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关键词： Chemotherapy   Doxorubicin   Nephrotoxicity   Oxyresveratrol   Dapagliflozin  

摘要： PurposeAmong the most undesirable effects that lead to the restriction of doxorubicin (DOX) use in chemotherapy is kidney damage. This research aimed to assess the possible defenses against DOX-induced nephrotoxicity offered by oxyresveratrol (ORES) and/or dapagliflozin (DAPA).MethodsFive groups of eight male Swiss albino rats each were created from a total of sixty-four. One intravenous injection of DOX (10 mg/kg) was given into the tail vein on the fourteenth day of the experiment;in the meantime, ORES (80 mg/kg) and DAPA (10 mg/kg) were given orally 14 days prior to the DOX injection and 2 days following the DOX *** rats given DOX, ORES and/or DAPA both successfully reduced the kidney weight, kidney/bodyweight ratio, and blood levels of creatinine, uric acid, and urea. They also increased final body weight and albumin serum levels. Additionally, lower serum concentrations of TNF-alpha and IL-6 were noted, along with a lower kidney content of caspase-3. Furthermore, the expression of the Bcl-2 gene was upregulated, as were the Nrf-2, PPAR-gamma, and HO-1 proteins, and there was a downregulation of the ATG-5, Keap-1, and NF-kappa B renal gene expression. These findings support a decrease in oxidative stress and relief of histopathological *** current study's findings suggest that ORES and/or DAPA pretreatment could be a viable therapeutic approach to ameliorate DOX-induced nephrotoxicity.

关键词： nobiletin   IL-4   DO11.10 mice   CD4+cells   GATA 3  

摘要： The polymethoxylated flavonoid nobiletin has been shown to have a broad range of biological functions. We found that nobiletin regulates cytokine production from T cells. In this study, we examined the mechanism for enhancement of IL-4 production by nobiletin. We investigated the key molecules for production of IL-4 by deep data-based analysis and we identified nine candidate genes. The mRNA expression levels of c Maf, Gata-3, Nfat 4, and Pparg genes were significantly elevated by treatment with nobiletin. From RNA sequence analysis, the Thl and Th2 differentiation pathway was shown to be dominantly affected by nobiletin. Furthermore, molecular network analysis showed that GATA-3 is one of the candidate molecules for enhancement of IL-4 production. Treatment of splenocytes including antigen-presenting cells with nobiletin was sufficient for the induction of IL-4 production from DO11.10 mouse CD4+ T cells. Treatment of B cells and dendritic cells with nobiletin induced IL-4 production from CD4+ cells. Splenocytes from DO11.10 mice that had been treated with nobiletin produced more IL-4 than did splenocytes from control mice. These results revealed that the polymethxylated flavonoid nobiletin specifically enhanced IL-4 production in vitro and in vivo.

关键词： bone marrow donor   HLA-C   NGS   novel allele  

摘要： Identification of the HLA-C*01:287, HLA-C*03:710, HLA-C*04:543, HLA-C*08:304 and HLA-C*16:228 alleles and confirmation of HLA-C*02:249, HLA-C*04:532 and HLA-C*03:693.

关键词： Interferon-gamma   Mesenchymal stem cells   N6-methyladenosine modification   Immunosuppression  

摘要： Introduction: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several pro-inflammatory factors to express immunosuppressive molecular profiles, which determines the therapeutic efficacy of MSCs in immune-mediated inflammatory diseases. Of those, interferon-y (IFN-y) is a key inducer for the expression of immunosuppressive molecular profiles;however, the mechanism underlying this effect is unknown. Objectives: To elucidate the regulation mechanism and biological functions of N6-methyladenosine (m6A) modification in the immunosuppressive functions by the IFN-y-licensing MSCs. Methods: Epitranscriptomic microarray analysis and MeRIP-qPCR assay were performed to identify the regulatory effect of WTAP in the IFN-y-licensing MSCs. RIP-qPCR, western blot, qRT-PCR and RNA stability assays were used to determine the regulation of WTAP/m6A/YTHDF1 signaling axis in the expression of immunosuppressive molecules. Further, functional capacity of T cells was tested using flow cytometry, and both DSS-induced colitis mice and CIA mice were constructed to clarify the effect of WTAP and YTHDF1 in MSC-mediated immunosuppression. Results: We identified that IFN-y increased the m6A methylation levels of immunosuppressive molecules, while WTAP deficiency abolished the IFN-y-induced promotion of m6A modification. IFN-y activated ERK signaling, which induced WTAP phosphorylation. Additionally, the stabilization of WTAP post-transcriptionally increased the mRNA expression of immunosuppressive molecules (IDO1, PD-L1, ICAM1, and VCAM1) in an m6A-YTHDF1-dependent manner;this effect further impacted the immuno-suppressive capacity of IFN-y licensing MSCs on activated T cells. Notably, WTAP/YTHDF1 overexpression enhanced the therapeutic efficacy of IFN-y licensing MSCs and restructures the ecology of inflammation in both colitis and arthritis models. Conclusion: Our results showed that m6A modification of IDO1, PD-L1, ICAM1, and VCAM1 mRNA medi-ate