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Li F, Li D, Yan X, Zhu F, Tang S, Liu J, Yan J, Chen H. Quercetin Promotes the Repair of Mitochondrial Function in H9c2 Cells Through the miR-92a-3p/Mfn1 Axis. Curr Pharm Biotechnol 2024; 25:1858-1866. [PMID: 38173217 DOI: 10.2174/0113892010266863231030052150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/25/2023] [Accepted: 10/04/2023] [Indexed: 01/05/2024]
Abstract
OBJECTIVE Cardiocerebrovascular disease is a severe threat to human health. Quercetin has a wide range of pharmacological effects such as antitumor and antioxidant. In this study, we aimed to determine how quercetin regulates mitochondrial function in H9c2 cells. METHODS An H9c2 cell oxygen glucose deprivation/reoxygenation (OGD/R) model was constructed. The expression of miR-92a-3p and mitofusin 1 (Mfn1) mRNA in the cells was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Changes in the mitochondrial membrane potential of cells were examined by JC-1 staining. ATP production in the cells was detected using a biochemical assay. Mitochondrial morphological changes were observed using transmission electron microscopy. Detection of miR-92a-3p binding to Mfn1 was done using dual luciferase. Western blotting was used to detect the protein expression of Mfn1 in the cells. RESULTS miR-92a-3p is essential in regulating cell viability, apoptosis, and tumor cell metastasis. OGD/R induced miR-92a-3p expression, decreased mitochondrial membrane potential and mitochondrial ATP production, and increased mitochondrial damage. Mitochondria are the most critical site for ATP production. Continued opening of the mitochondrial permeability transition pore results in an abnormal mitochondrial transmembrane potential. Both quercetin and inhibition of miR-29a-3p were able to downregulate miR-29a-3p levels, increase cell viability, mitochondrial membrane potential, and ATP levels, and improve mitochondrial damage morphology. Furthermore, we found that downregulation of miR-29a-3p upregulated the protein expression of Mfn1 in cells. Additionally, miR-92a-3p was found to bind to Mfn1 in a luciferase assay. miR- 29a-3p overexpression significantly inhibited the protein expression level of Mfn1. Quercetin treatment partially reversed the effects of miR-29a-3p overexpression in H9c2 cells. CONCLUSION Quercetin promoted the recovery of mitochondrial damage in H9c2 cells through the miR-92a-3p/Mfn1 axis.
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Affiliation(s)
- Fen Li
- Department of Neurology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, 430056, Hubei, China
| | - Dongsheng Li
- Department of Cardiology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, 430056, Hubei, China
| | - Xisheng Yan
- Department of Cardiology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, 430056, Hubei, China
| | - Fen Zhu
- Department of Cardiology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, 430056, Hubei, China
| | - Shifan Tang
- Department of Cardiology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, 430056, Hubei, China
| | - Jianguang Liu
- Department of Neurology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, 430056, Hubei, China
| | - Jie Yan
- Department of Forensic Science, Changsha, 410013, Hunan, China
| | - Haifeng Chen
- Department of Clinical Medicine, Jianghan University, Wuhan, 430056, Hubei, China
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Lin X, Zhao X, Chen Q, Wang X, Wu Y, Zhao H. Quercetin ameliorates ferroptosis of rat cardiomyocytes via activation of the SIRT1/p53/SLC7A11 signaling pathway to alleviate sepsis‑induced cardiomyopathy. Int J Mol Med 2023; 52:116. [PMID: 37859612 PMCID: PMC10635685 DOI: 10.3892/ijmm.2023.5319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Sepsis‑induced cardiomyopathy (SIC) is a manifestation of multiple organ failure as a result of sepsis and is a serious threat to life. Here, the effect and mechanisms of quercetin (QUE) in SIC were assessed. It was found that patients with SIC expressed lower serum levels of glutathione peroxidase 4 (GPX4) and SIRT1 but higher levels of CK‑MB, cTnI, TNF‑α, and IL‑6 compared with healthy individuals. A dose of 80 µM QUE increased the viability and reduced the ferroptosis of H9C2 cells treated with 1.0 µg/ml LPS in vitro. The administration of QUE decreased the levels of MDA, NADPH, lipid peroxidation and cytoplasmic cytochrome C and upregulated the levels of GSH and TOM 20, thus exerting an anti‑oxidative effect via mediating SIRT1 expression. It also activated the SIRT1/p53/SLC7A11 signaling pathway to reduce cellular Fe2+ and PTGS2 levels, decreased cell apoptosis rate, and upregulated the levels of GPX4 and ferritin to inhibit ferroptosis of H9C2 cells in vitro. Injection of QUE into rats activated the SIRT1/p53/SLC7A11 signaling pathway, reduced the levels of CK‑MB, cTnI, inflammatory cell infiltration, MDA, NADPH, cytoplasmic cytochrome C, cellular Fe2+, and PTGS2 but upregulated the levels of GSH, TOM 20, GPX4, and ferritin to alleviate SIC in a dose‑dependent manner in vivo. To conclude, QUE exerted an anti‑ferroptotic effect via activation of the SIRT1/p53/SLC7A11 signaling pathway to dampen SIC both in vivo and in vitro. These findings highlighted a potential therapeutic strategy for the management of SIC.
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Affiliation(s)
| | | | - Qingfeng Chen
- Department of Emergency and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
| | - Xiaoyue Wang
- Department of Emergency and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
| | - Yongya Wu
- Department of Emergency and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
| | - Hao Zhao
- Department of Emergency and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
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Yang L, Jian Y, Zhang ZY, Qi BW, Li YB, Long P, Yang Y, Wang X, Huang S, Huang J, Zhou LF, Ma J, Jiang CQ, Hu YH, Xiao WJ. Network-pharmacology-based research on protective effects and underlying mechanism of Shuxin decoction against myocardial ischemia/reperfusion injury with diabetes. World J Diabetes 2023; 14:1057-1076. [PMID: 37547579 PMCID: PMC10401449 DOI: 10.4239/wjd.v14.i7.1057] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/14/2023] [Accepted: 05/05/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Patients with diabetes mellitus are at higher risk of myocardial ischemia/ reperfusion injury (MI/RI). Shuxin decoction (SXT) is a proven recipe modi-fication from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" according to the traditional Chinese medicine theory. It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting. However, the underlying mechanism is still unclear.
AIM To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.
METHODS This paper presents an ensemble model combining network pharmacology and biology. The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT. In parallel, therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus, DisGeNet, Genecards, Drugbank, OMIM, and PharmGKB. The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery. The major results of bioinformatics analysis were subsequently validated by animal experiments.
RESULTS According to the hypothesis derived from bioinformatics analysis, SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein (LDL) and inhibiting the advanced glycation end products (AGE)-receptor for AGE (RAGE) signaling pathway. Subsequent animal experiments confirmed the hypothesis. The treatment with a dose of SXT (2.8 g/kg/d) resulted in a reduction in oxidized LDL, AGEs, and RAGE, and regulated the level of blood lipids. Besides, the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated, whereas Bcl-2 expression was up-regulated. The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats.
CONCLUSION This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes. Moreover, animal experiments verified that SXT could regulate the level of blood lipids, alleviate cardiomyocyte apoptosis, and improve cardiac function through the AGE-RAGE signaling pathway.
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Affiliation(s)
- Ling Yang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Yang Jian
- Department of Clinical Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Zai-Yuan Zhang
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
| | - Bao-Wen Qi
- South China Hospital of Shenzhen University, Shenzhen 518116, Guangdong Province, China
| | - Yu-Bo Li
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Pan Long
- Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Yao Yang
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Xue Wang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Shuo Huang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Jing Huang
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
| | - Long-Fu Zhou
- Department of Biomedical Engineering, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Jie Ma
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Chang-Qing Jiang
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Yong-He Hu
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
| | - Wen-Jing Xiao
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
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Nie W, Wu J, Yu X, Li Z, Cai X, Wei W, Wang C, Wang J. MicroRNA-186-5p inhibits H9c2 cells apoptosis induced by oxygen-glucose deprivation by targeting ERK1/2. J Thorac Dis 2023; 15:529-541. [PMID: 36910081 PMCID: PMC9992618 DOI: 10.21037/jtd-22-453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 12/02/2022] [Indexed: 02/24/2023]
Abstract
Background Serum miR-186-5p levels are increased in acute myocardial infarction (AMI) patients and might contribute to assessing the prognosis of AMI patients. In this study, we further investigated the underlying molecular mechanism of miR-186-5p that participated in the pathological processes of myocardial ischemia. Methods The AMI models of rats and oxygen-glucose deprivation (OGD) models of H9c2 cells were established. Bioinformatics databases, luciferase reporting, and western blotting assays were performed to identify the regulatory target of miR-186-5p. Transfection and functional experiments were conducted to further define the possible molecular mechanism of miR-186-5p during the process of glucose deficiency and hypoxia. Results The level of miR-186-5p was found to significantly decrease in H9c2 cells after OGD treatment, while it increased in the culture medium from OGD-treated H9c2 cells. Using bioinformatics databases, luciferase reporting, and western blotting assays, we identified that ERK1/2 might serve as the negative regulatory target of miR-186-5p. Combined with further transfection experiments, we indicated that miR-186-5p might inhibit the expression and activation of ERK1/2. This finding was also reflected in the reduction of their downstream cleaved caspase-3. Through functional experiments, we revealed that miR-186-5p might inhibit apoptosis and promote proliferation in OGD-treated H9c2 cells. Conclusions We demonstrated that miR-186-5p might suppress OGD-induced apoptosis in H9c2 cells by targeting the ERK1/2 pathway.
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Affiliation(s)
- Wennan Nie
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jia Wu
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiaoyang Yu
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhuolin Li
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiaomin Cai
- Department of Cardiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenyan Wei
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Cheng Wang
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Junjun Wang
- Department of Clinical Laboratory, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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Bai Y, Wu J, Yang Z, Wang X, Zhang D, Ma J. Mitochondrial quality control in cardiac ischemia/reperfusion injury: new insights into mechanisms and implications. Cell Biol Toxicol 2022; 39:33-51. [PMID: 35951200 DOI: 10.1007/s10565-022-09716-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/07/2022] [Indexed: 11/25/2022]
Abstract
The current effective method for the treatment of myocardial infarction is timely restoration of the blood supply to the ischemic area of the heart. Although reperfusion is essential for reestablishing oxygen and nutrient supplies, it often leads to additional myocardial damage, creating an important clinical dilemma. Reports from long-term studies have confirmed that mitochondrial damage is the critical mechanism in cardiac ischemia/reperfusion (I/R) injury. Mitochondria are dynamic and possess a quality control system that targets mitochondrial quantity and quality by modifying mitochondrial fusion, fission, mitophagy, and biogenesis and protein homeostasis to maintain a healthy mitochondrial network. The system of mitochondrial quality control involves complex molecular machinery that is highly interconnected and associated with pathological changes such as oxidative stress, calcium overload, and endoplasmic reticulum (ER) stress. Because of the critical role of the mitochondrial quality control systems, many reports have suggested that defects in this system are among the molecular mechanisms underlying myocardial reperfusion injury. In this review, we briefly summarize the important role of the mitochondrial quality control in cardiomyocyte function and focus on the current understanding of the regulatory mechanisms and molecular pathways involved in mitochondrial quality control in cardiac I/R damage.
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Affiliation(s)
- Yang Bai
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, No.2 Anzhen Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Jinjing Wu
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, No.2 Anzhen Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Zhenyu Yang
- Department of Endocrinology, South China Hospital of Shenzhen University, Shenzhen, People's Republic of China
| | - Xu'an Wang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, No.2 Anzhen Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Dongni Zhang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, No.2 Anzhen Road, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Jun Ma
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, No.2 Anzhen Road, Chaoyang District, Beijing, 100029, People's Republic of China.
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Lin J, Duan J, Wang Q, Xu S, Zhou S, Yao K. Mitochondrial Dynamics and Mitophagy in Cardiometabolic Disease. Front Cardiovasc Med 2022; 9:917135. [PMID: 35783853 PMCID: PMC9247260 DOI: 10.3389/fcvm.2022.917135] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/20/2022] [Indexed: 12/17/2022] Open
Abstract
Mitochondria play a key role in cellular metabolism. Mitochondrial dynamics (fusion and fission) and mitophagy, are critical to mitochondrial function. Fusion allows organelles to share metabolites, proteins, and mitochondrial DNA, promoting complementarity between damaged mitochondria. Fission increases the number of mitochondria to ensure that they are passed on to their offspring during mitosis. Mitophagy is a process of selective removal of excess or damaged mitochondria that helps improve energy metabolism. Cardiometabolic disease is characterized by mitochondrial dysfunction, high production of reactive oxygen species, increased inflammatory response, and low levels of ATP. Cardiometabolic disease is closely related to mitochondrial dynamics and mitophagy. This paper reviewed the mechanisms of mitochondrial dynamics and mitophagy (focus on MFN1, MFN2, OPA1, DRP1, and PINK1 proteins) and their roles in diabetic cardiomyopathy, myocardial infarction, cardiac hypertrophy, heart failure, atherosclerosis, and obesity.
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Affiliation(s)
- Jianguo Lin
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jinlong Duan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qingqing Wang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Siyu Xu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Simin Zhou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Kuiwu Yao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Eye Hospital China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Kuiwu Yao
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Deng B, Zhang Z, Zhou H, Zhang X, Niu S, Yan X, Yan J. MicroRNAs in Methamphetamine-Induced Neurotoxicity and Addiction. Front Pharmacol 2022; 13:875666. [PMID: 35496314 PMCID: PMC9046672 DOI: 10.3389/fphar.2022.875666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/31/2022] [Indexed: 12/21/2022] Open
Abstract
Methamphetamine (METH) abuse remains a significant public health concern globally owing to its strong addictive properties. Prolonged abuse of the drug causes irreversible damage to the central nervous system. To date, no efficient pharmacological interventions are available, primarily due to the unclear mechanisms underlying METH action in the brain. Recently, microRNAs (miRNAs) have been identified to play critical roles in various cellular processes. The expression levels of some miRNAs are altered after METH administration, which may influence the transcription of target genes to regulate METH toxicity or addiction. This review summarizes the miRNAs in the context of METH use, discussing their role in the reward effect and neurotoxic sequelae. Better understanding of the molecular mechanisms involved in METH would be helpful for the development of new therapeutic strategies in reducing the harm of the drug.
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Affiliation(s)
- Bi Deng
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhirui Zhang
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Huixuan Zhou
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xinran Zhang
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Shuliang Niu
- School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
| | - Xisheng Yan
- Department of Cardiovascular Medicine, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China
| | - Jie Yan
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
- *Correspondence: Jie Yan,
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Han X, Li C, Yang P, Jiang T. Potential mechanisms of Qili Qiangxin capsule to prevent pulmonary arterial hypertension based on network pharmacology analysis in a rat model. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:453. [PMID: 35571420 PMCID: PMC9096388 DOI: 10.21037/atm-22-901] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/30/2022] [Indexed: 11/08/2022]
Abstract
Background Qili Qiangxin capsule (QQC), a traditional Chinese medicine, has recently been approved to treat pulmonary arterial hypertension (PAH). However, the multi-target mechanism through which QQC acts on PAH has not been clarified. The objective of this study was to explore the pharmacological processes of QQC for treating PAH. Methods The rat model of PAH was established by administering monocrotaline (MCT). The impact of QQC on PAH was studied in treatment group that received QQC orally over a period of 4 weeks. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was searched for active compounds and QQC targets that were then identified and downloaded. Then, PAH-related targets were obtained from five databases [GeneCards, DrugBank, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), and PharmGKB]. The QQC targets for PAH were compiled after they had been overlapped with one another. Furthermore, the STRING network platform, the Cytoscape tool, networks of protein-protein interaction (PPI) were used, and core target analyses were carried out. Moreover, molecular docking techniques were employed in this research. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies of overlapping targets were carried out using the R software (version: 4.0.5; Lucent Technologies Co., Ltd., China). Finally, we verified the synergistic action mechanisms using western blotting and immunofluorescence analysis on PAH rats who were treated with or without QQC. Results The search of the TCMSP database showed that there were 11 active ingredients in QQC that treated PAH. PPI network showed that AKT1, TP53, JUN, and MAPK1 were the most important targets in the treatment of PAH. Moreover, Molecular docking techniques showed that the affinity between the bioactive compounds in QQC and their PAH targets was strong. In vivo experiments demonstrated that QQC may attenuate the progression of MCT-stimulated PAH in rats. Furthermore, the protective effect was mediated by inhibiting the PI3K/AKT pathway. The active compounds mainly included quercetin, kaempferol, formononetin, and luteolin, which had good docking scores and targeted the AKT protein. Conclusions QQC might activate the PI3K/AKT signaling pathway to ameliorate MCT-induced PAH. These findings support the clinical use of QQC and provide the foundation for further studies.
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Affiliation(s)
- Xiao Han
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chao Li
- Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ping Yang
- Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Tingbo Jiang
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China
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