Title:Cardioprotective Effects and in-silico Antioxidant Mechanism of L-Ergothioneine
in Experimental Type-2 Diabetic Rats
Volume: 20
Issue: 2
Author(s): Ayobami Dare *, Ahmed A Elrashedy, Mahendra L. Channa and Anand Nadar
Affiliation:
- Discipline of Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University
of KwaZulu-Natal, Westville Campus, Durban X54001, South Africa
Keywords:
Cardio-protection, diabetes, L-ergothioneine, molecular docking, molecular dynamics, cardiovascular disease (CVD).
Abstract:
Background: Diabetic cardiotoxicity is commonly associated with oxidative injury, inflammation,
and endothelial dysfunction. L-ergothioneine (L-egt), a diet-derived amino acid, has
been reported to decrease mortality and risk of cardiovascular injury, provides cytoprotection to tissues
exposed to oxidative damage, and prevents diabetes-induced perturbation.
Objective: This study investigated the cardioprotective effects of L-egt on diabetes-induced cardiovascular
injuries and its probable mechanism of action.
Methods: Twenty-four male Sprague-Dawley rats were divided into non-diabetic (n = 6) and diabetic
groups (n = 18). Six weeks after the induction of diabetes, the diabetic rats were divided into
three groups (n = 6) and administered distilled water, L-egt (35mg/kg), and losartan (20mg/kg) by
oral gavage for six weeks. Blood glucose and mean arterial pressure (MAP) were recorded pre-and
post-treatment, while biochemical, ELISA, and RT-qPCR analyses were conducted to determine inflammatory,
injury-related and antioxidant biomarkers in cardiac tissue after euthanasia. Also, an
in-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, Legt
increased body weight, antioxidant enzymes, upregulated Nrf2, HO-1, NQO1 expression, and
decreased Keap1 expression. The in-silico study showed that L-egt inhibits the Keap1-Nrf2 complex
by binding to the active site of Nrf2 protein, thereby preventing its degradation.
Conclusion: L-egt protects against diabetes-induced cardiovascular injury via the upregulation of
the Keap1-Nrf2 pathway and its downstream cytoprotective antioxidants.
