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Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. In vivo, MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous hematologic malignancy. Chemotherapy resistance and refractory relapses are the most important challenges in T-ALL. PI3K/Akt/mTOR pathway has been implicated in regulating cell survival, T-ALL development and resistance to chemotherapy. We explored the effects of AZD5363 (a potent pan-Akt inhibitor) alone and in combination with autophagy inhibitor hydroxycholoroquine sulfate (HCQ) in cultured CCRF-CEM, Jurkat and PF382 cells and a T-ALL xenograft mouse model., Methods: A xenograft mouse model was used to investigate the effect of AZD5363 on T-ALL progression. MTT assay, flow cytometry, siRNA, transmission electron microscopy and western blotting were performed in cultured CCRF-CEM, Jurkat and PF382 cells. The interaction between AZD5363 and HCQ was explored by molecular docking., Results: AZD5363 delayed T-ALL progression and increased the expression of cleaved caspase-3 and LC3B-II in mice. AZD5363 decreased cells viability by arresting cell cycle in the G1 phase and inducing apoptosis, and, significantly increased the number of autophagosomes (p < 0.01). The increased expression of cleaved caspase-3 and LC3B-II, and phosphorylation of Akt and mTOR were significantly, inhibited by AZD5363. HCQ blocked AZD5363-induced autophagy and enhanced AZD5363-induced cell death (p < 0.01)., Conclusions: AZD5363 suppressed T-ALL progression and its anti-leukemia activity was enhanced by HCQ in T-ALL cells, which might provide a potential therapeutic strategy for human T-ALL., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

T-cell acute lymphocytic leukemia (T-ALL) is the most common cancer in children, with a low survival rate because of drug resistance and a high recurrence rate. Targeted delivery of chemotherapy drugs can reduce their side effects and improve their efficacy. The abnormality of phosphatidylinositol-3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway plays a key role in T-ALL occurrence. AZD5363 is a selective Akt inhibitor with promising therapeutic potential for tumors encoded by the PI3K/Akt/mTOR pathway. However, the toxicity and side effects have limited its application in treating T-ALL. This study aimed to design a delivery system for targeting AZD5363 to T-ALL by sgc8c aptamer designed as mesoporous silica (mSiO 2 ) decorated with Au nanoparticles. The cell-specific targeting and cytotoxicity of mSiO 2 -Au-AZD5363-Apt were investigated. The mSiO 2 -Au nanovehicles were found feasible for AZD5363 delivery, with high loading efficiency and pH-responsive release in the acidic lysosome. More importantly, mSiO 2 -Au-AZD5363-Apt nanovehicles could specifically recognize and enter T-ALL cells in vitro and in vivo, effectively inhibiting the proliferation of CCRF-CEM cells. In conclusion, mSiO 2 -Au-AZD5363-Apt provided an effective therapeutic method for the targeted treatment of T-ALL., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The pathogenic mechanisms underlying the autonomic nervous system (ANS) dysfunction in patients with chronic migraine (CM) remain unclear. This study investigated the pathogenesis of ANS dysfunction in this population., Methods: A total of 60 patients diagnosed with CM and 60 healthy subjects were recruited to participate in this study. The pupil diameter, pupil contraction velocity, latency, amplitude, and the maximum gradient recovery time were examined before, at 2 min and at 5 min after the cold pressor test, which was combined with the pupillary light reflex method. A brain 3D T1-weighted structural imaging scan, resting-state functional magnetic resonance imaging scan, and diffusion tensor imaging (DTI) scan were also acquired., Results: Patients with CM exhibited a longer recovery time to the maximum gradient at 2 min and at 5 min after cold pressing compared with the control group ( P < 0.01 and P < 0.05, respectively). There was no significant difference in the pupil diameter, pupillary contraction velocity, latency, amplitude, blood pressure, or heart rate between the two groups (all P > 0.05). In the CM group, the regional homogeneity (ReHo) values of the left amygdala and left lateral hypothalamic area were significantly higher than those of other brain areas ( P < 0.001, Alphasim corrected). The DTI scan of the whole brain area showed a lack of significant difference in DTI indices, including FA, MD, AD, and RD values between the two groups ( P > 0.05, Alphasim corrected)., Conclusion: The dysfunction of the left amygdala and left lateral hypothalamic area may be related to ANS dysfunction in patients with CM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Luo, Guo, Yang, Li and Zhao.)

Background: It must be admitted that the incidence of colorectal cancer (CRC) was on the rise all over the world, but the related treatment had not caught up. Further research on the underlying pathogenesis of CRC was conducive to improving the survival status of current CRC patients., Methods: Differentially expressed genes (DEGs) screening were conducted based on "limma" and "RobustRankAggreg" package of R software. Weighted gene co-expression network analysis (WGCNA) was performed in the integrated DEGs that from The Cancer Genome Atlas (TCGA), and all samples of validation were from Gene Expression Omnlbus (GEO) dataset., Results: The terms obtained in the functional annotation for primary DEGs indicated that they were associated with CRC. The MEyellow stand out whereby showed the significant correlation with clinical feature (disease), and 4 hub genes, including ABCC13, AMPD1, SCNN1B and TMIGD1, were identified in yellow module. Nine datasets from Gene Expression Omnibus database confirmed these four genes were significantly down-regulated and the survival estimates for the low-expression group of these genes were lower than for the high-expression group in Kaplan-Meier survival analysis section. MEXPRESS suggested that down-regulation of some top hub genes may be caused by hypermethylation. Receiver operating characteristic curves indicated that these genes had certain diagnostic efficacy. Moreover, tumor-infiltrating immune cells and gene set enrichment analysis for hub genes suggested that there were some associations between these genes and the pathogenesis of CRC., Conclusion: This study identified modules that were significantly associated with CRC, four novel hub genes, and further analysis of these genes. This may provide a little new insights and directions into the potential pathogenesis of CRC., (© 2022. The Author(s).)

Background: Lithium carbonate (Li 2 CO 3 ) is widely used in the treatment of clinical-affective psychosis. Exposure to Li 2 CO 3 during pregnancy increases the risk of neural tube defects (NTDs) in offspring, which are severe birth defects of the central nervous system. The mechanism of Li 2 CO 3 -induced NTDs remains unclear., Methods: C57BL/6 mice were injected with different doses of Li 2 CO 3 intraperitoneally on gestational day 7.5 (GD7.5), and embryos collected at GD11.5 and GD13.5. The mechanisms of Li 2 CO 3 exposure-induced NTDs were determined utilizing immunohistochemistry, western blotting, EdU imaging, enzymatic method, gas chromatography-mass spectrometry (GC-MS), ELISA and HE staining., Results: The NTDs incidence was 33.7% following Li 2 CO 3 exposure. Neuroepithelial cell proliferation and phosphohistone H3 level were significantly increased in NTDs embryos, compared with control group (P < 0.01), while the expressing levels of p53 and caspase-3 were significantly decreased. IMPase and GSK-3β activity was inhibited in Li 2 CO 3 -treated maternal and embryonic neural tissues (P < 0.01 and P < 0.05, respectively), along with decreased levels of inositol and metabolites, compared with control groups (P < 0.01)., Conclusions: Lithium-induced NTDs model in C57BL/6 mice was established. Enhanced cell proliferation and decreased apoptosis following lithium exposure were closely associated with the impairment of inositol biosynthesis, which may contribute to lithium-induced NTDs., Impact: Impairment of inositol biosynthesis has an important role in lithium exposure-induced NTDs in mice model. Lithium-induced NTDs model on C57BL/6 mice was established. Based on this NTDs model, lithium-induced impairment of inositol biosynthesis resulted in the imbalance between cell proliferation and apoptosis, which may contribute to lithium-induced NTDs. Providing evidence to further understand the molecular mechanisms of lithium-induced NTDs and enhancing its primary prevention., (© 2020. International Pediatric Research Foundation, Inc.)