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Eur J Pharmacol ; 975: 176643, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38754539

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-52 E 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-52 E 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.


Subject(s)
Diabetes Mellitus, Experimental , Histone Deacetylase 2 , Kidney , Molecular Docking Simulation , Molecular Dynamics Simulation , Reperfusion Injury , Animals , Histone Deacetylase 2/metabolism , Male , Rats , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Kidney/drug effects , Kidney/pathology , Kidney/metabolism , Reperfusion Injury/drug therapy , Reperfusion Injury/pathology , Reperfusion Injury/metabolism , Oxidative Stress/drug effects , Cell Line , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/pathology , Diabetic Nephropathies/metabolism , Rats, Wistar
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