Sirtuin 3 (SIRT3), a mitochondrial protein, is involved in energy metabolism, cell apoptosis and mitochondrial function. However, the role of SIRT3 in neural stem cells (NSCs) remains unknown. In previous studies, we found that microglia activation-induced cytotoxicity negatively regulated survival of NSCs, along with mitochondrial dysfunction. The aim of this study was to investigate the potential neuroprotective effects of SIRT3 on the microglia activation-induced oxidative stress injury in NSCs and its possible mechanisms. In the present study, microglia-NSCs co-culture system was used to demonstrate the crosstalk between both cell types. The cytotoxicity of microglia activation by Amyloid-β (Aβ) resulted in the accumulation of reactive oxygen species (ROS) and down-regulation of SIRT3, manganese superoxide dismutase (MnSOD) gene expression in NSCs, concomitant to cell cycle arrest at G0/G1 phase, increased cell apoptosis rate and opening of the mitochondrial permeability transition pore (mPTP) and enhanced mitochondrial membrane potential (ΔΨm) depolarization. Furthermore, SIRT3 knockdown in NSCs via small interfering RNA (siRNA) accelerated cell injury, whereas SIRT3 overexpression provided resistance to microglia activation-induced oxidative stress cellular damage. The mechanisms of SIRT3 attenuated activated microglia-induced NSC dysfunction included the decreased mPTP opening and cyclophilin D (CypD) protein expression, inhibition of mitochondrial cytochrome C (Cyt C) release to cytoplasm, declined Bax/B-cell lymphoma 2 (Bcl-2) ratio and reduced caspase-3/9 activity. Taken together, these data imply that SIRT3 ameliorates microglia activation-induced oxidative stress injury through mitochondrial apoptosis pathway in NSCs, these results may provide a novel intervention target for NSC survival.

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Objective To assess the long-term cost effectiveness of dapagliflozin (DAPA) and saxagliptin (SAXA) separately or together in patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin (MET). Methods Five head-to-head randomised controlled trials of the efficacy of DAPA and SAXA in type 2 diabetes mellitus (T2DM) patients were found by searching PubMed, Embase and Cochrane from inception to October 2019. The lifetime disease progression and long-term effectiveness of therapy in patients were projected by the United Kingdom Prospective Diabetes Study Outcome Model 2 (UKPDS OM2) in three T2DM therapeutic groups: DAPA + SAXA, DAPA and SAXA. Each group used DAPA and/or SAXA as an add-on therapy to MET. The study took the perspective of Chinese healthcare service providers. Univariate, scenario and probabilistic sensitivity analyses were performed. Results The quality-adjusted life-years (QALYs) value of the DAPA + SAXA, SAXA and DAPA groups were 11.28, 11.26 and 11.45 years, respectively. The total costs were US$27,954.84, US$23,254.46 and US$25,608.49, respectively. DAPA was dominant over DAPA + SAXA. The DAPA + SAXA group presented an estimated QALY gain of 0.02 and a total cost increase of US$4700.39 over the SAXA group, with an incremental cost of US$217,530.10 per QALY. Compared with the SAXA group, the DAPA group had a QALY gain of 0.19 years and a total cost increase of US$2354.04, for an incremental cost of US$12,191.97 per QALY. The pharmacoeconomic results were robust to univariate, scenario and probabilistic sensitivity analyses. Conclusions Compared with DAPA + SAXA or SAXA, DAPA appears to be a cost-effective therapy as add-on to MET for Chinese patients whose T2DM is insufficiently controlled by MET. Shanshan Hu and Xun Deng contributed equally to this work.