Metformin is a widely used antidiabetic drug for type 2 diabetes that can play a cardioprotective role through multiple pathways. It is a recognized agonist of AMP-activated protein kinase (AMPK) that blocks mitochondrial complex I. The NLRP3 inflammasome has been demonstrated to be activated in diabetic cardiomyopathy (DCM). However, the role of metformin in regulating the NLRP3 signaling pathway in DCM remains unclear. It has been reported that AMPK can inhibit NLRP3 by activating autophagy. The aim of this study was to investigate whether metformin can inhibit the NLRP3 inflammasome by activating the AMPK/mTOR pathway in DCM. In this study, streptozotocin-induced C57BL/6 mice and high glucose-treated primary cardiomyocytes from neonatal mice were treated with metformin or an AMPK inhibitor compound C. Echocardiography, hematoxylin-eosin and Masson staining showed that the function and morphology of the diabetic hearts were improved after metformin treatment, whereas these parameters deteriorated after intervention with an AMPK inhibitor. Immunohistochemical staining, immunofluorescence staining and western blot assays indicated that the expression levels of mTOR, NLRP3, caspase-1, IL-1β and GSDMD-N were decreased in the diabetic model treated with metformin and were reversed after the administration of an AMPK inhibitor in vivo and in vitro . Mechanistically, our results demonstrated that metformin can activate AMPK, thus improving autophagy via inhibiting the mTOR pathway and alleviating pyroptosis in DCM. Thus, we provide novel information for the treatment of DCM.
Background/Aims: Diabetic cardiomyopathy (DCM) is a common complication of diabetes and can cause heart failure, arrhythmia and sudden death. The pathogenesis of DCM includes altered metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell death and extracellular matrix remodeling. Recently, pyroptosis, a type of programmed cell death related to inflammation, was proven to be activated in DCM. However, the molecular mechanisms underlying pyroptosis in DCM remain elusive. The long non-coding RNA (lncRNA) Kcnq1ot1 participates in many cardiovascular diseases. This study aims to clarify whether Kcnq1ot1 affects cardiac pyroptosis in DCM. Methods: AC16 cells and primary cardiomyocytes were incubated with 5.5 and 50 mmol/L glucose. Diabetic mice were induced with streptozotocin (STZ). Kcnq1ot1 was silenced both in vitro and in vivo. qRT-PCR was used to detect the expression level of Kcnq1ot1. Immunofluorescence, qRT-PCR and western blot analyses were used to detect the degree of pyroptosis. Echocardiography, hematoxylin and eosin staining, and Masson’s trichrome staining were used to detect the cardiac function and morphology in mice. Cell death and function were detected using TUNEL staining, immunofluorescence staining and Ca2+ measurements. Results: The expression of Kcnq1ot1 was increased in patients with diabetes, high glucose-induced cardiomyocytes and diabetic mouse cardiac tissue. Silencing Kcnq1ot1 alleviated pyroptosis by targeting miR-214-3p and caspase-1. Furthermore, silencing Kcnq1ot1 reduced cell death, cytoskeletal structure abnormalities and calcium overload in vitro and improved cardiac function and morphology in vivo. Conclusion: Kcnq1ot1 is overexpressed in DCM, and silencing Kcnq1ot1 inhibits pyroptosis by influencing miR-214-3p and caspase-1 expression. We clarified for the first time that Kcnq1ot1 could be a new therapeutic target for DCM.
Osteoporosis (OP) has been associated with cardiovascular disease. More specifically, osteoporosis was found to be an independent predictor of cardiovascular mortality. Recent studies revealed that platelets play a critical role in bone remodeling. Mean platelet volume (MPV) is an early marker of platelet activation, which is involved in the pathophysiology of coronary heart disease. However, little research has been conducted to investigate the relationship between MPV and OP. In this cross-sectional study, we investigated the relationship between platelet count, MPV, and bone mineral density (BMD) in 410 subjects in the geriatric department of the Second Affiliated Hospital, Harbin, China. Different biochemical parameters, platelet count, and MPV were determined, and bone mineral density (BMD) (g/cm(2)) was measured in the osteoporosis, osteopenia, and normal BMD groups. Mean age, systolic blood pressure (SBP), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and MPV increased gradually, and body mass index (BMI), decreased as BMD decreased. A negative correlation was present between MPV and the lumbar spine (L2-L4) and femoral neck BMD after adjusting other risk factors. Univariate analysis and multivariate analysis showed that MPV was significantly associated with lumbar spine L2-L4 BMD and femoral neck BMD (β = -0.285, P < 0.001 for lumbar spine L2-L4 BMD; β = -0.207, P < 0.001 for femoral neck BMD in multivariate model). The findings show that MPV is negatively correlated with BMD. Further studies on the involvement of MPV in osteoporosis may contribute to the evaluation of thrombotic risk in elderly patients with osteoporosis.
Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality in diabetes mellitus (DM) patients. Previous studies have shown that the transforming growth factor-beta 1 (TGF-b1)/Smad signaling pathway plays a key role in the development of myocardial fibrosis in DCM. Silymarin (SMN) is used clinically to treat liver disorders and acts by influencing TGF-b1. However, the possible effects of silymarin on DCM remain to be elucidated. In our study, the DM animal model was induced by streptozotocin (STZ) injection. Fasting blood glucose level was measured, and the structure and function of the heart were measured by hematoxylin and eosin (H&E) and Masson staining, echocardiography, and transmission electron microscopy (TEM). Western blot was used to detect the expression of TGF-b1, Smad2/3, phosphorylation Smad2/3(p-Smad2/ 3), and Smad7. Our results showed that silymarin downregulated blood glucose level and significantly improved cardiac fibrosis and collagen deposition in DM rats detected by H&E, Masson staining, and TEM assays. The echocardiography results showed that silymarin administration attenuated cardiac dysfunction in DM rats. Additionally, compared with untreated DM rats, levels of TGF-b1 and p-Smad2/3 were decreased, whereas Smad7 was increased following silymarin administration. These data demonstrate that silymarin ameliorates DCM through the inhibition of TGF-b1/Smad signaling, suggesting that silymarin may be a potential target for DCM treatment.
Objective To investigate the mechanism of H19 on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Methods Ovariectomized (OVX) mouse model was established. RNA immunoprecipitation and RNA pull‐down assays were performed to determine the correlation between H19 and forkhead box C2 (Foxc2). Chromatin immunoprecipitation assay was used to identify whether Foxc2 binds to the Wnt4 promoter region. Molecules expressions were measured by quantitative real‐time polymerase chain reaction and western blot. Results We found that H19 expression was reduced in the serum of patients with postmenopausal osteoporosis and BMSCs of OVX mice, and overexpression of H19 promoted osteogenic differentiation of BMSCs. Additionally, Foxc2 could bind to the Wnt4 promoter and promote its transcription. We also showed that H19 could bind to Foxc2, and H19/Foxc2 regulated Wnt promoter expression in a synergistic fashion, and H19/Foxc2 regulated osteogenic differentiation of BMSCs through Wnt‐β‐catenin pathway. Conclusion H19 and Foxc2 synergistically promoted osteogenic differentiation of BMSCs via Wnt‐β‐catenin pathway.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.