NAD+ metabolism restriction boosts high-dose melphanan efficacy in multiple myeloma patients
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ABSTRACT:
PROVIDER: PRJNA1043634 | ENA |
REPOSITORIES: ENA
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Project description:A novel strategy to hinder the progression of multiple myeloma involves inhibiting NAD+ production. While solely targeting the NAMPT enzyme proved ineffective, the Preiss-Handler pathway, especially NAPRT1, emerged as pivotal in rescuing cancer cells. Cells lacking NAPRT1 become more susceptible to oxidative stress, and the dual targeting of NAMPT/NAPRT1 increased the efficacy of chemotherapy in multiple myelom.
2024-12-24 | GSE248379 | GEO
Project description:Therapeutic strategies to treat acute kidney injury (AKI) are lacking. Preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. The underlying molecular mechanisms are unknown. A comparative transcriptome analysis after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal KYNU as necessary for CR-associated maintenance of nicotinamide adenine dinucleotide (NAD+) levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans.
2023-02-13 | PXD038328 | Pride
Project description:Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through up-regulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+/sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
2018-07-31 | GSE108379 | GEO
Project description:NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. Messenger RNA was isolated from quadriceps muscle of mice from three different age groups and three different genotypes. Wildtype mice were aged 4, 7, and 24 months. Mice deficient for Nampt in skeletal muscle (mNKO) were aged 7 months. Mice overexpressing Nampt in skeletal muscle were aged 4 and 24 months.
2016-07-22 | E-GEOD-74570 | biostudies-arrayexpress
Project description:Analysis of treatment at gene expression level in aged mice. Results provide important information of the response of drug modifying NAD metabolism which has been implicated in anti-aging effect of calorie restriction in aging process. Total RNA obtained from skeletal muscles and brain (cortex) subjected to calorie restriction or β-lapachone treatment compared to untreated control.
2011-05-01 | E-GEOD-23218 | biostudies-arrayexpress
Project description:NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.
2016-07-22 | GSE74570 | GEO
Project description:Overexpression of CYB5R3 and NQO1, two NAD+ producing enzymes, mimics aspects of caloric restriction
| PRJNA425944 | ENA
Project description:Analysis of treatment at gene expression level in aged mice. Results provide important information of the response of drug modifying NAD metabolism which has been implicated in anti-aging effect of calorie restriction in aging process.
2011-05-01 | GSE23218 | GEO
Project description:We developed a Copper-free, strain-promoted azide-alkyne cycloaddition reaction (SPAAC) to capture NAD-RNAs without RNA degradation. We examined the specificity of CuAAC and SPAAC reactions towards NAD+ vs. m7G, and found that both prefer NAD+ but also act on m7G. We show that m7G-capped RNA can be immuno-depleted, allowing for the specific identification of NAD-RNA via the SPAAC reaction and sequencing, which we name SPAAC-NAD-seq. Subjecting Arabidopsis RNA to both the original NAD captureSeq and SPAAC-NAD-seq, we found that more NAD+-capped RNA was identified by the latter, particularly those with low abundance. This led to the discovery of new gene ontology terms such as starch biosynthsis, intracellular protein transport and response to cadmium stress associated with genes that produce NAD-RNA. Furthermore, reads were uniformly distributed along gene bodies, which suggested that SPAAC-NAD-seq retained full-length sequence information. SPAAC-NAD-seq enables specific and efficient discovery of NAD-RNA in prokaryotes, and when combined with m7G-RNA depletion, in eukaryotes.
2021-04-14 | GSE162114 | GEO
Project description:To gain deeper insights into antibacterial mechanisms of NAD+ and bacterial adaptation, we generated and sequenced NAD+ resistant clones of Spn. For this purpose, Spn was cultivated in liquid medium with increasing concentrations (50 µM to 5 mM) of NAD+. After six passages, bacteria were plated on blood agar supplemented with 500 µM NAD+ and three clones were picked
2023-06-11 | E-MTAB-12644 | biostudies-arrayexpress