The renoprotective effect of curcumin against cisplatin-induced acute kidney injury in mice: involvement of miR-181a/PTEN axis.

Background: Nephrotoxicity, especially acute kidney injury (AKI), is the main dose-limiting toxicity of cisplatin. Although recent studies showed that curcumin prevented cisplatin-induced AKI effectively, further studies to understand the mechanism are required.Methods: We established an AKI mouse model. Male C57BL/6 mice were assigned to three groups: saline group (control), cisplatin group (CP), and curcumin + cisplatin group (CP + Cur). The CP group received a single intraperitoneal (i.p.) injection of cisplatin, while the control group received saline. The CP + Cur group received i.p. curcumin three days before cisplatin injection and curcumin administered for another three days until the day before euthanization. Renal injury was assessed by serological and histological analysis. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the phosphatase and tensin homolog (PTEN), and microRNA (miR)-181a expression in the renal tissues. Bioinformatics prediction and western blotting methods validated the targets of miR-181a in vitro.Results: Curcumin treatment alleviated cisplatin-induced nephrotoxicity as validated by the blood urea nitrogen (BUN) values, and histological analysis of kidneys. At the molecular level, curcumin treatment decreased miR-181a expression level, which was induced by cisplatin and restored the in vivo expression of PTEN, which was suppressed by cisplatin. We verified the direct regulation of PTEN by miR-181a in cultured human embryonic kidney 293T cells.Conclusions: We showed the involvement of miR-181a/PTEN axis in the renoprotective effect of curcumin against cisplatin-induced AKI, and provide new evidence on the ability of curcumin to alleviate cisplatin-induced nephrotoxicity.

Antitumor effects and molecular mechanisms of action of natural products in ovarian cancer.

Ovarian cancer is a common malignancy and the second leading cause of mortality among females with genital tract cancer. At present, postoperative platinum drugs and paclitaxel-based chemotherapy is the gold standard treatment for ovarian cancer. However, patients who receive this chemotherapy often develop cumulative toxic effects and are prone to chemotherapy resistance. Therefore, it is necessary to determine more effective treatment options that would be better tolerated by patients. Recent studies have reported the therapeutic effects of numerous natural products in patients with ovarian cancer. Notably, these natural ingredients do not induce adverse effects in healthy cells and tissues, suggesting that natural products may serve as a safe alternative treatment for ovarian cancer. The antitumor effects of natural products are attributed to suppression of cell proliferation and metastasis, stimulation of autophagy, improved chemotherapy sensitivity, and induction of apoptosis. The present review focused on the antitumor effects of several natural products, including curcumin, resveratrol, ginsenosides, (-)-epigallocatechin-3-gallate and quercetin, which are increasingly being investigated as therapeutic options in ovarian cancer, and discussed the molecular mechanisms involved in cell proliferation, apoptosis, autophagy, metastasis and sensitization.

MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression.

Ovarian cancer is a highly lethal malignancy in the female reproductive system. Platinum drugs, represented by cisplatin, are the first-line chemotherapeutic agents for treatment of various malignancies including ovarian cancer, but drug resistance leads to chemotherapy failure. MicroRNAs emerged as promising molecules in reversal of cisplatin resistance. MiR-186 was reported to be downregulated in the cisplatin-resistant ovarian cell lines and miR-186 expression increased cisplatin sensitivity. However, we found the bidirectional regulatory effects of miR-186 on cisplatin sensitivity for the first time that overexpression of miR-186 at low concentration increased the cisplatin sensitivity of ovarian cancer cells A2780/DDP, while high concentration of miR-186 decreased the cisplatin sensitivity. The survival assay in other types of cancer cell lines verified the bidirectional regulatory function of miR-186 on cisplatin sensitivity in dose and cell type dependent manners. MiR-186 suppressed the protein levels of PTEN and PIK3R3 dose-dependently, which are opposite regulatory molecules of the oncogenic AKT pathway. MiR-186 also enhanced the protein levels of apoptotic gene APAF1 dose-dependently. We proposed the final effects of PTEN and APAF1 outweighed PIK3R3 when miR-186 at low concentration so as to increase the cisplatin sensitivity of ovarian cancer cells, while the final effects of PIK3R3 outweighed PTEN and APAF1 when miR-186 at high concentration so as to decrease the cisplatin sensitivity. We concluded the outcome of regulation of these opposite functional molecules contributed to the bidirectional regulatory effects of miR-186 in ovarian cancer cisplatin sensitivity. It deserves more attentions when developing therapeutic strategies based on the bidirectional functional miRNAs.