Objective
Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone-marrow mesenchymal stem cells (BMSCs) may have the potential to treat RA. While BMSC-based therapy faces many challenges such as limited cell availability and reduced clinical feasibility, we herein demonstrate that substitution of gingival-derived mesenchymal stem cells (GMSCs) results in significantly improved therapeutic effects on established collagen-induced arthritis (CIA).
Methods
CIA has been induced with the immunization of type II collagen (CII) and CFA in DBA/1J mice. GMSCs were injected i.v. into mice on day 14 after immunization. In some experiments, injection of PC61 (anti-CD25 antibody) i.p. was used to delete Tregs in arthritic mice.
Results
Infusion of GMSCs in DBA/1J mice with CIA significantly decreased the severity of arthritis and pathology scores, and down-regulated inflammatory cytokine (IFN-γ, IL-17A) production. Infusion of GMSCs resulted in an increase in CD4+CD39+Foxp3+ cells in arthritic mice. These increases were noted early in spleen and LN and later in synovial fluid. The increased frequency of Foxp3+ Treg cells consisted of cells that were mainly Helios negative. Infusion of GMSCs partially interfered with the progress of CIA when Treg cells were depleted. Pre-treatment of GMSCs with CD39 or CD73 inhibitor significantly reversed the protective effect of GMSCs on CIA.
Conclusion
The role of GMSCs in controlling CIA pathology mostly depends upon CD39/CD73 signals and partially upon the induction of CD4+CD39+Foxp3+ Treg cells. GMSCs provide a promising approach for the treatment of autoimmune diseases.
BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by an abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and impaired neurogenesis. Urolithin A (UA), a gut-microbial metabolite of ellagic acid, has been reported to exert anti-inflammatory effects in the brain. However, it is unknown whether UA exerts its properties of anti-inflammation and neuronal protection in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD.MethodsMorris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia, Aβ deposition, and neurogenesis. The expression of inflammatory mediators were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The modulating effects of UA on cell signaling pathways were assayed by Western blotting.ResultsWe demonstrated that UA ameliorated cognitive impairment, prevented neuronal apoptosis, and enhanced neurogenesis in APP/PS1 mice. Furthermore, UA attenuated Aβ deposition and peri-plaque microgliosis and astrocytosis in the cortex and hippocampus. We also found that UA affected critical cell signaling pathways, specifically by enhancing cerebral AMPK activation, decreasing the activation of P65NF-κB and P38MAPK, and suppressing Bace1 and APP degradation.ConclusionsOur results indicated that UA imparted cognitive protection by protecting neurons from death and triggering neurogenesis via anti-inflammatory signaling in APP/PS1 mice, suggesting that UA might be a promising therapeutic drug to treat AD.
Metformin improves insulin sensitivity in insulin sensitive tissues such as liver, muscle and fat. However, the functional roles and the underlying mechanism of metformin action in pancreatic β cells remain elusive. Here we show that, under normal growth condition, metformin suppresses MIN6 β cell proliferation and promotes apoptosis via an AMPK-dependent and autophagy-mediated mechanism. On the other hand, metformin protects MIN6 cells against palmitic acid (PA)-induced apoptosis. Our findings indicate that metformin plays a dual role in β cell survival and overdose of this anti-diabetic drug itself may lead to potential β cell toxicity.
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