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Abstract

Background: Diabetic cardiotoxicity is commonly associated with oxidative injury, inflammation,and endothelial dysfunction. L-ergothioneine (L-egt), a diet-derived amino acid, hasbeen reported to decrease mortality and risk of cardiovascular injury, provides cytoprotection to tissuesexposed to oxidative damage, and prevents diabetes-induced perturbation.

Objective: This study investigated the cardioprotective effects of L-egt on diabetes-induced cardiovascularinjuries and its probable mechanism of action.

Methods: Twenty-four male Sprague-Dawley rats were divided into non-diabetic (n = 6) and diabeticgroups (n = 18). Six weeks after the induction of diabetes, the diabetic rats were divided intothree groups (n = 6) and administered distilled water, L-egt (35mg/kg), and losartan (20mg/kg) byoral gavage for six weeks. Blood glucose and mean arterial pressure (MAP) were recorded pre-andpost-treatment, while biochemical, ELISA, and RT-qPCR analyses were conducted to determine inflammatory,injury-related and antioxidant biomarkers in cardiac tissue after euthanasia. Also, anin-silico study, including docking and molecular dynamic simulations of L-egt toward the Keap1-Nrf2 protein complex, was done to provide a basis for the molecular antioxidant mechanism of Legt.

Results: Administration of L-egt to diabetic animals reduced serum triglyceride, water intake,MAP, biomarkers of cardiac injury (CK-MB, CRP), lipid peroxidation, and inflammation. Also, Legtincreased body weight, antioxidant enzymes, upregulated Nrf2, HO-1, NQO1 expression, anddecreased Keap1 expression. The in-silico study showed that L-egt inhibits the Keap1-Nrf2 complexby binding to the active site of Nrf2 protein, thereby preventing its degradation.

Conclusion: L-egt protects against diabetes-induced cardiovascular injury via the upregulation ofthe Keap1-Nrf2 pathway and its downstream cytoprotective antioxidants.

Keywords:Cardio-protection, diabetes, L-ergothioneine, molecular docking, molecular dynamics, cardiovascular disease (CVD).

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Graphical Abstract

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Medicinal Plants with Beneficial Properties on Diabetes and Hypertension

Diabetes and hypertension are real scourges of the 21st century. It is imperative to act in order to find innovative solutions to this problem. Taking medications such as hypoglycemic and antihypertensive drugs may aggravate certain underlying comorbidities, such as chronic kidney disease and cardiovascular disease. This significant drawback therefore requires ...read more

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