Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway.

BACKGROUND: Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear. AIM: To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism. METHODS: Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels. RESULTS: In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 µM) or fasudil (FA) (a ROCK inhibitor, 100 µM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes. CONCLUSION: Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.

A highly stable bimetallic organic framework for enhanced electrical performance of cellulose nanofiber-based triboelectric nanogenerators.

Triboelectric nanogenerators (TENGs) have garnered considerable attention as an emerging energy harvesting technology. To improve the electrical properties of the triboelectric materials in TENGs, various micro- and nanomaterials with strong charge-trapping capabilities are introduced as filler materials. However, the fillers generally perform a single function and lack long-term operational durability. Hence, further research is required to achieve stable and efficient TENGs. In this study, NH2 metal-organic frameworks (NH2-MOFs) were combined with a cellulose nanofiber (CNF) to prepare a composite film. NH2-MOFs have an aminated bimetallic organic backbone with strong charge-induction and charge-trapping capabilities. Thus, their addition significantly improved the stability, positive triboelectric properties and charge-trapping performance of the composite film. The optimized composite film and a fluorinated ethylene propylene film were used as triboelectric pairs to assemble a TENG. The electrical performance of the TENG was approximately 230% greater than that of a TENG with a pure CNF film and remained very stable for at least 90 days. These results demonstrate that NH2-MOFs are promising fillers for improving the performance of TENGs and expanding the range of materials used in TENG construction.

Effects of Fluorine-Based Modification on Triboelectric Properties of Cellulose.

The hydroxyl groups on the cellulose macromolecular chain cause the cellulose surface to have strong reactivity. In this study, 1H, 1H, 2H, 2H-perfluorodecyltriethoxysilane (PDOTES) was used to modify cellulose to improve its triboelectric properties, and a triboelectric nanogenerator (TENG) was assembled. The introduction of fluorine groups reduced the surface potential of cellulose and turned it into a negative phase, which enhanced the ability to capture electrons. The electrical properties increased by 30% compared with unmodified cellulose. According to the principles of TENGs, a self-powered human-wearable device was designed using PDOTES-paper, which could detect movements of the human body, such as walking and running, and facilitated a practical method for the preparation of efficient wearable sensors.

Association Between Socioeconomic Status and Prevalence of Cardio-Metabolic Risk Factors: A Cross-Sectional Study on Residents in North China.

Studies have found associations between cardio-metabolic disorders and socioeconomic status (SES) in developed areas. However, little epidemiological data are available on residents of less developed areas in North China. A cross-sectional study that consisted of 2,650 adults randomly selected from local residents was conducted on a developing province, Hebei. SES was assessed in terms of education, personal income per year, and occupation. The association between SES and metabolic syndrome (MetS) was determined by multivariate logistic regression. The weighted prevalence of MetS was 26.8% among residents of Hebei province. The lower prevalence of MetS and abdominal obesity was associated with increase in SES groups. After adjustments regarding age, sex, body mass index, living area, smoking, salt intake, and family history of diabetes, odds ratio (OR) for elevated blood pressure (BP) of individuals with higher SES level was 0.71 [95% confidence interval (CI): 0.542-0.921] compared with those with lower SES level. Cardio-metabolic risk factors were commonly identified among residents of Hebei province in north China and were associated with SES conditions. This study indicated that from a public health perspective, more attention should be paid to screening of cardio-metabolic disorders in less developed areas.

Liraglutide, a glucagon-like peptide-1 analog, inhibits high glucose-induced oxidative stress and apoptosis in neonatal rat cardiomyocytes.

Cardiomyocyte apoptosis serves an important role in diabetic cardiomyopathy. Liraglutide, a glucagon-like peptide-1 analog, has been indicated to exert a cardioprotective effect. However, the role of liraglutide on cardiomyocyte apoptosis in hyperglycemia is not fully understood. The aim of the current study was to assess whether liraglutide protects against high glucose (HG)-induced cardiomyocyte apoptosis in vitro. Sprague-Dawley neonatal rat cardiomyocytes were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 or 25 mmol/l D-glucose or 5.5 mmol/l D-glucose + 19.5 mmol/l mannitol, in the presence or absence of liraglutide (10 or 100 nmol/l). Cell viability was assessed via an MTT assay and early apoptosis rates were assessed via flow cytometry. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in cell supernatants were measured. Bcl-2 associated X (Bax), B-cell lymphoma-2 (Bcl-2) and cleaved/full caspase-3 protein levels were determined via western blotting. The results revealed that liraglutide effectively inhibited the HG-induced increase in early apoptosis and MDA content and markedly increased SOD activity. Furthermore, liraglutide markedly inhibited the HG-induced increase in Bax and cleaved caspase-3 protein expression, and upregulated the expression of Bcl-2. The present study demonstrated that liraglutide suppressed HG-induced oxidative stress and cardiomyocyte apoptosis. Thus, the anti-apoptotic actions of liraglutide may be attributable, in part, to the inhibition of Bax, the inhibition of caspase-3 activation and the upregualtion of Bcl-2.