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BACKGROUND: Interleukin-6 (IL-6) is a multifunctional glycoprotein that regulates the growth of some tumors, including prostate carcinomas due to signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinases 1/2 (ERK1/2), and AKT signaling pathways. Hesperetin, as a flavanone, has several biological properties such as antitumor and anti-inflammatory. OBJECTIVE: This study was carried out to evaluate the biological effects of hesperetin on the IL-6 gene expression and phosphorylated STAT3, AKT, and ERK1/2 signaling pathways in PC3 prostate cancer (PC) cells. MATERIALS AND METHODS: In this study, we used real-time quantitative polymerase chain reaction (RT-qPCR) and ELISA to evaluate IL-6 gene expression and IL-6 protein secretion, respectively, in the treated PC3 cells with 0, 400, 450, and 500 µM of hesperetin. Cell survival studies were done by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 48 h treatment with hesperetin, and cell apoptosis was determined by flow cytometry. The protein levels of activated signaling molecules (pSTAT3, pAKT, and pERK1/2) analyzed by immunoprecipitation technique. RESULTS: Hesperetin-treated PC3 cells resulted in reduction of cell viability. Hesperetin led to the elevation of phosphorylated STAT3, ERK1/2, and AKT signaling proteins after 48 h in a dose-dependent manner as compared to the control cells. IL-6 gene expression, as well as protein level, significantly increased (P < 0.05) in a dose-dependent pattern in treated PC3 with hesperetin compared to the control cells. Further, hesperetin exposure resulted in the induction of cell cycle arrest at G0/G1 phase. CONCLUSION: Hesperetin in PC3 cells led to elevation IL-6 gene expression, IL-6 protein secretion, pSTAT3, pERK1/2 and pAKT intracellular signaling proteins. Our results indicate that hesperetin treatment leads to the inhibition of cell proliferation and the induction of cell cycle arrest at the G1 phase. Hesperetin can be considered a potent agent which synchronizes and stops cell cycle at G0/G1 phase to apply suitable chemotherapeutic agents and radiotherapy in PC cells. SUMMARY: This study evaluates biological effects of hesperetin on the cell cycle, interleukin-6 gene expression and some phosphorylated signaling pathways in PC3 prostate cancer cells. Hesperetin resulted in the inhibition of cell proliferation via inducing G0/G1 phase arrest in spite of the elevation of interleukin-6 gene expression and phosphorylated AKT, STAT3, and ERK1/2 intracellular signaling proteins. Therefore, hesperetin can be considered a potent agent which synchronizes and stop cell cycle at G0/G1 phase so that suitable chemotherapeutic agents can be applied in PC3 prostate cancer cells. Abbreviations Used: PC: Prostate cancer, IL-6: Interleukin-6, STAT3: Signal transducer activator of transcription 3, ERK1/2: Extracellular signal-regulated kinases 1/2, IC50: Inhibitory concentration of 50%.
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INTRODUCTION: Gentamicin can lead to acute tubular injury and kidney dysfunction. This study aimed to evaluate the effect of Ferulago angulata on kidney function and other markers in rats with gentamicin-induced nephrotoxicity. MATERIALS AND METHODS: Forty-eight male Wistar rats were divided into the following groups: group 1, the controls; group 2, rats receiving gentamicin (120 mg/kg body weight per day, intraperitoneal) for 7 days without treatment; groups 3, 4 and 5, rats receiving gentamicin for 7 days and oral treatment with 200 mg/kg, 400 mg/kg, and 800 mg/kg body weight per day of Ferulago angulate extract, respectively. Measurements included serum levels of creatinine, urea, uric acid, lipids, ferric-reducing antioxidant power, and protein carbonyl; kidney and serum levels of malondialdehyde; and serum and renal levels of tumor necrosis factor-α. Histopathology of kidney tissue was examined as well as renal catalase, superoxide dismutase, and vitamin C. RESULTS: Compared to treatment with gentamicin only, treatment with Ferulago angulata resulted in a significantly higher high-density lipoprotein cholesterol, ferric-reducing antioxidant plasma, renal catalase, superoxide dismutase, and vitamin C levels. It was also associated with significantly lower serum levels of creatinine, urea, uric acid, malondialdehyde, protein carbonyl, tumor necrosis factor-α, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol. Ferulago angulate was linked with a lower renal gene expression of tumor necrosis factor-α. CONCLUSIONS: The present study suggests that Ferulago angulate extract has protective effects against nephrotoxicity due to gentamicin.
