Epigallocatechin Gallate Protects Diabetes Mellitus Rats Complicated with Cardiomyopathy through TGF-β1/JNK Signaling Pathway

Abstract

Background: Epigallocatechin gallate (EGCG) is the main component of rhubarb tannin, with antioxidant, anti-angiogenic, anti-cancer and antiviral activities. Diabetes mellitus (DM) is a high blood sugar and protein metabolism disorder syndrome, which is caused by absolute or relative factors, such as deficiency of insulin and oxidative stress. Diabetes cardiomyopathy (DCM) is one of the most frequent complications of DM. Objective: This study aims to explore whether EGCG can improve diabetic complication, myocardial fibrosis, in diabetic rats with an intraperitoneal injection of streptozotocin (STZ) through the transforming growth factor β1 (TGF-β1)/C-Jun N -terminal kinase (JNK) signaling pathway. Methods: 50 male SD rats were randomly divided into five groups, including the control group, model group, and EGCG drug groups (10 mg/kg, 20 mg/kg, 40 mg/kg), with 10 rats in each group. Rats, except for the control group, were intraperitoneally injected with STZ (65 mg/kg) to induce the diabetic rats model. EGCG drug groups were given distilled water according to the dose, while the control group and model group were given the same volume of distilled water for 12 weeks. The levels of glucose (GLU), triglyceride (TG), cholesterol (CHO), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in serum were detected by ELISA of all rats. Myocardial function was observed by HE, Masson staining and Sirius red staining in DCM rats. Immunohistochemistry was used to detect the expression of Collagen I (COL-I) and Collagen III (COL-III), and detect the degree of myocardial fibrosis of DM rats. Western blot was used to detect the expression of matrix metalloproteinases (MMPs), tissue inhibitor of matrix metalloproteinase (TIMPs), TGF-β1, JNK and p-JNK in the myocardium. Results: Compared to the model group, the levels of GLU, TG, CHO, and LDL in serum were decreased while the level of HDL in serum was increased in EGCG groups rats; cardiac index and left ventricular mass index were decreased while heart function was improved in EGCG groups rats; the expressions of the COL-I and COL-III were decreased in EGCG groups, and the high dose group was the best; the expressions of TGF-β1, JNK, p-JNK, and TIMP-1 were down-regulated, and the expression of MMP-9 was up-regulated in EGCG groups. Conclusion: The results demonstrated that EGCG could improve STZ-induced diabetic complication, i.e., myocardial fibrosis, in diabetic rats, and protect their heart through TGF-β1/JNK signaling pathway

Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions

“…166 TGF-β1/JNK was related to myocardial fibrosis in DCM. 167 In addition, JNK was involved in regulating NLRP3 inflammasome activation in macrophages. 168 IL-1β, IL-6, and TNF-α could stimulate JAK/STAT after binding to the receptor, thereby initiating the expression of downstream inflammation-related target genes.…”

“…JNK was a key upstream molecule of NF‐κB 165 and it could be activated by inflammatory cytokines such as TNF‐α, which induced IR 166 . TGF‐β1/JNK was related to myocardial fibrosis in DCM 167 . In addition, JNK was involved in regulating NLRP3 inflammasome activation in macrophages 168 .…”

The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools

“…There were some studies that have shown significant reductions in myocardial interstitial fibrosis. Epigallocatechin gallate (EGCG), a natural antioxidant, reduced high glucoseinduced oxidative stress and inhibited cardiac interstitial fibrosis in a diabetic rat model [38]; Curcumin, a natural polyphenol, reduced oxidative stress and inhibited Akt/GSK-3βinduced fibrosis in a diabetic rat model [39]; and N-acetylcysteine (NAC), a glutathione precursor, reduced high glucose-induced oxidative stress and inhibited interstitial fibrosis in a diabetic mice model [40]. Melatonin, a natural antioxidant, and Resveratrol, a natural polyphenol, also reduced oxidative stress and inhibited myocardial interstitial fibrosis in a diabetic rat model [41].…”

A Comprehensive Review of Natural Flavonoids with Anti-SARS-CoV-2 Activity

“…A study showed that EGCG and quercetin reduced insulin resistance, both in vivo and in vitro, and also reduced glucose metabolism in the liver [ 79 ]. A study in a rat model of diabetes showed that EGCG improved diabetes in rats and improved streptozotocin-induced complications [ 80 ]. Catechin is a naturally occurring product that has also been shown to have anti-diabetic activity.…”