Background/Aims: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. Methods: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. Results: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. Conclusion: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future.

Dear Editor, We previously designed and synthesized a novel benzimidazole compound, DHW-221. 1 Here, we evaluated its anti-NSCLC activity as a PI3K/mTOR dual-target inhibitor and comprehensively described for the first time the mechanism underlying the PI3K/AKT/mTOR signaling pathwaymediated antitumor effects of DHW-221. Our findings indicated that the antitumor activity of DHW-221 was significantly stronger than that of NVP-BEZ235, a dual PI3K/mTOR inhibitor currently undergoing a phase II clinical trial.The PI3K/AKT/mTOR pathway is a key mediator of receptor tyrosine kinase signal transduction. The PI3K family can be divided into three categories. 2 Class I PI3K and mTOR, sharing structural homology in the kinase domain, 3 are considered important targets for malignancy therapy. 4 Thus, the thought of blocking the PI3K/AKT/mTOR pathway by double inhibition of PI3K/mTOR was proposed. 5 Herein, we systematically elucidated the anti-NSCLC effects associated with DHW-221mediated dual PI3K/mTOR inhibition and identified the mechanism underlying this effect both in vitro and in vivo.First, we identified potential targets of DHW-221. Molecular docking indicated that DHW-221 fitted well into the PI3K-ATP binding pocket and formed hydrogen bonds with Gln859 and Arg770. For mTOR, DHW-221 precisely overlapped with it and formed two more hydrogen bonds (Val2240 and Thr2245) than NVP-BEZ235 (Figure 1A). Docking results with PI3Kβ/γ/δ are shown in Figure S1. Subsequent kinase assay suggested that DHW-221 significantly inhibits the kinase activity of the main PI3K isoforms 1 (IC 50 : PI3Kα,0.5 nM; PI3Kβ,1.9 nM; PI3Kγ,1.8 nM; PI3Kδ,0.74 nM), as well as that of mTOR (IC 50 : 3.9 nM) (Table S1). Cellular thermal shift assay was used to further evaluate the binding mode, the thermal stability of DHW-221 combined with PI3K/mTOR was concentration-dependently enhanced (Figure 1B).

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Background. Hand-foot syndrome (HFS) is a common systemic skin toxicity syndrome caused by chemotherapy agents. However, there is no uniform clinical treatment for HFS. It is reported that pyridoxine (vitamin B6) can be used to prevent HFS, but the evidence is insufficient. Aim. To determine whether pyridoxine can be used to prevent HFS caused by chemotherapy agents. Methods. Literature database searches were performed on PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure. The efficacy of pyridoxine was evaluated by the incidence of HFS (any grade) or severe HFS (grade ≥ 2). Results. Fourteen studies involving 1570 patients were included in this meta-analysis. There were no significant differences between the pyridoxine and control groups in the prevention of HFS (OR = 0.84, 95% CI 0.67-1.05, P = 0.09) or in the incidence of grade ≥ 2 HFS (OR = 0.87, 95% CI 0.70-1.09, P = 0.39, respectively). The subgroup analysis of pyridoxine dose also showed no significant difference between the two groups in preventing HFS grade ≥ 2 (OR = 0.79, 95% CI 0.62-0.99, P = 0.30). Conclusions. We did not find adequate evidence to support the idea that the use of pyridoxine can prevent HFS and reduce the incidence of HFS grade ≥ 2. However, the preventive use of pyridoxine might have a tendency to reduce the incidence of HFS.