Dopamine D2 receptor on CD4+ T cells is protective against inflammatory responses and signs in a mouse model of rheumatoid arthritis.

BACKGROUND: Dopamine is a neurotransmitter and has been found to regulate lymphocytes by acting on dopamine receptors (DRs). CD4+ T cells express all the five subtypes of DRs, D1R to D5R. Although CD4+ T cells have been involved in pathogenesis of rheumatoid arthritis (RA), roles of DRs expressed on these cells in RA are poorly understood. This study determined whether D2R expressed on CD4+ T cells regulates inflammatory responses and signs in collagen type II (CII)-induced arthritis (CIA), a mouse model of RA. METHODS: DBA/1 mice and C57BL/6 mice with global D1r or D2r deficiency (D1r-/- or D2r-/-) or CD4+ T cell-specific D2r deletion (D2rfl/fl/CD4Cre) were used to prepare CIA model by intradermal injection of CII. D2R agonist sumanirole was intraperitoneally administered in CIA mice. CD4+ T cells obtained from CIA mice were exposed to sumanirole or/and D2R antagonist L-741,626 in vitro. Arthritic symptoms were assessed by clinical arthritis scores. Flow cytometric assay measured frequencies of CD4+ T cell subsets (Th1, Th2, Th17 and Treg cells). Expression of specific transcription factors for the CD4+ T cell subsets was tested by Western blot. Cytokine production was estimated by quantitative PCR and ELISA. RESULTS: CIA mice manifested a bias of CD4+ T cells towards Th1 and Th17 cells. D2r-/- CIA mice showed a stronger bias towards Th1 and Th17 phenotypes than CIA mice, while D1r-/- CIA mice did not show the changes. CD4+ T cell-specific D2r deletion exacerbated both the polarization towards Th1 and Th17 cells and the symptoms of arthritis. Sumanirole administration in CIA mice ameliorated the bias of CD4+ T cells towards Th1 and Th17 phenotypes as well as arthritic symptoms. Sumanirole treatment of in vitro CD4+ T cells obtained from CIA mice promoted the shift to Treg cells, and the effect of sumanirole was blocked by L-741,626. CONCLUSIONS: D2R expressed on CD4+ T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA.

Xiaoaiping injection combined with chemotherapy for advanced gastric cancer: An updated systematic review and meta-analysis.

Aim: To evaluate the clinical efficacy and safety of Xiaoaiping injection combined with chemotherapy in the treatment of advanced gastric cancer by meta-analysis. Methods: Seven databases, including China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, Cochrane Library, PubMed, Embase, and Web of Science, were searched by computer for randomized controlled clinical trials of Xiaoaiping injection combined with chemotherapy in the treatment of gastric cancer. Risk of bias assessment and meta-analysis were performed by Review Manager 5.3 software. Results: There were 16 articles that met the inclusion criteria, with a total of 1,236 patients, 617 in the observation group and 619 in the control group. The results of meta-analysis showed that the observation group was better than chemotherapy alone control group in RR [OR = 1.86, p < 0.00001]; disease control rate (DCR) [OR = 2.45, p < 0.00001]; Karnofsky performance status (KPS) score [OR = 3.21, p < 0.00001] or [MD = 7.73, p = 0.001]. In terms of biochemical indicators, Xiaoaiping significantly reduced inflammation factors level, including tumor necrosis factor alpha (TNF-α) [MD = -15.00, p < 0.00001]; interleukin-6 (IL-6) [MD = -13.00, p < 0.00001]; C-reaction protein (CRP) [MD = -5.80, p < 0.00001]. Xiaoaiping could enhance immune function, significantly reducing myeloid-derived suppressor cells (MDSCs) [MD = -6.20, p < 0.00001] and Treg [MD = -1.70, p < 0.00001]. Xiaoaiping injection combined with chemotherapy could significantly decrease tumor markers, including carcinoembryonic antigen (CEA) [MD = -11.64, p < 0.00001]; CA199 [MD = -33.57, p = 0.02]; CA242 [MD = -20.66, p < 0.00001]; CA125 [MD = -12.50, p = 0.0005]. In the comparison of adverse reactions, the incidence rate of Xiaoaiping injection group was significantly lower than that of control group. The funnel plot showed that the left and right sides are basically symmetrical, and it can be considered that there is no obvious publication bias. Conclusion: Xiaoaiping injection combined with chemotherapy has better curative effect and less adverse reactions in the treatment of gastric cancer. However, limited by the quality of the included studies, more high-quality studies are still needed to be verified. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022353842], identifier [CRD42022353842].

Efficacy of gecko polysaccharide on suppressed immune response induced by cyclophosphamide in mice.

OBJECTIVE: To evaluate the efficacy of gecko polysaccharide on the cyclophosphamide-induced suppressed immune response in mice. METHODS: Polysaccharides were extracted from fresh gecko for the first time using an orthogonal method and protein was removed using Sevag reagent (chloroform:N-butanol, 5:1, v/v). The gecko polysaccharide (GPCE) content was determined by the phenol-concentrated sulfuric acid method. An immunocompromised mouse model was established by intraperitoneally injecting cyclophosphamide at 100 mg/kg into 48 mice. The effects of GPCE on immune regulation in mice were assessed by a thymus-spleen index, serum hemolysin levels, and the proliferation of splenic lymphocytes. Spleen cell CD4+, CD8+, and the CD4+/CD8+ ratio were evaluated by flow cytometry and the tumor necrosis factor-α (TNF-α) levels were measured by ELISA. RESULTS: The optimal extraction process for gecko polysaccharide included a 1:20 ratio of material to liquid (v/v), an extraction temperature of 60 ℃ and a time of 2 h. The polysaccharide content of the extract was 65.74%. GPCE was analyzed by HPLC and primarily contained glucose and small amounts of mannose, rha, and gal. Compared with the model, the thymus index, the spleen index were indices for GPCE increased with dose, whereas the high and medium groups exhibited significant differences (P < 0.05, P < 0.01). Higher doses of GPCE increased serum TNF-α levels and there was a significant difference between the medium and high GPCE doses and the model (P < 0.05, P < 0.01); The number of CD4+ cells and the CD4+/CD8+ ratio in the gecko polysaccharide group were increased (P < 0.05) and there was no statistical difference in the number of CD8+ cells in the gecko polysaccharide group (P > 0.05); The high GPCE dose significantly increased the level of serum hemolysin (P < 0.01). CONCLUSIONS: Gecko polysaccharide significantly improved the suppressed immune response induced by cyclophosphamide in mice and promoted the secretion of tumor necrosis factor. The mechanism of gecko polysaccharide as an antitumor agent warrants further study.