/p\\u003e\"},{\"header\":\"Materials and Methods\",\"content\":\"\\u003cp\\u003eThe sample of ezetimibe was provided by Sava Healthcare Ltd of Pune, India. Sava Healthcare Ltd of Pune, India, supplied the diclofenac sodium utilised as an internal standard, while Sigma Aldrich Chem.Co. of Mumbai, India, offered 97% pure piperine. Sigma-Aldrich in India supplied the medications, chemicals, and biochemical test kits for the research. All solvents and compounds were analytical-grade for HPLC. Analytical techniques used water filtered using a 0.25-\\u0026micro;m membrane and double-distilled.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eExperimental animals\\u003c/h2\\u003e \\u003cp\\u003eThe research utilized Sprague-Dawley rats. The National Institute of Nutrition, a public health, nutrition, and translational research entity in Hyderabad, India, under the Indian Council of Medical Research purchased 190\\u0026ndash;230 g male rats from an animal source. The seller's paperwork showed healthy, active rats. We set up our lab for 23\\u0026deg;C and 12:12 light:dark. The mice were kept in polypropylene cages and given an unrestricted supply of water in addition to a pellet diet [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. This study's use of animals was authorised by the Institutional Animal Ethics Committee (IAEC). The use of animals in toxicology was conducted in accordance with the standards established for animal care and procedures (Society of Toxicology USP 1989). Jeeva Life Sciences' Institutional IAEC, located in Uppal, Hyderabad, India (approval number: CPCSEA/IAEC/JLS/28/08/24/002). All procedures were carried out in accordance with CPCSEA guidelines.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eClassifying and preprocessing\\u003c/h3\\u003e\\n\\u003cp\\u003eTwo groups of five rats each were randomly allocated to the experiment after acclimatisation period of one week. Control animals on a regular diet were in Group 1. With regular pellet feed, Group 2 animals received a 10% fat, 2% cholesterol diet for 30 days. Documenting body weights before and after exams confirmed hypercholesterolaemia start.\\u003c/p\\u003e\\n\\u003ch3\\u003eTherapeutic intervention and pharmacological delivery\\u003c/h3\\u003e\\n\\u003cdiv class=\\\"Heading\\\"\\u003eTherapeutic intervention and pharmacological delivery\\u003c/div\\u003e \\u003cp\\u003eFour-week trial pharmaceutical interventions: Group 1 (Normal) was the normal saline control; group 2 (HFD) (high fat diet) was the disease control and received no pharmacological intervention; Group 3 (EZ) got EZ alone at 10 mg/kg/day as the medication control, Nevertheless, piperine (5 mg/kg/day) was administered alone to group 4 (PIP). At a dosage of 10 mg/kg/day for EZ and 5 mg/kg/day for piperine, Group 5 (EZ-PIP-5) was treated. Unit 6 (EZ-PIP-10) For oral treatment, maize oil was used. Group 1 and Group 2 received maize oil during the study. After 4 weeks, rats were slaughtered by cervical dislocation under ether anaesthesia after body weights were recorded [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e].\\u003c/p\\u003e\\n\\u003ch3\\u003ePropylthiouracil induced hyperlipidemia\\u003c/h3\\u003e\\n\\u003cp\\u003eMice received 10 mg/kg orally and 0.01% intravenously of propylthiouracil (PTU) for 7 days to develop hyperlipidaemia. Subjects took the experimental drug orally on day eight [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Seven groups of six rats were randomly assigned. A control was normal saline for Group I patients. After receiving PTU (10 mg/kg body weight) for 1\\u0026ndash;8 days, Class II rats with severe lipidemia were administered 400 mg/kg of cholesterol on day 8. For Group III, the regimen consists of ten days of sterol (400 mg/kg body weight) administered after eight days of PTU (10 mg/kg body weight) or EZ (10 mg/kg body weight) alone. The fourth group begins PTU (10 mg/kg body weight) for 1\\u0026ndash;8 days in addition to 400 mg/kg cholesterol, 10 mg/kg EZ, and 5 mg/kg piperine on day 8. Participants in Group V are administered 10 mg/kg body weight of PTU on days 1 through 8. On eighth day they get 400 mg/kg cholesterol, EZ, and piperine. Group VI: Give 10 mg of PTU per kilogramme of body weight for 8 days, starting on day 1. On day 8, provide 400 mg/kg cholesterol. Give 10 mg EZ per kilogramme on day 8. Give 20 mg piperine per kilogramme on day eight. For Group VII's hyperlipidemic rats, the recommended dosage was 10 mg/kg of body weight of Simvastatin given on the same day as 400 mg/kg of cholesterol and PTU given for 1 to 8 days. The results shown cholesterol testing kit results on the seventh day.\\u003c/p\\u003e\\n\\u003ch3\\u003eHyperlipidemic rat model caused by Triton\\u003c/h3\\u003e\\n\\u003cp\\u003eEach of the seven groups of rats consisted of six rats. Regular saline was given to the control group in Group I. One example of a Category II therapy is intravenous administration of Triton X-100 at a dose of 100 mg/kg. Triton X-100 (100 mg/kg body weight intraperitoneally) or EZ (10 mg/kg) were administered to the subjects in the third group. The fourth category of medications includes EZ (10 mg/kg), Triton X-100 (100 mg/kg intraperitoneally), Piperine (5 mg/kg), and Triton X-100. Triton X-100 (100 mg/kg intraperitoneally), EZ (10 mg/kg), and Piperine (10 mg/kg) make up the trio that comprises the sixth regimen. Step 6: Introduce the mixture intraperitoneally by mixing 100 mg/kg Triton X-100 with 10 mg/kg EZ and 20 mg/kg Piperine. Both Triton X-100 (100 mg/kg intraperitoneally) and Simvastatin (10 mg/kg) are part of Group VII [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]. In the results part cholesterol measurement kit results show lipid levels.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssessment of serum lipid metrics\\u003c/h2\\u003e \\u003cp\\u003eThe abdominal aorta blood was drawn and coagulated at room temperature. Serum was extracted after 10 minutes of 3000 rpm centrifugation. In order to analyse lipid markers such as overall cholesterol (TC), triglyceride levels (TG), HDL, LDL, which is and VLDL, the samples were stored at 4\\u0026deg;C [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e].\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eAssessment of hepatic lipid and functional parameters\\u003c/h3\\u003e\\n\\u003cp\\u003ePainstakingly, 0.5 g of rat livers were extracted and combined with 0.15 g of body mass per 1 mL of phosphate-buffered saline (PBS, pH 7.2). Centrifuging the mixture at 3000 rpm for 10 minutes separated the solids, and then the liquid phase was recovered and kept at 4\\u0026deg;C., liver enzyme tests, we measured hepatic lipids and serum glutamate, SGOT, SGPT, and ALP. Enzyme assay kits were used [\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e].\\u003c/p\\u003e\\n\\u003ch3\\u003eBiochemical and histopathological studies\\u003c/h3\\u003e\\n\\u003cp\\u003eStandard diagnostic kits were used to assess the concentrations of total lipids, total triglycerides, low-density lipoprotein, high-density lipoprotein, serum alanine aminotransferase, and total protein. We euthanised the animals and took their livers after blood collection during the experiment [\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. Before being embedded in paraffin for histological examination, the liver tissue specimens underwent washing in phosphate-buffered saline (PBS), fixation in 10% neutral buffered formalin, dehydration in rising alcohol grades, and storage. H\\u0026amp;E dyes were applied to paraffin-preserved ultrathin slices (5 \\u0026micro;m thickness) after microtomy. Using an Olympus E-330 imaging equipment and a BX51 light microscope from Tokyo, Japan, the slices were examined. Five slides each liver showed hepatotoxicity and liver damage.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eMolecular docking studies\\u003c/h2\\u003e \\u003cp\\u003eThe ligand's proper orientation in protein active sites was determined using a molecular docking research, which also helped to decrease false positives. The ligands utilised in this investigation were docked to the active regions of proteins using AutoDock, an advanced molecular docking tool [\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. Human lanosterol 14alpha-demethylase (3LD6) and These X-ray crystal structures of C-Reactive Protein (1B09) were sourced from the Protein Data Bank (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://www.rcsb.org/pdb\\u003c/span\\u003e\\u003cspan address=\\\"http://www.rcsb.org/pdb\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e). To make the protein crystal structures dockable, we added hydrogen atoms, ordered the bonds, and removed any ions, water, or ligands. We used Marvin Sketch 5.11.4 to make the ligands, which include ezetimibe, piperine, and a conjugate of the two.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eMTT Cytotoxicity Assay\\u003c/h2\\u003e \\u003cp\\u003eTo ascertain the cytotoxic effects of EZ, Piperine, and Group-VII, vero cells from Akkar Bitech Pune served as a control group. To evaluate the cytotoxic activity of the compounds following just minor modifications, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was employed [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]. We seeded 96-well plates with 3\\u0026times;10^5 cells/mL and incubated them at 37\\u0026deg;C for one day after adding 100 \\u0026micro;L of cells to each well, ensuring a density of 5% CO2. Each test sample's cells were treated in triplicate at different concentrations (0.39, 0.78, 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 \\u0026micro;g/mL). Twenty microlitres of a 5 mg/mL MTT stock solution was added to each well after 72 hours, after the cell monolayers had been washed three times with sterile PBS. After incubating at 37\\u0026deg;C for 4 hours, the wells were medium-free.To dissolve azan crystals, 200 \\u0026micro;L of acidified isopropanol was used in each well. A 0.073-milliliter solution of 0.04% hydrochloric acid in 100% isopropanol produced isopropanol. The formazan solutions' 570 nm absorbance was measured with a multiwell plate reader. Formula for calculating live cell percentage. An online software estimated this [\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e]. Optical density (OD) determines the medication concentration that inhibits 50% of cellular growth.\\u003c/p\\u003e \\u003cp\\u003e% viability = \\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\frac{\\\\text{M}\\\\text{e}\\\\text{a}\\\\text{n}\\\\:\\\\text{O}\\\\text{D}\\\\:\\\\text{T}\\\\text{r}\\\\text{e}\\\\text{a}\\\\text{t}\\\\text{e}\\\\text{d}\\\\:}{\\\\text{M}\\\\text{e}\\\\text{a}\\\\text{n}\\\\:\\\\text{O}\\\\text{D}\\\\:\\\\text{C}\\\\text{o}\\\\text{n}\\\\text{t}\\\\text{r}\\\\text{o}\\\\text{l}}\\\\)\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEstimation of EZ concentration in plasma\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec14\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eConfiguration of HPLC System\\u003c/h2\\u003e \\u003cp\\u003eHPLC reversed phase measured plasma pharmacological concentrations. The LC-10 AT-VP system from Shimadzu HPLC systems (Japan) employed an LC-20AT pump and SPD-10A UV detector. In the setup, the Phenomenex C18 analytical column (4.6 mm x 250 mm) was loaded with 5 \\u0026micro;m particles. A Rheodyne 7725-I auto-injector was used to inject a 25 \\u0026micro;L plasma sample. The combination of distilled water, acetonitrile, and 0.4% w/v phosphoric acid was filtered through a 0.25-\\u0026micro;m membrane in the proportions 1953:47. In this investigation, 22.0\\u0026deg;C and 1.2 mL/min were used. Up to 232.5 nm UV detection is effective [\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e].\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eDeproteination and plasma preparation\\u003c/h2\\u003e \\u003cp\\u003eOn the last day of the study, the drugs were given using the above method. Samples of blood were taken from the retro-orbital plexus at 30, 1, 2, 4, 12, 16, and 24 hours after ether anaesthesia. Next, mix 1 mL of blood with 50 εL of the freshly prepared 0.02% sodium EDTA solution in a centrifuge tube [\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e]. Samples remained at -20\\u0026deg;C until required. After 10 minutes of centrifugation at 3000 rpm, the material was blended with equal acetonitrile. Using cellulose acetate filter sheets, the organic layer was removed before being put into HPLC apparatus to measure EZ [\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e].\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eComparative statistics\\u003c/h2\\u003e \\u003cp\\u003eWe utilized GraphPad Prism 5.04 on Windows 10 to analyze the data. The data were taken from each iteration of the experimental process and presented as the mean standard deviation. Using Dunnett's test both in a one-way as well as a two-way variance analysis (ANOVA), we determined if there were significance levels. We considered P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001 and P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 to be statistically significant.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec18\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eImpact of concurrent treatment of EZ and piperine weight increase\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec19\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eFluctuations on body weight\\u003c/h2\\u003e \\u003cp\\u003eThe findings demonstrated that hyperlipidemia was effectively induced during 30 days, as the HFD group gained a significantly higher weight of 171.3 g compared to group-I (53.6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.94 g). The rat weights in the EZ group were around 65.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.13g, which was considerably lower than in group-I. A similar outcome was accomplished by PIP.Weights were normalised and did not differ from group-I when EZ was given with 5 mg/kg piperine. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e show that when the dosage of piperine was increased to 10 mg/kg and 20 mg/kg, respectively, a significant decrease in weight of -12.32\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.65g and \\u0026minus;\\u0026thinsp;7.13\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.35g was seen, in comparison to the initial weights.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eEZ \\u0026amp; piperine affect rat weight gain.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eInitial Weight\\u003c/p\\u003e \\u003cp\\u003e(g)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eFinal Weight\\u003c/p\\u003e \\u003cp\\u003e(g)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eWeight Gain\\u003c/p\\u003e \\u003cp\\u003e(g)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eLiver Weight\\u003c/p\\u003e \\u003cp\\u003e(g)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eRelative to Initial\\u003c/p\\u003e \\u003cp\\u003ebody (g/ 100g)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eRelative to Final\\u003c/p\\u003e \\u003cp\\u003ebody (g/ 100g)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e215.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e268.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;13.54\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e53.6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.94\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2.89\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e214.39\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e385.69\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10.69\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e171.3\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e10.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e6.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.84\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e206.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;17.94\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e272.14\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;16.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e65.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e7.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.38\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.61\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e4.12\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.62\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e226.75\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;18.53\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e302.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;17.62\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e75.89\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e6.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.57\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.48\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e4.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.53\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e195.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e259.86\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;15.02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e64.6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5.96\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.76\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.18\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e204.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e216.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;16.94\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e-12.32\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.32\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.58\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.97\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3.62\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.37\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e210.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.96\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e217.59\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;15.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e-7.13\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5.13\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.82\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe standard deviation of rat weight with a 6-sample size is shown. An one-way ANOVA was performed to assess the data, and Dunnett's test determined statistical significance. A notable difference was highlighted by *P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001 in comparison to group-I. aLoss of weight is indicated by negative readings. A significant change is shown by bP\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, when comparing the liver weight to the original body weight.\\u003c/p\\u003e \\u003cp\\u003eAn increase in dietary carbohydrates and lipids has been linked to obesity [\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e]. A few studies have indicated that various HFD strains cause obesity in rats and mice [\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e]. It is true that certain rat strains, such A/J and C57BL, can become overweight being fed high-fat. Whenever given the exact same HFD, SWR rats showed no signs of becoming overweight.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec20\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eHepatic weight variations\\u003c/h2\\u003e \\u003cp\\u003eEvery rat's liver was weighed, and its weight was later determined by dividing the difference between its starting and ending weights by 100 grammes. The first group showed notable increases in liver weight (10.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26g) compared to the starting body weight and 5.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36g compared to the end weight.Group I's livers put on extra pounds and deposited more cholesterol and fat as a result. The other groups' relative liver weights were within the normal range and did not change substantially from their starting and ending body weights, as seen in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec21\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eImpact of concurrent treatment of EZ and piperine on lipid metrics\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec22\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eLipid profile of serum\\u003c/h2\\u003e \\u003cp\\u003eThe high-fat diet raised serum lipid levels in rats. In contrast to normal rats, the HDF rats had a considerably higher TG content in their serum, reaching 246.31\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.54mmol/L. Using piperine as a sole treatment did not appreciably reduce the high TG, and the value stayed at 182.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95mmol/L. In the EZ group, there was no discernible drop in TG levels.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eEffect of EZ and piperine serum lipid profile on High fat diet method\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTG (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eTC (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eHDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eVLDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e96.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e224.31\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e112.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e85.32\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e21.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e246.31\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.54\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e312.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e275.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.86\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e56.22\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e221.37\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e286.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e95.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.68\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e30.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e43.48\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.18\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e197.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e259.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.48\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e84.12\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.47\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e37.47\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.17\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e182.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e226.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.06\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e76.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.59\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e35.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.56\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e167.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.37\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e203.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e70.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e46.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.22\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e26.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.09\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e152.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e186.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e61.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e51.23\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e21.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eWe have established that atherosclerosis and myocardial infarction can result from elevated blood cholesterol and low-density lipoprotein levels. There is evidence that elevated serum triglycerides (TGs) contribute to the worsening of atherosclerosis [\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e]. Drugs that reduce oxygen Many studies show that TG, LDL, and cholesterol prevent heart disease [\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e]. The antiatherogenic phenols gallic acid and linoleic acid in green tea extracts lower blood triglycerides and cholesterol and increase energy expenditure, fat oxidation, and stools [\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e]. Nevertheless, the TG levels dropped to 182.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95, 167.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.37, and 152.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.29 mmol/L when piperine was administered with EZ at 5, 10, and 20 mg/kg, respectively. There were also noticeable shifts in the TC concentrations. The HDF group's TC level was 312.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.64 mmol/L, which was lower than the usual group. The simultaneous treatment of EZ and piperine at 10 and 20 mg/kg reduced TC levels significantly. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e\\u0026ndash;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e shows that HDL levels increased following EZ treatment and simultaneously with piperine at all doses. Therefore, the efficacy of piperine therapy was enhanced when administered in conjunction with EZ. The lipid-lowering action of EZ was therefore significantly enhanced by the co-administration of piperine (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e and Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eAnti-hyperlipidemic activity for EZ heads on Propylthiouracil induced hyperlipidemic rats\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTG (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eTC (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eHDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eVLDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e95.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.63\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e172.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.69\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e93.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e83.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.39\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e18.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e236.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.84\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e269.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e215.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e52.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e139.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e213.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e149.68\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e36.59\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e31.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e126.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e195.86\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e123.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.06\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e40.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e26.59\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e118.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e169.84\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e112.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.05\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e52.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.98\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e24.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e109.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e156.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.05\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e106.58\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e59.84\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.46\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e20.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.32\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e101.23\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e142.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e82.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.05\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e67.21\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e18.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SEM (n\\u0026thinsp;=\\u0026thinsp;6) values are shown. After ANOVA, The statistical analysis was conducted using Dunnett's test. We compared the outcomes to those of the control group, the hyperlipidemic control, and the standard (a\\u0026thinsp;=\\u0026thinsp;p ⋤ 0.01, b\\u0026thinsp;=\\u0026thinsp;p\\u0026thinsp;\\u0026le;\\u0026thinsp;0.05), with p-values ranging from 0.01 to 0.05 for the control group and 0.05 for hyperlipidemic control.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eAbnormal lipid profiles are a common pathogenic outcome of diabetes, found in 40% of diabetics. Diabetes causes hyperglycaemia, hypercholesterolaemia, and hypertriglyceridemia due to organ dysfunction in the heart, arteries, kidneys, eyes, and neurones [\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e]. In hyperlipidaemia, oxidative stress, lipid peroxidation, and reactive oxygen species (ROS) may only develop in a state of excess total cholesterol, or TC, and high-density lipoprotein cholesterol (LDL). Moreover, DNA and mitochondrial membrane oxidation are the primary contributors to significant cellular damage resulting from elevated ROS levels [\\u003cspan additionalcitationids=\\\"CR43\\\" citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e]. Studies have shown that OS is essential for the development and progression of several human disorders, such as CVI, CVD, and DM [\\u003cspan additionalcitationids=\\\"CR46\\\" citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eAccordingly, natural flavonoids like piperine have demonstrated strong antioxidant capabilities, which can halt or slow the progression of diseased states caused by harmful situations. More than that, persistent hyperlipidaemia raises the odds of developing advanced heart diseases such atherosclerosis [\\u003cspan citationid=\\\"CR48\\\" class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e]. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e shows the results of routine blood tests for total cholesterol (TC), total lipids (TG), low-density lipoprotein (LDL-C), and very low-density lipoprotein (VLDL-C) in rats that were put on a high-fat diet (HFD) to determine the effects of hyperlipidaemia.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eAnti-hyperlipidemic activity for EZ heads on Triton induced hyperlipidemic rat\\u0026rsquo;s\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTG (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eTC (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eHDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eVLDL (mmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e165.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e80.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e68.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e20.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.24\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e223.47\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.63\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e259.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e201.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e52.31\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.41\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e130.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.85\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e195.84\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e152.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.59\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e39.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.94\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e33.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e124.13\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.04\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e185.74\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.86\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e146.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e46.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.56\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e28.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e115.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e179.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e124.75\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.61\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e52.31\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.67\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e26.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e106.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e165.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.62\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e109.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.05\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e56.98\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.83\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e20.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.24\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e101.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e156.22\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e98.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e63.51\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.46\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e19.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThese results are provided as Mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SEM with a sample size of 6. We then utilised Dunnett's test for statistical analysis. Comparisons were made with the control group, hyperlipidemic control, and benchmarks. The significance levels were There are two outcomes: A and B, both with p-values less than or equal to 0.05.\\u003c/p\\u003e \\u003cp\\u003eRats as controls and atorvastatin-treated rats were compared to the EZ and piperin treatments. In rats given 5, 10, or 20 mg piperin, total cholesterol fell similarly to atorvastatin (10 mg). With 10 mg EZ, total cholesterol dropped significantly. Supporting these findings is the observation that rats without hyperlipidaemia had lower levels of TG, HDL, LDL, and VLDL. When rats were given ezetimibe and piperine together, the high-fat diet had less of an impact on them. Due to HFD, there was a significant rise in blood total cholesterol, triglycerides, LDL, and VLDL and a significant fall in HDL (p 0.01). After EZ was given, total cholesterol, triglycerides, LDL, and VLDL levels significantly decreased (bp\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). EZ therapy also significantly raised HDL values.\\u003c/p\\u003e \\u003cp\\u003eExamining lipid profile parameters changes caused by cholesterol intake and persistent high-fat diet consumption has helped determine the effects of pathophysiological alterations on blood homeostasis and EZ-piperin. We created hyperlipidaemia in rats by feeding them saturated fat and injecting propylthiouracil and triton X-100 orally. The injection of cholesterol raises plasma cholesterol levels. Triton X-100 and Propylthiouracil raised lipid levels and boosted duodenal cell cholesterol absorption into the bloodstream. Hyperlipidaemia was explored by measuring TC, TG, LDL, and HDL after a high-fat meal, Propylthiouracil, and Triton X-100 treatment developed it. Unsurprisingly, the control group's cholesterol levels were significantly lower than those of the high-fat diet group. Total cholesterol levels are higher in hyperlipidaemia, according to the data. The results show that EZ-Piperine significantly decreased total cholesterol when compared to the group on a high-fat diet. The HFD group had greater total and low-density lipoprotein levels when contrasted with the negativity control group. Unlike the high-fat diet groups treated with Propylthiouracil and Triton X-100, EZ-piperine significantly reduced TG and LDL levels in this research. Curiously, as compared to animals treated with EZ alone, mice given EZ-piperine (20 mg) exhibited remarkable improvements in HDL, triglyceride, and cholesterol levels.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec23\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eHepatic lipid profile\\u003c/h2\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e shows blood lipid levels matched liver tissue homogenate lipid characteristics (TC and TG). however, piperine had a larger action when compared to EZ alone. Lipids in the liver were unaffected by EZ's ability to reduce blood lipid levels. Nevertheless, when compared to the individual medications, the combined effects of EZ and piperine were far more effective. For both TGs and TCs, the outcomes were comparable.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec24\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eHepatic function test\\u003c/h2\\u003e \\u003cp\\u003eHFF rats' high lipid content in hepatic tissues may cause oxidative damage and large elevations in SGOT, SGPT, and ALP (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e). Both EZ and piperine significantly lowered these increases. The groups given medication or piperine alone had enzyme levels within the normal range despite a significant drop, indicating improved liver function. Taking both drugs together boosted liver function. Curiously, piperine dose-dependently increased hepatic activity, even at 10 mg/kg (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003e, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig7\\\" class=\\\"InternalRef\\\"\\u003e7\\u003c/span\\u003e and Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig8\\\" class=\\\"InternalRef\\\"\\u003e8\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eAfter being administered different dosages of EZ and piperine, rats that were treated with propylthiouracil (TRITON X-100), given a high-fat diet (HFD), or received no treatment whatsoever had their liver enzyme activity and total protein levels measured (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003e and Table\\u0026nbsp;\\u003cspan refid=\\\"Tab7\\\" class=\\\"InternalRef\\\"\\u003e7\\u003c/span\\u003e). The enzymatic activities of liver function (SGOT, SGPT, and ALP) were found to be elevated in rats that were subjected to a high-fat diet (HFD), administered propylthiouracil (PT), or caused hyperlipidaemia, according to the results. Results were similar across dosages in the combination EZ and piperine groups., and in the groups treated with either compound alone, demonstrating substantial and normalising effects. At doses two times greater than the level of HFD, Propylthiouracil, and Triton X-100 (10 mg), EZ and piperine (at 10 and 20 mg) were just as effective as HFD, Propylthiouracil, and Triton X-100. In addition, both the 10 mg and 20 mg doses of EZ and piperine had a notable impact; however, the ideal dosage for hyperlipidaemia was found to be 20 mg.\\u003c/p\\u003e \\u003cp\\u003eInterestingly, SGPT and ALP activities responded better to EZ with piperine's lowering effect than to EZ alone or combinations below 20 mg. After p.o. therapy with group VII (10 and 20 mg/kg), SGOT and SGPT levels significantly lowered (cp\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). After treatment with EZ and piperine, ALP enzyme activity considerably lowered (dp\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). EZ and piperine restored total protein levels in HDF-induced hyperlipidemic rats. Taking atorvastatin helped reduce hyperlipidemia-related levels of total protein, the SGOT, SGPT, and ALP in rats that were given a high-fat diet.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab5\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 5\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eHepatic lipid profile effects of EZ and piperine using High fat diet method\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTG (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eTC (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eSGOT (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eSGPT (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eALP (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e25.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e12.67\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e26.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e28.96\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5.23\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e48.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e40.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.24\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e75.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.32\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e85.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.32 \\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e12.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.64 \\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e38.76\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e24.67\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e35.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.42 \\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e40.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.24 \\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4.52\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.85 \\u003csup\\u003ed\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e31.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.51\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e23.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e30.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26 \\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e35.62\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.52 \\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.05\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e20.56\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15.86\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e34.62\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.08\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e32.69\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.04\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e17.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e12.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e30.68\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e30.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.16\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e12.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.22\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e26.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.35 \\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.34 \\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.57 \\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab6\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 6\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eHepatic lipid profile effects of EZ and piperine using PIU method\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTG (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eTC (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eSGOT (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eSGPT (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eALP (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e28.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e28.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e30.59\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.94\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e7.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e46.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.41\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e38.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.86\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e79.41\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.69\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e90.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.57\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e15.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e40.31\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e26.74\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.76\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e40.67\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e45.76\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.51\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e35.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e20.48\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.58\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e35.69\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e40.11\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e6.89\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e25.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18.95\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e35.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.37\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e36.93\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4.97\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e19.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e26.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e35.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4.02\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e15.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.19\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e20.87\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.41\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e22.13\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.16\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.61\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab7\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 7\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eHepatic lipid profile effects of EZ and piperine using Triton X-100 induce method\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTG (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eTC (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eSGOT (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eSGPT (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eALP (U/mmol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e28.93\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.39\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e29.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e32.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e8.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e52.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e45.89\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.14\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e82.41\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.62\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e92.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.85\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e16.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.74\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e43.12\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.24\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e32.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e40.56\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.43\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e45.79\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.76\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e6.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.69\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e35.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e36.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.22\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e37.16\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.15\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e41.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.43\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.28\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e26.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e20.79\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e35.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.18\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e35.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.05\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4.75\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.36\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e20.69\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e32.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.32\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e31.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.04\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.51\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e14.79\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9.76\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e28.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.26\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e27.41\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.01\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.24\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.34\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eWhen there are six samples, the results are shown as the mean plus or minus the standard error of the mean. Statistical significance is determined when ap\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01 and bp\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05, in comparison to the normal control group. If cp\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01 and dp\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05, then there is statistical significance when compared to the HFD control group.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cdiv id=\\\"Sec25\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eHistopathological Examination\\u003c/h2\\u003e \\u003cp\\u003eFigure \\u003cspan refid=\\\"Fig9\\\" class=\\\"InternalRef\\\"\\u003e9\\u003c/span\\u003e shows that hepatic tissue samples from rats with HFD-induced hyperlipidaemia were more disorganised, had fatty alterations, and condensed nuclei than those from rats without HFD, It showed a well-structured liver with a central vein, bile duct, and cord-shaped hepatocytes.. Hepatocytes treated with EZ showed an improvement in cellular histoarchitectural shape, although the histopathology profile was unique from that of rats treated with piperine, which had condensed nuclei (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab8\\\" class=\\\"InternalRef\\\"\\u003e8\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eNAFLD prevalence ranges from 10\\u0026ndash;35%. contingent upon the demographic surveys and diagnostic methodologies employed. However, out of all chronic liver illnesses, the United States has the highest prevalence rate at 75% [\\u003cspan citationid=\\\"CR50\\\" class=\\\"CitationRef\\\"\\u003e50\\u003c/span\\u003e]. Theoretically, by influencing metabolic and lipid profiles, high-fat diets (HFDs) may exacerbate non-alcoholic fatty liver disease (NAFLD) [\\u003cspan additionalcitationids=\\\"CR52\\\" citationid=\\\"CR51\\\" class=\\\"CitationRef\\\"\\u003e51\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR53\\\" class=\\\"CitationRef\\\"\\u003e53\\u003c/span\\u003e]. Biochemical and histological results showed hepatic mutilation in 90-day high-fat diet (HFD) rats. When treated with EZ and piperine, enzyme activity decreased temporarily, demonstrating that the two drugs protected against hyperlipidaemia. Piperine and cobmination EZ shown to have considerable antihyperlipidemic and hepatoprotective properties, as indicated by the reduced incidence of high-fat diet-induced NAFLD.\\u003c/p\\u003e \\u003cp\\u003eCardiovascular disease can cause hyperlipidaemia, which is characterised by minimal and extremely low density lipoprotein cholesterol as well as high total cholesterol. WHO estimates that 40% of the global population suffers from hyperlipidaemia. This is concerning because high cholesterol is considered the leading cause of death (Organisation, 2019). Approximately 23.6% of adult Africans have dyslipidaemia, according to meta-analyses [\\u003cspan citationid=\\\"CR54\\\" class=\\\"CitationRef\\\"\\u003e54\\u003c/span\\u003e], whereas 31% of Asians are at high risk for hyperlipidaemia, according to other reports [\\u003cspan citationid=\\\"CR55\\\" class=\\\"CitationRef\\\"\\u003e55\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eFatty liver and myopathy are two of the several disorders that are more common in people with hyperlipidaemia. The impact of group VII on hepatic cells and skeletal muscle structure was investigated in this investigation. Histology confirms biochemical results in this research. Under the light microscope, liver tissue sections taken from the negative control group revealed a typical histological layout of the surrounding hepatocytes (A) and central vein (CV). In the positive control group, the liver portion had a few inflammatory cells, diffuse fatty change surrounding hepatocytes, a clogged cardiovascular system, enlarged sinusoids, and bile duct dilatation (B). Fewer fat vacuoles in hepatocytes, dilated sinusoids, minor congestion around the portal region, and modest bile duct dilatation (C) were seen in the liver tissues of animals treated with EZ solution. In contrast, animals given EZ and piperine exhibited a return to normal hepatic cord organisation around the portal vein and sinusoids. Pattern of hepatocytes known as mild cord. Mild haemorrhage and dilatation of the sinusoidal space. The Kupffer cells are operating normally (D). There was modest dilatation of the sinusoidal gaps and haemorrhage in the extrahepatic area (E), but the hepatocytes and periportal and centrilobular regions seemed normal. Periportal liver sinusoidal space dilatation was modest. (F), but otherwise the hepatocytes and periportal and centrilobular regions seemed normal. Hepatocyte cord pattern in a normal state. A few number of lymphocytes are present around the portal of entry. It seemed like the sinusoids and Kupffer cells were OK. A few number of lymphocytes are present around the portal of entry. G: No signs of fibrosis.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab8\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 8\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eEffect of EZ-piperine alone and combination on histopathological changes\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGroups\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eVacuolization of\\u003c/p\\u003e \\u003cp\\u003eHepatocytes\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEnlargement Sinusoids\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eKupffer-Cell\\u003c/p\\u003e \\u003cp\\u003eInfiltration\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVascular Congestion\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e+++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e+++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e+++\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e++\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e( ):Nil;(+):mild;(++):Moderate;(+++):Severe.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec26\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eMolecular interaction studies\\u003c/h2\\u003e \\u003cp\\u003eTwo distinct receptors, human C-reactive protein (PDB ID: 1B09) and human lanosterol 14-alpha-demethylase (PDB ID: 3LD6), were analysed using molecular docking simulations to see how our formulations interacted with them. In order to better understand how our formulation interacts with these proteinsWe performed molecular docking experiments. To further our comprehension of the interaction between our formulation and these proteins, we performed molecular docking tests.\\u003c/p\\u003e \\u003cp\\u003eThe molecular docking results demonstrate that all of the compounds had lower binding energies relative to the gold standard medication Atorvastatin (-9.2 Kcal/mole) when applied to the human C-reactive protein receptor. Ezetimibe has two hydrogen bonds with amino acid residues Lys114 and Glu88 and a dock score of -8.4 Kcal/mole when taken alone. In contrast, our phytochemical piperic acid has a dock score of just \\u0026minus;\\u0026thinsp;6.6 Kcal/mole, suggesting that it does not interact significantly with the receptor on its own. Thr41, Ala92, Thr90, and Tyr73 are the amino acids with which piperic acid forms hydrogen bonds (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab9\\\" class=\\\"InternalRef\\\"\\u003e9\\u003c/span\\u003e \\u0026amp; Table\\u0026nbsp;\\u003cspan refid=\\\"Tab10\\\" class=\\\"InternalRef\\\"\\u003e10\\u003c/span\\u003e). Ezetimibe and piperic acid, when formed into a conjugate, demonstrated promising outcomes. The conjugate docked with a binding score of -7.9 Kcal/mole, and it formed hydrogen bonds with Arg116 and Ser44 (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig10\\\" class=\\\"InternalRef\\\"\\u003e10\\u003c/span\\u003e \\u0026amp; Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig11\\\" class=\\\"InternalRef\\\"\\u003e11\\u003c/span\\u003e). Accordingly, it appears that piperic acid will have a more favourable effect when combined with Ezetimibe rather than when used alone. In both cases, the hydrogen connection between piperic acid and Ser44 remains intact. However, when compared to being used alone, the way Ezetimibe interacts in conjugate formulation is completely different.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab9\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 9\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eMolecular docking studies Interaction with 1B09\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eS. No\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eName of the compound\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eDock Score (kcal/mol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInteraction Type\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eAmino acid involved\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eInteraction with structural feature\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eDistance (Ǻ)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEzetimibe\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-8.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eLys114\\u003c/p\\u003e \\u003cp\\u003eGlu88\\u003c/p\\u003e \\u003cp\\u003eVal111\\u003c/p\\u003e \\u003cp\\u003eVal111\\u003c/p\\u003e \\u003cp\\u003eVal86, Val94\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003cp\\u003eO of OH\\u003c/p\\u003e \\u003cp\\u003eAzatidine phenyl\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e4.44\\u003c/p\\u003e \\u003cp\\u003e4.35\\u003c/p\\u003e \\u003cp\\u003e5.39\\u003c/p\\u003e \\u003cp\\u003e4.95\\u003c/p\\u003e \\u003cp\\u003e5.27, 6.45\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePiperic acid\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-6.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-σ\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eThr41\\u003c/p\\u003e \\u003cp\\u003eAla92\\u003c/p\\u003e \\u003cp\\u003eTyr73\\u003c/p\\u003e \\u003cp\\u003eThr90\\u003c/p\\u003e \\u003cp\\u003eVal86\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eO of C\\u0026thinsp;=\\u0026thinsp;O\\u003c/p\\u003e \\u003cp\\u003eO of OH\\u003c/p\\u003e \\u003cp\\u003eO of benzodioxol\\u003c/p\\u003e \\u003cp\\u003eO of benzodioxol\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3.74\\u003c/p\\u003e \\u003cp\\u003e3.23\\u003c/p\\u003e \\u003cp\\u003e5.37\\u003c/p\\u003e \\u003cp\\u003e4.56\\u003c/p\\u003e \\u003cp\\u003e4.85\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEzetimibe and piperic acid conjugate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-7.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eArg116\\u003c/p\\u003e \\u003cp\\u003eSer44\\u003c/p\\u003e \\u003cp\\u003eTyr73\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eO of COO\\u003c/p\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5.75\\u003c/p\\u003e \\u003cp\\u003e3.78\\u003c/p\\u003e \\u003cp\\u003e6.92\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e4.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAtorvastatin\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-9.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eUnfavourable doner-doner\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ePhe42\\u003c/p\\u003e \\u003cp\\u003ePro42\\u003c/p\\u003e \\u003cp\\u003eTyr31\\u003c/p\\u003e \\u003cp\\u003eArg82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eOH of COOH\\u003c/p\\u003e \\u003cp\\u003eOH of COOH\\u003c/p\\u003e \\u003cp\\u003ephenyl\\u003c/p\\u003e \\u003cp\\u003eOH of COOH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5.66\\u003c/p\\u003e \\u003cp\\u003e5.09\\u003c/p\\u003e \\u003cp\\u003e5.52\\u003c/p\\u003e \\u003cp\\u003e5.12\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab10\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 10\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eMolecular docking studies Interaction with 3LD6\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eS. No\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eName of the compound\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eDock Score (kcal/mol)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInteraction Type\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eAmino acid involved\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eInteraction with structural feature\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eDistance (Ǻ)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEzetimibe\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-10.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ePHE34\\u003c/p\\u003e \\u003cp\\u003eTYR31\\u003c/p\\u003e \\u003cp\\u003eTRP39\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e6.23\\u003c/p\\u003e \\u003cp\\u003e4.56\\u003c/p\\u003e \\u003cp\\u003e4.44\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePiperic acid\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-7.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eUnfavourable doner-doner\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eHis89\\u003c/p\\u003e \\u003cp\\u003ePhe34\\u003c/p\\u003e \\u003cp\\u003eIle79\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eO of COOH\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003cp\\u003eO of COOH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3.47\\u003c/p\\u003e \\u003cp\\u003e5.19\\u003c/p\\u003e \\u003cp\\u003e3.60\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEzetimibe and piperic acid conjugate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-11.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003eπ-sulphur\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eARG82\\u003c/p\\u003e \\u003cp\\u003ePhe34\\u003c/p\\u003e \\u003cp\\u003eTyr 31\\u003c/p\\u003e \\u003cp\\u003eTrp39\\u003c/p\\u003e \\u003cp\\u003eMet81\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eFlurine\\u003c/p\\u003e \\u003cp\\u003ePhenyl and fluro-benzene\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003cp\\u003ePhenyl\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5.53\\u003c/p\\u003e \\u003cp\\u003e6.06\\u003c/p\\u003e \\u003cp\\u003e6.74\\u003c/p\\u003e \\u003cp\\u003e4.10\\u003c/p\\u003e \\u003cp\\u003e6.30\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e4.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAtorvastatin\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-8.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eH-bond\\u003c/p\\u003e \\u003cp\\u003eπ-π\\u003c/p\\u003e \\u003cp\\u003ehalogeb\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eAsn61\\u003c/p\\u003e \\u003cp\\u003eThr76\\u003c/p\\u003e \\u003cp\\u003ePhe66\\u003c/p\\u003e \\u003cp\\u003eGlu128, ASP140\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003cp\\u003eO of COOH\\u003c/p\\u003e \\u003cp\\u003ePyrrole\\u003c/p\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5.42\\u003c/p\\u003e \\u003cp\\u003e4.09\\u003c/p\\u003e \\u003cp\\u003e6.27\\u003c/p\\u003e \\u003cp\\u003e5.02\\u003c/p\\u003e \\u003cp\\u003e5.54\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eMolecular docking studies on the human C-reactive protein receptor revealed that, with the exception of piperic acid, all substances exhibited lower binding energies than the gold standard medication atorvastatin (-8.7 Kcal/mole). With three π-π bonds with amino acid residues Phe34, Tyr31, and Trp39, the medication Ezetimibe alone has a dock score of -10.6 Kcal/mole. However, with a dock score of just \\u0026minus;\\u0026thinsp;7.2 Kcal/mole, our phytochemical piperic acid has not demonstrated significant interaction with that receptor on its own. Piperic acid forms hydrogen bonds with the amino acid His89. Ezetimibe and piperic acid, when formed into a conjugate, demonstrated promising outcomes. Conjugate binding dock scores were \\u0026minus;\\u0026thinsp;11.5 Kcal/mole, and hydrogen bond interactions were observed with Arg82 and Phe34. Phe34, Tyr31, and Trp39 are amino acid residues that form π-π bonds with this compound.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec27\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eMTT Cytotoxicity Assay\\u003c/h2\\u003e \\u003cp\\u003eTo confirm their safety, we evaluated EZ's cytotoxic effects using the MTT test., an optimised combination of EZ and pipierine, and piperine on normal Vero cells after 72 hours of treatment. In a manner that depends on the drug decreased the number of viable Vero cells compared to the control, with an IC50 value of 36.54 \\u0026micro;g/mL (refer to Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig12\\\" class=\\\"InternalRef\\\"\\u003e12\\u003c/span\\u003e for details). Compared to the optimal combination of EZ and piperine, the medication suppressed cells more effectively at 259 \\u0026micro;g/mL. According to experiments on typical Vero cells, EZ plus piperine was significantly safer than EZ alone [\\u003cspan citationid=\\\"CR56\\\" class=\\\"CitationRef\\\"\\u003e56\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe optimal outcomes from the pharmacological studies regarding in vitro characterization and cell survival were derived from an enhanced combination of EZ and piperine. Consequently, pharmacological research was undertaken on the optimized combination of EZ and piperine to elucidate the effect of the EZ solution on reducing cholesterol levels.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec28\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePharmacokinetic studies\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec29\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eEnhancement of plasma concentration of EZ\\u003c/h2\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab11\\\" class=\\\"InternalRef\\\"\\u003e11\\u003c/span\\u003e presents the estimated plasma concentrations of EZ at different intervals post-injection. The concentration of EZ reached a maximum of 24.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.36 \\u0026micro;g/mL after 2 hours, then declining to half its value after 4 hours, EZ T1/2 and Cmax values match prior reports. Within 4.36 hours of administration, the highest plasma concentration of 159.86\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.54 \\u0026micro;g/mL was achieved after co-delivery of EZ and piperine at dosages of 10\\u0026thinsp;+\\u0026thinsp;20 mg, which was 100% more than the peak value when EZ was given alone. For twenty-four hours, the target plasma concentration was maintained. Piperine at 30 mg/kg did not change concentration. Thus, piperine and EZ enhanced the drug's plasma levels and slowed its elimination, confirming its improved action [\\u003cspan citationid=\\\"CR57\\\" class=\\\"CitationRef\\\"\\u003e57\\u003c/span\\u003e]. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig13\\\" class=\\\"InternalRef\\\"\\u003e13\\u003c/span\\u003e shows the evolution of the EZ plasma concentration following its concurrent treatment with piperine and with the passage of time (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig13\\\" class=\\\"InternalRef\\\"\\u003e13\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab11\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 11\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003ePharmacokinetic studies of pure EZ solution and combination of EZ and Piperine solution\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePharmacokinetic Parameters\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEZ solution\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePiperine solution\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEZ and piperine solution\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIntercept\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.278799\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.560009\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1.820917\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSlope\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e-0.03723\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e-0.01811\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e-0.02158\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCo (mcg/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e19.00198\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e36.30855\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e66.20892\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eK (hr-1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.085744\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.041701\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.049706\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDose (mg)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDose\\u0026nbsp;(mcg)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10000\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVd (mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e526.261\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e275.4172\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e151.037\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVd (L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.526261\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.275417\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.151037\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003et1/2 (hr)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8.082205\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e16.61823\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13.94199\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCl (L/hr)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e45.12369\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11.48523\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7.507444\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAUC-o-t (mcg.hr/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4.875494\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9.202138\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e16.67723\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAUC 1-t (mcg.hr/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e202.0825\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e573.825\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1053.75\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAUC 1-inf(mcg.hr/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e29.03996\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e323.2522\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e391.5022\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAUC total (mcg.hr/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e235.998\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e906.2793\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1461.929\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCmax (mcg.hr/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e24.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e61.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e159.86\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTmax (mL/min)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThe majority of the small chemicals approved for use in medicine this decade have originated in nature. Some have speculated that the drug development process may be enhanced by shifting focus from finding new chemical entities to combining existing drugs. Increased dose, inadequate absorption, insufficient bioavailability, and patient noncompliance are further pharmacological drawbacks. Black pepper includes around 5 to 9 percent piperine, which is an active chemical component. It was recognised as a safe spice by the FDA, which categorised it as a herb. It would appear that the safe dosage of piperine, 15\\u0026ndash;20 mg per person per day, split, far above the human LD50 dose. Piperine can enhance the effectiveness of xenobiotics and decrease the dose frequency. The adverse effects and toxicity of the medication can be alleviated by co-administering piperine, which improves bioavailability at the site of action and reduces the required dosage. Lipid-rich plaque builds up in the coronary arteries and other major arteries, causing atherosclerosis. In vulnerable persons, a high-fat diet raises cholesterol and obesity risk. There is a correlation between cardiovascular disorders, particularly coronary artery disease, and an increased prevalence of hyperlipidaemia [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. To raise the likelihood of ischaemic heart disease, blood lipid levels, overall cholesterol levels, and triglycerides must all be below average. according to several studies Cholesterol feeding is routinely employed to increase blood and tissue cholesterol levels in animal models utilized for investigating metabolic disorders associated with hypercholesterolemia.\\u003c/p\\u003e \\u003cp\\u003eHesperetin and piperine, two active compounds derived from plants, show tremendous potential as potential treatments and preventatives for several diseases. The neuroprotective properties of both drugs, such as antioxidant, anti-inflammatory, and hazardous protein aggregation inhibition, have been demonstrated in several studies. These chemicals have limited therapeutic use due to low bioavailability and insufficient solubility. Consequently, the pharmacological effects are not up to par since the blood concentrations are too low. We are attempting to develop amorphous systems as a solution to these issues. The scientists took into account the compounds' beneficial effect on enhancing bioavailability when they developed the dispersions.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eTaking EZ with piperine at the same time can increase its efficacy by a factor of several, according to this study. EZ is already an excellent medicine for hyperlipidaemia. In vivo activity experiments showed piperine was a bio-enhancer at 20 mg/kg. Piperine improved EZ absorption and bioavailability without liver damage. The objective is to create effective formulations that target the molecular mechanisms that cause this activity, so that dosing is less frequent and the dosage remains adequate. It is important to understand how EZ and piperine interact with each other to ensure their safe and effective co-administration.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eEZ\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eEzetimibe\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLDL\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLower levels of high-density lipoprotein\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003etotal cholesterol\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTG\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003etriglycerides\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eVLDL\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003every low-density lipoprotein\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHDI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eherb-drug interaction\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIAEC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eInstitutional Animal Ethics Committee\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePTU\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003epropylthiouracil\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHFD\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ehigh-fat diet\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eNAFLD\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003enon-alcoholic fatty liver disease\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCV\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ecentral vein.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003eI hereby declare that this submission is entirely my own work, in my own words, and that all sources used in researching it are fully acknowledged and all quotations properly identified.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe use of animals in toxicology was conducted in accordance with the standards established for animal care and procedures (Society of Toxicology USP 1989). Jeeva Life Sciences\\u0026apos; Institutional Animal Ethics Committee (IAEC), located in Uppal, Hyderabad, India (approval number:\\u0026nbsp;CPCSEA/IAEC/JLS/28/08/24/002).\\u0026nbsp;All procedures were carried out in accordance with CPCSEA guidelines.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent to Participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll the authors have read and agreed to the final copy of the finding as contained in the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe datasets/information used for this study is available on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe author(s) received no specific funding for this work.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026apos; contributions\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eConceptualization:\\u003c/em\\u003e K.M. and S.P.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFormal analysis and investigation:\\u003c/em\\u003e K.M. and S.P.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eWriting - original draft preparation:\\u003c/em\\u003e S.P.N.B. and A.K.C.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eWriting - review and editing:\\u003c/em\\u003e S.P.N.B., K.M., A.K.C. and S.P.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eCritically revised:\\u003c/em\\u003e\\u0026nbsp; A.K.C. and S.P.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFunding acquisition:\\u003c/em\\u003e None\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eResources:\\u003c/em\\u003e S.P.N.B.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eSupervision:\\u003c/em\\u003e K.M.\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors read and approved the final manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors thank to University college of pharmaceutical sciences, Palamuru University for supporting this research work.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eHandelsman Y, Jellinger PS, Guerin CK, Bloomgarden ZT, Brinton EA, Budoff MJ, et al. 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Front Pharmacol. 2012;3:24.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEl-Sheekh MM, Daboor SM, Swelim MA, Mohamed S. Production and characterization of antimicrobial active substance from Spirulina platensis. Iran J Microbiol. 2014;6:112\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAltunkaynak A, \\u0026Ouml;zger M, \\u0026Ccedil;akmakci M. Water Consumption Prediction of Istanbul City by Using Fuzzy Logic Approach. Water Resour Manage. 2005;19:641\\u0026ndash;54.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eConkov\\u0026aacute; E, Laciakov\\u0026aacute; A, P\\u0026aacute;storov\\u0026aacute; B, Seidel H, Kov\\u0026aacute;c G. The effect of zearalenone on some enzymatic parameters in rabbits. Toxicol Lett. 2001;121:145\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKameshwara KK, Sandoval-Hernandez A, Shields R, Dhanda KR. A false promise? Decentralization in education systems across the globe. Int J Educational Res. 2020;104:101669.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNoubiap JJ, Bigna JJ, Nansseu JR, Nyaga UF, Balti EV, Echouffo-Tcheugui JB, et al. Prevalence of dyslipidaemia among adults in Africa: a systematic review and meta-analysis. Lancet Glob Health. 2018;6:e998\\u0026ndash;1007.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWu P-H, Aroush DR-B, Asnacios A, Chen W-C, Dokukin ME, Doss BL, et al. A comparison of methods to assess cell mechanical properties. Nat Methods. 2018;15:491\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pharmacology-and-toxicology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"phat\",\"sideBox\":\"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/phat/Default.aspx\",\"title\":\"BMC Pharmacology and Toxicology\",\"twitterHandle\":\"@BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Piperine, Ezitamibe, Propylthiouracil, Triton X-100, Bioavailability, and anti-hyperlipidemic properties\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-5194363/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-5194363/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eThe antihyperlipidemic action of Ezetimibe (EZ) is influenced by its secondary metabolite, piperine. Independent risk factors for cardiovascular illnesses, including atherosclerosis, include hyperlipidaemia. Preventing cardiovascular events and death in patients requires the use of antihyperlipidemic medications. We set out to find a way to make the BCS II lipid-lowering medication EZ more water-soluble. EZ is now very poorly soluble. Increasing the bioavailability of other medications is possible using piperine, a bioenhancer, without changing their base properties or improving their effectiveness.\\u003c/p\\u003e\\u003ch2\\u003eMethod\\u003c/h2\\u003e \\u003cp\\u003eAt dosages of 10 and 5\\u0026ndash;20 mg/kg b.w., the antihyperlipidemic efficacy of EZ with piperine was evaluated in vivo. Hyperlipidaemia in rats was tested using rats induced with propylthiouracil and rats administered Triton X-100. Propylthiouracil with piperine, 400 mg/kg body weight, should be administered together. Notably, there were notable increases in the blood concentrations of all three types of cholesterol (lipid levels, LDL, total cholesterol, and very low-density lipoprotein ) (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). It resulted in HDL production (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). One intraperitoneal Triton X-100 dosage increased lipids.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eLower levels of high-density lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), and very low-density lipoprotein (VLDL) were significantly reduced by EZ at 100 mg/kg b.w. and piperine at 200 mg/kg b.w., respectively (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01 and p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). Liver histology studies provided further evidence supporting the present findings. Areas of concentrated periportal lymphocytes and hepatocytes formed a cord pattern in rats with hyperlipidaemia. It seemed like the hepatocytes, periportal area, and centrilobular part of the liver were all normal in the group who had the treatment. An analysis of the EZ plasma drug concentration with time was carried out in a research. The medication's most effective concentration (Cmax) was determined to be within 4 hours after delivery, and The quantified concentration of the active medication was detectable in the bloodstream for 24 hours.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e \\u003cp\\u003eThe antioxidant and antihyperlipidemic properties of EZ when combined with piperine are particularly noteworthy. This suggests that EZ may have further applications in the treatment of hyperlipidaemia and atherosclerosis as a result of its capacity to increase the drug's oral absorption and availability.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Characterization and interactions between piperine and ezetimibe in their Anti-hyperlipidemic efficacy using Biopharmaceutics and Pharmacokinetics\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-11-26 09:44:53\",\"doi\":\"10.21203/rs.3.rs-5194363/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-10-07T06:49:38+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-10-03T13:53:48+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-10-03T13:52:26+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Pharmacology and Toxicology\",\"date\":\"2024-10-02T17:33:37+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pharmacology-and-toxicology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"phat\",\"sideBox\":\"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/phat/Default.aspx\",\"title\":\"BMC Pharmacology and Toxicology\",\"twitterHandle\":\"@BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"01b06744-1218-469e-a2b3-6f7427c8cb0b\",\"owner\":[],\"postedDate\":\"November 26th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-01-20T16:04:47+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-5194363\",\"link\":\"https://doi.org/10.1186/s40360-025-00836-z\",\"journal\":{\"identity\":\"bmc-pharmacology-and-toxicology\",\"isVorOnly\":false,\"title\":\"BMC Pharmacology and Toxicology\"},\"publishedOn\":\"2025-01-14 15:58:02\",\"publishedOnDateReadable\":\"January 14th, 2025\"},\"versionCreatedAt\":\"2024-11-26 09:44:53\",\"video\":\"\",\"vorDoi\":\"10.1186/s40360-025-00836-z\",\"vorDoiUrl\":\"https://doi.org/10.1186/s40360-025-00836-z\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-5194363\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-5194363\",\"identity\":\"rs-5194363\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}