Project description:To evaluate whether NAD+-boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts IFNg and IL-17 secretion with greater effects on TH17 polarization. RNA-seq analysis implicates NR blunting of sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. NR administration increases SQSTM1 and reduces reactive oxygen species (ROS) levels. Furthermore NR activates NRF2, and genetic knockdown of NRF2 and of the NRF2-dependent gene, SQSTM1 diminish NR amelioratory effects. Metabolomic analysis identify that NAD+-boosting increases arginine and fumarate biosynthesis and genetic knockdown of argininosuccinate lyase ameliorates NR-effects on IL-17 production. Hence, NR via amino acid metabolites orchestrate NRF2 activation, augments CD4+ T cell antioxidant defenses and attenuates TH17 responsiveness. Oral NR supplementation in healthy volunteers similarly increase serum arginine, SQSTM1 and antioxidant enzyme gene expression and blunts TH17 immune responsiveness, supporting evaluation of NAD+-boosting in CD4+ T cell linked inflammation.
Project description:Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder with hallmarks of beta-amyloid (Aβ) plaques and neurofibrillary tangles. In light of the suboptimal benefit of Aβ clearing drugs to patients, the association between metabolic disorders and AD provides an alternative angle to understand the role of metabolic dysfunction in AD pathogenesis and the potential of modulating metabolism for improved therapeutic development. We investigated the effects of metabolic and nutritional modulators, namely, high fructose consumption as a potential risk, and docosahexaenoic acid (DHA) and nicotinamide riboside (NR) as potentially beneficial, on cell type specific transcriptomic responses in the hippocampus and hypothalamus of an AD mouse model. Fructose-induced metabolic syndrome increased expression of complement component 3 in ependymal cells and inflammatory genes in microglia, which were normalized by DHA and NR. NR and DHA led to reversals of Aβ signatures across cell types and targeted different aspects of microglial reactivity between AD and metabolically challenged AD. Our study supports the impact of metabolic regulation on neuroinflammation and provides molecular support for utilizing metabolic modulators for AD intervention.
Project description:We performed microarrays to identify change of gene expression under NR, CR, and RM and found differentially expressed genes between each condition.
Project description:Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Most lncRNA have been proven to have biological and clinical significance in acute myeloid leukemia (AML), but further studies remain to be needed. In this study, we investigated lncRNA NR-104098 in AML and its specific mechanism. The microarray analysis was performed on NB4 cells. Based on the related analysis results, we identified that lncRNA NR-104098 is a suppressor gene that is significantly upregulated in AML cells. lncRNA NR-104098 could inhibit proliferation and induce differentiation in AML cells in vitro, and also play main role in the mouse xenografts. Mechanically, it was confirmed that lncRNA NR-104098 may effectively inhibit EZH2 transcription by directly binding E2F1 and recruiting E2F1 to EZH2 promoter. In addition, ATPR can significantly increase the expression of lncRNA NR-104098, whereas knocking down NR104098 can inhibit the inhibitory effect of ATPR on the proliferation and induction differentiation of AML cells. Taken together, these results lead to a deeper insight into the mechanism of ATPR induces AML differentiation and inhibits proliferation by inhibiting EZH2 on transcriptional level.