Network-pharmacology-based study on the mechanism of fibrates regulating HIF-1A in the treatment of ischemic stroke

Network-pharmacology-based study on the mechanism of fibrates regulating HIF-1A in the treatment of ischemic stroke | 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 Article Network-pharmacology-based study on the mechanism of fibrates regulating HIF-1A in the treatment of ischemic stroke Fengjiao Yang, Ya Yan, Yun Gu, Pengyu Wang, Min Wang, Jianjie Chen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4261750/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 Ischemic stroke (IS) is a serious threat to people's health, its occurrence risk is closely related to lipid levels and genes. Fibrates are commonly used as adjunctive therapy for IS in clinical practice, some studies have reported that hypoxia-inducible factor (HIF1A) is associated with the occurrence risk of various diseases, so it is important to explore the mechanism of fibrates regulate HIF1A in the treatment of IS. Firstly, the potential targets of fibrates, IS, HIF1A and HIF1A-related genes were obtained through various databases, then their common targets were obtained through Venny 2.1.0. The PPI network of fibrates and HIF1A-related genes was plotted by String platform and Cytoscape3.8.1 software. KEGG pathways of drugs, diseases, HIF1A and HIF1A related genes were obtained by Metascape platform. Finally, molecular docking of fibrates and HIF1A was performed by AutoDock software. In this study, the structure of five fibrates were obtained by reviewing the literature and pharmacopoeia. The common targets of five fibrates and IS showed that only 3 fibrates contained HIF1A. KEGG pathway analysis and molecular docking results showed that fibrates can better regulate HIF1A to treat IS, its main action pathways are pathways in cancer, kaposi sarcoma-associated herpesvirus infection and HIF-1 signaling pathway. Biological sciences/Neuroscience/Blood brain barrier Biological sciences/Neuroscience/Cell death in the nervous system Biological sciences/Neuroscience/Diseases of the nervous system Fibrates IS HIF1A Network pharmacology Molecular docking Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction In recent years, the establishment of stroke centers has made stroke patients get more effective treatment, but the incidence of stroke still shows an increasing trend every year 1 . IS accounts for about 80% of stroke 2 . At present, recombinant tissue plasminogen activator is the mainly therapeutic drug of IS 3 . It is well known that thrombolysis and mechanical thrombectomy are the most effective methods for the treatment of IS 4 , but mechanical thrombectomy is risky, it may lead to bleeding, which will further aggravate brain damage. Therefore, some thrombolytic drugs are often used to treat IS, but the use of thrombolytic drugs has strict time limits, thrombolytic therapy must be performed within 4.5 hours after the occurrence of IS, which leads to many patients not receiving effective treatment 5 , 6 . Therefore, some anti-platelet drugs, anti-coagulants and neuroprotective drugs are commonly used to prevent and treat IS in clinical practice 7 . With the increasing aging of the population, the incidence of IS has also increased, which has brought a large economic burden to society and families of patients 8 , 9 . Therefore, the effective prevention of IS is important to improving people's quality of life. Effective intervention the high risk factors of IS is the most effective and fundamental measure to reduce the occurrence of IS. The results of investigation and research show that blood lipid levels are closely related to the occurrence risk of IS 10 , and hyperlipidemia is a high risk factor for IS. Therefore, early use of lipid-lowering drugs can effectively prevent the occurrence of IS when blood lipid levels are abnormal 11 . Fibrates belong to the lipid-lowering drugs of phenoxyaromatic acid class, it can exert lipid-lowering effects by lowering low-density lipoprotein and cholesterol. In addition, fibrates can enhance lipoprotein esterase activity, accelerate proteolysis, reduce lipoprotein synthesis in the liver, lower low-density lipoproteins and triglycerides, elevate high-density lipoproteins, which can prevent blood clotting and promoting thrombolysis, it may effectively reduce the occurrence risk of IS 12 , 13 . Fenofibrate, clofibrate, bezafibrate and gemfibrozil are the most commonly used fibrates in clinical practice. Pirinic acid has not been used in clinical practice, but its lipid-lowering effect has been widely studied in the laboratory. The chemical structures of the 5 fibrates are shown in Fig. 1 . The pathogenesis of IS is complex, which is often caused by the interaction of multiple biological factors, biological functions and biological pathways. The occurrence of IS often causes various reactions such as energy metabolism disorders, oxidative stress, inflammatory response and neuronal damage 14 , 15 . Therefore, it is necessary to use multi-target drugs to treat IS in order to achieve better therapeutic effects in clinical practice. Network pharmacology emphasizes the analysis of the relationship among drugs, genes and diseases from the systemic level and the overall perspective of biological network. The integrity and systematization of network pharmacology are consistent with the complex pathogenesis of diseases, so it has been widely used to explain the mechanism of drugs in treating diseases, which can promote the rational use of drugs in clinical practice. In this study, the methods of network pharmacology and molecular docking were used to illustrate the relationship between fibrates and HIF1A in the treatment of IS, we hope to provide some reference for the follow-up study of fibrates regulating HIF1A in the prevention and treatment of IS. 2. Materials and methods 2.1. Common targets of fibrates and IS In this study, targets for fenofibrate, pirinixic acid, clofibrate, bezafibrate, and gemfibrozil were obtained through Swiss Target Prediction platform ( http://www.swisstargetprediction.ch/ ) 16 and CTD platform ( http://ctdbase.org/ ) 17 , then the duplicate targets were removed, finally, the final targets of each drug was obtained. Targets of IS was obtained through Genecard database ( https://www.genecards.org/ ) 18 , OMIM database ( https://omim.org/ ) 19 , DrugBank database ( https://www.drugbank.com/ ) 19 , TTD database ( https://db.idrblab.net/ttd/ ) 20 and DisGeNET database ( https://www.disgenet.org/ ) 21 , the obtained targets were summarized, then duplicated targets were removed to obtain the final targets of IS. Finally, the common targets of each drug and IS was obtained through the Venny 2.1.0 ( https://bioinfogp.cnb.csic.es/tools/venny/ ) 22 . 2.2. Common targets of HIF1A-related genes and fenofibrate, pirinixic Acid, clofibrate Targets of HIF1A-related genes were obtained through the GEPIA2 platform ( http://gepia2.cancer-pku.cn/ ) 23 , then common targets of fenofibrate, pirinixic acid, clofibrate and HIF1A related genes were obtained through the Venny 2.1.0. 2.3. PPI Network diagram of the common targets of fenofibrate, pirinixic acid, clofibrate and HIF1A-related genes The common targets of fenofibrate, pirinixic acid, clofibrate and HIF1A-related genes were imported into the String platform ( https://string-db.org/ ) 24 , the parameter was set to moderate reliability (0.400), unassociated nodes are hidden, then the PPI network data table is exported. The PPI network data sheets were introduced into Cytoscape3.8.2, then the PPI network diagram of fenofibrate, pirinixic acid, clofibrate and HIF1A related genes were obtained. 2.4. Enrichment analysis of common targets of fibrates and IS The common gene sets of fenofibrate, pirinixic acid, clofibrate and IS are imported Metascape platform ( http://www.metascape.org/ ) 25 , then KEGG enrichment analysis was performed. Finally, the related pathways of HIF1A were obtained from the KEGG enrichment analysis results of the above 3 fibrates and IS, then the KEGG pathways bubble diagram was plotted, which could explore the action pathway of fibrates regulating HIF-1A in the prevention and treatment of IS. 2.5. Molecular docking of HIF1A and fibrates HIF1A receptor protein was obtained through Uniprot database ( https://www.uniprot.org/ ) 26 , then HIF1A receptor protein was imported into the PDB database to obtain the protein structure of HIF1A. The 3D chemical structures of fenofibrate, pirinixic acid and clofibrate were obtained by relevant software. The water molecules of HIF1A receptor protein and drug components were removed by PyMOL software, then the HIF1A receptor protein was imported into AutoDock software to perform hydrogenation and calculated charge operations. The docking pocket and docking parameters were set in AutoDock Vina software to perform molecular docking between HIF1A receptor protein and small molecule ligands of drug active compounds. 3. Results 3.1. Screening of relevant targets 3.1.1. Gene sets of fibrates In this study, the targets of five fibrates were collected through the Swiss Target Prediction platform and CTD platform, the final obtained targets are shown in Table 1 . The results show that the targets number of pirinixic acid is the most and the targets number of gemfilozil is the least. Table 1 The targets number of five fibrates Fibrates Swiss Target Prediction CTD Total number of targets The number of repeated targets The final number of targets Fenofibrate 100 763 863 16 847 Pirinixic Acid 100 7642 7742 59 7683 Clofibrate 100 3133 3233 30 3203 Bezafibrate 100 249 349 9 340 Gemfibrozil 100 104 204 6 199 3.1.2. Gene sets of IS 3041 targets of IS were collected in the Genecard database, 129 targets of IS were collected in the OMIM database, 0 targets of IS were collected in the TTD database, 15 targets of IS were collected in the DisGeNET database. 61 targets of IS were collected in DrukBank database, a total of 3246 targets were obtained, 69 duplicated targets were removed, finally, 3177 targets were obtained. 3.1.3. Common gene sets of fibrates and IS The Venn diagram of the common targets of fibrates and IS is shown in Fig. 2 . It can be seen that pirinixic acid has the most targets, in addition, the common targets of pirinixic acid and IS are also the most, which has 1119. Gemfibrozil has the fewest targets, the common targets of gemfibrozil and IS is also the lowest, which has 91. 3.1.4. Common gene sets of HIF1A-related genes and fibrates In this study, the gene set of HIF1A-related genes was obtained through the GEPIA2 platform, which has 100, the Venn diagram of HIF1A-related genes and fibrates was obtained through the Venny 2.1.0, the result is shown in Fig. 3 . The results showed that the HIF1A-related genes and pirinixic acid has the most common targets, which has 43, HIF1A-related genes and gemfibrozil has the least common targets, which has 1. 3.2. The PPI network diagram and core targets screening of fibrates The PPI network diagram of the common gene sets of fenofibrate, pirinixic acid, clofibrate and HIF1A-related genes are shown in Fig. 4 . The results showed that the correlation of fenofibrate and HIF1A-related genes was weak, the PPI network diagram of their common genes had 3 nodes and 2 edges. There was a strong correlation between pirinixic acid and HIF1A-related genes, the PPI network diagram of their common genes had 30 nodes and 37 edges. In the PPI network diagram, nodes represent genes, edges represent relationships among genes. Bezafibrate and gemfibrozil do not contain the HIF1A, and bezafibrate, gemfibrozil and HIF1A-related genes have few common targets, so their PPI network diagrams are not shown. 3.3. KEGG enrichment analysis of fibrates regulating HIF1A in the treatment of IS KEGG pathways of fibrates regulating HIF1A in the treatment of IS were analyzed, the results are shown in Fig. 5 . the results showed that there were fewer pathways related to HIF1A in fenofibrate treatment of IS, which has 9, pirinixic acid has the same number of pathways associated with the HIF-1A gene as clofibrate in the treatment of IS, which has 15. KEGG pathway analysis showed that fibrates mainly regulate HIF1A involved in pathways in cancer, kaposi sarcoma-associated herpesvirus infection, th17 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, proteoglycans in cancer, thyroid hormone signaling pathway, central carbon metabolism in cancer and HIF-1 signaling pathway play a role in the prevention and treatment of IS. Bezafibrate and gemfibrozil do not contain HIF1A, so bubble diagram of their KEGG pathways are not shown. 3.4. The KEGG pathway enrichment analysis of fibrates and HIF1A-related genes The KEGG pathway analysis results of fibrates regulating HIF1A-related genes in the treatment of IS are shown in Fig. 6 , it shows that there are 21 KEGG pathways belongs to pirinixic acid and HIF1A-related genes, there are 8 KEGG pathways belongs to clofibrate and HIF1A-related genes. KEGG pathway analysis showed that pirinixic acid mainly regulated the regulation of actin cytoskeleton, oocyte meiosis and focal adhesion pathway of HIF1A-related genes to play a role in the prevention and treatment of IS, clofibrate mainly regulates pathways in cancer, leukocyte transendothelial migration and cAMP signaling pathway of HIF1A-related genes to play a role in the prevention and treatment of IS. In this study, the KEGG pathway of fenofibrate and HIF1A-related genes was not found, so the action pathway of fenofibrate and HIF1A-related genes was not analyzed. Bezafibrate and gemfibrozil do not contain HIF1A and the above two drugs and HIF1A-related genes have only a few common targets, so their KEGG pathway bubble diagram are not shown. 3.5. The molecular docking of fibrates and HIF1A The common gene sets of five fibrates and IS was analyzed, the results showed that only the common gene sets of fenofibrate, pirinixic acid, clofibrate and IS contained the HIF1A. Molecular docking was performed between the above three drugs and HIF1A, the binding energies of the three drugs and HIF1A are shown in Table 2 . The molecular docking diagram is shown in Table 2 and Fig. 7 , it shows that the binding energy of the above three drugs and HIF1A is less than − 5 KJ/mol, which indicates that these drugs can better bind to HIF1A, so the above three drugs can better regulate HIF1A to play a role in the prevention and treatment of IS. Table 2 Binding energies of fibrates and HIF1A Fibrates Binding energy (KJ/mol) Fenofibrate -7.5 Pirinixic acid -7.1 Clofibrate -5.6 4. Discussion Many risk factors can lead to the occurrence of IS, among which hyperlipidemia is a high risk factor 27 . Fibrates are commonly used as lipid-lowering drugs in clinical practice, it are peroxisome proliferator-activated receptor α (PPARα) agonists 28 , it can activate the transcription factor PPARα to bind to another transcription factor RXR, which increases the gene transcription and protein expression. fibrates can play a role in regulating lipid and stable plaque, in addition, fibrates also can play a role in anti-atherosclerosis and reduce ischemia-reperfusion injury by increasing the activity of various enzymes and participating in oxidative stress response. Therefore, fibrates are often used to the prevention and adjuvant treatment of IS 29 . IS is a severe vascular event with local or complete blood flow restriction in brain tissue caused by plaque occlusion of internal carotid artery or middle cerebral artery 30 . It has the characteristics of high morbidity, high mortality and high disability rate, which is a global public health problem 31 , 32 . The main factors of leading to brain injury include excitotoxicity of cells, energy metabolism disorders, calcium overload, oxidative stress, cell apoptosis, autophagy and inflammatory response in the pathological process of IS 33 – 35 . However, only a few drugs can effectively treat IS in clinical practice, so the prevention of IS is very important. In recent years, it has been reported that HIF1A can participate in the pathological process of a variety of diseases, which is associated with oxidative stress response 36 , 37 . It has been reported that oxidative stress response is related to IS 38 . Fibrates have been widely used as an adjuvant therapy drug of IS, it has a good curative effect. therefore, the relationship between fibrates in the treatment of IS and HIF1A was explored in this study, the results showed that only the common target of fenofibrate, pirinixic acid, clofibrate and IS contained the HIF1A, and these 3 fibrates could play a role in the prevention and treatment of IS through HIF1A. Bezafibrate and gemfibrozil do not contain HIF1A, their mechanism of action needs further study in the future. The occurrence and progression of IS are closely related to ion channels, enzyme reactions and hormone reactions. KEGG pathway enrichment analysis showed that fibrates can regulate HIF1A to prevent and treat IS through Th17 cell differentiation, thyroid hormone signaling pathway and HIF-1 signaling pathway. The pathway of Th17 cells differentiation is related to a variety of inflammatory factors such as TGF-β, IL-17A, IL-6, IL-21 and IL-22, which are involved in the occurrence and progression of many inflammatory reactions and autoimmune diseases 39 . Fibrates may reduce the occurrence of vascular inflammation reactions by inhibiting inflammatory factors, which can reduce the level of HIF1A factor, it can increase cerebral blood perfusion and reduce the occurrence of cerebral hypoxia and ischemia symptoms. When IS occurs, the hypothalamic-pituitary-thyroid axis will respond to the ischemic/hypoxic environment, it will reduce the levels of T3 and FT3 and increase the levels of T4 and TSH. On the contrary, if the levels of T3 and FT3 increase and the levels of T4 and TSH decrease, it means that the patient has already enters the recovery period of IS 40 . Therefore, the thyroid hormone signaling pathway is involved in the whole pathological process of IS, the changes of thyroid hormone levels can reflect the disease state of patients, so the prevention and treatment of IS can be formulated by studying thyroid hormone levels. KEGG pathway analysis showed that the pathological process of IS is associated with the HIF-1 signaling pathway, HIF-1 is a heterodimeric transcription factor, it consists of HIF-1α and HIF-1β 41 , HIF-1α can regulate the expression of some hormones such as erythropoietin and vascular endothelial growth factor 42 . These hormones are related to the function of the development of collateral vessels, blood viscosity and the protection of nerve cells. HIF1A can improve the state of cerebral ischemia and hypoxia by regulating the levels of these hormones, which can reduce the occurrence of IS and promote the recovery of IS. KEGG pathway analysis showed that renal cell carcinoma, thyroid hormone signaling pathway, focal adhesion and pathways in cancer were the main KEGG pathways of fibrates regulating HIF1A-related genes in the treatment of IS, among which pirinixic acid and HIF1A-related genes had the most KEGG pathways, which indicated that pirinixic acid may be closely related to HIF1A in the treatment of IS. The results of this study show that only fenofibrate, pirinixic acid and clofibrate contained HIF1A among the fibrates, so molecular docking was performed between the above 3 fibrates and HIF-1A gene. Molecular docking results showed that fenofibrate, pirinixic acid and clofibrate could be closely connected to HIF1A, which can be speculated that fenofibrate, pirinixic acid and clofibrate can better regulate HIF-1A to play a role in the prevention and adjuvant treatment of IS. Therefore, when dyslipidemia and hypoxia occur in the body, fibrates can activate HIF-1A to regulate blood lipid levels, protect nerve cells and promote the development of collateral vessels, which can reduce the occurrence risk of IS. Benzafibrate and Gemfibrozil do not contain HIF1A, which may regulate other factors to play a role in the prevention and treatment of IS. 5. Conclusion Fibrates are related to a variety of biological factors in the prevention and treatment of IS, among which fenofibrate, pirinixic acid and clofibrate can regulate HIF1A to participate in the pathological process of IS. Pirinixic acid has a strong correlation with HIF1A and HIF1A-related genes in the treatment of IS. KEGG pathway analysis showed that the above 3 fibrates could regulate HIF1A to participate in the pathological process of IS, the main KEGG pathways were pathways in cancer, kaposi sarcoma-associated herpesvirus infection, Th17 cell differentiation, and PD-L1 expression and PD-1 checkpoint pathway in cancer, proteoglycans in cancer, thyroid hormone signalingpathway, central carbon metabolismin cancer and HIF-1 signaling pathway. Molecular docking results showed that the binding energies of fenofibrate, pirinixic acid, clofibrate and HIF-1A were all less than − 5 KJ/mol, which indicated that the above drugs could be better combined with HIF1A, so fenofibrate, pirinixic acid and clofibrate could better regulate HIF1A to play the role of preventing and treatment IS. In conclusion, fibrates can play a role in the prevention and treatment of IS through multiple targets, multiple pathways, multiple hormones and multiple biological reactions. Abbreviations HIF1A Hypoxia-inducible factor IS Ischemic stroke PPARα Peroxisome proliferator-activated receptorα Declarations Data availability Data supporting the findings of this study are included in the article. The database used in this study is a public database. Disclosure of conflict of interest None. Author contributions Conceptualization, P.W.; Methodology, Y.Y.; Software, F.Y.; Validation, X.D.; Formal analysis, M.W.; Resources, J.C.; Data curation, P.W.; Writing-original draft preparation, F.Y.; Writing-review and editing, G.W.; Supervision, Y.G.; Project administration, G.W. All authors have read and agreed to the published version of the manuscript. Funding This work was supported by the The National Natural Science Foundation of China [grant number 82160244], Natural Science Foundation of Yunnan Province [grant number 202001BA070001-133], Local university joint project of Science and Technology Department of Yunnan province [grant number 202001BA070001-156], Cultivating Plan Program for the Leader in Science and Technology of Yunnan Province [grant number D-2017057] and Study on the effect of Qiangli Tianma Duzhong capsule on HT-22 nerve cells in the treatment of ischemic stroke [grant number 2023KBG080]. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. References Wang, L. et al. Nrf 2 regulates oxidative stress and its role in cerebral ischemic stroke. Antioxidants (Basel). 11(12), 2377. http://dx.doi.org/10.3390/antiox11122377 (2022). Cui, Y. et al. ACSL 4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain. Behav. Immun. 93, 312–321. http://dx.doi.org/10.1016/j.bbi.2021.01.003 (2021). Wang, Q. et al. A novel perspective on ischemic stroke: a review of exosome and noncoding RNA studies. Brain. Sci. 12(8), 1000. http://dx.doi.org/10.3390/brainsci12081000 (2022). Andrabi, S. S., Parvez, S. & Tabassum, H. Ischemic stroke and mitochondria: mechanisms and targets. Protoplasma. 257(2), 335–343. http://dx.doi.org/10.1007/s00709-019-01439-2 (2020). Chen, H., He, Y., Chen, S., Qi, S. & Shen, J. Therapeutic targets of oxidative/nitrosative stress and neuroinflammation in ischemic stroke: Applications for natural product efficacy with omics and systemic biology. Pharmacol. Res. 158, 104877. http://dx.doi.org/10.1016/j.phrs.2020.104877 (2020). Zhao, A. et al. A review of neuroprotective effects and mechanisms of ginsenosides from panax ginseng in treating ischemic stroke. Front. Pharmacol. 13, 946752. http://dx.doi.org/10.3389/fphar.2022.946752 (2022). Chojnowski, K., Opielka, M., Nazar, W., Kowianski, P. & Smolenski, R. T. Neuroprotective effects of guanosine in ischemic stroke-small steps towards effective therapy. Int. J. Mol. Sci. 22(13), 6898. http://dx.doi.org/10.3390/ijms22136898 (2021). Bangad, A., Abbasi, M. & de Havenon, A. Secondary ischemic stroke prevention. Neurotherapeutics. 20(3), 721–731. http://dx.doi.org/10.1007/s13311-023-01352-w (2023). Zhong, X., Sun, Y., Lu, Y. & Xu, L. Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex. Front. Immunol. 14, 1164258. http://dx.doi.org/10.3389/fimmu.2023.1164258 (2023). Yuan, S., Tang, B., Zheng, J. & Larsson, S. C. Circulating lipoprotein lipids, apolipoproteins and ischemic stroke. Ann. Neurol. 88(6), 1229–1236. http://dx.doi.org/10.1002/ana.25916 (2020). Kim, J. S. Role of blood lipid levels and lipid-lowering therapy in stroke patients with different levels of cerebral artery diseases: reconsidering recent stroke guidelines. J. Stroke. 23(2), 149–161. http://dx.doi.org/10.5853/jos.2021.01249 (2021). Carrion, A. F., Lindor, K. D. & Levy, C. Safety of fibrates in cholestatic liver diseases. Liver. Int. 41(6), 1335–1343. http://dx.doi.org/10.1111/liv.14871 (2021). Kim, N. H. & Kim, S. G. Fibrates revisited: potential role in cardiovascular risk reduction. Diabetes. Metab. J. 44(2), 213–221. http://dx.doi.org/10.4093/dmj.2020.0001 (2020). Huang, Q., Cai, G., Liu, T. & Liu, Z. Relationships among gut microbiota, ischemic stroke and its risk factors: based on research evidence. Int. J. Gen. Med. 15, 2003–2023. http://dx.doi.org/10.2147/IJGM.S353276 (2022). Jung, K. H. & Seong, S. Y. Role of inflammasomes in neuroinflammation after ischemic stroke. Encephalitis. 1(4), 89–97. http://dx.doi.org/10.47936/encephalitis.2021.00073 (2021). Shang, L. et al . Mechanism of Sijunzi Decoction in the treatment of colorectal cancer based on network pharmacology and experimental validation. J. Ethnopharmacol. 302, 115876. http://dx.doi.org/10.1016/j.jep.2022.115876 (2023). Zhu, W. et al . The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease based on network pharmacology and molecular docking. Ann. Med. 54(1), 541–552. http://dx.doi.org/10.1080/07853890.2022.2034931 (2022). Mo, L. et al . Integrated bioinformatic analysis of the shared molecular mechanisms between osteoporosis and atherosclerosis. Front. Endocrinol (Lausanne). 13, 950030. http://dx.doi.org/10.3389/fendo.2022.950030 (2022). Kang, P. et al . A network pharmacology and molecular docking strategy to explore potential targets and mechanisms underlying the effect of curcumin on osteonecrosis of the femoral head in systemic lupus erythematosus. Biomed. Res. Int . 2021, 5538643. http://dx.doi.org/10.1155/2021/5538643 (2021). Liu, P., Xu, H., Shi, Y., Deng, L. & Chen, X. Potential molecular mechanisms of plantain in the treatment of gout and hyperuricemia based on network pharmacology. Evid. Based. Complement. Alternat. Med . 2020, 3023127. http://dx.doi.org/10.1155/2020/3023127 (2020). He, S., Wang, T., Shi, C., Wang, Z. & Fu, X. Network pharmacology-based approach to understand the effect and mechanism of Danshen against anemia. J. Ethnopharmacol. 282, 114615. http://dx.doi.org/10.1016/j.jep.2021.114615 (2022). Qiu, Z. K. et al . A network pharmacology study with molecular docking to investigate the possibility of licorice against posttraumatic stress disorder. Metab. Brain. Dis. 36(7), 1763–1777. http://dx.doi.org/10.1007/s11011-021-00816-2 (2021). Zhao, X. et al . The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis. Front. Oncol. 12, 992468. http://dx.doi.org/10.3389/fonc.2022.992468 (2022). Aihaiti, Y. et al . Therapeutic effects of naringin in rheumatoid arthritis: network pharmacology and experimental validation. Front. Pharmacol. 12, 672054. http://dx.doi.org/10.3389/fphar.2021.672054 (2021). Xiang, C. et al . Network pharmacology and molecular docking to elucidate the potential mechanism of ligusticum chuanxiong against osteoarthritis. Front. Pharmacol. 13, 854215. http://dx.doi.org/10.3389/fphar.2022.854215 (2022). Zhang, L. et al . Exploring the mechanisms underlying the therapeutic effect of Salvia miltiorrhiza in diabetic nephropathy using network pharmacology and molecular docking. Biosci. Rep. 41(6), BSR20203520. http://dx.doi.org/10.1042/BSR20203520 (2021). Si Larbi, M. T. et al . Ischemic and non-ischemic stroke in young adults - a look at risk factors and outcome in a developing country. Cureus. 13(8), e17079. http://dx.doi.org/10.7759/cureus.17079 (2021). Hadjivasilis, A., Kouis, P., Kousios, A. & Panayiotou, A. The effect of fibrates on kidney function and chronic kidney disease progression: a systematic review and meta-analysis of randomised studies. J. Clin. Med. 11(3), 768. http://dx.doi.org/10.3390/jcm11030768 (2022). Montaigne, D., Butruille, L. & Staels, B. PPAR control of metabolism and cardiovascular functions. Nat. Rev. Cardiol. 18(12), 809–823. http://dx.doi.org/10.1038/s41569-021-00569-6 (2021). Kearns, K. N. et al . Microglia modulate cortical spreading depolarizations after ischemic stroke: a narrative review. Neurocrit. Care. 37(Suppl 1), 133–138. http://dx.doi.org/10.1007/s12028-022-01469-4 (2022). Li, Y. et al . Inflammatory cytokines and risk of ischemic stroke: a mendelian randomization study. Front. Pharmacol. 12, 779899. http://dx.doi.org/10.3389/fphar.2021.779899 (2022). Li, C. et al . Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke. Pharmacol. Res. 174, 105933. http://dx.doi.org/10.1016/j.phrs.2021.105933 (2021). Pluta, R., Januszewski, S. & Czuczwar, S. J. The role of gut microbiota in an ischemic stroke. Int. J. Mol. Sci. 22(2), 915. http://dx.doi.org/10.3390/ijms22020915 (2021). Guo, X. et al . Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idellal Val.) fed with the high non-protein energy diets. Fish. Physiol. Biochem. 41(2), 331–43. http://dx.doi.org/10.1007/s10695-014-9986-8 (2015). Peng, T. et al . Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo. Int. J. Biol. Sci. 18(11), 4578–4594. http://dx.doi.org/10.7150/ijbs.69892 (2022). Janbandhu, V. et al . Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell. Stem. Cell. 29(2), 281–297.e12. http://dx.doi.org/10.1016/j.stem.2021.10.009 (2022). Arias-Cavieres, A. et al . A HIF1a-dependent pro-oxidant state disrupts synaptic plasticity and impairs spatial memory in response to intermittent hypoxia. eNeuro . 7(3), ENEURO.0024-20.2020. http://dx.doi.org/10.1523/ENEURO.0024-20.2020 (2020). Kim, S. et al . The antioxidant enzyme Peroxiredoxin-1 controls stroke-associated microglia against acute ischemic stroke. Redox. Biol. 54, 102347. http://dx.doi.org/10.1016/j.redox.2022.102347 (2022). Wang, J. et al . Th17 cells and IL-17A in ischemic stroke. Mol. Neurobiol. 10, 26. http://dx.doi.org/10.1007/s12035-023-03723-y (2023). Murolo, M., Di Vincenzo, O., Cicatiello, A. G., Scalfi, L. & Dentice, M. Cardiovascular and neuronal consequences of thyroid hormones alterations in the ischemic stroke. Metabolites. 13(1), 22. http://dx.doi.org/10.3390/metabo13010022 (2022). He, Q. et al . Biological functions and regulatory mechanisms of hypoxia-inducible factor-1α in ischemic stroke. Front. Immunol. 12, 801985. http://dx.doi.org/10.3389/fimmu.2021.801985 (2021). Li, J. et al . HIF1A and VEGF regulate each other by competing endogenous RNA mechanism and involve in the pathogenesis of peritoneal fibrosis. Pathol. Res. Pract. 215(4), 644–652. http://dx.doi.org/10.1016/j.prp.2018.12.022 (2019). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4261750","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":293420007,"identity":"b85000dd-bf9f-4cf7-b4f8-24818da1610f","order_by":0,"name":"Fengjiao Yang","email":"","orcid":"","institution":"College of Pharmacy, Dali University","correspondingAuthor":false,"prefix":"","firstName":"Fengjiao","middleName":"","lastName":"Yang","suffix":""},{"id":293420012,"identity":"f0950eab-492d-4588-a11c-84d56003f39e","order_by":1,"name":"Ya Yan","email":"","orcid":"","institution":"College of Pharmacy, Dali University","correspondingAuthor":false,"prefix":"","firstName":"Ya","middleName":"","lastName":"Yan","suffix":""},{"id":293420013,"identity":"b65a9852-d714-4639-b99a-8c1fae6dabb4","order_by":2,"name":"Yun Gu","email":"","orcid":"","institution":"Department of Pharmacy, the First Affiliated Hospital of Dali University","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Gu","suffix":""},{"id":293420014,"identity":"ebb3160f-3794-435b-afaf-74a620173d09","order_by":3,"name":"Pengyu Wang","email":"","orcid":"","institution":"School of clinical medicine, Dali University","correspondingAuthor":false,"prefix":"","firstName":"Pengyu","middleName":"","lastName":"Wang","suffix":""},{"id":293420015,"identity":"d0415bab-22fb-42f6-9d8a-357177ec7c95","order_by":4,"name":"Min Wang","email":"","orcid":"","institution":"School of clinical medicine, Dali University","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Wang","suffix":""},{"id":293420016,"identity":"04df9cda-ca57-4125-8ff7-02cddc92554c","order_by":5,"name":"Jianjie Chen","email":"","orcid":"","institution":"School of clinical medicine, Dali University","correspondingAuthor":false,"prefix":"","firstName":"Jianjie","middleName":"","lastName":"Chen","suffix":""},{"id":293420017,"identity":"983b83e8-07e8-415f-a052-471b1338c645","order_by":6,"name":"Xiaoshan Du","email":"","orcid":"","institution":"Department of Geriatrics, South District of Hefei First People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoshan","middleName":"","lastName":"Du","suffix":""},{"id":293420018,"identity":"a3f1a77c-924c-4b33-bb0e-efc0bccdb7f4","order_by":7,"name":"Guangming Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYJCCAx8qJOQYDjA3HGBgYCZKB+PBGWcsjBkOMBKvhfkwb1tFYgNQCwNRWgzOr04AapFI7zt+sPEAQ4V1YgP72QP4tdx4u+HgnHMSuTPPAC1iOJOe2MCTl4BXi9mNsxsOvCmTyN1wAOS2tsOJDRI8BoS18LBJpBucfwjU8o8YLed7NxzkaZNIMLgBDgEitNjf4N0ADGQJw5k3gLYkHEs3buPJwa9Fsv/s5g8fKurk+c4nH/7wocZatp/9DH4tDBIJSBwQmw2/eiDgP0BQySgYBaNgFIx0AAAJtVhQqyoy8QAAAABJRU5ErkJggg==","orcid":"","institution":"School of clinical medicine, Dali University","correspondingAuthor":true,"prefix":"","firstName":"Guangming","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-04-13 12:29:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4261750/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4261750/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55082290,"identity":"ea989b82-d49c-459f-be48-39179576afc0","added_by":"auto","created_at":"2024-04-22 10:10:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29729,"visible":true,"origin":"","legend":"\u003cp\u003eChemical structure of fibrates: (a): fenofibrate; (b): pirinixic acid; (c): clofibrate; (d): bezafibrate; (e): gemfibrozil\u003c/p\u003e","description":"","filename":"F1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/d55cd0b088be45441f1b243e.jpg"},{"id":55082292,"identity":"21539cd0-0bb2-48f9-8917-09733d6c36bc","added_by":"auto","created_at":"2024-04-22 10:10:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46118,"visible":true,"origin":"","legend":"\u003cp\u003eVenn diagram of common targets of fibrates and IS :(a): Venn diagram of common targets of fenofibrate and IS; (b): Venn diagram of the common targets of pirinixic acid and IS; (c): Venn diagram of the common targets of clofibrate and IS; (d): Venn diagram of the common targets of bezafibrate and IS; (e): Venn diagram of common targets of gemfibrozil and IS\u003c/p\u003e","description":"","filename":"F2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/285796f40feb3283cc40a32b.jpg"},{"id":55082294,"identity":"38d27967-9df3-43dd-99a3-48afffd729df","added_by":"auto","created_at":"2024-04-22 10:10:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42815,"visible":true,"origin":"","legend":"\u003cp\u003eVenn diagram of common targets of fibrates and HIF1A-related genes :(a): Venn diagram of common targets of fenofibrate and HIF1A-related genes; (b): Venn diagram of common targets of pirinixic acid and HIF1A-related genes; (c): Venn diagram of common targets of clofibrate and HIF1A-related genes; (d): Venn diagram of common targets of bezafibrate and HIF1A-related genes; (e): Venn diagram of common targets of gemfibrozil and HIF1A-related genes\u003c/p\u003e","description":"","filename":"F3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/b32c6f1c3b0787000c7a37db.jpg"},{"id":55082791,"identity":"7f6ab085-2073-4bf6-8be9-21b86c055039","added_by":"auto","created_at":"2024-04-22 10:18:58","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":50703,"visible":true,"origin":"","legend":"\u003cp\u003ePPI network diagram of common targets of fibrates and HIF1A-related genes: (a): PPI network diagram of common targets of fenofibrate and HIF1A-related genes; (b): PPI network diagram of common targets of pirinixic acid and HIF1A-related genes; (c): PPI network diagram of common targets of clofibrate and HIF1A-related genes\u003c/p\u003e","description":"","filename":"F4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/231518272bb35633b45ba8de.jpg"},{"id":55082792,"identity":"3f3a5c97-687b-4a71-9920-625b6d7214b1","added_by":"auto","created_at":"2024-04-22 10:18:59","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":82747,"visible":true,"origin":"","legend":"\u003cp\u003eKEGG pathway bubble diagram of fibrates regulating HIF1A in the treatment of IS. (a): KEGG pathway bubble diagram of fenofibrate regulating HIF1A in the treatment of IS; (b): KEGG pathway bubble diagram of pirinixic acid regulating HIF1A in the treatment of IS; (c): KEGG pathway bubble diagram of clofibrate regulating HIF1A in the treatment of IS.\u003c/p\u003e","description":"","filename":"F5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/c90e395f9cdb20a157d3f977.jpg"},{"id":55082291,"identity":"8852e801-1cdb-4040-9903-b796b3325004","added_by":"auto","created_at":"2024-04-22 10:10:58","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":30508,"visible":true,"origin":"","legend":"\u003cp\u003eKEGG pathway bubble diagram of fibrates regulating HIF1A-related genes in the treatment of IS: (a): KEGG pathway bubble diagram of pirinixic acid regulating HIF1A-related genes in the treatment of IS; (b): KEGG pathway bubble diagram of clofibrate regulating HIF1A-related genes in the treatment of IS.\u003c/p\u003e","description":"","filename":"F6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/9a914fc27a944b6b8f6da2fa.jpg"},{"id":55082296,"identity":"408837d6-1429-4252-b482-ac4be832ef3e","added_by":"auto","created_at":"2024-04-22 10:10:59","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":45201,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular docking diagram of fibrates and HIF1A: (a): molecular docking diagram of fenofibrate and HIF1A; (b): molecular docking diagram of pirinixic acid and HIF1A; (c): molecular docking diagram of clofibrate and HIF1A\u003c/p\u003e","description":"","filename":"F7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/a84bad9f7dc450f6d3b2d334.jpg"},{"id":59596781,"identity":"f168022b-dff1-4f1f-aab8-883c016fec64","added_by":"auto","created_at":"2024-07-03 16:03:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":943236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4261750/v1/583a1662-348b-40cb-b62d-834adbed30dc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Network-pharmacology-based study on the mechanism of fibrates regulating HIF-1A in the treatment of ischemic stroke","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eIn recent years, the establishment of stroke centers has made stroke patients get more effective treatment, but the incidence of stroke still shows an increasing trend every year \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. IS accounts for about 80% of stroke \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. At present, recombinant tissue plasminogen activator is the mainly therapeutic drug of IS \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. It is well known that thrombolysis and mechanical thrombectomy are the most effective methods for the treatment of IS \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, but mechanical thrombectomy is risky, it may lead to bleeding, which will further aggravate brain damage. Therefore, some thrombolytic drugs are often used to treat IS, but the use of thrombolytic drugs has strict time limits, thrombolytic therapy must be performed within 4.5 hours after the occurrence of IS, which leads to many patients not receiving effective treatment \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Therefore, some anti-platelet drugs, anti-coagulants and neuroprotective drugs are commonly used to prevent and treat IS in clinical practice \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWith the increasing aging of the population, the incidence of IS has also increased, which has brought a large economic burden to society and families of patients \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Therefore, the effective prevention of IS is important to improving people's quality of life. Effective intervention the high risk factors of IS is the most effective and fundamental measure to reduce the occurrence of IS. The results of investigation and research show that blood lipid levels are closely related to the occurrence risk of IS \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, and hyperlipidemia is a high risk factor for IS. Therefore, early use of lipid-lowering drugs can effectively prevent the occurrence of IS when blood lipid levels are abnormal \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Fibrates belong to the lipid-lowering drugs of phenoxyaromatic acid class, it can exert lipid-lowering effects by lowering low-density lipoprotein and cholesterol. In addition, fibrates can enhance lipoprotein esterase activity, accelerate proteolysis, reduce lipoprotein synthesis in the liver, lower low-density lipoproteins and triglycerides, elevate high-density lipoproteins, which can prevent blood clotting and promoting thrombolysis, it may effectively reduce the occurrence risk of IS \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Fenofibrate, clofibrate, bezafibrate and gemfibrozil are the most commonly used fibrates in clinical practice. Pirinic acid has not been used in clinical practice, but its lipid-lowering effect has been widely studied in the laboratory. The chemical structures of the 5 fibrates are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe pathogenesis of IS is complex, which is often caused by the interaction of multiple biological factors, biological functions and biological pathways. The occurrence of IS often causes various reactions such as energy metabolism disorders, oxidative stress, inflammatory response and neuronal damage \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Therefore, it is necessary to use multi-target drugs to treat IS in order to achieve better therapeutic effects in clinical practice. Network pharmacology emphasizes the analysis of the relationship among drugs, genes and diseases from the systemic level and the overall perspective of biological network. The integrity and systematization of network pharmacology are consistent with the complex pathogenesis of diseases, so it has been widely used to explain the mechanism of drugs in treating diseases, which can promote the rational use of drugs in clinical practice. In this study, the methods of network pharmacology and molecular docking were used to illustrate the relationship between fibrates and HIF1A in the treatment of IS, we hope to provide some reference for the follow-up study of fibrates regulating HIF1A in the prevention and treatment of IS.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003e2.1. Common targets of fibrates and IS\u003c/h2\u003e\n \u003cp\u003eIn this study, targets for fenofibrate, pirinixic acid, clofibrate, bezafibrate, and gemfibrozil were obtained through Swiss Target Prediction platform (\u003cspan\u003e\u003cspan\u003ehttp://www.swisstargetprediction.ch/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e16\u003c/span\u003e\u003c/sup\u003e and CTD platform (\u003cspan\u003e\u003cspan\u003ehttp://ctdbase.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e17\u003c/span\u003e\u003c/sup\u003e, then the duplicate targets were removed, finally, the final targets of each drug was obtained. Targets of IS was obtained through Genecard database (\u003cspan\u003e\u003cspan\u003ehttps://www.genecards.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e18\u003c/span\u003e\u003c/sup\u003e, OMIM database (\u003cspan\u003e\u003cspan\u003ehttps://omim.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e19\u003c/span\u003e\u003c/sup\u003e, DrugBank database (\u003cspan\u003e\u003cspan\u003ehttps://www.drugbank.com/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e19\u003c/span\u003e\u003c/sup\u003e, TTD database (\u003cspan\u003e\u003cspan\u003ehttps://db.idrblab.net/ttd/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e20\u003c/span\u003e\u003c/sup\u003e and DisGeNET database (\u003cspan\u003e\u003cspan\u003ehttps://www.disgenet.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e21\u003c/span\u003e\u003c/sup\u003e, the obtained targets were summarized, then duplicated targets were removed to obtain the final targets of IS. Finally, the common targets of each drug and IS was obtained through the Venny 2.1.0 (\u003cspan\u003e\u003cspan\u003ehttps://bioinfogp.cnb.csic.es/tools/venny/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\"\u003e\n \u003ch2\u003e2.2. Common targets of HIF1A-related genes and fenofibrate, pirinixic Acid, clofibrate\u003c/h2\u003e\n \u003cp\u003eTargets of HIF1A-related genes were obtained through the GEPIA2 platform (\u003cspan\u003e\u003cspan\u003ehttp://gepia2.cancer-pku.cn/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e23\u003c/span\u003e\u003c/sup\u003e, then common targets of fenofibrate, pirinixic acid, clofibrate and HIF1A related genes were obtained through the Venny 2.1.0.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2.3. PPI Network diagram of the common targets of fenofibrate, pirinixic acid, clofibrate and HIF1A-related genes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe common targets of fenofibrate, pirinixic acid, clofibrate and HIF1A-related genes were imported into the String platform (\u003cspan\u003e\u003cspan\u003ehttps://string-db.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e24\u003c/span\u003e\u003c/sup\u003e, the parameter was set to moderate reliability (0.400), unassociated nodes are hidden, then the PPI network data table is exported. The PPI network data sheets were introduced into Cytoscape3.8.2, then the PPI network diagram of fenofibrate, pirinixic acid, clofibrate and HIF1A related genes were obtained.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003e2.4. Enrichment analysis of common targets of fibrates and IS\u003c/h2\u003e\n \u003cp\u003eThe common gene sets of fenofibrate, pirinixic acid, clofibrate and IS are imported Metascape platform (\u003cspan\u003e\u003cspan\u003ehttp://www.metascape.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e25\u003c/span\u003e\u003c/sup\u003e, then KEGG enrichment analysis was performed. Finally, the related pathways of HIF1A were obtained from the KEGG enrichment analysis results of the above 3 fibrates and IS, then the KEGG pathways bubble diagram was plotted, which could explore the action pathway of fibrates regulating HIF-1A in the prevention and treatment of IS.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\"\u003e\n \u003ch2\u003e2.5. Molecular docking of HIF1A and fibrates\u003c/h2\u003e\n \u003cp\u003eHIF1A receptor protein was obtained through Uniprot database (\u003cspan\u003e\u003cspan\u003ehttps://www.uniprot.org/\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e\u003cspan\u003e26\u003c/span\u003e\u003c/sup\u003e, then HIF1A receptor protein was imported into the PDB database to obtain the protein structure of HIF1A. The 3D chemical structures of fenofibrate, pirinixic acid and clofibrate were obtained by relevant software. The water molecules of HIF1A receptor protein and drug components were removed by PyMOL software, then the HIF1A receptor protein was imported into AutoDock software to perform hydrogenation and calculated charge operations. The docking pocket and docking parameters were set in AutoDock Vina software to perform molecular docking between HIF1A receptor protein and small molecule ligands of drug active compounds.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Screening of relevant targets\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e3.1.1. Gene sets of fibrates\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIn this study, the targets of five fibrates were collected through the Swiss Target Prediction platform and CTD platform, the final obtained targets are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The results show that the targets number of pirinixic acid is the most and the targets number of gemfilozil is the least.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe targets number of five fibrates\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSwiss Target Prediction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCTD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal number of targets\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe number of repeated targets\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThe final number of targets\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFenofibrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e863\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e847\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePirinixic Acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7642\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7742\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7683\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClofibrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3203\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBezafibrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e340\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGemfibrozil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.1.2. Gene sets of IS\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e3041 targets of IS were collected in the Genecard database, 129 targets of IS were collected in the OMIM database, 0 targets of IS were collected in the TTD database, 15 targets of IS were collected in the DisGeNET database. 61 targets of IS were collected in DrukBank database, a total of 3246 targets were obtained, 69 duplicated targets were removed, finally, 3177 targets were obtained.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e3.1.3. Common gene sets of fibrates and IS\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe Venn diagram of the common targets of fibrates and IS is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. It can be seen that pirinixic acid has the most targets, in addition, the common targets of pirinixic acid and IS are also the most, which has 1119. Gemfibrozil has the fewest targets, the common targets of gemfibrozil and IS is also the lowest, which has 91.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.1.4. Common gene sets of HIF1A-related genes and fibrates\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIn this study, the gene set of HIF1A-related genes was obtained through the GEPIA2 platform, which has 100, the Venn diagram of HIF1A-related genes and fibrates was obtained through the Venny 2.1.0, the result is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The results showed that the HIF1A-related genes and pirinixic acid has the most common targets, which has 43, HIF1A-related genes and gemfibrozil has the least common targets, which has 1.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2. The PPI network diagram and core targets screening of fibrates\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe PPI network diagram of the common gene sets of fenofibrate, pirinixic acid, clofibrate and HIF1A-related genes are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The results showed that the correlation of fenofibrate and HIF1A-related genes was weak, the PPI network diagram of their common genes had 3 nodes and 2 edges. There was a strong correlation between pirinixic acid and HIF1A-related genes, the PPI network diagram of their common genes had 30 nodes and 37 edges. In the PPI network diagram, nodes represent genes, edges represent relationships among genes. Bezafibrate and gemfibrozil do not contain the HIF1A, and bezafibrate, gemfibrozil and HIF1A-related genes have few common targets, so their PPI network diagrams are not shown.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3. KEGG enrichment analysis of fibrates regulating HIF1A in the treatment of IS\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eKEGG pathways of fibrates regulating HIF1A in the treatment of IS were analyzed, the results are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. the results showed that there were fewer pathways related to HIF1A in fenofibrate treatment of IS, which has 9, pirinixic acid has the same number of pathways associated with the HIF-1A gene as clofibrate in the treatment of IS, which has 15. KEGG pathway analysis showed that fibrates mainly regulate HIF1A involved in pathways in cancer, kaposi sarcoma-associated herpesvirus infection, th17 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, proteoglycans in cancer, thyroid hormone signaling pathway, central carbon metabolism in cancer and HIF-1 signaling pathway play a role in the prevention and treatment of IS. Bezafibrate and gemfibrozil do not contain HIF1A, so bubble diagram of their KEGG pathways are not shown.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4. The KEGG pathway enrichment analysis of fibrates and HIF1A-related genes\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe KEGG pathway analysis results of fibrates regulating HIF1A-related genes in the treatment of IS are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, it shows that there are 21 KEGG pathways belongs to pirinixic acid and HIF1A-related genes, there are 8 KEGG pathways belongs to clofibrate and HIF1A-related genes. KEGG pathway analysis showed that pirinixic acid mainly regulated the regulation of actin cytoskeleton, oocyte meiosis and focal adhesion pathway of HIF1A-related genes to play a role in the prevention and treatment of IS, clofibrate mainly regulates pathways in cancer, leukocyte transendothelial migration and cAMP signaling pathway of HIF1A-related genes to play a role in the prevention and treatment of IS. In this study, the KEGG pathway of fenofibrate and HIF1A-related genes was not found, so the action pathway of fenofibrate and HIF1A-related genes was not analyzed. Bezafibrate and gemfibrozil do not contain HIF1A and the above two drugs and HIF1A-related genes have only a few common targets, so their KEGG pathway bubble diagram are not shown.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5. The molecular docking of fibrates and HIF1A\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe common gene sets of five fibrates and IS was analyzed, the results showed that only the common gene sets of fenofibrate, pirinixic acid, clofibrate and IS contained the HIF1A. Molecular docking was performed between the above three drugs and HIF1A, the binding energies of the three drugs and HIF1A are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The molecular docking diagram is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, it shows that the binding energy of the above three drugs and HIF1A is less than \u0026minus;\u0026thinsp;5 KJ/mol, which indicates that these drugs can better bind to HIF1A, so the above three drugs can better regulate HIF1A to play a role in the prevention and treatment of IS.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBinding energies of fibrates and HIF1A\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBinding energy (KJ/mol)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFenofibrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePirinixic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClofibrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-5.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMany risk factors can lead to the occurrence of IS, among which hyperlipidemia is a high risk factor \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Fibrates are commonly used as lipid-lowering drugs in clinical practice, it are peroxisome proliferator-activated receptor α (PPARα) agonists \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, it can activate the transcription factor PPARα to bind to another transcription factor RXR, which increases the gene transcription and protein expression. fibrates can play a role in regulating lipid and stable plaque, in addition, fibrates also can play a role in anti-atherosclerosis and reduce ischemia-reperfusion injury by increasing the activity of various enzymes and participating in oxidative stress response. Therefore, fibrates are often used to the prevention and adjuvant treatment of IS \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIS is a severe vascular event with local or complete blood flow restriction in brain tissue caused by plaque occlusion of internal carotid artery or middle cerebral artery \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. It has the characteristics of high morbidity, high mortality and high disability rate, which is a global public health problem \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The main factors of leading to brain injury include excitotoxicity of cells, energy metabolism disorders, calcium overload, oxidative stress, cell apoptosis, autophagy and inflammatory response in the pathological process of IS \u003csup\u003e\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. However, only a few drugs can effectively treat IS in clinical practice, so the prevention of IS is very important. In recent years, it has been reported that HIF1A can participate in the pathological process of a variety of diseases, which is associated with oxidative stress response \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. It has been reported that oxidative stress response is related to IS \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Fibrates have been widely used as an adjuvant therapy drug of IS, it has a good curative effect. therefore, the relationship between fibrates in the treatment of IS and HIF1A was explored in this study, the results showed that only the common target of fenofibrate, pirinixic acid, clofibrate and IS contained the HIF1A, and these 3 fibrates could play a role in the prevention and treatment of IS through HIF1A. Bezafibrate and gemfibrozil do not contain HIF1A, their mechanism of action needs further study in the future.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe occurrence and progression of IS are closely related to ion channels, enzyme reactions and hormone reactions. KEGG pathway enrichment analysis showed that fibrates can regulate HIF1A to prevent and treat IS through Th17 cell differentiation, thyroid hormone signaling pathway and HIF-1 signaling pathway. The pathway of Th17 cells differentiation is related to a variety of inflammatory factors such as TGF-β, IL-17A, IL-6, IL-21 and IL-22, which are involved in the occurrence and progression of many inflammatory reactions and autoimmune diseases \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Fibrates may reduce the occurrence of vascular inflammation reactions by inhibiting inflammatory factors, which can reduce the level of HIF1A factor, it can increase cerebral blood perfusion and reduce the occurrence of cerebral hypoxia and ischemia symptoms. When IS occurs, the hypothalamic-pituitary-thyroid axis will respond to the ischemic/hypoxic environment, it will reduce the levels of T3 and FT3 and increase the levels of T4 and TSH. On the contrary, if the levels of T3 and FT3 increase and the levels of T4 and TSH decrease, it means that the patient has already enters the recovery period of IS \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Therefore, the thyroid hormone signaling pathway is involved in the whole pathological process of IS, the changes of thyroid hormone levels can reflect the disease state of patients, so the prevention and treatment of IS can be formulated by studying thyroid hormone levels. KEGG pathway analysis showed that the pathological process of IS is associated with the HIF-1 signaling pathway, HIF-1 is a heterodimeric transcription factor, it consists of HIF-1α and HIF-1β \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, HIF-1α can regulate the expression of some hormones such as erythropoietin and vascular endothelial growth factor \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. These hormones are related to the function of the development of collateral vessels, blood viscosity and the protection of nerve cells. HIF1A can improve the state of cerebral ischemia and hypoxia by regulating the levels of these hormones, which can reduce the occurrence of IS and promote the recovery of IS. KEGG pathway analysis showed that renal cell carcinoma, thyroid hormone signaling pathway, focal adhesion and pathways in cancer were the main KEGG pathways of fibrates regulating HIF1A-related genes in the treatment of IS, among which pirinixic acid and HIF1A-related genes had the most KEGG pathways, which indicated that pirinixic acid may be closely related to HIF1A in the treatment of IS.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe results of this study show that only fenofibrate, pirinixic acid and clofibrate contained HIF1A among the fibrates, so molecular docking was performed between the above 3 fibrates and HIF-1A gene. Molecular docking results showed that fenofibrate, pirinixic acid and clofibrate could be closely connected to HIF1A, which can be speculated that fenofibrate, pirinixic acid and clofibrate can better regulate HIF-1A to play a role in the prevention and adjuvant treatment of IS. Therefore, when dyslipidemia and hypoxia occur in the body, fibrates can activate HIF-1A to regulate blood lipid levels, protect nerve cells and promote the development of collateral vessels, which can reduce the occurrence risk of IS. Benzafibrate and Gemfibrozil do not contain HIF1A, which may regulate other factors to play a role in the prevention and treatment of IS.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFibrates are related to a variety of biological factors in the prevention and treatment of IS, among which fenofibrate, pirinixic acid and clofibrate can regulate HIF1A to participate in the pathological process of IS. Pirinixic acid has a strong correlation with HIF1A and HIF1A-related genes in the treatment of IS. KEGG pathway analysis showed that the above 3 fibrates could regulate HIF1A to participate in the pathological process of IS, the main KEGG pathways were pathways in cancer, kaposi sarcoma-associated herpesvirus infection, Th17 cell differentiation, and PD-L1 expression and PD-1 checkpoint pathway in cancer, proteoglycans in cancer, thyroid hormone signalingpathway, central carbon metabolismin cancer and HIF-1 signaling pathway. Molecular docking results showed that the binding energies of fenofibrate, pirinixic acid, clofibrate and HIF-1A were all less than \u0026minus;\u0026thinsp;5 KJ/mol, which indicated that the above drugs could be better combined with HIF1A, so fenofibrate, pirinixic acid and clofibrate could better regulate HIF1A to play the role of preventing and treatment IS. In conclusion, fibrates can play a role in the prevention and treatment of IS through multiple targets, multiple pathways, multiple hormones and multiple biological reactions.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIF1A\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHypoxia-inducible factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIschemic stroke\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPARα\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeroxisome proliferator-activated receptorα\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting the findings of this study are included in the article. The database used in this study is a public database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of conflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, P.W.; Methodology, Y.Y.; Software, F.Y.; Validation, X.D.; Formal analysis, M.W.; Resources, J.C.; Data curation, P.W.; Writing-original draft preparation, F.Y.; Writing-review and editing, G.W.; Supervision, Y.G.; Project administration, G.W. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the The National Natural Science Foundation of China [grant number 82160244], Natural Science Foundation of Yunnan Province [grant number 202001BA070001-133], Local university joint project of Science and Technology Department of Yunnan province [grant number 202001BA070001-156], Cultivating Plan Program for the Leader in Science and Technology of Yunnan Province [grant number D-2017057] and Study on the effect of Qiangli Tianma Duzhong capsule on HT-22 nerve cells in the treatment of ischemic stroke [grant number 2023KBG080]. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang, L. \u003cem\u003eet al.\u003c/em\u003e Nrf\u003csub\u003e2\u003c/sub\u003e regulates oxidative stress and its role in cerebral ischemic stroke. Antioxidants (Basel). 11(12), 2377. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3390/antiox11122377\u003c/span\u003e\u003cspan address=\"10.3390/antiox11122377\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCui, Y. \u003cem\u003eet al.\u003c/em\u003e ACSL\u003csub\u003e4\u003c/sub\u003e exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain. Behav. Immun. 93, 312\u0026ndash;321. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.bbi.2021.01.003\u003c/span\u003e\u003cspan address=\"10.1016/j.bbi.2021.01.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, Q. \u003cem\u003eet al.\u003c/em\u003e A novel perspective on ischemic stroke: a review of exosome and noncoding RNA studies. Brain. Sci. 12(8), 1000. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3390/brainsci12081000\u003c/span\u003e\u003cspan address=\"10.3390/brainsci12081000\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrabi, S. S., Parvez, S. \u0026amp; Tabassum, H. Ischemic stroke and mitochondria: mechanisms and targets. Protoplasma. 257(2), 335\u0026ndash;343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s00709-019-01439-2\u003c/span\u003e\u003cspan address=\"10.1007/s00709-019-01439-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, H., He, Y., Chen, S., Qi, S. \u0026amp; Shen, J. Therapeutic targets of oxidative/nitrosative stress and neuroinflammation in ischemic stroke: Applications for natural product efficacy with omics and systemic biology. Pharmacol. Res. 158, 104877. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.phrs.2020.104877\u003c/span\u003e\u003cspan address=\"10.1016/j.phrs.2020.104877\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao, A. \u003cem\u003eet al.\u003c/em\u003e A review of neuroprotective effects and mechanisms of ginsenosides from panax ginseng in treating ischemic stroke. Front. Pharmacol. 13, 946752. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fphar.2022.946752\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2022.946752\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChojnowski, K., Opielka, M., Nazar, W., Kowianski, P. \u0026amp; Smolenski, R. T. Neuroprotective effects of guanosine in ischemic stroke-small steps towards effective therapy. Int. J. Mol. Sci. 22(13), 6898. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3390/ijms22136898\u003c/span\u003e\u003cspan address=\"10.3390/ijms22136898\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBangad, A., Abbasi, M. \u0026amp; de Havenon, A. Secondary ischemic stroke prevention. Neurotherapeutics. 20(3), 721\u0026ndash;731. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s13311-023-01352-w\u003c/span\u003e\u003cspan address=\"10.1007/s13311-023-01352-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong, X., Sun, Y., Lu, Y. \u0026amp; Xu, L. Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex. Front. Immunol. 14, 1164258. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fimmu.2023.1164258\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2023.1164258\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan, S., Tang, B., Zheng, J. \u0026amp; Larsson, S. C. Circulating lipoprotein lipids, apolipoproteins and ischemic stroke. Ann. Neurol. 88(6), 1229\u0026ndash;1236. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1002/ana.25916\u003c/span\u003e\u003cspan address=\"10.1002/ana.25916\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, J. S. Role of blood lipid levels and lipid-lowering therapy in stroke patients with different levels of cerebral artery diseases: reconsidering recent stroke guidelines. J. Stroke. 23(2), 149\u0026ndash;161. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.5853/jos.2021.01249\u003c/span\u003e\u003cspan address=\"10.5853/jos.2021.01249\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarrion, A. F., Lindor, K. D. \u0026amp; Levy, C. Safety of fibrates in cholestatic liver diseases. Liver. Int. 41(6), 1335\u0026ndash;1343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1111/liv.14871\u003c/span\u003e\u003cspan address=\"10.1111/liv.14871\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, N. H. \u0026amp; Kim, S. G. Fibrates revisited: potential role in cardiovascular risk reduction. Diabetes. Metab. J. 44(2), 213\u0026ndash;221. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.4093/dmj.2020.0001\u003c/span\u003e\u003cspan address=\"10.4093/dmj.2020.0001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang, Q., Cai, G., Liu, T. \u0026amp; Liu, Z. Relationships among gut microbiota, ischemic stroke and its risk factors: based on research evidence. Int. J. Gen. Med. 15, 2003\u0026ndash;2023. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.2147/IJGM.S353276\u003c/span\u003e\u003cspan address=\"10.2147/IJGM.S353276\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung, K. H. \u0026amp; Seong, S. Y. Role of inflammasomes in neuroinflammation after ischemic stroke. Encephalitis. 1(4), 89\u0026ndash;97. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.47936/encephalitis.2021.00073\u003c/span\u003e\u003cspan address=\"10.47936/encephalitis.2021.00073\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShang, L. \u003cem\u003eet al\u003c/em\u003e. Mechanism of Sijunzi Decoction in the treatment of colorectal cancer based on network pharmacology and experimental validation. J. Ethnopharmacol. 302, 115876. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.jep.2022.115876\u003c/span\u003e\u003cspan address=\"10.1016/j.jep.2022.115876\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu, W. \u003cem\u003eet al\u003c/em\u003e. The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease based on network pharmacology and molecular docking. Ann. Med. 54(1), 541\u0026ndash;552. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1080/07853890.2022.2034931\u003c/span\u003e\u003cspan address=\"10.1080/07853890.2022.2034931\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMo, L. \u003cem\u003eet al\u003c/em\u003e. Integrated bioinformatic analysis of the shared molecular mechanisms between osteoporosis and atherosclerosis. Front. Endocrinol (Lausanne). 13, 950030. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fendo.2022.950030\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2022.950030\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang, P. \u003cem\u003eet al\u003c/em\u003e. A network pharmacology and molecular docking strategy to explore potential targets and mechanisms underlying the effect of curcumin on osteonecrosis of the femoral head in systemic lupus erythematosus. \u003cem\u003eBiomed. Res. Int\u003c/em\u003e. 2021, 5538643. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1155/2021/5538643\u003c/span\u003e\u003cspan address=\"10.1155/2021/5538643\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu, P., Xu, H., Shi, Y., Deng, L. \u0026amp; Chen, X. Potential molecular mechanisms of plantain in the treatment of gout and hyperuricemia based on network pharmacology. \u003cem\u003eEvid. Based. Complement. Alternat. Med\u003c/em\u003e. 2020, 3023127. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1155/2020/3023127\u003c/span\u003e\u003cspan address=\"10.1155/2020/3023127\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe, S., Wang, T., Shi, C., Wang, Z. \u0026amp; Fu, X. Network pharmacology-based approach to understand the effect and mechanism of Danshen against anemia. J. Ethnopharmacol. 282, 114615. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.jep.2021.114615\u003c/span\u003e\u003cspan address=\"10.1016/j.jep.2021.114615\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQiu, Z. K. \u003cem\u003eet al\u003c/em\u003e. A network pharmacology study with molecular docking to investigate the possibility of licorice against posttraumatic stress disorder. Metab. Brain. Dis. 36(7), 1763\u0026ndash;1777. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s11011-021-00816-2\u003c/span\u003e\u003cspan address=\"10.1007/s11011-021-00816-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao, X. \u003cem\u003eet al\u003c/em\u003e. The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis. Front. Oncol. 12, 992468. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fonc.2022.992468\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2022.992468\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAihaiti, Y. \u003cem\u003eet al\u003c/em\u003e. Therapeutic effects of naringin in rheumatoid arthritis: network pharmacology and experimental validation. Front. Pharmacol. 12, 672054. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fphar.2021.672054\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2021.672054\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiang, C. \u003cem\u003eet al\u003c/em\u003e. Network pharmacology and molecular docking to elucidate the potential mechanism of ligusticum chuanxiong against osteoarthritis. Front. Pharmacol. 13, 854215. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fphar.2022.854215\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2022.854215\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang, L. \u003cem\u003eet al\u003c/em\u003e. Exploring the mechanisms underlying the therapeutic effect of Salvia miltiorrhiza in diabetic nephropathy using network pharmacology and molecular docking. Biosci. Rep. 41(6), BSR20203520. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1042/BSR20203520\u003c/span\u003e\u003cspan address=\"10.1042/BSR20203520\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSi Larbi, M. T. \u003cem\u003eet al\u003c/em\u003e. Ischemic and non-ischemic stroke in young adults - a look at risk factors and outcome in a developing country. Cureus. 13(8), e17079. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.7759/cureus.17079\u003c/span\u003e\u003cspan address=\"10.7759/cureus.17079\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHadjivasilis, A., Kouis, P., Kousios, A. \u0026amp; Panayiotou, A. The effect of fibrates on kidney function and chronic kidney disease progression: a systematic review and meta-analysis of randomised studies. J. Clin. Med. 11(3), 768. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3390/jcm11030768\u003c/span\u003e\u003cspan address=\"10.3390/jcm11030768\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMontaigne, D., Butruille, L. \u0026amp; Staels, B. PPAR control of metabolism and cardiovascular functions. Nat. Rev. Cardiol. 18(12), 809\u0026ndash;823. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1038/s41569-021-00569-6\u003c/span\u003e\u003cspan address=\"10.1038/s41569-021-00569-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKearns, K. N. \u003cem\u003eet al\u003c/em\u003e. Microglia modulate cortical spreading depolarizations after ischemic stroke: a narrative review. Neurocrit. Care. 37(Suppl 1), 133\u0026ndash;138. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s12028-022-01469-4\u003c/span\u003e\u003cspan address=\"10.1007/s12028-022-01469-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, Y. \u003cem\u003eet al\u003c/em\u003e. Inflammatory cytokines and risk of ischemic stroke: a mendelian randomization study. Front. Pharmacol. 12, 779899. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fphar.2021.779899\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2021.779899\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, C. \u003cem\u003eet al\u003c/em\u003e. Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke. Pharmacol. Res. 174, 105933. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.phrs.2021.105933\u003c/span\u003e\u003cspan address=\"10.1016/j.phrs.2021.105933\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePluta, R., Januszewski, S. \u0026amp; Czuczwar, S. J. The role of gut microbiota in an ischemic stroke. Int. J. Mol. Sci. 22(2), 915. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3390/ijms22020915\u003c/span\u003e\u003cspan address=\"10.3390/ijms22020915\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo, X. \u003cem\u003eet al\u003c/em\u003e. Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idellal Val.) fed with the high non-protein energy diets. Fish. Physiol. Biochem. 41(2), 331\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s10695-014-9986-8\u003c/span\u003e\u003cspan address=\"10.1007/s10695-014-9986-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng, T. \u003cem\u003eet al\u003c/em\u003e. Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo. Int. J. Biol. Sci. 18(11), 4578\u0026ndash;4594. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.7150/ijbs.69892\u003c/span\u003e\u003cspan address=\"10.7150/ijbs.69892\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJanbandhu, V. \u003cem\u003eet al\u003c/em\u003e. Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell. Stem. Cell. 29(2), 281\u0026ndash;297.e12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.stem.2021.10.009\u003c/span\u003e\u003cspan address=\"10.1016/j.stem.2021.10.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArias-Cavieres, A. \u003cem\u003eet al\u003c/em\u003e. A HIF1a-dependent pro-oxidant state disrupts synaptic plasticity and impairs spatial memory in response to intermittent hypoxia. \u003cem\u003eeNeuro\u003c/em\u003e. 7(3), ENEURO.0024-20.2020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1523/ENEURO.0024-20.2020\u003c/span\u003e\u003cspan address=\"10.1523/ENEURO.0024-20.2020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, S. \u003cem\u003eet al\u003c/em\u003e. The antioxidant enzyme Peroxiredoxin-1 controls stroke-associated microglia against acute ischemic stroke. Redox. Biol. 54, 102347. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.redox.2022.102347\u003c/span\u003e\u003cspan address=\"10.1016/j.redox.2022.102347\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, J. \u003cem\u003eet al\u003c/em\u003e. Th17 cells and IL-17A in ischemic stroke. Mol. Neurobiol. 10, 26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s12035-023-03723-y\u003c/span\u003e\u003cspan address=\"10.1007/s12035-023-03723-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurolo, M., Di Vincenzo, O., Cicatiello, A. G., Scalfi, L. \u0026amp; Dentice, M. Cardiovascular and neuronal consequences of thyroid hormones alterations in the ischemic stroke. Metabolites. 13(1), 22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3390/metabo13010022\u003c/span\u003e\u003cspan address=\"10.3390/metabo13010022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe, Q. \u003cem\u003eet al\u003c/em\u003e. Biological functions and regulatory mechanisms of hypoxia-inducible factor-1α in ischemic stroke. Front. Immunol. 12, 801985. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.3389/fimmu.2021.801985\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2021.801985\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, J. \u003cem\u003eet al\u003c/em\u003e. HIF1A and VEGF regulate each other by competing endogenous RNA mechanism and involve in the pathogenesis of peritoneal fibrosis. Pathol. Res. Pract. 215(4), 644\u0026ndash;652. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.prp.2018.12.022\u003c/span\u003e\u003cspan address=\"10.1016/j.prp.2018.12.022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","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":"Fibrates, IS, HIF1A, Network pharmacology, Molecular docking","lastPublishedDoi":"10.21203/rs.3.rs-4261750/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4261750/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIschemic stroke (IS) is a serious threat to people's health, its occurrence risk is closely related to lipid levels and genes. Fibrates are commonly used as adjunctive therapy for IS in clinical practice, some studies have reported that hypoxia-inducible factor (HIF1A) is associated with the occurrence risk of various diseases, so it is important to explore the mechanism of fibrates regulate HIF1A in the treatment of IS. Firstly, the potential targets of fibrates, IS, HIF1A and HIF1A-related genes were obtained through various databases, then their common targets were obtained through Venny 2.1.0. The PPI network of fibrates and HIF1A-related genes was plotted by String platform and Cytoscape3.8.1 software. KEGG pathways of drugs, diseases, HIF1A and HIF1A related genes were obtained by Metascape platform. Finally, molecular docking of fibrates and HIF1A was performed by AutoDock software. In this study, the structure of five fibrates were obtained by reviewing the literature and pharmacopoeia. The common targets of five fibrates and IS showed that only 3 fibrates contained HIF1A. KEGG pathway analysis and molecular docking results showed that fibrates can better regulate HIF1A to treat IS, its main action pathways are pathways in cancer, kaposi sarcoma-associated herpesvirus infection and HIF-1 signaling pathway.\u003c/p\u003e","manuscriptTitle":"Network-pharmacology-based study on the mechanism of fibrates regulating HIF-1A in the treatment of ischemic stroke","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-22 10:10:54","doi":"10.21203/rs.3.rs-4261750/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":"5be9484c-eba4-4b4e-a215-4cd9ab1aba1d","owner":[],"postedDate":"April 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30926937,"name":"Biological sciences/Neuroscience/Blood brain barrier"},{"id":30926938,"name":"Biological sciences/Neuroscience/Cell death in the nervous system"},{"id":30926939,"name":"Biological sciences/Neuroscience/Diseases of the nervous system"}],"tags":[],"updatedAt":"2024-07-03T15:54:57+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-22 10:10:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4261750","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4261750","identity":"rs-4261750","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}