The receptor-interacting protein kinase 3 (RIPK3) plays crucial roles in programmed necrosis and innate inflammatory responses. However, a little is known about the involvement of RIPK3 in NKT cell-mediated immune responses. Here, we demonstrate that RIPK3 plays an essential role in NKT cell function via activation of the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5). RIPK3-mediated activation of PGAM5 promotes the expression of cytokines by facilitating nuclear translocation of NFAT and dephosphorylation of dynamin-related protein 1 (Drp1), a GTPase is essential for mitochondrial homoeostasis. Ripk3−/− mice show reduced NKT cell responses to metastatic tumour cells, and both deletion of RIPK3 and pharmacological inhibition of Drp1 protects mice from NKT cell-mediated induction of acute liver damage. Collectively, the results identify a crucial role for RIPK3-PGAM5-Drp1/NFAT signalling in NKT cell activation, and further suggest that RIPK3-PGAM5 signalling may mediate crosstalk between mitochondrial function and immune signalling.
We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid- (A) peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1␣,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble A levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH) 2 D 3 during the period of plaque formation reduced soluble and insoluble plaque-associated A, particularly in the hippocampus in which the VDR is abundant and P-gp induction is greatest after 1,25(OH) 2 D 3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease.
The multiplex RFMP assay is an accurate and sensitive means to detect entecavir and lamivudine resistance mutations, simultaneously. The method is expected to enable early and efficient diagnosis of multiple drug resistance mutations for optimal management of CHB.
The present study evaluated rate and extent of alveolar bone formation in dental implant dehiscence defects following guided bone regeneration(GBR) and implantation of xenogeneic freeze‐dried demineralized bone matrix (xDBM). A total of 16 titanium plasma‐sprayed (TPS) and 16 hydroxyapatite‐coated (HA) titanium cylinder implants were inserted in 4 mongrel dogs following extraction of the mandibular premolar teeth. Four implant sites per jaw quadrant (2 TPS and 2 HA implant sites) were prepared into extraction sockets in each dog. Buccal alveolar bone was removed to create 3 x 5 mm dehiscence defects. Two jaw quadrants in separate animals received GBR, GBR+xDBM, xDBM (control), or gingival flap surgery alone (GFS; control). Thus, four conditions were available for each implant type (TPS or HA): GBR, GBR+xDBM; xDBM and GFS. The animals received fluorescent bone labels to allow observations of rate and extent of bone formation. Animals were sacrificed at 12 weeks postsurgery and block sections were harvested for histologic analysis. There were no apparent histologic differences between TPS and HA implant defects. GBR and GBR+xDBM resulted in almost complete bone closure of the dental implant dehiscence defect. Rate of bone formation appeared higher following GBR alone. Extent of bone formation appeared somewhat greater following GBR+xDBM; however, delayed. xDBM alone did not adequately resolve the bony defect. In conclusion, GBR results in rapid, clinically relevant bone closure of dental implant dehiscence defects. Adjunctive implantation of xDBM does not appear to significantly improve the healing response in the model used.
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