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Objective: To investigate the effect of interleukin-12 (IL-12) on liver lesions and oxidative stress pathway in Sjogren's syndrome mice, and to clarify the possible mechanism of liver lesions in Sjogren's syndrome. Methods: Saliva flow rate, liver function, liver pathology and IL-12 level were measured in NOD, IL-12 knockout (IL-12KO) NOD and C57BL/6 (B6) mice. Different concentrations of IL-12 and JAK2, TYK2 inhibitors were applied to mouse hepatoma cells. The oxidative stress index of mouse serum and cell culture supernatants of each group were determined. Results: Compared with the other two groups of mice, the NOD mice had significantly higher GOT and GPT (P<0.05), and decreased serum GSH-PX, SOD and CAT(P<0.05). CAT, GSH, GSH-PX and SOD were decreased, while MDA was increased in mice treated with different concentrations of IL-12. JAK2/TYK2 inhibitors reversed regulatory effects of IL-12 on SOD, GSH and MDA in hepatoma cells (P<0.05). Conclusion: IL-12 may aggravated liver damage of Sjögren's syndrome through promoting oxidative stress of hepatocytes. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to investigate the effect of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) on diabetic retinopathy (DR) and its underlying mechanism. Methods In vivo, MSC-sEVs were injected intravitreally into diabetic rats to determine the therapeutic efficacy. In vitro, MSC-sEVs with/without miR-22-3p inhibition were cocultured with advanced glycation end-products (AGEs)-induced microglia with/without NLRP3 overexpression to explore the molecular mechanism. Results In vivo, MSC-sEVs inhibited NLRP3 inflammasome activation, suppressed microglial activation, decreased inflammatory cytokines levels in the retina, and alleviated DR as evidenced by improved histological morphology and blood-retinal barrier function. Based on miRNA sequencing of MSC-sEVs, bioinformatic software, and dual-luciferase reporter assay, miR-22-3p stood out as the critical molecule for the role of MSC-sEVs in regulating NLRP3 inflammasome activation. Diabetic rats had lower level of miR-22-3p in their retina than those of control and sEV-treated rats. Confocal microscopy revealed that sEV could be internalized by microglia both in vivo and in vitro. In vitro, compared with sEV, the anti-inflammation effect of sEVmiR-22-3p(−) on AGEs-induced microglia was compromised, as they gave a lower suppression of NLRP3 inflammasome activation and inflammatory cytokines. In addition, NLRP3 overexpression in microglia damped the anti-inflammatory effect of sEV. Conclusion These results indicated that MSC-sEVs alleviated DR via delivering miR-22-3p to inhibit NLRP3 inflammasome activation. Our findings indicate that MSC-sEVs might be a potential therapeutic method for DR. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the novel key genes and biological processes that may lead to primary Sjögren' s syndrome (pSS). Methods: We downloaded datasets about peripheral blood samples of pSS patients and healthy controls (GSE51092, GSE84844, and GSE66795) from Gene Expression Omnibus database. The weighted co‐expression network analysis and differential expression analysis first were implemented. After that, protein–protein network interaction and Support Vector Machines were applied in the meantime to take intersection for key genes. Moreover, we conducted immune cell infiltration analysis to explore the relationship between the gene expression and concentration of immune cells in peripheral blood. Lastly, the expression of key genes was verified in pSS patients and murine models by reverse‐transcription polymerase chain reaction. Meanwhile, correlation analysis of gene expression and disease activity was also performed. Results: Only 1 key gene, interferon induced with helicase c domain 1 (IFIH1), was identified to be both significantly up‐regulated and important for the diagnosis of pSS. The increased expression of IFIH1 in peripheral blood was confirmed in data sets, patients and non‐obese diabetic (NOD) mice. Its expression was correlated with disease activity in patients as well. In addition, the IFIH1 expression was also increased in spleen and salivary glands infiltrated with lymphocytes in NOD mice. Furthermore, immune cell infiltration analysis showed that the expression of IFIH1 was positively correlated with the proportion of memory B cells and activated dendritic cells, and negatively correlated with the proportion of macrophage M0. Conclusions: Here, bioinformatics analyses and experimental assays were performed to provide a new insight for understanding of pSS. IFIH1 may be a new diagnostic marker or therapeutic target for pSS. [ABSTRACT FROM AUTHOR]

Emerging studies have reported the expansion of myeloid‐derived suppressor cells (MDSCs) in some autoimmune disorders, such as systemic lupus erythematosus (SLE), but the detailed molecular mechanisms of the aberrant expansion in SLE are still unclear. In the present study, we confirmed that the increased MDSCs positively correlated with disease activity in SLE patients. The suppressive capacity of MDSCs from patients with high activity was lower than that of MDSCs from patients with low activity. Moreover, the potential precursors for MDSCs, common myeloid progenitors (CMPs) and granulocyte–monocyte progenitors (GMPs), were markedly increased in the bone marrow (BM) aspirates of SLE patients. As an important regulator of cell fate decisions, aberrant activation of Notch signalling was reported to participate in the pathogenesis of SLE. We found that the expression of Notch1 and its downstream target gene hairy and enhancer of split 1 (Hes‐1) increased markedly in GMPs from SLE patients. Moreover, the Notch1 signalling inhibitor DAPT profoundly relieved disease progression and decreased the proportion of MDSCs in pristane‐induced lupus mice. The frequency of GMPs was also decreased significantly in lupus mice after DAPT treatment. Furthermore, the inhibition of Notch1 signalling could limit the differentiation of MDSCs in vitro. The therapeutic effect of DAPT was also verified in Toll‐like receptor 7 (TLR7) agonist‐induced lupus mice. Taken together, our results demonstrated that Notch1 signalling played a crucial role in MDSC differentiation in SLE. These findings will provide a promising therapy for the treatment of SLE. [ABSTRACT FROM AUTHOR]