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Results for “NAMPT”

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3 recordsLinked to original sources

PubMed2026

Epidermal NAD+ deficiency induces IL-36-mediated skin inflammation and acanthosis.

Nicotinamide adenine dinucleotide (NAD+) is essential for cellular metabolism, DNA repair, and stress responses. NAD+ is synthesized from nicotinamide, nicotinic acid (collectively termed niacin), and tryptophan. In humans, deficiencies in these nutrients result in pellagra, marked by dermatitis, diarrhea, and dementia. The dermatitis associated with pellagra typically manifests as photodermatosis in sun-exposed areas. This study examined the effects of NAD+ deficiency on skin homeostasis using epidermis-specific Nampt-conditional KO (Nampt-cKO) mice. These mice displayed substantial NAD+ depletion, reduced poly(ADP-ribose) polymerase (PARP) activity, and increased DNA damage. Consequently, Nampt-cKO mice developed spontaneous skin inflammation and epidermal hyperplasia. RNA-seq and IHC analyses demonstrated increased IL-36 cytokine expression, suggesting that DNA repair-related genomic stress triggers keratinocyte-driven IL-36 production, which promotes inflammation. Furthermore, reduced COL17A1 expression and elevated thymic stromal lymphopoietin (TSLP) levels were observed. NAD+ repletion by transdermal supplementation of nicotinamide mononucleotide (NMN) suppressed the rise of IL-36 levels and skin inflammation. These findings underscore the importance of Nampt-mediated NAD+ metabolism for epidermal stability and indicate that NAD+ depletion may contribute to IL-36-mediated skin inflammation, offering insights for therapeutic strategies in inflammatory skin disorders.

Animals↗

PubMed2026

USP22 alleviates oxidative stress-induced BMSCs senescence by stabilizing SPI1 protein.

BACKGROUND: Therapeutic efficacy of bone marrow mesenchymal stem cell (BMSC) transplantation is often compromised by cellular senescence and diminished osteogenic potential induced by oxidative stress. Nevertheless, the underlying molecular mechanisms remain poorly understood. This study explores the role of ubiquitin-specific peptidase 22 (USP22) in regulating oxidative stress-induced BMSCs senescence. METHODS: BMSCs were exposed to H2O2 to mimics oxidative stress conditions. An ovariectomy‑induced osteoporotic rat model was established. Cell viability was assessed by CCK8 assay. ROS level and NAD+ level were measured by the DHE probe and kit, respectively. SA-β-gal staining was employed to detect cellular senescence. Mineralization was determined using ARS staining. Protein-DNA interactions (SPI1-NAMPT promoter) were examined through ChIP and luciferase reporter assays. Co-IP and ubiquitination assays were performed to validate USP22-SPI1 binding and post-translational modifications. RESULTS: SPI1 expression declined in H2O2-treated BMSCs and osteoporotic rat model, and its overexpression rescued H2O2-induced BMSCs senescence and osteogenic differentiation impairment. Mechanistically, SPI1 mediated protection on oxidative stress-induced BMSCs senescence by transcriptionally activating NAMPT expression and elevating NAD+ level. In addition, USP22 stabilized SPI1 protein through deubiquitination modification. As expected, USP22 overexpression alleviated oxidative stress-induced BMSCs senescence and osteogenic differentiation impairment, while these effects were reversed by SPI1 knockdown. CONCLUSION: USP22 mitigated oxidative stress-induced BMSCs senescence and preserved osteogenic capacity by promoting NAMPT transcription through deubiquitinating and stabilizing SPI1 protein.

Oxidative Stress↗

PubMed2024

Activated NAD+ biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells.

PARP inhibitors have been developed as anti-cancer agents based on synthetic lethality in homologous recombination deficient cancer cells. However, resistance to PARP inhibitors such as olaparib remains a problem in clinical use, and the mechanisms of resistance are not fully understood. To investigate mechanisms of PARP inhibitor resistance, we established a BRCA1 knockout clone derived from the pancreatic cancer MIA PaCa-2 cells, which we termed C1 cells, and subsequently isolated an olaparib-resistant C1/OLA cells. We then performed RNA-sequencing and pathway analysis on olaparib-treated C1 and C1/OLA cells. Our results revealed activation of cell signaling pathway related to NAD+ metabolism in the olaparib-resistant C1/OLA cells, with increased expression of genes encoding the NAD+ biosynthetic enzymes NAMPT and NMNAT2. Moreover, intracellular NAD+ levels were significantly higher in C1/OLA cells than in the non-olaparib-resistant C1 cells. Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.

Humans↗