NAD+ Modulates the Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells via Akt Signaling Pathway
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200494 | GEO | 2022/04/27
REPOSITORIES: GEO
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Project description:Nicotinamide adenine dinucleotide hydrate (NAD+) acts as the essential component of the tricarboxylic citric acid (TCA) cycle and has important functions in diverse biological processes. However, the roles of NAD+ in regulating adult neural stem/progenitor cells (aNSPCs) remain largely unknown. Here, we show that NAD+ exposure leads to the reduced proliferation and neuronal differentiation of aNSPCs and induces the apoptosis of aNSPCs. In addition, NAD+ exposure inhibits the morphological development of neurons. Mechanistically, RNA sequencing revealed that the transcriptome of aNSPCs is altered by NAD+ exposure. NAD+ exposure significantly decreases the expression of multiple genes related to ATP metabolism and the PI3k-Akt signaling pathway. Collectively, our findings provide some insights into the roles and mechanisms in which NAD+ regulates aNSPCs and neuronal development.
| S-EPMC9029130 | biostudies-literature
Project description:NAD+ Modulates the Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells via Akt Signaling Pathway
| PRJNA824821 | ENA
Project description:BackgroundGlioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs' alteration remain unkown.MethodsWe collected EVs in the culture medium of three classic glioblastoma cell lines, U87 and A172 (male cell lines), and LN229 (female cell line). U87, A172, and LN229 were co-cultured with their corresponding EVs, respectively. Mouse NPCs (mNPCs) were co-cultured with glioblastoma-derived EVs. The proliferation and migration of tumor cells and mNPCs after EVs treatment were examined. Proteomic analysis and western blotting were utilized to identify the underlying mechanisms of glioblastoma-derived EVs-induced alterations in mNPCs.ResultsWe first show that glioblastoma cell lines U87-, A172-, and LN229-derived EVs were essential for glioblastoma cell prolifeartion and migration. We then demonstrated that glioblastoma-derived EVs dramatically promoted NPC proliferation and migration. Mechanistic studies identify that glioblastoma-derived EVs achieve their functions via activating PI3K-Akt-mTOR pathway in mNPCs. Inhibiting PI3K-Akt pathway reversed the elevated prolfieration and migration of glioblastoma-derived EVs-treated mNPCs.ConclusionOur findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy. Video Abstract.
| S-EPMC8756733 | biostudies-literature
Project description:Neural stem/progenitor cells (NSPCs) are self?renewing, multipotent cells and remain in the human brain throughout an individual's lifetime. NSPCs are activated by brain damage and contribute towards repair and motor function recovery in the central nervous system (CNS). It was previously reported that miR?29 was involved in regulating proliferation, differentiation and survival in hepatocellular carcinoma, and osteoblast and mantle cell lymphoma; however, the effects of miR?29 on NSPCs remain unclear. In the present study, it was demonstrated via Cell Counting Kit?8 assays that overexpression of miR?29 promoted the viability of NPSCs, and downregulated the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) protein. Additionally, treatment with a PTEN?specific inhibitor (VO?OHpic trihydrate) abolished the effects of the miR?29 inhibitor on PTEN expression, as determined via western blotting. Flow cytometry and 5?bromo?2?deoxyuridine (BrdU) staining revealed that overexpression of miR?29 further promoted the proliferation of NSPCs; however, knocking down miR?29 inhibited cell proliferation. VO?OHpic trihydrate reversed the effects of miR?29 knockdown on cell proliferation. Furthermore, it was observed that overexpression of miR?29 increased the phosphorylation levels of AKT. Collectively, the results indicated that overexpression of miR?29 promoted the proliferation of cultured rat NSPCs and decreased the expression of PTEN protein, and that the activation of Akt may be a potential underlying mechanism. The present findings may provide novel insight for the development of strategies for stem cell?mediated treatment of CNS diseases.
| S-EPMC6691275 | biostudies-literature
Project description:Pyruvate is a glycolytic metabolite used for energy production and macromolecule biosynthesis. However, little is known about its potential functions in tumorigenesis. Here,we report that exogenous pyruvate inhibits the proliferation of different types of cancer cells. This inhibitory effect of pyruvate on cell growth is attributed to its function as a signal molecule to repress histone gene expression, which leads to less compact chromatin structure and misregulation of genome-wide gene expression. Pyruvate represses histone gene expression by inducing the expression of NAD + biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), which increases NAD + levels and NAD + /NADH ratio. This increase activates the histone deacetylase activity of SIRT1. Chromatin immunoprecipitation analysis indicates that pyruvate enhances SIRT1 binding at histone gene promoters where it reduces histone acetylation. Although pyruvate delays cell entry into S phase, pyruvate represses histone gene expression independent of cell cycle progression. Moreover, we find that administration of pyruvate significantly reduces histone expression and retards tumor growth in xenograft mice without significant side effects. Using tissues from cervical cancer patients, we find intracellular pyruvate concentrations inversely correlate with histone protein levels. Together, we uncover a previously unknown function of pyruvate in histone gene expression and characterize pyruvate as a potential anti-cancer agent.
2019-12-05 | GSE135831 | GEO
Project description:Neural progenitor (NP) cells are the multipotent cells that produce neurons and glia in the central nervous system. Compounds regulating their proliferation are key to both understanding brain development and unlocking their potential in regenerative repair. We discuss a chemical screen that unexpectedly identified inhibitors of Erk signaling potently promoting the self-renewing divisions of fetal NP cells. This occurred through crosstalk between Erk and Akt signaling cascades. The crosstalk mechanism is cell type-specific, and is not detected in adult NP cells as well as brain tumor cells. The mechanism was also shown to be independent from the GSK-3 signaling pathway, which has been reported to be a major regulator of NP cell homeostasis and inhibitors to which were also identified in the screen. In vitro Erk inhibition led to the prolonged rapid expansion of fetal NP cells while retaining their multipotency. In vivo inhibitor administration significantly inhibited the neuronal differentiation, and resulted in increased proliferative progenitor cells in the ventricular/subventricular zone (VZ/SVZ) of the embryonic cortex. Our results uncovered a novel regulating pathway for NP cell proliferation in the developing brain. The discovery provides a pharmacological basis for in vitro expansion and in vivo manipulation of NP cells.
| S-EPMC4876380 | biostudies-literature
Project description:BackgroundNeuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system.MethodologyWe have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain.ResultsWe have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo.ConclusionsThis work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical agents to facilitate neuronal renewal.
| S-EPMC4772272 | biostudies-literature
Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.
2021-08-25 | GSE135999 | GEO
Project description:Xrn1 Modulates Mitochondrial NAD Levels through NAD-Capped RNA Decay
2021-06-10 | MSV000087605 | MassIVE
Project description:The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.
| S-EPMC4986639 | biostudies-literature