Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism.

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid malignancies and resistant to chemotherapy. Novel therapeutic strategy is required for better management of ATC. In this work, we show that artesunate, an antimalarial drug, is active against chemoresistant ATC cells. Artesunate dose-dependently inhibits growth and induces apoptosis in chemo-sensitive (8505C and KAT-4) and -resistant (8505C-r and KAT-4-r) ATC cells, and acts synergistically with doxorubicin. Using multiple xenograft mouse models, artesunate is active against chemo-sensitive and -resistant ATC cells in vivo at doses that do not cause toxicity in mice. Our mechanism analysis reveals that artesunate acts on ATC cells through suppressing mitochondrial functions without affecting glycolysis, leading to oxidative stress and damage, regardless of whether they are sensitive or resistant to chemotherapy. Interestingly, KAT-4-r cells demonstrate decreased glycolysis, increased mitochondrial membrane potential and mitochondrial respiration compared to KAT-4 cells whereas such phenomenon is not observed between 8505C and 8505C-r cells. This suggests that some but not all ATC cells gain enhanced mitochondrial biogenesis after prolonged exposure to chemotherapy drug, which may explain the different sensitivities of 8505C-r and KAT-4-r to artesunate. Our work demonstrates that artesunate is a potential addition to the treatment armamentarium for ATC, particularly those with chemoresistance. Our findings also highlight the therapeutic value of targeting mitochondria in chemoresistant ATC.

MicroRNA-18 promotes apoptosis of islet ß-cells via targeting NAV1.

The detailed pathogenesis of diabetes mellitus (DM) remains to be fully elucidated. The purpose of the present study was to explore the role of microRNA (miR)-18 in DM and its underlying mechanisms, providing novel ideas for the treatment of the disease. After inflammatory factor-mediated induction, miR-18 expression in the islet ß-cell line MIN6 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-18 mimics and miR-18 inhibitor were then constructed and transfected into MIN6 cells. The mRNA levels of pro-insulin in MIN6 cells were also detected by RT-qPCR. Released insulin levels and insulin secretion function of MIN6 cells were accessed by ELISA and glucose-stimulated insulin secretion assay, respectively. Apoptosis of MIN6 cells was detected by a terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end labeling assay and western blot analysis of apoptotic proteins. The binding interaction of miR-18 and neuron navigator 1(NAV1), a constituent of the phosphoinositide 3-kinase (PI3K)/AKT pathway, was assessed using a dual-luciferase reporter gene assay. Finally, the regulatory effect of miR-18 on the PI3K/AKT pathway was determined by western blot analysis. After induction of inflammatory factors in MIN6 cells, miR-18 expression was markedly upregulated. Transfection with miR-18 mimics inhibited pro-insulin levels, as well as insulin production and secretion capacity. miR-18 knockdown partially abrogated the inhibited insulin secretion capacity induced by interleukin-1ß (IL-1ß) treatment. In addition, apoptosis of MIN6 cells was increased by miR-18 mimics. The dual-luciferase reporter gene assay confirmed the direct binding of miR-18 to NAV1. Western blot analysis suggested that miR-18 markedly inhibited the PI3K/AKT pathway in MIN6 cells. In conclusion, miR-18 expression is upregulated by IL-1ß induction in islet ß-cells. It was demonstrated that miR-18 promotes apoptosis of islet ß-cells at least partially by inhibiting NAV1 expression and insulin production via suppression of the PI3K/AKT pathway.

Modified Chuanhu anti-gout mixture, a traditional Chinese medicine, protects against potassium oxonate-induced hyperuricemia and renal dysfunction in mice.

OBJECTIVE: Acute gout is a painful, inflammatory arthritis that features a rapidly escalating inflammatory response resulting from the formation of monosodium urate crystals in the affected joint space. Previously, we found that Chuanhu anti-gout mixture (CAGM) had similar effects as colchicine against gout in the clinic. Subsequently, to improve its effectiveness and efficacy, we modified the original formulation of CAGM. The current study evaluated the effectiveness of the modified formulation in mice. METHODS: Potassium oxonate (PO) was used to establish a mouse model of hyperuricemia. Plasma levels of uric acid and creatine were determined using the respective test kits. Hepatic xanthine oxidase (XOD) expression was examined by enzyme-linked immunosorbent assay. To explore the underlying mechanism, renal urate transporter 1 (URAT1) mRNA levels were evaluated by quantitative real-time PCR. Allopurinol and benzbromarone were used as reference drugs. RESULTS: The original CAGM and its modified high-dose formulation significantly reduced serum uric acid and creatine levels in hyperuricemic mice. In addition, the CAGM-treated groups displayed lower mRNA levels of hepatic XOD and renal URAT1. CONCLUSIONS: CAGM and its modified formulation significantly ameliorated PO-induced hyperuricemia in mice, which might be partially attributable to reductions of hepatic XOD and renal URAT1 levels.