Abstract
Chronic diabetes mellitus is reported to be associated with acute kidney injury. The enzyme histone deacetylase-2 (HDAC-2) was found to be upregulated in diabetes-related kidney damage. Alpha-cyperone (α-CYP) is one of the active ingredients of Cyperus rotundus that possesses antioxidant and anti-inflammatory effects. We evaluated the effect of α-CYP on improving oxidative stress and tissue inflammation following renal ischemia/reperfusion (I/R) injury in diabetic rats. The effect of α-CYP on HDAC-2 expression in renal homogenates and in the NRK-52E cell line was evaluated following renal I/R injury and high glucose conditions, respectively. Molecular docking was used to investigate the binding of α-CYP with the HDAC-2 active site. Both renal function and oxidative stress were shown to be impaired in diabetic rats due to renal I/R injury. Significant improvements in kidney/body weight ratio, creatinine clearance, serum creatinine, blood urea nitrogen (BUN), and uric acid were observed in diabetic rats treated with α-CYP (50 mg/kg) two weeks prior to renal I/R injury. α-CYP treatment also improved histological alterations in renal tissue and lowered levels of malondialdehyde, myeloperoxidase, and hydroxyproline. Treatment with α-CYP suppressed the increased HDAC-2 expression in the renal tissue of diabetic rats and in the NRK-52E cell line. The molecular docking reveals that α-CYP binds to HDAC-2 with good affinity, ascertained by molecular dynamics simulations and binding free energy analysis. Overall, our data suggest that α-CYP can effectively prevent renal injury in diabetic rats by regulating oxidative stress, tissue inflammation, fibrosis and inhibiting HDAC-2 activity.
| Original language | English |
|---|---|
| Article number | 176643 |
| Journal | European Journal of Pharmacology |
| Volume | 975 |
| DOIs | |
| Publication status | Published - 15 Jul 2024 |
| MoE publication type | A1 Journal article-refereed |
Funding
The authors concede the support by the G.E.S's Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research Nashik; Institute of Pharmacy, Nirma University, Ahmedabad; and Government Polytechnic, Jalgaon. The Sigrid Jus\u00E9lius Foundation, Biocenter Finland Bioinformatics and Drug Discovery and Chemical Biology networks, CSC IT Center for Science, Joe, Pentti and Tor Borg Memorial Fund and Prof. Mark Johnson and Dr. Jukka Lehtonen are gratefully acknowledged for the excellent computational infrastructure at the \u00C5bo Akademi University. We would also like to thank Dr. Outi M. H. Salo-Ahen for constructive feedback on the computational part.
Keywords
- HDAC-2
- molecular dynamics simulations
- Docking
