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Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [NR or placebo]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237555 | GEO | 2023/07/18

REPOSITORIES: GEO

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Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [healthy or psoriasis]

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.

2023-07-18 | GSE237552 | GEO

Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [NR or placebo]

Project description:Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [NR or placebo]

| PRJNA995628 | ENA

Transcription profiling of human neuroblastoma cell line IMR-32 overexpressiong SQSTM1 and DPP3 to identify activators for the antioxidant response element

Project description:The antioxidant response element (ARE) is a cis-acting regulatory enhancer element found in the 5 flanking region of many phase II detoxification enzymes. Upregulation of ARE-dependent target genes is known to have neuroprotective effects; yet, the mechanism of activation is largely unknown. By screening an arrayed collection of approximately 15,000 full-length expression cDNAs in the human neuroblastoma cell line IMR-32 with an ARE-luciferase reporter, we have identified several cDNAs not previously associated with ARE activation. A subset of cDNAs, including sequestosome 1 (SQSTM1) and dipeptidylpeptidase III (DPP3), activated the ARE in primary mouse-derived cortical neurons. Overexpression of SQSTM1 and DPP3 in IMR-32 cells stimulated NRF2 nuclear translocation and led to increased levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), a protein which is transcriptionally regulated by the ARE. When transfected into IMR-32 neuroblastoma cells that were depleted of transcription factor NRF2 by RNA interference, SQSTM1 and DPP3 were unable to activate the ARE or induce NQO1 expression, indicating that the ARE activation upon ectopic expression of these cDNAs is mediated by NRF2. Studies with pharmacological inhibitors indicated that 1-phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) signaling are also essential for activity. Lastly, overexpression of these cDNAs conferred partial resistance to hydrogen peroxide induced toxicity, consistent with the induction of antioxidant and phase II detoxification enzymes which can protect from oxidative stress. This work and other such studies may provide mechanisms for activating the ARE in the absence of general oxidative stress, and a novel therapeutic approach to degenerative diseases and aging. Samples were taken from duplicate transfections of different antioxidant response element activators

2007-11-01 | E-GEOD-6451 | biostudies-arrayexpress

Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects

Project description:Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects

| PRJNA995626 | ENA

Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [healthy or psoriasis]

Project description:Boosting NAD preferentially blunts TH17 inflammation via arginine biosynthesis and redox regulatory control in control and psoriasis subjects [healthy or psoriasis]

| PRJNA995627 | ENA

Prophylactic or therapeutic NAD+ repletion can prevent or rescue HFpEF, but dietary intervention and weight loss cannot

Project description:Left ventricular (LV) diastolic dysfunction is a hallmark of Heart Failure with preserved Ejection Fraction (HFpEF), an escalating global health challenge. We demonstrated selective depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) and the rate-limiting enzyme of the NAD+ biosynthetic salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in human myocardium with LV diastolic dysfunction. We showed that NAD+ can be replenished in human myocardium with diastolic impairment ex vivo, despite reduced NAMPT expression. In a murine model of HFpEF [a combination exposure to high-fat diet (HFD) and L-NG-Nitro arginine methyl ester (L-NAME)], we compared the benefits of NAD+ precursor supplementation versus dietary intervention. We tested NAD+ repletion by nicotinamide riboside (NR) supplementation using two clinically-relevant strategies: 1) Prophylactic NR repletion before HFpEF onset, and 2) Therapeutic NR repletion after the development of HFpEF. We found that dietary intervention (replacement of HFD and L-NAME with healthy diet) restored myocardial insulin-dependent glucose uptake and glycolysis but did not rescue HFpEF. In contrast, both NAD+ repletion strategies prevented or rescued HFpEF, respectively, plausibly due to restoration of myocardial iron homeostasis, recoupling of glycolysis to the TCA cycle, and upregulation of antioxidant defense.

2024-08-09 | PXD033027 | Pride

A genomic screen for activators of the antioxidant response element

Project description:The antioxidant response element (ARE) is a cis-acting regulatory enhancer element found in the 5’ flanking region of many phase II detoxification enzymes. Upregulation of ARE-dependent target genes is known to have neuroprotective effects; yet, the mechanism of activation is largely unknown. By screening an arrayed collection of approximately 15,000 full-length expression cDNAs in the human neuroblastoma cell line IMR-32 with an ARE-luciferase reporter, we have identified several cDNAs not previously associated with ARE activation. A subset of cDNAs, including sequestosome 1 (SQSTM1) and dipeptidylpeptidase III (DPP3), activated the ARE in primary mouse-derived cortical neurons. Overexpression of SQSTM1 and DPP3 in IMR-32 cells stimulated NRF2 nuclear translocation and led to increased levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), a protein which is transcriptionally regulated by the ARE. When transfected into IMR-32 neuroblastoma cells that were depleted of transcription factor NRF2 by RNA interference, SQSTM1 and DPP3 were unable to activate the ARE or induce NQO1 expression, indicating that the ARE activation upon ectopic expression of these cDNAs is mediated by NRF2. Studies with pharmacological inhibitors indicated that 1-phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) signaling are also essential for activity. Lastly, overexpression of these cDNAs conferred partial resistance to hydrogen peroxide induced toxicity, consistent with the induction of antioxidant and phase II detoxification enzymes which can protect from oxidative stress. This work and other such studies may provide mechanisms for activating the ARE in the absence of general oxidative stress, and a novel therapeutic approach to degenerative diseases and aging. Keywords: overexpression of different antioxidant response element activators

2007-02-22 | GSE6451 | GEO

Nicotinamide riboside augments the human skeletal muscle NAD+ 1 metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

Project description:NAD+is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.

2019-08-29 | GSE133261 | GEO

Voluntary running and IV nicotinamide riboside synergise to boost mouse skeletal muscle NAD+ without impacting OXPHOS capacity or insulin sensitivity

Project description:In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity, but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but metabolic effects of NR and PT treatment were modest. We conclude that chronic elevation of skeletal muscle NAD+ by intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimes.

2022-02-08 | GSE194193 | GEO

Pereira2020 - NRF2–p53 integrated-systems model of oxidative stress

Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2. The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).

2021-10-29 | MODEL2110270001 | BioModels

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