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Norisoboldine (NOR), a natural aryl hydrocarbon receptor (AhR) agonist, has been demonstrated to attenuate ulcerative colitis (UC) and induce the generation of Treg cells. Under UC condition, hypoxia widely exists in colonic mucosa, and secondary changes of microRNAs (miRs) expressions and glycolysis contribute to Treg differentiation. At present, we worked for exploring the deep mechanisms for NOR-promoted Treg differentiation in hypoxia and its subsequent anti-UC action from the angle of AhR/miR or AhR/glycolysis axis. Results showed that NOR promoted Treg differentiation in hypoxia and the effect was stronger relative to normoxia. It activated AhR in CD4+ T cells under hypoxic microenvironment; CH223191 (a specific AhR antagonist) and siAhR-3 abolished NOR-promoted Treg differentiation. Furthermore, the progress of glycolysis, levels of Glut1 and HK2, and expression of miR-31 rather than miR-219 and miR-490 in CD4+ T cells were downregulated by NOR treatment under hypoxic microenvironment. However, HK2 plasmid but not miR-31 mimic significantly interfered NOR-enhanced Treg polarization. In addition, NOR reduced NAD+ and SIRT1 levels, facilitated the ubiquitin-proteasomal degradation of SUV39H1 protein, and inhibited the enrichment of H3K9me3 at −1, 201 to −1,500 region of Foxp3 promoter in CD4+ T cells under hypoxic microenvironment, which was weakened by HK2 plasmid, CH223191, and siAhR-3. Finally, the correlation between NOR-mediated activation of AhR, repression of glycolysis, regulation of NAD+/SIRT1/SUV39H1/H3K9me3 signals, induction of Treg cells, and remission of colitis was confirmed in mice with DSS-induced colitis by using CH223191 and HK2 plasmid. In conclusion, NOR promoted Treg differentiation and then alleviated the development of colitis by regulating AhR/glycolysis axis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway.

Alpinetin, a flavonoid compound extracted from the seeds of Alpinia katsumadai Hayata, has been demonstrated to exert massive biological properties. This study aimed to evaluate the effect of alpinetin on dextran sulfate sodium (DSS)-induced colitis, and elucidate the potential mechanisms. Alpinetin significantly alleviated colitis in mice, accompanied with restored Th17/Treg balance in colons. In vitro, alpinetin directly promoted Treg differentiation but exerted little effect on Th17 differentiation, and the action was in an aryl hydrocarbon receptor (AhR)-dependent manner. It acted as a potential AhR activator, evidenced by increased expression of CYP1A1, dissociation of AhR/HSP90 complexes, AhR nuclear translocation, XRE-driven luciferase reporter gene and DNA-binding activity of AhR/ARNT/XRE in T cells. Furthermore, alpinetin significantly promoted expression of miR-302 but not others, and restrained expression of DNMT-1 and methylation level of Foxp3 promoter region in CD4+ T cells and colons of colitis mice. However, the association of CREB and Foxp3 promoter region but not expression, nuclear translocation and DNA-binding activity of CREB was up-regulated by alpinetin in CD4+ T cells. The relationship of alpinetin-adjusted AhR activation, expressions of miR-302 and DNMT-1, association of CREB and Foxp3 promoter region, and Treg differentiation was confirmed by using CH223191, siAhR, miR-302 inhibitor and pcDNA3.1(+)-mDNMT-1. Finally, CH223191 abolished the amelioration of alpinetin on colitis, induction of Treg cells and regulation of miR-302/DNMT-1/CREB signals in colons of colitis mice. In conclusion, alpinetin ameliorated colitis in mice via activating AhR, regulating miR-302/DNMT-1/CREB signals, therefore promoting Treg differentiation.

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PurposeRadiation therapy (RT) induces an immune response, but the relationship of this response with tumor type is not fully understood. This meta-analysis further elucidated this relationship by analyzing the changes in T lymphocyte subsets in different tumors before and after radiotherapy.MethodsWe searched English-language electronic databases including PubMed, EMBASE, and the Cochrane Library to collect studies on the changes in peripheral blood CD3+ T lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes before and after radiotherapy in tumor patients from January 2015 to April 2021. The quality of the included literature was evaluated using the NOS scale provided by the Cochrane Collaboration, and statistical software RevMan 5.4 was used to analyze the included literature. P<0.05 was considered to indicate statistical significance.ResultsA total of 19 studies in 16 articles involving 877 tumor patients were included. All data were collected within 1 month before or after radiotherapy. Meta-analysis showed that numbers of CD3+ T lymphocytes (SMD: -0.40; 95% CI [-0.75, -0.04]; p = 0.03) and CD4+ T lymphocytes (SMD: -0.43; 95% CI: [-0.85, -0.02]; p = 0.04) were significantly reduced after radiotherapy compared with before treatment, but there was no statistically significant difference for CD8+ T lymphocytes (SMD: 0.33; 95% CI: [-0.88, 0.74]; p = 0.12). Subgroup analysis showed that peripheral blood T lymphocytes decreased in head and neck cancer. However, in prostate cancer and breast cancer, there was no significant change in peripheral blood. 1 month after radiotherapy, it has a potential proliferation and activation effect on lymphocytes in esophageal cancer and lung cancer. The results showed that CD8+T lymphocytes increased in peripheral blood after SBRT. Radiotherapy alone reduced CD3+ T lymphocyte numbers.ConclusionsWithin 1 month of radiotherapy, patients have obvious immunological changes, which can cause apoptosis and reduction of T lymphocytes, and affect the balance of peripheral blood immune cells. The degree of immune response induced by radiotherapy differed between tumor types.