A combination of Psidium guajava and Aloe vera Aqueous Extracts Prevents Ethanol-Induced Gastric Ulcer in Rats through Suppression of Oxidative Stress and Gastric Inflammation

A combination of Psidium guajava and Aloe vera Aqueous Extracts Prevents Ethanol-Induced Gastric Ulcer in Rats through Suppression of Oxidative Stress and Gastric Inflammation | 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 A combination of Psidium guajava and Aloe vera Aqueous Extracts Prevents Ethanol-Induced Gastric Ulcer in Rats through Suppression of Oxidative Stress and Gastric Inflammation Thiery Tania Meseme, Julius Tanayen Kihdze, Francis Desiré Tatsinkou Bomba, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6582938/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Gastric ulcers are a common gastrointestinal disorder for which there is need to search for a better prevention method or treatment options. Accordingly, the aim of this study was to assess the protective effect of a combination of Psidium guajava and Aloe vera extracts against ethanol-induced gastric ulcers in rats. Methodology: The gastric ulcer was induced in rats using one oral dose of absolute ethanol (5mL/kg body weight). A combination of P. guajava and A. vera at doses of 125, 250 and 500mg/kg b.w and omeprazole 20mg/kg b.w were given by gavage daily for 21 days prior to the induction of ulcers. The stomachs of rats were analyzed both macroscopically and biochemically 24 hours following ethanol administration. Results: Pretreatment of rats with the combination of P. guajava and A. vera extracts significantly (P<0.05) reduced ulcer index induced by ethanol. Also, administration of the plant extracts reduced stomach content of malondialdehyde, and enhanced stomach antioxidant enzymes (superoxide dismutase and catalase) activities as well as glutathione content in ethanol-intoxicated rats. Furthermore, the plant extract significantly (P<0.05) decreased the stomach level of pro-inflammatory cytokines such as TNF-α, INF-δ, IL-1β and IL-6. The efficacy of the combination of plant extracts at 250 and 500 mg/kg b.w was comparable to that of Omeprazole. Conclusion: Overall, findings from this study revealed that the combination of P. guajava and A. vera aqueous extracts displayed gastro-protective effect on ethanol-induced gastric ulcer, likely through the suppression of oxidative stress and gastric inflammation. Drug Discovery, Design, & Development Psidium guajava Aloe vera gastric ulcer oxidative stress antioxidants anti-inflammatory Figures Figure 1 Introduction Gastric ulcers are a common gastrointestinal disorder that affect millions of people worldwide, and can cause significant discomfort and even life-threatening complications [1]. In Africa, the prevalence of gastric ulcers is relatively high, with studies reporting rates ranging from 2.5% to 17% in different regions [2]. In Cameroon, a study published in 2016 found that the prevalence of gastric ulcers was 7.7%, with men being more commonly affected than women [3]. The pathogenesis of gastric ulcers is multifactorial and involves a complex interplay between multiple factors that contribute to the disruption of the balance between gastro-protective and aggressive factors in the upper gastrointestinal tract [4]. Moreover, reactive oxygen species (ROS), the primary mediators of oxidative stress, and other pro-inflammatory factors are excessively produced at the site of gastric ulcers by white blood cells, therefore exacerbating stomach injury [5]. One of the most common causes of gastric ulcers is the infection with the bacterium Helicobacter pylori , which can damage the protective layer of mucus that lines the stomach and duodenum, allowing acid and other digestive juices to irritate and erode the underlying tissue [6]. Other causes of gastric ulcers include long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and excessive alcohol consumption which can damage the protective lining of the stomach, or increase acid production and irritate the stomach lining [7]. The current therapeutic approach for gastric ulcer typically involves the use of proton pump inhibitors (PPIs), which are drugs that reduce the production of stomach acid and help to promote healing of the ulcer [8]. Other drugs, such as histamine H 2 -receptor antagonists and antacids, may also be used to reduce acid production and alleviate symptoms [8]. Although these drugs can be effective in treating gastric ulcers, they have several limitations. For example, sustained administration of PPIs has been associated with headache, diarrhea, nausea and weakness [8]. Overall, while conventional drugs remain a common approach for the treatment of gastric ulcers, their limitations and potential side effects highlight the need for alternative options that are safe, effective, and well-tolerated. Accordingly, search for new therapies and approaches to manage gastric ulcers are necessary to improve patient outcomes and quality of life. In recent years, there has been increasing interest in the therapeutic benefits of natural remedies, particularly those derived from plants. Psidium guajava and Aloe vera are two such plants. P. guajava , commonly known as “guava”, is a tropical fruit tree. The fruit and leaves of the plant have been used in many cultures for their medicinal properties, including the treatment of diarrhea, dysentery, and digestive disorders [9]. A. vera is a succulent plant that grows in various climates, including tropical and subtropical regions of Africa. The plant has been used for centuries for the treatment of wounds, burns, and skin irritations [10]. Phytochemical investigation reported that these plants are rich source of bioactive compounds such as polysaccharides, tannins, polyphenols and anthraquinones which are known for their anti-inflammatory, antioxidant, anti-microbial and immune-modulating properties [11] [12]. In addition, P. guajava and A. vera have been found to display gastro-protective effect through the inhibition of gastric acid secretion [13] and the promotion of mucosal healing [14], respectively. Considering the complex pathophysiology of gastric ulcers, a multi-targeting agent or a combination of agents targeting various aspects of the pathogenesis of gastric ulcers and having gastro-protective action would be beneficial for the prevention and/or treatment of the disease. Knowing that plants contain a variety of bioactive molecules acting differently, we hypothesized that the combination of P. guajava and A. vera could be highly effective in preventing gastric ulcers. Thus, the capacity of the combination of extracts from P. guajava and A. vera to protect rats against ethanol-induced gastric ulcers was examined in the present investigation. Materials and Methods Reagent Trichloroacetic acid, thiobarbituric acid, naphthylethylenediamide, sulphanilamide, phosphoric acid, and Dithiobis (2-Nitrobenzoic acid) (DTNB) were purchased from Sigma Aldrich (Germany). Tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1beta (IL-1β), interferon gamma (IFN-γ) elisa kit were pucharased from R&D Systems, USA. All additional reagents and chemicals utilized in the research are commercially accessible and were of analytical quality. Collection and authentication of plant materials Fresh leaves of P. guajava and A. vera were harvested in Bomaka, Buea (Cameroon) in March 2022. The identification of the species was done at the National Herbarium of Cameroon with voucher specimen number: HNC-Num 60041 and HNC-Num 17027 were given to P. guajava and A. vera respectively. Animals and Ethical Consideration Young male Wistar rats (8-10 weeks old) weighing between 150-200g were used. They were provided by the Medical Research and Applied Biochemistry Laboratory, Faculty of Health Sciences, University of Buea; and maintained under standard conditions (clean cages placed in a well-ventilated house with photoperiod of 12 h light and 12 h dark cycle). The animals were fed with conventional commercial diet and water ad libitum. All the procedures followed the ARRIVE guidelines on animal care and were approved by the Institutional Animal Care and Use Committee of the University of Buea-Cameroon (UB-IACUC N°07/2023). Preparation of plant extracts Fresh leaves of P. guajava and A. vera were air-dried at room temperature and ground into fine powder using an electric blender. Two hundred grams of each powder were soaked separately for 24 hours in 2 L of distilled water with regular shaking. Each mixture was then filtered using Whatman paper N ͦ 1 and the filtrate obtained was dried in an oven at 40 ͦ C to yield a dark semi-solid extract with the weight of 81g and 41g respectively for P. guajava and A. vera . Induction of gastric ulcer by oral administration of 95 % ethanol The animals were distributed into 6 groups of 5 animals each and treated orally for 21 days as follows: Group 1 was given 20 mg/kg body weight (b.w) omeprazole and served as positive control. Group 2, 3, and 4 were given a mixture of P. guajava and A. vera extracts (1:1, w/w) at the dose of 125, 250, and 500 mg/kg b.w respectively, and served as treatment groups. Group 5 and 6 were given 10 mL/kg b.w distilled water and served as ulcer model and normal control respectively. After the last treatment, the animals were deprived of food, with free access to water for 24 h. Then, animals of groups 1 to 5 were given 95% ethanol (5 mL/kg b.w) to induce gastric ulcers. After 24 h, the animals were killed by decapitation under anesthesia (mixture of diazepam 2mg/kg b.w and ketamine 100mg/kg b.w). Blood samples were collected in dry tubes and centrifuged (3000 rpm, 10 min, 4 ͦ C). The serum obtained was used to assess the level of pro-inflammatory cytokines. The stomach was then excised, rinsed with normal saline (0.9% NaCl), weighed, and used for assessing the severity of ulceration and preparation of 10% homogenates for biochemical analysis. Measurement of ulcer severity The gastric tissues specimens were gently rinsed with normal saline (0.9% NaCl) to remove blood clots and then examined macroscopically. The length of the ulcers (mm) was measured using a Vernier Caliper and the gastric ulcer index (UI) and percent ulcer protection was calculated. The mean of the ulcer lengths per rat was expressed as the ulcer index. Measurement of cytokine levels A homogenate of stomach tissue was created using ice-cold phosphate buffer (0.1 M; pH 7.4; total volume of 10 mL) that contained 0.2% Halt Protease Inhibitor Cocktail EDTA-Free (Thermo Fisher Scientific). The homogenization was performed using a Potter homogenizer. Subsequently, the homogenate was centrifuged (17000×g; 20 min; 4°C) and the supernatant was collected and used for the measurement of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and IFN-γ), both in serum and stomach homogenates using the respective Quantikine ELISA kit (R&D Systems, USA), as directed by the manufacturer. Measurement of Oxidative Stress Makers The levels of oxidative stress markers in the stomach tissues (10% w/v) were evaluated by measuring the stomach content of Malondialdehyde (MDA), as index of lipid peroxidation. In addition, the activity of the anti-oxidant superoxide dismutase (SOD), and catalase (CAT) as well as the content of cellular reduced glutathione (GSH)), was also assessed Determination of MDA content The level of Malondialdehyde (MDA) in the stomach was assessed to evaluate lipid peroxidation, following the procedure outlined by Djeungoue et al. [15]. In summary, 0.5 mL of 20% trichloroacetic acid and 1 mL of 0.67% thiobarbituric acid were combined with 1 mL of supernatant from the tissue homogenate. This mixture was then placed in a water bath at 90 ͦ C for one hour. Afterwards, the mixture underwent centrifugation at 3000 rpm for a duration of 10 minutes. The supernatant collected was used to measure the absorbance at 546 nm. The concentration of MDA was quantified by using its molar extinction coefficient (ε = 1.56 × 10 5 M -1 .cm -1 ) expressed as µmol of MDA per gram of tissue. Determination of Catalase Activity Catalase activity in the stomach was determined by method described by Njayou et al. [16] with slight modifocation. Briefly, a total of 250 µL of homogenate supernatant was combined with 250 µL of phosphate buffer (50 mM), followed by the sequential addition of 1 mL of hydrogen peroxide (30 mM) to the mixture. The absorbance was measured at 340 nm at intervals of 30, 60, and 90 seconds after introducing hydrogen peroxide (H 2 O 2 ) into the reaction medium, employing a spectrophotometer. The calculation of catalase activity was performed using the designated formula. Where AA is average absorbance; ε is the extinction coefficient (ε H 2 O 2 = 43.6 M -1 .cm -1 ); Vt is the total volume of the supernatant and Vs is the volume of supernatant used for assay. Catalase activity was expressed as µmol of H 2 O 2 consumed per mg of protein. Determination of reduced glutathione level The level of reduced glutathione (GSH) in the stomach was measured using the method outlined by Kouam et al. [17]. A volume of 20 µL from the tissue homogenate supernatant was combined with 3 mL of Ellman reagent, which consists of 5 mg of DTNB (Disthio-bis (2-nitrobenzoic acid) in 250 mL of phosphate buffer). This mixture was allowed to stand at room temperature for 1 hour, after which the absorbance was measured with a spectrophotometer at a wavelength of 405 nm. The concentration of GSH was determined using the molar extinction coefficient (ƐGSH = 13,600 M -1 .cm -1 ) and was expressed in micromoles of protein. Assessment of superoxide dismutase activity Total superoxide dismutase was measured using the method outlined by Sun et al [18]. This approach is founded on the principle that the xanthine oxidase system serves as a superoxide generator, which inhibits the reduction of nitroblue tetrazolium. After adding a 1.0 mL mixture of ethanol and chloroform (5/3, v/v) to an equal volume of the sample, the activity was evaluated in the ethanol phase of the homogenate following centrifugation. The absorbance obtained from nitroblue tetrazolium reduction to blue formazan by superoxide was determined spectrophotometrically at 560 nm. One unit of SOD was considered as the amount of enzyme causing 50% inhibition in the nitroblue tetrazolium reduction rate. Statistical analysis The data are expressed as mean ± standard deviation (n=5). To compare the mean values across different treatment groups, one-way analysis of variance (ANOVA) was used, followed by Dunnett’s post hoc test when significant differences in variances were identified. A significance level of P < 0.05 was used to determine meaningful differences between the groups. The analyses were conducted with Prism Version 5.03 statistical software (Graph Pad Inc., USA). Results Gross Evaluation of Gastric Mucosa As illustrated by Figure 1, administration of 95% ethanol induced severe gastric ulcer while rats receiving distilled water (normal control) showed no signs of ulceration. However, pre-treatment of rats with the combination of P. guajava and A. vera extract significantly diminished the gastric injury and ulcer index when compared to the ulcerated group. The inhibition percentage of the ulcer index in rats pre-treated with the combination of P. guajava and A. vera extract increased in a dose dependent manner. The ulcerated rats produced the lowest gastric mucus content while animal group pre-treated with the combination of P. guajava and A. vera (500 mg/kg) and omeprazole (20mg/kg) showed a significant increase in mucus weight (g) with respect to the ulcerated group as shown in table 1. Effect of a combination of P. guajava and A. vera pre-treatment, on lipid peroxidation (MDA) and anti-oxidant enzymes. The ulcer model rats revealed a major reduction in antioxidant (SOD, CAT, and GSH) endogenous enzyme activities. Rats pretreated with a combination of P. guajava and A. vera and pre-treatment with omeprazole demonstrated an elevation of all antioxidant activities with respect to the ulcer control rats, as shown in Table 2. The CAT activity and SOD enzyme activities as well as GSH content were significantly (P<0.05) higher at a dose of 500 mg/kg of a combination of P. guajava and A. vera extract and omeprazole 20mg/kg than in ulcer model rats. Also, the MDA content was significantly (P<0.05) lower at a dose of 500 mg/kg of a combination of P. guajava and A. vera extract and omeprazole 20 mg/kg compared to ulcer control rats. Effect of a Combination of P. guajava and A. vera Pre-treatment, on Gastric Inflammatory Parameters. The ulcer control rats revealed a major increase in inflammatory cytokines (TNF-α, IFN-ϒ, IL-1β, IL-6). Rats pretreated with a combination of P. guajava and A. vera and pre-treatment with omeprazole demonstrated a decrease in all inflammatory cytokines with respect to the ulcer control rats, as shown in table 3. The levels of TNF-α, IFN-ϒ, IL-1β and IL-6 were significantly (P<0.05) lower at a dose of 500 mg/kg of a combination of P. guajava and A. vera extract and omeprazole 20mg/kg than ulcer model rats (Table 3). Discussion The consumption of alcohol is recognized as a major factor contributing to gastric ulcers in humans; therefore, researchers have utilized an animal model of gastric injury induced by ethanol to replicate the conditions humans may face, allowing them to investigate the anti-ulcer effects of natural products or novel therapies aimed at providing gastric protection [19]. Oral administration of absolute ethanol in the animal model is destructive to stomach tissue, since it penetrates rapidly and easily into the gastric mucosa, producing gastric lesions [19] thus, making it useful in determining the anti-ulcer capacity of drugs, as well as the likely pathways involved in this process [20]. Such lesions are characterized by extensive sub-mucosal edema, hemorrhage, desquamation of epithelial cells and infiltration of inflammatory cells, which are typical characteristics of alcohol-induced damage in humans [19]. In this study, a gastric ulcer model was created using 95% ethanol (5 ml/kg). Ethanol is a common cause of gastric ulcers and induces gastric damage through multiple mechanisms, including dehydration, which impairs the mucosal cell barriers, and cytotoxic effects. This cytotoxicity leads to the activation of leukocytes that release reactive oxygen species (ROS) and inflammatory cytokines, both of which can contribute to cell death. P. guajava , and A. vera are natural plants that have shown protective, antioxidant, and anti-inflammatory properties in various studies conducted in different in vivo models over periods of 2 weeks or 21 days; hence, a duration of 21 days was chosen for this investigation [13]. Three treatment doses were chosen based on prior studies, and the dose-response relationships for anti-gastric ulcer effects were evaluated in rats with ethanol-induced gastritis that received oral treatment with 125, 250, and 500 mg/kg of a blend of of P. guajava and A. vera over 21 days. Our findings indicated that among the three dosage levels of the P. guajava and A. vera combination, 500 mg/kg exhibited the strongest protective effect against gastric ulcers. The elevated gastric ulcer index (GUI) in rats exposed to ethanol underscores the significant ulcerogenic potential of ethanol, which aligns with existing research [21]. The marked decrease in the gastric ulcer index (GUI) and the improved protective index (PI) resulting from the combination of P. guajava and A. vera indicate a strong anti-ulcer effect that rivals that of omeprazole, a widely recognized anti-ulcer medication. Additionally, pre-treating with a combination of P. guajava, A. vera , and omeprazole led to fewer gastric lesions in the gastric wall mucosa; it also resulted in increased mucus levels in ethanol-treated rats, likely due to heightened production of prostaglandin E2 in the gastric mucosa. Moreover, we investigated the role of inflammatory cytokines, lipid peroxidation, and antioxidant enzyme pathways to understand the mechanisms behind the anti-ulcer effects of the P. guajava and A. vera combination. The administration of ethanol prompts the infiltration of neutrophils; It triggers the immune response of T lymphocytes, leading to a chain reaction of inflammation, oxidative stress, and the death of epithelial cells. A significant increase in the levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β can cause considerable damage to the gastrointestinal mucosa, worsening the level of inflammation in the human body [22]. In this study, we observed that pre-treatment with a combination of P. guajava, A. vera, and omeprazole resulted in reduced production of inflammatory cytokines. During the occurrence of gastric ulcers, macrophages produce TNF-α, hindering the healing process in various ways, which includes reducing gastric microcirculation, promoting neutrophil infiltration, and triggering inflammatory signaling pathways, leading to the production of additional inflammatory cytokines that further amplify its production [19]. IL-6, IFN-γ, and IL-1β are pro-inflammatory cytokines that play a crucial role in the process of acute inflammation. Elevated levels of these cytokines activate neutrophils, macrophages, and lymphocytes at the inflammation site, enhancing the production of inflammatory mediators and worsening gastric mucosal injury [23]. In line with earlier studies, [24] our findings demonstrated that the oral intake of ethanol initiates a localized inflammatory response, raising the levels of inflammatory cytokines in the gastric tissue. Nevertheless, the pre-treatment with a combination of P. guajava and A. vera along with omeprazole mitigated this detrimental effect, resulting in decreased levels of the inflammatory markers TNF-α, IL-6, IL-1β, and IFN-γ. Alcohol administration leads to the degradation of the gastric wall mucosal barrier through the action of reactive oxygen species (ROS) and the up-regulation of cytokines, which causes damage due to oxidative stress [25]. In this research, intubation with ethanol resulted in significant oxidative-stress-related damage in rats suffering from ethanol-induced ulcers; this finding aligns with prior studies [26]. An imbalance in redox state between the generation of reactive oxygen species (ROS) and the scavenging action of antioxidants can lead to oxidative stress, primarily driven by infiltrating inflammatory cells as the major source of ROS [20]. The superoxide radical anions (O2−), produced by neutrophils, react with lipids, leading to lipid peroxidation [20]. This investigation showed that the redox balance was disrupted due to elevated lipid peroxidation (measured as MDA), along with a reduction in antioxidant enzymes like GSH, SOD, and CAT in the gastric tissues with ulcers. The rise in MDA levels was linked to an increase in reactive oxygen species (ROS) alongside a reduction in antioxidant enzymes [20]. The combination of P. guajava and A. vera, along with omeprazole pre-treatment, notably reduced lipid peroxidation (measured as MDA) and restored the diminished levels of GSH, SOD, and catalase activity in the ulcerated gastric mucosa. The pairing of P. guajava and A. vera exhibits significant anti-lipid peroxidation properties and the ability to scavenge free radicals [20]. This finding suggests that plant extracts can boost antioxidant activity, likely due to the presence of antioxidant phytochemicals in these plants. Both P. guajava and A. vera are abundant in phenolic compounds, which may contribute to the improved antioxidant effects. Research indicates that intake of antioxidant-rich phenolic compounds is linked to the prevention of chronic illnesses such as cancer, diabetes, and cardiovascular diseases. This study indicates that phenolic compounds have positive effects on gastro-protective activity [26]. This research has potential limitations. While the study observed the gastro-protective effects of a combination of P. guajava and A. vera, the underlying mechanism of action were not explored in depth. Additional studies, such as mechanistic investigations are necessary to understand the specific pathways. Also, the study utilized a rat model to simulate ethanol-induced gastric ulcers. While animal models provide valuable insights, there may be differences in the response to treatment between rats and humans, limiting the direct translation of findings to clinical applications. Conclusion The findings of the current research indicated that the combination of P. guajava and A. vera at a dosage of 500mg/kg reduced ethanol-induced gastric ulcers through its antioxidant and anti-inflammatory properties. The gastro-protective capability of P. guajava and A. vera may be linked to the rich presence of phytochemical compounds such as total polyphenols, flavonoids, and tannins. Consequently, P. guajava and A. vera may serve as a promising anti-ulcer agent for treating gastric ulcers, demonstrating an anti-ulcer effect similar to that of omeprazole. Nevertheless, additional studies are necessary to further investigate the underlying mechanisms of action. Abbreviations A. vera: Aloe vera CAT: Catalase GSH: Reduced Glutathione H. pylori: Helicobacter pylori MDA: Malondialdehyde NSAIDs: Non-steroidal anti-inflammatory drugs P. guajava: Psidium guajava, PGs: Prostaglandins PPIs: Proton pump inhibitors SOD: Superoxide Dimutase UI: Ulcer index Declarations Funding The authors declare that there is no funding to report Acknowledgments The authors are grateful to the Department of Biomedical Sciences, Faculty of Health Sciences of the University of Buea for providing the facilities for this research. CRediT Authorship Contribution Statement Thiery Tania Meseme : Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Writing – review & editing. Julius Tanayen Kihdze : Conceptualization , supervision, validation, resources, Visualization, Project administration, Writing – original draft, Writing – review & editing. Francis Desiré Tatsinkou Bomba : Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Writing – review & editing Eléonore Ngounou: Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Writing – review & editing. Arnaud Fondjo Kouam: Conceptualization, Investigation, Methodology, Resources, Formal analysis, Validation, Supervision, Visualization, Project administration, Writing – original draft, Writing – review & editing Emmanuel Acha Asongalem: Conceptualization , supervision, validation, resources, Visualization, Project administration, Writing – original draft, Writing – review & editing. Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability statement All data generated or analyzed during this study are included in this manuscript and the raw data will be made available upon request References Ciciliato MP, De Souza MC, Tarran CM, De Castilho ALT, Vieira AJ, Rozza AL: Anti-Inflammatory Effect of Vanillin Protects the Stomach against Ulcer Formation. 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Afr J Biotechnol. 2012, 11:8612–5. 10.5897/AJB12.034 Tables Table 1: Effect of a combination of P. guajava and A. vera on Gastric ulcer index, Gastric protective index and Gastric mucus weight Groups Parameters Gastric Ulcer Index Gastric Protective Index Gastric Mucus (g) Mean ± SD P-value (Dunnett) Mean ± SD P-value (Dunnett) Omeprazole 20mg/Kg + ET-OH 1.1±0.53 0.29 67±7.3 1.8±0.84* 0.024 P. guajava + A. vera 125mg/Kg + ET-OH 3.2±2.78 0.97 2.6±49 1.2±0.45 0.368 P. guajava + A. vera 250mg/Kg + ET-OH 2.53±2.95 0.96 24±27 1.4±0.55 0.168 P. guajava + A. vera 500mg/Kg + ET-OH 1±0.0 0.22 68±9.7 1.8±0.84* 0.024 Ulcer model (distilled H2O +ET-OH) 3.3±2.06 / 0.0±32 0.46±0.11 / Normal control (Distilled H 2 O 10mL/Kg) 0±0.0* 0.039 100±0.0 2.4±1.14* 0.0007 Data are expressed as mean ± SD, n=5; *denotes significant difference with ethanol treated group, p<0.05 using ANOVA followed by Dunnett’s post hoc test. GUI: Gastric ulcer index, GPI: Gastric protective index and GM: Gastric mucus weight, ET-OH: Ethanol. Table 2: Effect of the combination of P. guajava and A. vera on oxidative stress Groups Oxidative Stress Parameters MDA ( 𝜇 mol/g tissue) GSH (U/mg tissue CAT (U/mg tissue) SOD (U/mg tissue) Mean ± SD P-value (Dunnett) Mean ± SD P-value (Dunnett) Mean ± SD P-value (Dunnett) Mean ± SD p-value (Dunnett) Omeprazole 20mg/Kg+ ET-OH. 11.52±1.81* <0.0001 3.53±0.47* <0.0001 0.427±0.05* <0.0001 25.39±0.77* 0.0037 P. guajava + A. vera 125mg/Kg+ ET-OH. 20.44±2.98 0.08 1.4±0.15 0.90 0.295±0.02 0.106 19.13±1.29 0.976 P. guajava + A. vera 250mg/Kg+ ET-OH. 17.6±2.20 0.0007 2.15±0.10 0.003 0.323±0.08 0.016 21.56±2.02 0.294 P. guajava + A. vera 500mg/Kg+ ET-OH. 11.38±2.54* <0.0001 3.43±0.48* <0.0001 0.403±0.03* <0.0001 25.93±4.56* 0.0018 Ulcer model (distilled H2O +ET-OH) 24.13±1.09 / 1.19±0.12 / 0.213±0.05 / 17.91±0.90 / Normal control (Distilled H 2 O 10mL/Kg) 11.87±0.72* <0.0001 3.33±0.49* <0.0001 0.433±0.091* <0.0001 25.86±7.24* 0.0019 Data are expressed as mean ± SD, n=5; *denotes significant difference with ethanol treated group, p<0.05 using ANOVA followed by Dunnett’s post hoc test. MDA: Malondialdehyde, GSH: Reduced glutathione, SOD: Superoxide dismutase and CAT: catalase, ET-OH: Ethanol. Table 3: Effect of the combination of P. guajava and A. vera pre-treatment on gastric tissue cytokine profile Groups Cytokines Profile TNF-α (pg/mL) IFN-γ (pg/mL) IL-1β (pg/mL) IL-6 (pg/mL) Mean ± SD P-value (Dunnett) Mean ± SD P-value (Dunnett) Mean ± SD P-value (Dunnett) Mean ± SD P-value (Dunnett) Omeprazole 20mg/Kg+ET-OH. 134.1±7.50* <0.0001 121.2±19.62* <0.0001 124.6±7.67* <0.0001 283.3±5.66* <0.0001 P. guajava + A. Vera 125mg/Kg+ET-OH. 210.5±15.77 <0.0001 269.8±22.31 0.0002 232.3±9.62 <0.0001 324.4±25.64 <0.0001 P. guajava + A. vera 250mg/Kg+ET-OH. 200.3±31.41 <0.0001 223.4±54.41 <0.0001 166.9±14.74 <0.0001 305.3±23.11 <0.0001 P. guajava + A. vera 500mg/Kg+ET-OH. 135.3±8.81* <0.0001 109.9±17.39* <0.0001 124.4±11.76* <0.0001 280.3±6.66* <0.0001 Ulcer model (distilled H2O +ET-OH) 326.7±17.97 / 341.0±9.58 / 284.2±23.75 / 443.9±12.87 / Normal control (Distilled H 2 O 10mL/Kg) 134.5±24.03* <0.0001 114.7±11.87* <0.0001 123.4±9.18 <0.0001 281.4±16.94 * <0.0001 Data are expressed as mean ± SD, n=5; *denotes significant difference with ethanol treated group, p<0.05 using ANOVA followed by Dunnett’s post hoc test. TNF-α: Tumor necrosis factor alpha, IL-6: interleukin 6, IL-1β: interleukin 1beta, IFN-γ: interferon gamma, ET-OH: Ethanol. Additional Declarations The authors declare no competing interests. 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Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaounde 1, Cameroon","correspondingAuthor":true,"prefix":"","firstName":"Arnaud","middleName":"Fondjo","lastName":"Kouam","suffix":""},{"id":451394288,"identity":"37aa5cd6-f151-42c5-9e0b-64c300576f1c","order_by":5,"name":"Emmanuel Acha Asongalem","email":"","orcid":"","institution":"Pharmacology Laboratory, Department of Biomedical Sciences, Faculty of Health Sciences, University of Buea, PO Box 63, Buea, Cameroon","correspondingAuthor":false,"prefix":"","firstName":"Emmanuel","middleName":"Acha","lastName":"Asongalem","suffix":""}],"badges":[],"createdAt":"2025-05-03 08:34:16","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-6582938/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6582938/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82015787,"identity":"a9cf8766-f0a4-4fe9-8d3b-0013610789bc","added_by":"auto","created_at":"2025-05-06 03:32:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":239494,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6582938/v1/a385cf18891731bbec376a9d.jpg"},{"id":82016131,"identity":"a54f59cd-3afa-4046-a942-2310e282d8d3","added_by":"auto","created_at":"2025-05-06 03:40:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1554141,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6582938/v1/1bbce6ba-09e4-4106-aee5-584da5e32405.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eA combination of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ePsidium guajava\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eAloe vera\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e Aqueous Extracts Prevents Ethanol-Induced Gastric Ulcer in Rats through Suppression of Oxidative Stress and Gastric Inflammation\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric ulcers are a common gastrointestinal disorder that affect millions of people worldwide, and can cause significant discomfort and even life-threatening complications [1]. In Africa, the prevalence of gastric ulcers is relatively high, with studies reporting rates ranging from 2.5% to 17% in different regions [2]. In Cameroon, a study published in 2016 found that the prevalence of gastric ulcers was 7.7%, with men being more commonly affected than women [3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe pathogenesis of gastric ulcers is multifactorial and involves a complex interplay between multiple factors that contribute to the disruption of the balance between gastro-protective and aggressive factors in the upper gastrointestinal tract [4]. Moreover, reactive oxygen species (ROS), the primary mediators of oxidative stress, and other pro-inflammatory factors are excessively produced at the site of gastric ulcers by white blood cells, therefore exacerbating stomach injury \u0026nbsp;[5]. One of the most common causes of gastric ulcers is the infection with the bacterium \u003cem\u003eHelicobacter pylori\u003c/em\u003e, which can damage the protective layer of mucus that lines the stomach and duodenum, allowing acid and other digestive juices to irritate and erode the underlying tissue [6]. Other causes of gastric ulcers include long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and excessive alcohol consumption which can damage the protective lining of the stomach, or increase acid production and irritate the stomach lining [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe current therapeutic approach for gastric ulcer typically involves the use of proton pump inhibitors (PPIs), which are drugs that reduce the production of stomach acid and help to promote healing of the ulcer [8]. Other drugs, such as histamine H\u003csub\u003e2\u003c/sub\u003e-receptor antagonists and antacids, may also be used to reduce acid production and alleviate symptoms [8]. Although these drugs can be effective in treating gastric ulcers, they have several limitations. For example, sustained administration of PPIs has been associated with headache, diarrhea, nausea and weakness [8]. Overall, while conventional drugs remain a common approach for the treatment of gastric ulcers, their limitations and potential side effects highlight the need for alternative options that are safe, effective, and well-tolerated. Accordingly, search for new therapies and approaches to manage gastric ulcers are necessary to improve patient outcomes and quality of life.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn recent years, there has been increasing interest in the therapeutic benefits of natural remedies, particularly those derived from plants. \u003cem\u003ePsidium guajava\u003c/em\u003e and \u003cem\u003eAloe vera\u003c/em\u003e are two such plants. \u003cem\u003eP. guajava\u003c/em\u003e, commonly known as “guava”, is a tropical fruit tree. The fruit and leaves of the plant have been used in many cultures for their medicinal properties, including the treatment of diarrhea, dysentery, and digestive disorders [9]. \u0026nbsp;\u003cem\u003eA. vera\u0026nbsp;\u003c/em\u003eis a succulent plant that grows in various climates, including tropical and subtropical regions of Africa. The plant has been used for centuries for the treatment of wounds, burns, and skin irritations [10]. Phytochemical investigation reported that these plants are rich source of bioactive compounds such as polysaccharides, tannins, polyphenols and anthraquinones which are known for their anti-inflammatory, antioxidant, anti-microbial and immune-modulating properties [11] [12]. In addition, \u003cem\u003eP. guajava\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;A. vera\u003c/em\u003e have been found to display gastro-protective effect through the inhibition of gastric acid secretion [13] and the promotion of mucosal healing [14], respectively.\u003c/p\u003e\n\u003cp\u003eConsidering the complex pathophysiology of gastric ulcers, a multi-targeting agent or a combination of agents targeting various aspects of the pathogenesis of gastric ulcers and having gastro-protective action would be beneficial for the prevention and/or treatment of the disease. Knowing that plants contain a variety of bioactive molecules acting differently, we hypothesized that the combination of\u003cem\u003e\u0026nbsp;P. guajava and A. vera\u003c/em\u003e could be highly effective in preventing gastric ulcers. Thus, the capacity of the combination of extracts from\u003cem\u003e\u0026nbsp;P. guajava and A. vera\u003c/em\u003e to protect rats against ethanol-induced gastric ulcers was examined in the present investigation.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eReagent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrichloroacetic acid, thiobarbituric acid, naphthylethylenediamide, sulphanilamide, phosphoric acid, and Dithiobis (2-Nitrobenzoic acid) (DTNB) were purchased from Sigma Aldrich (Germany). Tumor necrosis factor alpha (TNF-\u0026alpha;), interleukin 6 (IL-6), interleukin 1beta (IL-1\u0026beta;), interferon gamma (IFN-\u0026gamma;) elisa kit were pucharased from R\u0026amp;D Systems, USA. All additional reagents and chemicals utilized in the research are commercially accessible and were of analytical quality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCollection and authentication of plant materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFresh leaves of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e were harvested in Bomaka, Buea (Cameroon) in March 2022. The identification of the species was done at the National Herbarium of Cameroon with voucher specimen number: HNC-Num 60041 and HNC-Num 17027 were given to \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnimals and Ethical Consideration\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYoung male Wistar rats (8-10 weeks old) weighing between 150-200g were used. They were provided by the Medical Research and Applied Biochemistry Laboratory, Faculty of Health Sciences, University of Buea; and maintained under standard conditions (clean cages placed in a well-ventilated house with photoperiod of 12 h light and 12 h dark cycle). The animals were fed with conventional commercial diet and water ad libitum. All the procedures followed the ARRIVE guidelines on animal care and were approved by the Institutional Animal Care and Use Committee of the University of Buea-Cameroon (UB-IACUC N\u0026deg;07/2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreparation of plant extracts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFresh leaves of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e were air-dried at room temperature and ground into fine powder using an electric blender. Two hundred grams of each powder were soaked separately for 24 hours in 2 L of distilled water with regular shaking. Each mixture was then filtered using Whatman paper N ͦ 1 and the filtrate obtained was dried in an oven at 40 ͦ C to yield a dark semi-solid extract with the weight of 81g and 41g respectively for \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInduction of gastric ulcer by oral administration of 95 % ethanol\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe animals were distributed into 6 groups of 5 animals each and treated orally for 21 days as follows: Group 1 was given 20 mg/kg body weight (b.w) omeprazole and served as positive control. Group 2, 3, and 4 were given a mixture of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extracts (1:1, w/w) at the dose of 125, 250, and 500 mg/kg b.w respectively, and served as treatment groups. Group 5 and 6 were given 10 mL/kg b.w distilled water and served as ulcer model and normal control respectively. \u0026nbsp;After the last treatment, the animals were deprived of food, with free access to water for 24 h. Then, animals of groups 1 to 5 were given 95% ethanol (5 mL/kg b.w) to induce gastric ulcers. After 24 h, the animals were killed by decapitation under anesthesia (mixture of diazepam 2mg/kg b.w and ketamine 100mg/kg b.w). Blood samples were collected in dry tubes and centrifuged (3000 rpm, 10 min, 4 ͦ C). The serum obtained was used to assess the level of pro-inflammatory cytokines. The stomach was then excised, rinsed with normal saline (0.9% NaCl), weighed, and used for assessing the severity of ulceration and preparation of 10% homogenates for biochemical analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasurement of ulcer severity\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe gastric tissues specimens were gently rinsed with normal saline (0.9% NaCl) to remove blood clots and then examined macroscopically. The length of the ulcers (mm) was measured using a Vernier Caliper and the gastric ulcer index (UI) and percent ulcer protection was calculated. The mean of the ulcer lengths per rat was expressed as the ulcer index.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"471\" height=\"43\" 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\" alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasurement of cytokine levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA homogenate of stomach tissue was created using ice-cold phosphate buffer (0.1 M; pH 7.4; total volume of 10 mL) that contained 0.2% Halt Protease Inhibitor Cocktail EDTA-Free (Thermo Fisher Scientific). The homogenization was performed using a Potter homogenizer. Subsequently, the homogenate was centrifuged (17000\u0026times;g; 20 min; 4\u0026deg;C) and the supernatant was collected and used for the measurement of pro-inflammatory cytokines (TNF-\u0026alpha;, IL-6, IL-1\u0026beta;, and IFN-\u0026gamma;), both in serum and stomach homogenates using the respective Quantikine ELISA kit (R\u0026amp;D Systems, USA), as directed by the manufacturer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasurement of Oxidative Stress Makers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe levels of oxidative stress markers in the stomach tissues (10% w/v) were evaluated by measuring the stomach content of Malondialdehyde (MDA), as index of lipid peroxidation. In addition, the activity of the anti-oxidant superoxide dismutase (SOD), and catalase (CAT) as well as the content of cellular reduced glutathione (GSH)), was also assessed\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of MDA content\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe level of Malondialdehyde (MDA) in the stomach was assessed to evaluate lipid peroxidation, following the procedure outlined by Djeungoue et al. [15]. In summary, 0.5 mL of 20% trichloroacetic acid and 1 mL of 0.67% thiobarbituric acid were combined with 1 mL of supernatant from the tissue homogenate. This mixture was then placed in a water bath at 90 ͦ C for one hour. Afterwards, the mixture underwent centrifugation at 3000 rpm for a duration of 10 minutes. The supernatant collected was used to measure the absorbance at 546 nm. The concentration of MDA was quantified by using its molar extinction coefficient (\u0026epsilon; = 1.56 \u0026times; 10\u003csup\u003e5\u0026nbsp;\u003c/sup\u003eM\u003csup\u003e-1\u003c/sup\u003e.cm\u003csup\u003e-1\u003c/sup\u003e) expressed as \u0026micro;mol of MDA per gram of tissue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of Catalase Activity\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCatalase activity in the stomach was determined by method described by Njayou et al. [16] with slight modifocation. Briefly, a total of 250 \u0026micro;L of homogenate supernatant was combined with 250 \u0026micro;L of phosphate buffer (50 mM), followed by the sequential addition of 1 mL of hydrogen peroxide (30 mM) to the mixture. The absorbance was measured at 340 nm at intervals of 30, 60, and 90 seconds after introducing hydrogen peroxide (H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e) into the reaction medium, employing a spectrophotometer. The calculation of catalase activity was performed using the designated formula.\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"160\" height=\"41\" src=\"data:image/png;base64,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\" alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003eWhere AA is average absorbance; \u0026epsilon; is the extinction coefficient (\u0026epsilon; H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e= 43.6 M\u003csup\u003e-1\u003c/sup\u003e.cm\u003csup\u003e-1\u003c/sup\u003e); Vt is the total volume of the supernatant and Vs is the volume of supernatant used for assay. Catalase activity was expressed as \u0026micro;mol of H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003econsumed per mg of protein.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of reduced glutathione level\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe level of reduced glutathione (GSH) in the stomach was measured using the method outlined by Kouam et al. [17]. A volume of 20 \u0026micro;L from the tissue homogenate supernatant was combined with 3 mL of Ellman reagent, which consists of 5 mg of DTNB (Disthio-bis (2-nitrobenzoic acid) in 250 mL of phosphate buffer). This mixture was allowed to stand at room temperature for 1 hour, after which the absorbance was measured with a spectrophotometer at a wavelength of 405 nm. The concentration of GSH was determined using the molar extinction coefficient (ƐGSH = 13,600 M\u003csup\u003e-1\u003c/sup\u003e .cm\u003csup\u003e-1\u003c/sup\u003e) and was expressed in micromoles of protein.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of superoxide dismutase activity\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal superoxide dismutase was measured using the method outlined by Sun et al [18]. This approach is founded on the principle that the xanthine oxidase system serves as a superoxide generator, which inhibits the reduction of nitroblue tetrazolium. After adding a 1.0 mL mixture of ethanol and chloroform (5/3, v/v) to an equal volume of the sample, the activity was evaluated in the ethanol phase of the homogenate following centrifugation. The absorbance obtained from nitroblue tetrazolium reduction to blue formazan by superoxide was determined spectrophotometrically at 560 nm.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"521\" height=\"43\" 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\" alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003eOne unit of SOD was considered as the amount of enzyme causing 50% inhibition in the nitroblue tetrazolium reduction rate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are expressed as mean \u0026plusmn; standard deviation (n=5). To compare the mean values across different treatment groups, one-way analysis of variance (ANOVA) was used, followed by Dunnett\u0026rsquo;s post hoc test when significant differences in variances were identified. A significance level of P \u0026lt; 0.05 was used to determine meaningful differences between the groups. The analyses were conducted with Prism Version 5.03 statistical software (Graph Pad Inc., USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eGross Evaluation of Gastric Mucosa\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs illustrated by Figure 1, administration of 95% ethanol induced severe gastric ulcer while rats receiving distilled water (normal control) showed no signs of ulceration. However, pre-treatment of rats with the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extract significantly diminished the gastric injury and ulcer index when compared to the ulcerated group. The inhibition percentage of the ulcer index in rats pre-treated with the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extract increased in a dose dependent manner. The ulcerated rats produced the lowest gastric mucus content while animal group pre-treated with the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e (500 mg/kg) and omeprazole (20mg/kg) showed a significant increase in mucus weight (g) with respect to the ulcerated group as shown in table 1.\u003c/p\u003e\n\u003ch3\u003eEffect of a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e pre-treatment, on lipid peroxidation (MDA) and anti-oxidant enzymes.\u003c/h3\u003e\n\u003cp\u003eThe ulcer model rats revealed a major reduction in antioxidant (SOD, CAT, and GSH) endogenous enzyme activities. Rats pretreated with a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e and pre-treatment with omeprazole demonstrated an elevation of all antioxidant activities with respect to the ulcer control rats, as shown in Table 2. The CAT activity and SOD enzyme activities as well as GSH content were significantly (P\u0026lt;0.05) higher at a dose of 500 mg/kg of a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extract and omeprazole 20mg/kg than in ulcer model rats. Also, the MDA content was significantly (P\u0026lt;0.05) lower at a dose of 500 mg/kg of a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extract and omeprazole 20 mg/kg compared to ulcer control rats.\u003c/p\u003e\n\u003ch3\u003eEffect of a Combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e Pre-treatment, on Gastric Inflammatory Parameters.\u003c/h3\u003e\n\u003cp\u003eThe ulcer control rats revealed a major increase in inflammatory cytokines (TNF-α, IFN-ϒ, IL-1β, IL-6). Rats pretreated with a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e and pre-treatment with omeprazole demonstrated a decrease in all inflammatory cytokines with respect to the ulcer control rats, as shown in table 3. The levels of TNF-α, IFN-ϒ, IL-1β and IL-6 were significantly (P\u0026lt;0.05) lower at a dose of 500 mg/kg of a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extract and omeprazole 20mg/kg than ulcer model rats (Table 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe consumption of alcohol is recognized as a major factor contributing to gastric ulcers in humans; therefore, researchers have utilized an animal model of gastric injury induced by ethanol to replicate the conditions humans may face, allowing them to investigate the anti-ulcer effects of natural products or novel therapies aimed at providing gastric protection [19].\u003c/p\u003e\n\u003cp\u003eOral administration of absolute ethanol in the animal model is destructive to stomach tissue, since it penetrates rapidly and easily into the gastric mucosa, producing gastric lesions [19] thus, making it useful in determining the anti-ulcer capacity of drugs, as well as the likely pathways involved in this process [20]. Such lesions are characterized by extensive sub-mucosal edema, hemorrhage, desquamation of epithelial cells and infiltration of inflammatory cells, which are typical characteristics of alcohol-induced damage in humans [19].\u003c/p\u003e\n\u003cp\u003eIn this study, a gastric ulcer model was created using 95% ethanol (5 ml/kg). Ethanol is a common cause of gastric ulcers and induces gastric damage through multiple mechanisms, including dehydration, which impairs the mucosal cell barriers, and cytotoxic effects. This cytotoxicity leads to the activation of leukocytes that release reactive oxygen species (ROS) and inflammatory cytokines, both of which can contribute to cell death.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e, and \u003cem\u003eA. vera\u003c/em\u003e are natural plants that have shown protective, antioxidant, and anti-inflammatory properties in various studies conducted in different in vivo models over periods of 2 weeks or 21 days; hence, a duration of 21 days was chosen for this investigation [13]. Three treatment doses were chosen based on prior studies, and the dose-response relationships for anti-gastric ulcer effects were evaluated in rats with ethanol-induced gastritis that received oral treatment with 125, 250, and 500 mg/kg of a blend of of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e over 21 days. Our findings indicated that among the three dosage levels of the \u003cem\u003eP. guajava and A. vera\u0026nbsp;\u003c/em\u003ecombination, 500 mg/kg exhibited the strongest protective effect against gastric ulcers. The elevated gastric ulcer index (GUI) in rats exposed to ethanol underscores the significant ulcerogenic potential of ethanol, which aligns with existing research [21]. The marked decrease in the gastric ulcer index (GUI) and the improved protective index (PI) resulting from the combination of \u003cem\u003eP. guajava\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;A. vera\u003c/em\u003e indicate a strong anti-ulcer effect that rivals that of omeprazole, a widely recognized anti-ulcer medication. Additionally, pre-treating with a combination of \u003cem\u003eP. guajava, A. vera\u003c/em\u003e, and omeprazole led to fewer gastric lesions in the gastric wall mucosa; it also resulted in increased mucus levels in ethanol-treated rats, likely due to heightened production of prostaglandin E2 in the gastric mucosa. Moreover, we investigated the role of inflammatory cytokines, lipid peroxidation, and antioxidant enzyme pathways to understand the mechanisms behind the anti-ulcer effects of the P. guajava and A. vera combination. The administration of ethanol prompts the infiltration of neutrophils; It triggers the immune response of T lymphocytes, leading to a chain reaction of inflammation, oxidative stress, and the death of epithelial cells. A significant increase in the levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β can cause considerable damage to the gastrointestinal mucosa, worsening the level of inflammation in the human body [22]. In this study, we observed that pre-treatment with a combination of \u003cem\u003eP. guajava, A. vera,\u003c/em\u003e and omeprazole resulted in reduced production of inflammatory cytokines. During the occurrence of gastric ulcers, macrophages produce TNF-α, hindering the healing process in various ways, which includes reducing gastric microcirculation, promoting neutrophil infiltration, and triggering inflammatory signaling pathways, leading to the production of additional inflammatory cytokines that further amplify its production [19]. IL-6, IFN-γ, and IL-1β are pro-inflammatory cytokines that play a crucial role in the process of acute inflammation. Elevated levels of these cytokines activate neutrophils, macrophages, and lymphocytes at the inflammation site, enhancing the production of inflammatory mediators and worsening gastric mucosal injury [23]. In line with earlier studies, \u0026nbsp;[24] our findings demonstrated that the oral intake of ethanol initiates a localized inflammatory response, raising the levels of inflammatory cytokines in the gastric tissue. Nevertheless, the pre-treatment with a combination of P. guajava and A. vera along with omeprazole mitigated this detrimental effect, resulting in decreased levels of the inflammatory markers TNF-α, IL-6, IL-1β, and IFN-γ.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlcohol administration leads to the degradation of the gastric wall mucosal barrier through the action of reactive oxygen species (ROS) and the up-regulation of cytokines, which causes damage due to oxidative stress [25]. In this research, intubation with ethanol resulted in significant oxidative-stress-related damage in rats suffering from ethanol-induced ulcers; this finding aligns with prior studies [26]. An imbalance in redox state between the generation of reactive oxygen species (ROS) and the scavenging action of antioxidants can lead to oxidative stress, primarily driven by infiltrating inflammatory cells as the major source of ROS [20]. The superoxide radical anions (O2−), produced by neutrophils, react with lipids, leading to lipid peroxidation [20]. This investigation showed that the redox balance was disrupted due to elevated lipid peroxidation (measured as MDA), along with a reduction in antioxidant enzymes like GSH, SOD, and CAT in the gastric tissues with ulcers. The rise in MDA levels was linked to an increase in reactive oxygen species (ROS) alongside a reduction in antioxidant enzymes [20]. The combination of P. guajava and A. vera, along with omeprazole pre-treatment, notably reduced lipid peroxidation (measured as MDA) and restored the diminished levels of GSH, SOD, and catalase activity in the ulcerated gastric mucosa. The pairing of P. guajava and A. vera exhibits significant anti-lipid peroxidation properties and the ability to scavenge free radicals [20]. This finding suggests that plant extracts can boost antioxidant activity, likely due to the presence of antioxidant phytochemicals in these plants. Both P. guajava and A. vera are abundant in phenolic compounds, which may contribute to the improved antioxidant effects. Research indicates that intake of antioxidant-rich phenolic compounds is linked to the prevention of chronic illnesses such as cancer, diabetes, and cardiovascular diseases. This study indicates that phenolic compounds have positive effects on gastro-protective activity [26]. This research has potential limitations. While the study observed the gastro-protective effects of a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera,\u003c/em\u003e the underlying mechanism of action were not explored in depth. Additional studies, such as mechanistic investigations are necessary to understand the specific pathways. Also, the study utilized a rat model to simulate ethanol-induced gastric ulcers. While animal models provide valuable insights, there may be differences in the response to treatment between rats and humans, limiting the direct translation of findings to clinical applications.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of the current research indicated that the combination of P. guajava and A. vera at a dosage of 500mg/kg reduced ethanol-induced gastric ulcers through its antioxidant and anti-inflammatory properties. The gastro-protective capability of P. guajava and A. vera may be linked to the rich presence of phytochemical compounds such as total polyphenols, flavonoids, and tannins. Consequently, P. guajava and A. vera may serve as a promising anti-ulcer agent for treating gastric ulcers, demonstrating an anti-ulcer effect similar to that of omeprazole. Nevertheless, additional studies are necessary to further investigate the underlying mechanisms of action.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u0026nbsp;\u003cem\u003eA. vera: Aloe vera\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCAT: Catalase\u003c/p\u003e\n\u003cp\u003eGSH: Reduced Glutathione\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eH. pylori: Helicobacter pylori\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMDA: Malondialdehyde\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNSAIDs: Non-steroidal anti-inflammatory drugs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eP. guajava: Psidium guajava,\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePGs: Prostaglandins\u003c/p\u003e\n\u003cp\u003ePPIs: Proton pump inhibitors\u003c/p\u003e\n\u003cp\u003eSOD: Superoxide Dimutase\u003c/p\u003e\n\u003cp\u003eUI: Ulcer index\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no funding to report\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the Department of Biomedical Sciences, Faculty of Health Sciences of the University of Buea for providing the facilities for this research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT Authorship Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThiery Tania Meseme\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Writing – review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJulius Tanayen Kihdze\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eConceptualization\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003esupervision, validation, resources, Visualization, Project administration, Writing – original draft, Writing – review \u0026amp; editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrancis Desiré Tatsinkou Bomba\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEléonore Ngounou:\u003c/strong\u003e Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Writing – review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eArnaud Fondjo Kouam:\u003c/strong\u003e Conceptualization, Investigation, Methodology, Resources, Formal analysis, Validation, Supervision, Visualization, Project administration, Writing – original draft, Writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmmanuel Acha Asongalem:\u0026nbsp;\u003c/strong\u003eConceptualization\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003esupervision, validation, resources, Visualization, Project administration, Writing – original draft, Writing – review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this manuscript and the raw data will be made available upon request\u003c/p\u003e"},{"header":"References","content":" \u003col\u003e\n \u003cli\u003eCiciliato MP, De Souza MC, Tarran CM, De Castilho ALT, Vieira AJ, Rozza AL: Anti-Inflammatory Effect of Vanillin Protects the Stomach against Ulcer Formation. 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Am J Physiol-Gastrointest Liver Physiol. 1997, 272:G809\u0026ndash;14.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e Yoo J-H, Park E-J, Kim SH, Lee H-J: Gastroprotective effects of fermented lotus root against ethanol/HCl-induced gastric mucosal acute toxicity in rats. Nutrients. 2020, 12:808.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e Boutemine I-M, Amri M, Amir Z-C, et al.: Gastro-protective, therapeutic and anti-inflammatory activities of Pistacia lentiscus L. fatty oil against ethanol-induced gastric ulcers in rats. J Ethnopharmacol. 2018, 224:273\u0026ndash;82.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e Antonisamy P, Subash-Babu P, Alshatwi AA, Aravinthan A, Ignacimuthu S, Choi KC, Kim J-H: Gastroprotective effect of nymphayol isolated from Nymphaea stellata (Willd.) flowers: contribution of antioxidant, anti-inflammatory and anti-apoptotic activities. Chem Biol Interact. 2014, 224:157\u0026ndash;63.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e Abdel-Salam OM, Czimmer J, Debreceni A, Szolcs\u0026aacute;nyi J, M\u0026oacute;zsik G: Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview. J Physiol-Paris. 2001, 95:105\u0026ndash;27.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e Okewumi TA, Oyeyemi AW: Gastro-protective activity of aqueous Carica papaya seed extract on ethanol induced gastric ulcer in male rats. Afr J Biotechnol. 2012, 11:8612\u0026ndash;5. 10.5897/AJB12.034\u003c/li\u003e\n \u003c/ol\u003e\n"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Effect of a combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e on Gastric ulcer index, Gastric protective index and Gastric mucus weight\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"855\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 668px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 277px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastric Ulcer Index\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastric Protective Index\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 270px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastric Mucus (g)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 187px;\"\u003e\n \u003cp\u003eOmeprazole 20mg/Kg + ET-OH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e1.1\u0026plusmn;0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e67\u0026plusmn;7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e1.8\u0026plusmn;0.84*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 187px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 125mg/Kg + ET-OH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e3.2\u0026plusmn;2.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e2.6\u0026plusmn;49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 187px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 250mg/Kg + ET-OH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e2.53\u0026plusmn;2.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e24\u0026plusmn;27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 187px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 500mg/Kg + ET-OH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e1\u0026plusmn;0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e68\u0026plusmn;9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e1.8\u0026plusmn;0.84*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 187px;\"\u003e\n \u003cp\u003eUlcer model (distilled H2O +ET-OH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e3.3\u0026plusmn;2.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0\u0026plusmn;32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.46\u0026plusmn;0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 187px;\"\u003e\n \u003cp\u003eNormal control (Distilled H\u003csub\u003e2\u003c/sub\u003eO 10mL/Kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 172px;\"\u003e\n \u003cp\u003e0\u0026plusmn;0.0*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e100\u0026plusmn;0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e2.4\u0026plusmn;1.14*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.0007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed as mean \u0026plusmn; SD, n=5; *denotes significant difference with ethanol treated group, p\u0026lt;0.05 using ANOVA followed by Dunnett\u0026rsquo;s \u003cem\u003epost hoc\u003c/em\u003e test. GUI: Gastric ulcer index, GPI: Gastric protective index and GM: Gastric mucus weight, ET-OH: Ethanol.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Effect of the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u0026nbsp;\u003c/em\u003eon oxidative stress\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"907\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"8\" style=\"width: 787px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOxidative Stress Parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMDA (\u003c/strong\u003e\u003cstrong\u003e𝜇\u003c/strong\u003e\u003cstrong\u003emol/g tissue)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSH (U/mg tissue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCAT (U/mg tissue)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOD (U/mg tissue)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003eOmeprazole 20mg/Kg+ ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e11.52\u0026plusmn;1.81*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3.53\u0026plusmn;0.47*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.427\u0026plusmn;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e25.39\u0026plusmn;0.77*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.0037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 125mg/Kg+ ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e20.44\u0026plusmn;2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.295\u0026plusmn;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e19.13\u0026plusmn;1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.976\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 250mg/Kg+ ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e17.6\u0026plusmn;2.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.0007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2.15\u0026plusmn;0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.323\u0026plusmn;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e21.56\u0026plusmn;2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.294\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 500mg/Kg+ ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e11.38\u0026plusmn;2.54*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3.43\u0026plusmn;0.48*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.403\u0026plusmn;0.03*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e25.93\u0026plusmn;4.56*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.0018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003eUlcer model (distilled H2O +ET-OH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e24.13\u0026plusmn;1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1.19\u0026plusmn;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.213\u0026plusmn;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e17.91\u0026plusmn;0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003eNormal control (Distilled H\u003csub\u003e2\u003c/sub\u003eO 10mL/Kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e11.87\u0026plusmn;0.72*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3.33\u0026plusmn;0.49*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.433\u0026plusmn;0.091*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e25.86\u0026plusmn;7.24*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.0019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed as mean \u0026plusmn; SD, n=5; *denotes significant difference with ethanol treated group, p\u0026lt;0.05 using ANOVA followed by Dunnett\u0026rsquo;s \u003cem\u003epost hoc\u003c/em\u003e test. MDA: Malondialdehyde, GSH: Reduced glutathione, SOD: Superoxide dismutase and CAT: catalase, ET-OH: Ethanol.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Effect of the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e pre-treatment on gastric tissue cytokine profile\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"929\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"8\" style=\"width: 806px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCytokines Profile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTNF-\u0026alpha; (pg/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIFN-\u0026gamma;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(pg/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 210px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL-1\u0026beta; (pg/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL-6 (pg/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Dunnett)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eOmeprazole 20mg/Kg+ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e134.1\u0026plusmn;7.50*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e121.2\u0026plusmn;19.62*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e124.6\u0026plusmn;7.67*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e283.3\u0026plusmn;5.66*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. Vera\u003c/em\u003e 125mg/Kg+ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e210.5\u0026plusmn;15.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e269.8\u0026plusmn;22.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.0002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e232.3\u0026plusmn;9.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e324.4\u0026plusmn;25.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 250mg/Kg+ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e200.3\u0026plusmn;31.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e223.4\u0026plusmn;54.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e166.9\u0026plusmn;14.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e305.3\u0026plusmn;23.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. guajava\u003c/em\u003e+\u003cem\u003eA. vera\u003c/em\u003e 500mg/Kg+ET-OH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e135.3\u0026plusmn;8.81*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e109.9\u0026plusmn;17.39*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e124.4\u0026plusmn;11.76*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e280.3\u0026plusmn;6.66*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eUlcer model (distilled H2O +ET-OH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e326.7\u0026plusmn;17.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e341.0\u0026plusmn;9.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e284.2\u0026plusmn;23.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e443.9\u0026plusmn;12.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eNormal control (Distilled H\u003csub\u003e2\u003c/sub\u003eO 10mL/Kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e134.5\u0026plusmn;24.03*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e114.7\u0026plusmn;11.87*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e123.4\u0026plusmn;9.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e281.4\u0026plusmn;16.94\u003cem\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed as mean \u0026plusmn; SD, n=5; *denotes significant difference with ethanol treated group, p\u0026lt;0.05 using ANOVA followed by Dunnett\u0026rsquo;s \u003cem\u003epost hoc\u003c/em\u003e test. TNF-\u0026alpha;: Tumor necrosis factor alpha, IL-6: interleukin 6, IL-1\u0026beta;: interleukin 1beta, IFN-\u0026gamma;: interferon gamma, ET-OH: Ethanol.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Buea","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Psidium guajava, Aloe vera, gastric ulcer, oxidative stress, antioxidants, anti-inflammatory","lastPublishedDoi":"10.21203/rs.3.rs-6582938/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6582938/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eGastric ulcers are a common gastrointestinal disorder for which there is need to search for a better prevention method or treatment options. Accordingly, the aim of this study was to assess the protective effect of a combination of \u003cem\u003ePsidium guajava\u003c/em\u003e and \u003cem\u003eAloe vera\u003c/em\u003e extracts against ethanol-induced gastric ulcers in rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodology: \u003c/strong\u003eThe gastric ulcer was induced in rats using one oral dose of absolute ethanol (5mL/kg body weight). A combination of \u003cem\u003eP. guajava\u003c/em\u003eand \u003cem\u003eA. vera\u003c/em\u003e at doses of 125, 250 and 500mg/kg b.w and omeprazole 20mg/kg b.w were given by gavage daily for 21 days prior to the induction of ulcers. The stomachs of rats were analyzed both macroscopically and biochemically 24 hours following ethanol administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003ePretreatment of rats with the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003e extracts significantly (P\u0026lt;0.05) reduced ulcer index induced by ethanol. Also, administration of the plant extracts reduced stomach content of malondialdehyde, and enhanced stomach antioxidant enzymes (superoxide dismutase and catalase) activities as well as glutathione content in ethanol-intoxicated rats. Furthermore, the plant extract significantly (P\u0026lt;0.05) decreased the stomach level of pro-inflammatory cytokines such as TNF-α, INF-δ, IL-1β and IL-6. The efficacy of the combination of plant extracts at 250 and 500 mg/kg b.w was comparable to that of Omeprazole.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eOverall, findings from this study revealed that the combination of \u003cem\u003eP. guajava\u003c/em\u003e and \u003cem\u003eA. vera\u003c/em\u003eaqueous extracts displayed gastro-protective effect on ethanol-induced gastric ulcer, likely through the suppression of oxidative stress and gastric inflammation.\u003c/p\u003e","manuscriptTitle":"A combination of Psidium guajava and Aloe vera Aqueous Extracts Prevents Ethanol-Induced Gastric Ulcer in Rats through Suppression of Oxidative Stress and Gastric Inflammation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 03:32:42","doi":"10.21203/rs.3.rs-6582938/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e1bfb611-1bc0-4be9-a6a7-6c1dfeeedac1","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48023219,"name":"Drug Discovery, Design, \u0026 Development"}],"tags":[],"updatedAt":"2025-05-06T03:32:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-06 03:32:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6582938","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6582938","identity":"rs-6582938","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}