The combination of exercise and metformin inhibits TGF-β1/Smad pathway to attenuate myocardial fibrosis in db/db mice by reducing NF-κB–mediated inflammatory response

Liu, Jingjing; Lu, Jiao; Zhang, Liumei; Liu, Yuting; Zhang, Yuan; Gao, Yaran; Yuan, Xinmeng; Xiang, Mengqi; Tang, Qiang

doi:10.1016/j.biopha.2022.114080

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…High blood glucose levels can alter cardiac metabolism and function, leading to cardiac stiffness, as well as systolic and relaxation dysfunction [ 38 ]. Moreover, persistent hyperglycemia increases the inflammatory response, which exacerbates myocardial fibrosis [ 39 ]. Cardiac fibrosis impairs the contractile function of the heart and leads to impaired ventricular relaxation, which eventually leads to ventricular hypertrophy, reduced cardiac output, and heart failure [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

Chun-peng,

Tian,

Xue

2024

Heliyon

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Section: Discussionmentioning

confidence: 99%

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

Chun-peng,

Tian,

Xue

2024

Heliyon

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“…Studies have identified the increased expression of Smad7 in CFs as a critical strategy for improving myocardial fibrosis in DCM. Therefore, Smad7 has emerged as a potential hotspot [ 40 ]. Sal B, which is extracted from Salvia miltiorrhiza Bunge, has shown a potential protective effect on myocardial fibrosis induced by DCM.…”

Section: Discussionmentioning

confidence: 99%

Salvianolic acid B ameliorates myocardial fibrosis in diabetic cardiomyopathy by deubiquitinating Smad7

Luo,

Fu,

Wang

et al. 2023

Chin Med

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Background Salvianolic acid B (Sal B), a water-soluble phenolic compound derived from Salvia miltiorrhiza Bunge, is commonly used in Traditional Chinese Medicine to treat cardiovascular disease. In our previous study, Sal B protected against myocardial fibrosis induced by diabetic cardiomyopathy (DCM). This study aimed to investigate the ameliorative effects and potential mechanisms of Sal B in mitigating myocardial fibrosis induced by DCM. Methods Various methods were used to investigate the effects of Sal B on myocardial fibrosis induced by DCM in vivo and in vitro. These methods included blood glucose measurement, echocardiography, HE staining, Masson’s trichrome staining, Sirius red staining, cell proliferation assessment, determination of hydroxyproline levels, immunohistochemical staining, evaluation of fibrosis-related protein expression (Collagen-I, Collagen-III, TGF-β1, p-Smad3, Smad3, Smad7, and α-smooth muscle actin), analysis of Smad7 gene expression, and analysis of Smad7 ubiquitin modification. Results The animal test results indicated that Sal B significantly improved cardiac function, inhibited collagen deposition and phenotypic transformation, and ameliorated myocardial fibrosis in DCM by upregulating Smad7, thereby inhibiting the TGF-β1 signaling pathway. In addition, cell experiments demonstrated that Sal B significantly inhibited the proliferation, migration, phenotypic transformation, and collagen secretion of cardiac fibroblasts (CFs) induced by high glucose (HG). Sal B significantly decreased the ubiquitination of Smad7 and stabilized the protein expression of Smad7, thereby increasing the protein expression of Smad7 in CFs and inhibiting the TGF-β1 signaling pathway, which may be the potential mechanism by which Sal B mitigates myocardial fibrosis induced by DCM. Conclusion This study revealed that Sal B can improve myocardial fibrosis in DCM by deubiquitinating Smad7, stabilizing the protein expression of Smad7, and blocking the TGF-β1 signaling pathway.

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“…Metformin (300 mg kg −1 day −1 ) was administered intragastrically to the MET, EMA, and EMC groups ( n = 18) from weeks 11–14 [ 23 ]. Rats in the control, PRE, and EXE groups ( n = 12) were administered the same amount of ultra-pure water.…”

Section: Methodsmentioning

confidence: 99%

Aerobic exercise and metformin on intermuscular adipose tissue (IMAT): insights from multimodal MRI and histological changes in prediabetic rats

Yu,

Xing,

Fan

et al. 2023

Diabetol Metab Syndr

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Background Physical exercise is the first-line intervention for prediabetes, and metformin is the most widely used oral insulin-sensitizing agent. Moreover, intermuscular adipose tissue (IMAT) directly affects insulin resistance by helping maintain glucose homeostasis. Here, we evaluated the effects of moderate aerobic exercise and/or metformin on histological IMAT parameters in non-streptozotocin-induced prediabetes. Methods Male Wistar rats with prediabetes fed a high-fat diet and high-sugar drinks were randomly assigned to high-fat diet (PRE), metformin (MET), moderate aerobic exercise (EXE), combined therapy (EMC), or EMC + compound-c (EMA) groups for 4 weeks. Multimodal magnetic resonance imaging (MRI) was then performed, and tissue-specific inflammation and energy and lipid metabolism were evaluated in IMAT. Results The EXE group had lower inflammatory factor levels, lipid metabolism, and mitochondrial oxidative stress, and shorter IMAT adipocyte diameters than the MET group. The MET group exhibited lower IL-1β and Plin5 expression than the PRE group. Furthermore, the IMAT of the EMC group had lower TNF-α and phosphorylated NF-κB levels and higher GLUT1 and GLUT4 expression than the PRE group. Multimodal MRI revealed significant changes in transverse-relaxation time 2, apparent diffusion coefficient, and fractional anisotropy values in the IMAT and muscles, as well as lower IMAT% values in the EXE and EMC groups than in the MET and PRE groups. Conclusion Moderate aerobic exercise training can effectively improve IMAT function and structure via the AMP-activated protein kinase pathway in prediabetes. Combining metformin with moderate aerobic exercise might elicit modest synergy, and metformin does not counterbalance the beneficial effects of exercise.

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The combination of exercise and metformin inhibits TGF-β1/Smad pathway to attenuate myocardial fibrosis in db/db mice by reducing NF-κB–mediated inflammatory response

Cited by 5 publications

References 45 publications

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

Salvianolic acid B ameliorates myocardial fibrosis in diabetic cardiomyopathy by deubiquitinating Smad7

Aerobic exercise and metformin on intermuscular adipose tissue (IMAT): insights from multimodal MRI and histological changes in prediabetic rats

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