Dihydromyricetin Attenuates Diabetic Cardiomyopathy by Inhibiting Oxidative Stress, Inflammation and Necroptosis via Sirtuin 3 Activation

Abstract

Dihydromyricetin (DHY), the main flavonoid component in Ampelopsis grossedentata, has important benefits for health. The present study aimed to investigate the exact effects and possible mechanisms of DHY on diabetic cardiomyopathy (DCM). Male C57BL/6 mice and sirtuin 3 (SIRT3) knockout (SIRT3-KO) mice were injected with streptozotocin (STZ) to induce a diabetic model. Two weeks later, DHY (250 mg/kg) or carboxymethylcellulose (CMC) were administrated once daily by gavage for twelve weeks. We found that DHY alleviated fasting blood glucose (FBG) and triglyceride (TG) as well as glycosylated hemoglobin (HbA1c) levels; increased fasting insulin (FINS); improved cardiac dysfunction; ameliorated myocardial hypertrophy, fibrosis and injury; suppressed oxidative stress, inflammasome and necroptosis; but improved SIRT3 expression in STZ-induced mice. Neonatal rat cardiomyocytes were pre-treated with DHY (80 μM) with or without high glucose (HG) stimulation. The results showed that DHY attenuated cell damage but improved SIRT3 expression and inhibited oxidative stress, inflammasome and necroptosis in cardiomyocytes with high glucose stimulation. Moreover, the above protective effects of DHY on DCM were unavailable in SIRT3-KO mice, implying a promising medical potential of DHY for DCM treatment. In sum, DHY improved cardiac dysfunction; ameliorated myocardial hypertrophy, fibrosis and injury; and suppressed oxidative stress, inflammation and necroptosis via SIRT3 activation in STZ-induced diabetic mice, suggesting DHY may serve as a candidate for an agent to attenuate diabetic cardiomyopathy.

Dihydromyricetin alleviates gentamicin induced vascular dysfunction through inhibition of ROS/NF-κB activation

“…It downregulates NF-κB expression through inhibition of IKK phosphorylation, the rate limiting step in NF-κB phosphorylation and activation. Moreover, DHM blocks the degradation of (IkBa) which is an inhibitor of NF-κB activation [41,42]. It is important to mention that, the upregulation of NF-κB and TNF-α expression in aortic tissues strongly matches the previously reported increase in their renal levels upon GTN administration.…”

Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3‐Energized and Microenvironment‐Modulated Hydrogel Microspheres to Impede Osteoarthritis

“…Molecular docking showed a possible binding between DMY and the SIRT3 protein at the GLU-296, PRO-297, THR-257, GLN-260, THR-255, LYS-288, PRO-289, or ASP-290 sites, with a binding energy of −6.64 kcal mol −1 (Figure 1C). Murine chondrocytes exposed to IL-1𝛽 were treated with different concentration gradients of DMY to investigate its activation on SIRT3 in vitro according to the previous reports, [26][27][28] both at the transcriptional (Figure 1D) and translational level (Figure 1E,F) and without compromising cell viability (Figure S1A, Supporting Information). We observed that the agonism of SIRT3 by DMY not only promoted cartilage ECM anabolic metabolism (collagen type II, COLII and aggrecan, ACAN) but also restrained the degradation activities of collagenases (matrix metalloproteinase 13, MMP13) and proteoglycanases (ADAM metallopeptidase with thrombospondin type 1 motif 5, ADAMTS5) (Figure 1H,I and Figure S1B,C, Supporting Information).…”

Targeting the programmed cell death (PCD) signaling mechanism with natural substances for the treatment of diabetic cardiomyopathy (DCM)

“…Currently, there is limited basic research on natural product treatments targeting necrotic apoptosis, and further studies should be conducted to explore effective drugs for targeting necrotic apoptosis in the treatment of DCM. Chen et al (Chen et al, 2023) found that DHY can alleviate high glucose‐induced cardiac dysfunction, myocardial fibrosis, and cardiac remodeling in male C57BL/6 mice model. In vitro and in vivo experiments, DHY reduced the production of superoxide and mitochondrial oxidative damage in cardiac cells and inhibited the expression of IL‐1β and NLRP3, indicating that DHY alleviated oxidative stress and inflammation in DCM.…”