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Induction of oral tolerance by vaccination with type 1 diabetes mellitus (T1DM)-associated autoantigens exhibits great potential in preventing and treating this autoimmune disease. However, antigen degradation in the gastrointestinal tract (GIT) limits the delivery efficiency of oral antigens. Previously, bacterium-like particles (BLPs) have been used to deliver a single-chain insulin (SCI-59) analog (BLPs-SCI-59) or the intracellular domain of insulinoma-associated protein 2 (IA-2ic) (BLPs-IA-2ic). Both monovalent BLPs vaccines can suppress T1DM in NOD mice by stimulating the corresponding antigen-specific oral tolerance, respectively. Here, we constructed two bivalent BLPs vaccines which simultaneously deliver SCI-59 and IA-2ic (Bivalent vaccine-mix or Bivalent vaccine-SA), and evaluated whether there is an additive beneficial effect on tolerance induction and suppression of T1DM by treatment with BLPs-delivered bi-autoantigens. Compared to the monovalent BLPs vaccines, oral administration of the Bivalent vaccine-mix could significantly reduce morbidity and mortality in T1DM. Treatment with the bivalent BLPs vaccines (especially Bivalent vaccine-mix) endowed the mice with a stronger ability to regulate blood glucose and protect the integrity and function of pancreatic islets than the monovalent BLPs vaccines treatment. This additive effect of BLPs-delivered bi-autoantigens on T1DM prevention may be related to that SCI-59- and IA-2-specific Th2-like immune responses could be induced, which was more beneficial for the correction of Th1/Th2 imbalance. In addition, more CD4+CD25+Foxp3+ regulatory T cells (Tregs) were induced by treatment with the bivalent BLPs vaccines than did the monovalent BLPs vaccines. Therefore, multiple autoantigens delivered by BLPs maybe a promising strategy to prevent T1DM by efficiently inducing antigen-specific immune tolerance. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a worldwide public health problem. MicroRNAs (miRNAs) have been reported to be associated with GDM progression. We intended to figure out the function of miR-342-3p in the insulin resistance (IR) and liver gluconeogenesis in GDM. GDM mouse models were established by intraperitoneal injection of streptozocin. The expression of miR-342-3p and regulatory factor X3 (Rfx3) in placenta and pancreatic tissues of GDM mice were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). GDM mice were treated with lentivirus-mediated antagomir-miR-342-3p for miR-342-3p downregulation. Enzyme-linked immunosorbent assay, hematoxylin-eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and periodic acid-Schiff staining were conducted to detect the influence of miR-342-3p knockdown on the levels of blood glucose, insulin, biochemical indices as well as the apoptosis and pathological changes in placenta or pancreatic tissues of GDM mice. The binding between Rfx3 and miR-342-3p was validated by dual luciferase reporter assays. miR-342-3p was upregulated and Rfx3 was downregulated in placenta and pancreatic tissues of GDM mice. Moreover, miR-342-3p bound with Rfx3 3'-UTR and therefore downregulated the expression of Rfx3. miR-342-3p expression was negatively correlated to Rfx3 expression in placenta tissues of GDM mice. In addition, miR-342-3p depletion decreased the levels of blood glucose, insulin, biochemical indices as well as restrained the apoptosis and pathological changes in GDM mouse placenta and pancreatic tissues. Furthermore, Rfx3 silencing countervailed the alleviative influence of miR-342-3p downregulation on IR and liver gluconeogenesis in GDM mice. Collectively, downregulation of miRNA-342-3p inhibits IR and liver gluconeogenesis in GDM by upregulating Rfx3, which may provide novel insight for GDM treatment.