Optimal Regimen of N-Acetylcysteine on Chromium-Induced Renal Cell Damage.

Chromium (Cr) is a well-known heavy metal that can cause renal damage. The production of reactive oxygen species (ROS) due to chromium-induced toxicity induces cell dysfunction, apoptosis, and death. N-acetylcysteine (NAC) is an antioxidant used as an antidote for chromium-induced toxicity. However, the optimal regimen and protective mechanisms of NAC are not fully understood in human renal cells. Our results showed that exposure to 10 µM K2Cr2O7, a toxic Cr(VI) compound, induced apoptosis and production of intracellular ROS in the human proximal tubular epithelial cell line HK-2. Supplements of 600 or 1000 µg/mL NAC inhibited intracellular ROS in HK-2 cells exposed to Cr(VI) and significantly increased cell viability within 2 h of Cr(VI)-induced cytotoxicity. Moreover, Cr(VI) induced the expression of apoptosis markers, including cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerase, cleaved-caspase 8, and cleaved-caspase 9, and altered the expression ratio of Bax/Bcl-xL. Expression of apoptosis markers within 2 h of Cr(VI)-induced cytotoxicity in cells treated with 600 µg/mL NAC was significantly suppressed. However, delayed treatment with NAC at 4 h and 8 h after exposure to Cr did not suppress the activation of apoptotic pathways. In summary, our study reports the optimum timing and dose of NAC for the protection of human renal proximal tubular cells from Cr(VI)-induced cell death. The NAC treatment strategy described could be applied in clinical practice to suppress renal cell apoptosis, which in turn could rescue renal function.

Optimal dosage and early intervention of L-ascorbic acid inhibiting K2Cr2O7-induced renal tubular cell damage.

Chromium poisoning can cause renal failure and death. Chromium intoxication may be managed using L-ascorbic acid (vitamin C) therapy. However, the evidence supporting the effectiveness of this treatment is insufficient, and the mechanism of action has not been clarified in renal cells. In this study, our results showed that the optimal regimen of L-ascorbic acid therapy in human epithelial renal proximal tubule cells, HK-2 cells, was 30 µg/mL. Supplementation of L-ascorbic acid with 30 µg/mL and within 8 h of chromium intoxication (K2Cr2O7, Cr6+) was effective to inhibit renal tubular cell damage by blocking generation of free radicals, cell apoptosis, and autophagy. Intracellular chromium concentrations were estimated using electrothermal atomic absorption spectrometry. Treatment of L-ascorbic acid within 8 h of chromium intoxication significantly decreased the entry of chromium into the cells. Moreover, concomitant administration of L-ascorbic acid with repeatedly dosing at 8-hourly intervals had a better protective effect at lower concentration of L-ascorbic acid when compared to single dosing of L-ascorbic acid at an early time point of chromium intoxication. These findings might help physicians develop effective therapy strategies in renal failure.

Isolinderalactone enhances the inhibition of SOCS3 on STAT3 activity by decreasing miR-30c in breast cancer.

Development of an efficient treatment for triple-negative breast cancer is an urgent issues. Compounds from plant extracts are a potential source of novel cancer treatment. Isolinderalactone, a kind of sesquiterpenoids compound, was purified from the root of Lindera strychnifolia and Neolitsea daibuensis and shows anti-inflammatory and anticancer capacity. In the present study, isolinderalactone induced apoptosis in MDA-MB-231 cells which is a kind of triple-negative breast cancer cell line through induction of an intrinsic mitochondria-mediated and caspase-independent cell death. Treatment of isolinderalactone increased the protein level of the suppressor of cytokine signaling 3 (SCOS3), decreased phosphorylation of the signal transducer and activator of transcription 3 (STAT3), and suppressed expression of the down-stream genes of the X-linked inhibitor of apoptosis protein in MDA-MB-231 cells. Our results further showed that the level of SOCS3 expression was induced by isolinderalactone due to inhibiting the microRNA hsa-miR-30c-5p (miR-30c) expression. In addition, intraperitoneal injection of isolinderalactone induced apoptosis in a xenograft breast tumor while it did not significantly affect the histology of liver, kidney and lung of the treated mice. In conclusion, isolinderalactone induces apoptosis in MDA-MB­231 cells and suppresses STAT3 signaling pathway through regulation of SOCS3 and miR-30c. It may become a novel treatment for triple-negative breast cancer in the future.