Tanshinone IIA (Tan IIA), a compound extracted from Salvia miltiorrhiza, can improve type II diabetes, while the molecular mechanisms underlying Tan IIA-mediated protective effects in diabetic nephropathy are unclear. This study explored the protective actions of Tan IIA on renal tissues in streptozotocin (STZ)-induced diabetic nephropathy. Materials and Methods: Tan IIA (2, 4, 8 mg/kg/day) was daily administered to STZtreated rats by intraperitoneal injection for 42 days. The morphologic pathology was evaluated by hematoxylin-eosin and Masson's trichrome staining, and transmission electron microscopy. The protein expression levels in renal tissues were evaluated by Western blotting and immunohistochemistry; the mRNA expression level was determined by quantitative realtime PCR. Results: Tan IIA at 2 and 4 mg/kg attenuated the increase in the levels of uric acid and blood urea nitrogen and restored the reduction in the superoxide dismutase activity in the serum of the diabetic rats. Tan IIA at 2 and 4 mg/kg, but not 8 mg/kg, ameliorated the thickening of renal tubule in the diabetic rats; Tan IIA at 2 and 4 and 8 mg/kg attenuated the thickening of glomerular basement membrane and the collagen deposition in the renal tissues of the diabetic rats. Tan IIA treatment at 2, 4, 8 mg/kg decreased the expression levels of transforming growth factor-beta1, TSP-1, Grp78 and CHOP in the diabetic rats. Tan IIA at 2 and 4 and 8 mg/kg attenuated the increase in the protein levels of p-PERK, p-elf2α and ATF-4 from the renal tissues of diabetic rats, while the protein level of AFT-6 and the mRNA expression levels of XBP-1t, XBP-1s and p58IPK in the renal tissues were not affected by STZ or Tan IIA treatment. Conclusion: Tan IIA-mediated protective effects on the STZ-induced diabetic nephropathy may be associated with the reduced endoplasmic reticulum stress via attenuating PERK signaling activities.

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT-8/5-Fu cells and provided evidence that activated nuclear factor erythroid 2-related factor (Nrf2) deficiency induced by the curcumin altered the B-cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 expression ratio, which led to the induction of apoptosis in HCT-8/5-Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

Resistance is a major concern when administering chemotherapy to patients with non-small cell lung cancer (NSCLC). Chemosensitizer are agents that can reverse resistance to chemotherapeutic drugs, thereby enhancing the chemosensitivity of tumor cells. Thus, their development will improve therapeutic efficacy in cancer. However, few effective chemosensitizer have been identified to date. Piperlongumine (PL) has been shown to effectively reverse resistance to chemotherapeutic drugs in several types of cancers. However, the mechanisms associated with the chemotherapy resistance reversal effect of PL and its regulation of target factors in chemotherapy resistance cells are still unclear. This study investigated the reversal effect of PL both in vitro and in vivo, and provided evidence that PL inhibited the phosphorylation of Akt via the accumulation of reactive oxygen species in chemotherapy resistance cells. Consequently, various Akt activation-dependent genes caused a reduction of drug efflux and induction of apoptosis in cisplatin-resistant A549 NSCLC cells. Our results indicate that Akt phosphorylation may play a functional role in the reversal effect of PL and contribute, at least in part, to the treatment outcomes of patients with chemotherapy resistance.

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