RESUMEN
Monocytes are key effectors in autoimmunity-related diseases in the central nervous system (CNS) due to the critical roles of these cells in the production of proinflammatory cytokines, differentiation of T-helper (Th) cells, and antigen presentation. The JAK-STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines signaling. However, the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis (MS) is unclear. Here, we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis (EAE), a model for MS. JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6Chi monocytes and monocyte-derived dendritic cells in EAE mice. In parallel, the proportion of GM-CSF+CD4+ T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition, which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue damage. Together, our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes.
RESUMEN
Tolerogenic dendritic cells (tolDCs) facilitate the suppression of autoimmune responses by differentiating regulatory T cells (Treg). The dysfunction of immunotolerance results in the development of autoimmune diseases, such as rheumatoid arthritis (RA). As multipotent progenitor cells, mesenchymal stem cells (MSCs), can regulate dendritic cells (DCs) to restore their immunosuppressive function and prevent disease development. However, the underlying mechanisms of MSCs in regulating DCs still need to be better defined. Simultaneously, the delivery system for MSCs also influences their function. Herein, MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ, maximizing efficacy in vivo. The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines. In the collagen-induced arthritis (CIA) mice model, alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39+CD73+ on MSCs. These enzymes hydrolyze ATP to adenosine and activate A2A/2B receptors on immature DCs, further promoting the phenotypic transformation of DCs to tolDCs and regulating naïve T cells to Tregs. Therefore, encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression. This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.
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Eight new C-diterpenoid alkaloid arabinosides, named aconicarmichosides E-L (-), were isolated from an aqueous extract of the lateral roots of (Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds -, together with the previously reported four neoline 14--arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0 mg/kg (i.p.), as compared with the black control, compounds , , and - exhibited analgesic effects with >65.6% inhibitions against acetic acid-induced writhing of mice. Structure-activity relationship was also discussed.
RESUMEN
Chronic inflammatory response often involves in the progression of disease in all organ system.While inflammation has been a highlight topic of study in many decades for patho-genesis or identifying drug targets to disease-associated inflam-mation.In this paper,the main fundamental research areas of projects funded by NSFC on inflammation during 2010 ~2015 are reviewed.The features and research types of projects are an-alyzed.
RESUMEN
Amyloid beta-peptides (Aβ) are known to undergo active transport across the blood-brain barrier, and cerebral amyloid angiopathy has been shown to be a prominent feature in the majority of Alzheimer׳s disease. Quercetin is a natural flavonoid molecule and has been demonstrated to have potent neuroprotective effects, but its protective effect on endothelial cells under Aβ-damaged condition is unclear. In the present study, the protective effects of quercetin on brain microvascular endothelial cells injured by fibrillar Aβ 1-40 (fAβ 1-40) were observed. The results show that fAβ 1-40-induced cytotoxicity in human brain microvascular endothelial cells (hBMECs) can be relieved by quercetin treatment. Quercetin increases cell viability, reduces the release of lactate dehydrogenase, and relieves nuclear condensation. Quercetin also alleviates intracellular reactive oxygen species generation and increases superoxide dismutase activity. Moreover, it strengthens the barrier integrity through the preservation of the transendothelial electrical resistance value, the relief of aggravated permeability, and the increase of characteristic enzyme levels after being exposed to fAβ 1-40. In conclusion, quercetin protects hBMECs from fAβ 1-40-induced toxicity.
RESUMEN
Neuropathological, clinical epidemiology and animal models studies provide clear evidence for the activation of neuroinflammation in Alzheimer's disease (AD), and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is linked with reduced risk to develop the disease. But the clinical trials got a negative outcome with traditional NSAIDs treating AD. The therapeutic effects of NSAIDs on Alzheimer's disease are still not clear based on the present research. Profound study for anti-inflammatory mechanisms and standardized clinical trials are needed. As cause and effect relationships between neuroinflammation and AD are being worked out, the challenge is how to realize the effect of traditional NSAIDs on treating AD.
RESUMEN
Aim To discover lead compound whose function is similar to EPO.Methods A high-throughput Fluorescent Polarization(FP) assay was established for screening ligand of EPO receptor from small molescules and natural products.In the FP assay,EPO receptor was abstracted from FVA cell.EPO was labeled with FITC.Results The optimized concentration of FITC-EPO was 10~(-9) mol?L~(-1).Different concentrations of DMSO(VDMSO/Vtotal: 0%,0.5%,1%,2.5%,5%) didn′t affect the FP assay.The value of Z′ in the FP assay was 0.78.Conclusion The assay was robust and of high sensitivity.