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Background: Centromere protein U (CENP-U) is a component of the kinetochore and can regulate the cell cycle as a receptor of polo-like kinase 1 (PLK1). Recent studies have partially identified the role of CENP-U in tumor progression, but the underlying mechanisms of CENP-U in tumor immunity remain obscure. Methods: We performed pan-cancer analysis to evaluate the role of CENP-U in immunity and proliferation with data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE) datasets, and Genotype-Tissue Expression (GTEx) project. Results of CENP-U expression and related clinicopathological data were obtained to show the expression levels, prognosis, tumor progression, immune neoantigens, and immune checkpoints of CENP-U in 33 tumors. The Tumor Immune Estimation Resource (TIMER) dataset was used to analyze immune infiltration scores.Results: Results of the pan-cancer analysis demonstrated that CENP-U is differentially expressed in normal tissues and common tumor tissues. Moreover, differentially expressed CENP-U was also identified between matched normal and tumor tissues, and the high expression level of CENP-U was associated with poor prognosis for 33 kinds of tumor except for that of thymoma (THYM) and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC). Furthermore, the correlation between CENP-U expression and immune checkpoints and immune neoantigens was determined. In addition, CENP-U expression was correlated with tumor-infiltrating immune cells especially in THYM but not in lung squamous cell carcinoma (LUSC), esophageal carcinoma (ESCA), or lung adenocarcinoma (LUAD). Finally, gene set enrichment analysis (GSEA) indicated that CENP-U is critically involved in tumor proliferation, immunity, and metabolism.Conclusions: CENP-U, a mitosis-related kinase, was found to be differentially expressed across different cancer types and to play an important role in tumor progression and immunity. CENP-U holds the potential to be a prognostic marker, whose targeting may provide therapeutic benefit.

Mechanical allodynia, which develops in patients of diabetes mellitus as a neuropathic manifestation, remains without an effective treatment. The aim of the present study was to investigate the effects and potential mechanisms underlying resveratrol (reS) in a rat model of streptozocin (STZ)-induced diabetic mechanical allodynia (dMa). The rat model of dMa was established by the administration of an intraperitoneal injection of STZ. From day 8 post-STZ injection, rats were administered with an intragastric injection of various doses of RES for 14 consecutive days. The von Frey filaments were applied to detect the paw withdrawal threshold and evaluate the analgesic effects of reS. Based on the dose-effect curve, the ed 50 of RES was calculated. Immunofluorescence staining and western blotting were performed to detect the expression of purinergic receptor P2X3 (P2X3r) in the dorsal root ganglion (drG) and spinal dorsal horn (SdH) following reS ed50 treatment. The results indicated that reS significantly alleviated mechanical allodynia in dMa model rats in a dose-dependent manner. compared with the control group, the expression of P2X3r in drG neurons and SdH terminals was markedly decreased following the administration of reS ed50 (P<0.05). collectively, the results indicated that reS displayed a dose-dependent analgesic effect on dMa model rats. Furthermore, P2X3r expression downregulation in the drG and SdH may be a mechanism underlying the analgesic effects of reS on dMa-related behaviors.

Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox‐induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox‐induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol‐requiring enzyme 1α (IRE1α)/spliced X‐box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox‐treated hearts. CaMKII inhibition with KN‐93 ameliorated Dox‐induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox‐induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox‐treated hearts. The IRE1α inhibitor 4μ8C blocked the protective effect of CaMKII inhibition against Dox‐induced cardiotoxicity. Mechanistically, 4μ8C prevented the effects of CaMKII inhibition on Dox‐induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox‐treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13‐TSP1 axis regulates CaMKII activation and exacerbates Dox‐induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.

AIM: To investigate the expression and effect of histone deacetylase 7 (HDAC7) in human retinal microvascular endothelial cells (HRMECs) under high glucose condition and related mechanism, and the expression of HDAC7 in the retinal tissue in diabetic rats. METHODS: The expression of HDAC7 in HRMECs under high glucose and the retinal tissue from normal or diabetic rats were detected with immunohistochemistry and Western blot. LV-shHDAC7 HRMECs were used to study the effect of HDAC7 on cell activities. Cell count kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), flow cytometry, scratch test, Transwell test and tube formation assay were used to examine the ability of cell proliferation, migration, and angiogenesis. Finally, a preliminary exploration of its mechanism was performed by Western blot. RESULTS: The expression of HDAC7 was both up-regulated in retinal tissues of diabetic rats and high glucose-treated HRMECs. Down-regulation of HDAC7 expression significantly reduced the ability of proliferation, migration, and tube formation, and reversed the high glucose-induced high expression of CDK1/Cyclin B1 and vascular endothelial growth factor in high glucose-treated HRMECs. CONCLUSION: High glucose can up-regulate the expression of HDAC7 in HRMECs. Down-regulation of HDAC7 can inhibit HRMECs activities. HDAC7 is proposed to be involved in pathogenesis of diabetic retinopathy and a therapeutic target.