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Medicinal evaluation and molecular docking study of osajin as an anti-inflammatory, antioxidant, and antiapoptotic agent against sepsis-associated acute kidney injury in rats.

ABSTRACT: Despite efforts to find effective drugs for sepsis-associated acute kidney injury (SA-AKI), mortality rates in patients with SA-AKI have not decreased. Our study evaluated the protective effects of isoflavone osajin (OSJ) on SA-AKI in rats by targeting inflammation, oxidative stress, and apoptosis, which represent the cornerstones in the pathophysiological mechanism of SA-AKI. Polymicrobial sepsis was induced in rats via the cecal ligation and puncture (CLP) technique. Markers of oxidative stress were evaluated in kidney tissues using biochemical methods. The expression of interleukin-33 (IL-33), 8-hydroxydeoxyguanosine (8-OHdG), caspase-3, and kidney injury molecule-1 (KIM-1) was evaluated as indicators of inflammation, DNA damage, apoptosis, and SA-AKI respectively in the kidney tissues using immunohistochemical and immunofluorescent detection methods. The CLP technique significantly (p < 0.001) increased lipid peroxidation (LPO) levels and significantly (p < 0.001) decreased the activities of superoxide dismutase and catalase in kidney tissues. In the renal tissues, strong expression of IL-33, 8-OHdG, caspase-3, and KIM-1 was observed with severe degeneration and necrosis in the tubular epithelium and intense interstitial nephritis. In contrast, the administration of OSJ significantly (p < 0.001) reduced the level of LPO, markedly improved biomarkers of antioxidant status, decreased the levels of serum creatinine and urea, lowered the expression of IL-33, 8-OHdG, caspase-3, and KIM-1 and alleviated changes in renal histopathology. A promising binding score was found via a molecular docking investigation of the OSJ-binding mode with mouse IL-33 (PDB Code: 5VI4). Therefore, OSJ protects against SA-AKI by suppressing the IL-33/LPO/8-OHdG/caspase-3 pathway and improving the antioxidant system.

SUBMITTER: Alhilal M

PROVIDER: S-EPMC11262233 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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Medicinal evaluation and molecular docking study of osajin as an anti-inflammatory, antioxidant, and antiapoptotic agent against sepsis-associated acute kidney injury in rats.

Alhilal Mohammad M Erol Huseyin Serkan HS Yildirim Serkan S Cakir Ahmet A Koc Murat M Alhilal Suzan S Dereli Esra E Alkanoglu Omer O Ay Volkan V Can Ismail I Halici Mesut Bunyami MB

Renal failure 20240721 2

Despite efforts to find effective drugs for sepsis-associated acute kidney injury (SA-AKI), mortality rates in patients with SA-AKI have not decreased. Our study evaluated the protective effects of isoflavone osajin (OSJ) on SA-AKI in rats by targeting inflammation, oxidative stress, and apoptosis, which represent the cornerstones in the pathophysiological mechanism of SA-AKI. Polymicrobial sepsis was induced in rats <i>via</i> the cecal ligation and puncture (CLP) technique. Markers of oxidativ ...[more]

PMID: 39034431

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Project description:Ethnopharmacological relevanceSepsis is a systemic inflammatory response syndrome caused by an infection in the body, and accompanying acute kidney injury (AKI) is a common complication of sepsis. It is associated with increased mortality and morbidity. Forsythia Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a commonly used traditional Chinese medicine.Aims of the studyThis study aimed to elucidate the protective effect of Forsythiaside A (FTA) on sepsis-induced AKI by downregulating inflammatory and apoptotic responses, and exploring its underlying mechanism.MethodsSeptic AKI was induced through intraperitoneal injection of LPS (10 mg/kg) using male C57BL/6 mice and pretreated with FTA or control saline. First, we assessed the degree of renal injury by creatinine, blood urea nitrogen measurement, and HE staining of renal tissue; secondly, the inflammation and apoptosis were measured byELISA, qPCR, and TUNEL immunofluorescence; finally, the mechanism was explored by computer molecular docking and Western blot.ResultsOur data showed that FTA markedly attenuated pathological kidney injuries, alleviated the elevation of serum BUN and Creatinine, suggesting the renal protective effect of FTA. Notably, FTA significantly inhibited the renal expression of proinflammatory cytokine IL-1β, IL-6, and TNF-α both at protein and mRNA levels and attenuated cell apoptosis in the kidney, as measured by caspase-3 immunoblot and TUNEL assay, indicating its anti-Inflammation and antiapoptotic properties. Mechanistically, administration of LPS resulted in robust endoplasmic reticulum (ER) stress responses in the kidney, evidenced by glucose-regulated protein 78(GRP78) upregulation, protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation, eukaryotic initiation factor 2 alpha (elF2α) phosphorylation and C/EBP homologous protein (CHOP) overexpression, which could be significantly blocked by FTA pretreatment. Dynamic simulation and molecular docking were performed to provide further insight.ConclusionsCollectively, our data suggest that FTA ameliorates sepsis-induced acute kidney injury via its anti-inflammation and antiapoptotic properties by regulating PERK signaling dependent ER stress responses.

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Medicinal evaluation and molecular docking study of osajin as an anti-inflammatory, antioxidant, and antiapoptotic agent against sepsis-associated acute kidney injury in rats.

Publications

Medicinal evaluation and molecular docking study of osajin as an anti-inflammatory, antioxidant, and antiapoptotic agent against sepsis-associated acute kidney injury in rats.

Similar Datasets

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