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1.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201564

RESUMO

Obesity increases the risk of hip osteoarthritis (OA). Recent studies have shown that adipokine extracellular nicotinamide phosphoribosyltransferase (eNAMPT or visfatin) induces the production of IL-6 and matrix metalloproteases (MMPs) in chondrocytes, suggesting it may promote articular cartilage degradation. However, neither the functional effects of extracellular visfatin on human articular cartilage tissue, nor its expression in the joint of hip OA patients of varying BMI, have been reported. Hip OA joint tissues were collected from patients undergoing joint replacement surgery. Cartilage explants were stimulated with recombinant human visfatin. Pro-inflammatory cytokines and MMPs were measured by ELISA and Luminex. Localisation of visfatin expression in cartilage tissue was determined by immunohistochemistry. Cartilage matrix degradation was determined by quantifying proteoglycan release. Expression of visfatin was elevated in the synovial tissue of hip OA patients who were obese, and was co-localised with MMP-13 in areas of cartilage damage. Visfatin promoted the degradation of hip OA cartilage proteoglycan and induced the production of pro-inflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs. The elevated expression of visfatin in the obese hip OA joint, and its functional effects on hip cartilage tissue, suggests it plays a central role in the loss of cartilage integrity in obese patients with hip OA.


Assuntos
Cartilagem Articular/patologia , Citocinas/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Osteoartrite do Quadril/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/metabolismo , Quimiocinas/metabolismo , Condrócitos/metabolismo , Citocinas/sangue , Articulação do Quadril/metabolismo , Articulação do Quadril/fisiopatologia , Humanos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/sangue , Obesidade/metabolismo , Técnicas de Cultura de Órgãos , Osteoartrite do Quadril/patologia , Proteoglicanas/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202251

RESUMO

Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis.


Assuntos
Citocinas/genética , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Psoríase/etiologia , Psoríase/metabolismo , Transdução de Sinais , Adulto , Idoso , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Células Endoteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/metabolismo , Psoríase/patologia
3.
J Photochem Photobiol B ; 221: 112238, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34130091

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is a crucial coenzyme in energy production. The imbalance of NAD+ synthesis has been found to trigger age-related diseases, such as metabolic disorders, cancer, and neurodegenerative diseases. Also, UV irradiation induces NAD+ depletion in the skin. In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and essential for NAD+ homeostasis. However, but few studies have focused on the role of NAMPT in response to UV irradiation. Here, we show that NAMPT prevents NAD+ depletion in epidermal keratinocytes to protect against the mild-dose UVA and UVB (UVA/B)-induced proliferation defects. We showed that poly(ADP-ribose) polymerase (PARP) inhibitor rescued the NAD+ depletion in UVA/B-irradiated human keratinocytes, confirming that PAPR transiently exhausts cellular NAD+ to repair DNA damage. Notably, the treatment with a NAMPT inhibitor exacerbated the UVA/B-induced loss of energy production and cell viability. Moreover, the NAMPT inhibitor abrogated the sirtuin-1 (SIRT1)-mediated deacetylation of p53 and significantly inhibited the proliferation of UVA/B-irradiated cells, suggesting that the NAMPT-NAD+-SIRT1 axis regulates p53 functions upon UVA/B stress. The supplementation with NAD+ intermediates, nicotinamide mononucleotide and nicotinamide riboside, rescued the UVA/B-induced phenotypes in the absence of NAMPT activity. Therefore, NAD+ homeostasis is likely essential for the protection of keratinocytes from UV stress in mild doses. Since the skin is continuously exposed to UVA/B irradiation, understanding the protective role of NAMPT in UV stress will help prevent and treat skin photoaging.


Assuntos
NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta , Acrilamidas/química , Acrilamidas/metabolismo , Acrilamidas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia
4.
Aging (Albany NY) ; 13(12): 16381-16403, 2021 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-34175838

RESUMO

Cardiac senescence is associated with cardiomyopathy which is a degenerative disease in the aging process of the elderly. The present study investigates using multiple experimental approaches whether the natural flavone acacetin could attenuate myocardial senescence in C57/BL6 mice and H9C2 rat cardiac cells induced by D-galactose. We found that the impaired heart function in D-galactose-induced accelerated aging mice was improved by oral acacetin treatment in a dose-dependent manner. Acacetin significantly countered the increased serum advanced glycation end products, the myocardial telomere length shortening, the increased cellular senescence marker proteins p21 and p53, and the reduced mitophagy signaling proteins PINK1/Parkin and Sirt6 expression in aging mice. In H9C2 rat cardiac cells, acacetin alleviated cell senescence induced by D-galactose in a concentration-dependent manner. Acacetin decreased p21 and p53 expression, up-regulated PINK1/Parkin, LC3II/LC3I ratio, pLKB1, pAMPK and Sirt6, and reversed the depolarized mitochondrial membrane potential in aging cardiac cells. Mitophagy inhibition with 3-methyladenine or silencing Sirt6 abolished the protective effects of acacetin against cardiac senescence. Further analysis revealed that acacetin effect on Sirt6 was mediated by Sirt1 activation and increase of NAD+/NADH ratio. These results demonstrate that acacetin significantly inhibits in vivo and in vitro cardiac senescence induced by D-galactose via Sirt1-mediated activation of Sirt6/AMPK signaling pathway, thereby enhancing mitophagy and preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorders related to aging.


Assuntos
Envelhecimento/patologia , Flavonas/farmacologia , Mitofagia/efeitos dos fármacos , Miocárdio/patologia , Acetilação , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Cardiotônicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Galactose , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , Sirtuínas/metabolismo
5.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070254

RESUMO

We evaluated the utility of optical redox imaging (ORI) to identify the therapeutic response of triple-negative breast cancers (TNBC) under various drug treatments. Cultured HCC1806 and MDA-MB-231 cells treated with FK866 (nicotinamide phosphoribosyltransferase (Nampt) inhibitor), FX11 (lactate dehydrogenase A inhibitor), paclitaxel, and their combinations were subjected to ORI, followed by imaging fluorescently labeled reactive oxygen species (ROS). Cell growth inhibition was measured by a cell viability assay. We found that both cell lines experienced significant NADH decrease and redox ratio (Fp/(NADH+Fp)) increase due to FK866 treatment; however, HCC1806 was much more responsive than MDA-MB-231. We further studied HCC1806 with the main findings: (i) nicotinamide riboside (NR) partially restored NADH in FK866-treated cells; (ii) FX11 induced an over 3-fold NADH increase in FK866 or FK866+NR pretreated cells; (iii) FK866 combined with paclitaxel caused synergistic increases in both Fp and the redox ratio; (iv) FK866 sensitized cells to paclitaxel treatments, which agrees with the redox changes detected by ORI; (v) Fp and the redox ratio positively correlated with cell growth inhibition; and (vi) Fp and NADH positively correlated with ROS level. Our study supports the utility of ORI for detecting the treatment responses of TNBC to Nampt inhibition and the sensitization effects on standard chemotherapeutics.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citocinas , Nicotinamida Fosforribosiltransferase , Neoplasias de Mama Triplo Negativas , Acrilamidas/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Feminino , Humanos , Microscopia de Fluorescência , Naftalenos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Oxirredução/efeitos dos fármacos , Piperidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/patologia
6.
DNA Cell Biol ; 40(7): 1026-1036, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34101492

RESUMO

NAD is mainly biosynthesized by the enzymatic action of nicotinamide phosphoribosyltransferase (NAMPT) through the salvage pathway. NAD is indispensable for the proper function and metabolism of all living cells, including cancer cells. Our previous researches revealed that inhibition of NAMPT by miRNA (miR) could suppress NAD levels and thereby hinder the growth and promotion of breast cancer (BC). Therefore, the current study was undertaken to investigate the inhibitory effects of miR-613 on NAMPT and BC cells' survival. Bioinformatics analysis and luciferase reporter assay confirmed that NAMPT 3'-untranslated region is a direct target for miR-613. The expression of miR-613 was noticed to be significantly decreased in both clinical tissue samples and BC cells by real-time PCR. Following transfection with miR-613 mimic, the expression of miR-613 was elevated in the BC cells leading to inhibition of NAMPT expression at both mRNA and protein level as measured by real-time PCR and western blotting, respectively. Inhibition of NAMPT led to a remarkable reduction in the concentration of NAD in the BC cells. The transfection also declined cell viability roughly 40% in MD Anderson-Metastatic Breast-231 (MDA-MB-231) cells. Consistently, the apoptosis rate was remarkably increased, around 65% in these cells as assayed by labeling the cells with Annexin V-fluorescein isothiocyanate (FITC) and Propidium Iodide. Targeting the NAMPT-mediated NAD salvage pathway by miR-613 is a novel approach for managing BC, which is worth further investigation.


Assuntos
Neoplasias da Mama/metabolismo , Citocinas/genética , MicroRNAs/genética , Nicotinamida Fosforribosiltransferase/genética , Adulto , Apoptose/genética , Neoplasias da Mama/genética , Morte Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Citocinas/metabolismo , Feminino , Humanos , Irã (Geográfico) , MicroRNAs/metabolismo , Pessoa de Meia-Idade , NAD/genética , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo
7.
Biomed Pharmacother ; 140: 111693, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029951

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) maintains mitochondrial function and protects against cerebral ischemic injury by improving energy metabolism. Notoginsenoside R1 (R1), a unique constituent of Panax notoginseng, has been shown to promote the proliferation and tube formation of human umbilical vein endothelial cells. Whether R1 has proangiogenesis on the activation of NAMPT in ischemic stroke remains unclear. The purpose of this study was to investigate the pharmacodynamic effect and mechanism of R1 on angiogenesis after ischemic stroke. We used male Sprague-Dawley (SD) rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). R1 was administered via intraperitoneal (i.p.) injection immediately after ischemia induction. The promotion of R1 on angiogenesis were detected by immunofluorescence staining, 3D stereoscopic imaging and transmission electron microscopy detection. HBMEC cells were pretreated with different concentrations of R1 for 12 h before oxygen-glucose deprivation/reoxygenation (OGD/R) exposure. Afterward, scratch assay, EdU staining and tube formation were determined. Western blot analyses of proteins, including those involved in angiogenesis, NAMPT-SIRT1 cascade, VEGFR-2, and Notch signaling, were conducted. We showed that R1 significantly restored cerebral blood flow, improved mitochondrial energy metabolism and promoted angiogenesis. More importantly, incubation with 12.5-50 µM R1 significantly increased the migration, proliferation and tube formation of HBMECs in vitro. The promotion of R1 on angiogenesis were associated with the NAMPT-NAD+-SIRT1 cascade and Notch/VEGFR-2 signaling pathway, which was partially eliminated by inhibitors of NAMPT and SIRT1. We demonstrated that R1 promotes post-stroke angiogenesis via activating NAMPT-NAD+-SIRT1 cascade. The modulation of Notch signaling and VEGFR-2 contribute to the post-stroke angiogenesis. These findings offer insight for exploring new therapeutic strategies for neurorestoration via R1 treatment after ischemic stroke.


Assuntos
Isquemia Encefálica/metabolismo , Citocinas/metabolismo , Ginsenosídeos/farmacologia , NAD/metabolismo , Neovascularização Patológica/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Receptores Notch/metabolismo , Sirtuína 1/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/metabolismo , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Neovascularização Patológica/tratamento farmacológico , Panax notoginseng/química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Nat Commun ; 12(1): 2620, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976173

RESUMO

Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.


Assuntos
Citocinas/genética , Melanoma/genética , Nicotinamida Fosforribosiltransferase/genética , Fator de Transcrição STAT1/metabolismo , Neoplasias Cutâneas/genética , Macrófagos Associados a Tumor/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Células HEK293 , Humanos , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Knockout , Nicotinamida Fosforribosiltransferase/metabolismo , Células RAW 264.7 , RNA-Seq , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Células THP-1 , Macrófagos Associados a Tumor/metabolismo , Regulação para Cima , Efeito Warburg em Oncologia
9.
Bioorg Med Chem Lett ; 41: 128007, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798699

RESUMO

NAD+ is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD+ have been linked to numerous diseases including metabolic disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD+ is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD+ salvage pathway. We previously showed that NAMPT activators increase NAD+ levels in vitro and in vivo. Herein we describe the optimization of our NAMPT activator prototype (SBI-0797812) leading to the identification of 1-(4-((4-chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea (34) that showed far more potent NAMPT activation and improved oral bioavailability.


Assuntos
Citocinas/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Ureia/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
10.
Int J Mol Sci ; 22(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918226

RESUMO

Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.


Assuntos
Envelhecimento/metabolismo , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Animais , Humanos
11.
Eur J Pharmacol ; 900: 174062, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798596

RESUMO

Polycystic ovary syndrome is a common endocrine disorder worldwide. Recently, quercetin has been extensively investigated as a therapeutic option in patients with PCOS. Therefore, this study aimed to investigate the mechanisms underlying quercetin's positive effects by modulating key components of energy homeostasis and adipose tissue hormones in rats with letrozole-induced PCOS. Eighteen female Wistar rats were divided into three groups including control group (received carboxy methylcellulose (CMC 0.5%)), letrozole-induced PCOS ± quercetin group (received 1 mg/kg letrozole in CMC 0.5%), and letrozole-induced PCOS +/+ quercetin group (received same dose of letrozole + 100 mg/kg quercetin in CMC 0.5%). The estrous cycle, biochemical and hormonal parameters, as well as insulin resistance (IR) were evaluated in all groups. Western blotting was used to assess the expression levels of sirtuin-1 (SIRT-1), 5' AMP-activated protein kinase (AMPK), and adiponectin in target tissues of rats. The expression levels of visfatin and resistin were also evaluated through Real-time polymerase chain reaction (PCR). Treatment with quercetin improved the PCOS related disturbances in estrous cycle, lipid profile, serum levels of testosterone, estradiol and progesterone, and IR. Besides, the expression levels of AMPK and SIRT-1 in ovarian tissue were upregulated in the rats which received quercetin. Quercetin also reversed the PCOS-induced alteration in adipose tissue levels of adiponectin, visfatin, and resistin. Modulation of energy homeostasis through key components involved in this axis, as well as regulation of hormones releasing from adipose tissue may be the main underlying mechanisms for positive effects of quercetin in PCOS.


Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Quercetina/uso terapêutico , Sirtuína 1/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônios/sangue , Resistência à Insulina , Letrozol , Metabolismo dos Lipídeos/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar , Resistina/metabolismo
12.
Adipocyte ; 10(1): 201-215, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33853482

RESUMO

Visfatin reportedly induces the expression of proinflammatory cytokines. Severe grades of intervertebral disc disease (IVDD) exhibit higher expression of visfatin than mild ones. However, the direct relationship between visfatin and IVDD remains to be elucidated. This study aimed to clarify whether stimulation of visfatin in IVDD is mediated by IL-6. To investigate the role of visfatin in IVDD, a rat model of anterior disc puncture was established by injecting visfatin or PBS using a 27-gauge needle. Results revealed an obvious aggravation of the histological morphology of IVDD in the visfatin group. On treating human NP cellswith visfatin, the levels of collagenII and aggrecan decreased and those of matrix metallopeptidase 3 and IL-6 gradually increased. A rapid increase in ERK, JNK, and p38 phosphorylation was also noted after visfatin treatment. Compared to those treated with visfatin alone, NP cells pretreated with ERK1/2, JNK, and p38 inhibitors or siRNA targeting p38, ERK, and JNK exhibited a significant suppression of IL-6. Our data represent the first evidence that visfatin promotes IL-6 expression in NP cells via the JNK/ERK/p38-MAPK signalling pathways. Further, our findings suggest epidural fat and visfatin as potential therapeutic targets for controlling IVDD-associated inflammation.


Assuntos
Interleucina-6/genética , Degeneração do Disco Intervertebral/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Adulto , Idoso , Animais , Células Cultivadas , Feminino , Humanos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Adulto Jovem
13.
J Am Soc Nephrol ; 32(6): 1355-1370, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795425

RESUMO

BACKGROUND: The activation of NAD+-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. METHODS: Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). RESULTS: At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of db/db mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD+ and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. CONCLUSIONS: Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD+ salvage pathway, both of which indicate NMN legacy effects on DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , NAD/metabolismo , Mononucleotídeo de Nicotinamida/uso terapêutico , Sirtuína 1/metabolismo , Albuminúria/etiologia , Albuminúria/urina , Animais , Claudina-1/metabolismo , Citocinas/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epigênese Genética/efeitos dos fármacos , Mesângio Glomerular/patologia , Hemoglobina A Glicada/metabolismo , Histonas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mononucleotídeo de Nicotinamida/administração & dosagem , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Podócitos/patologia , Sirtuína 1/genética , Taxa de Sobrevida , Fatores de Tempo
14.
Nat Commun ; 12(1): 1353, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649309

RESUMO

Cells are under threat of osmotic perturbation; cell volume maintenance is critical in cerebral edema, inflammation and aging, in which prominent changes in intracellular or extracellular osmolality emerge. After osmotic stress-enforced cell swelling or shrinkage, the cells regulate intracellular osmolality to recover their volume. However, the mechanisms recognizing osmotic stress remain obscured. We previously clarified that apoptosis signal-regulating kinase 3 (ASK3) bidirectionally responds to osmotic stress and regulates cell volume recovery. Here, we show that macromolecular crowding induces liquid-demixing condensates of ASK3 under hyperosmotic stress, which transduce osmosensing signal into ASK3 inactivation. A genome-wide small interfering RNA (siRNA) screen identifies an ASK3 inactivation regulator, nicotinamide phosphoribosyltransferase (NAMPT), related to poly(ADP-ribose) signaling. Furthermore, we clarify that poly(ADP-ribose) keeps ASK3 condensates in the liquid phase and enables ASK3 to become inactivated under hyperosmotic stress. Our findings demonstrate that cells rationally incorporate physicochemical phase separation into their osmosensing systems.


Assuntos
Lubrificação , Pressão Osmótica , Poli Adenosina Difosfato Ribose/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Citocinas/metabolismo , Células HEK293 , Humanos , MAP Quinase Quinase Quinases/química , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/ultraestrutura , Modelos Moleculares , Mutação/genética , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Domínios Proteicos
15.
Neurochem Res ; 46(5): 1291-1304, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713324

RESUMO

Alleviating microglia-mediated neuroinflammation bears great promise to reduce neurodegeneration. Nicotinamide phosphoribosyltransferase (NAMPT) may exert cytokine-like effect in the brain. However, it remains unclear about role of NAMPT in microglial inflammation. Also, it remains unknown about effect of NAMPT inhibition on microglial inflammation. In the present study, we observed that FK866 (a specific noncompetitive NAMPT inhibitor) dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory mediator (interleukin (IL)-6, IL-1ß, inducible nitric oxide synthase, nitric oxide and reactive species) level increase in BV2 microglia cultures. FK866 also significantly inhibited LPS-induced polarization change in microglia. Furthermore, LPS significantly increased NAMPT expression and nuclear factor kappa B (NF-κB) phosphorylation in microglia. FK866 significantly decreased NAMPT expression and NF-κB phosphorylation in LPS-treated microglia. Finally, conditioned medium from microglia cultures co-treated with FK866 and LPS significantly increased SH-SY5Y and PC12 cell viability compared with conditioned medium from microglia cultures treated with LPS alone. Our study strongly indicates that NAMPT may be a promising target for microglia modulation and NAMPT inhibition may attenuate microglial inflammation.


Assuntos
Acrilamidas/farmacologia , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Microglia/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Ratos
16.
Endocrinology ; 162(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33543238

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.


Assuntos
Tecido Adiposo/metabolismo , Citocinas/metabolismo , Metabolismo Energético/fisiologia , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Adulto , Animais , Citocinas/genética , Ácidos Graxos/metabolismo , Feminino , Humanos , Lipólise/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/genética , Período Pós-Prandial
17.
Int J Mol Sci ; 22(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535537

RESUMO

Adiposity is associated with an increased risk of various types of carcinoma. One of the plausible mechanisms underlying the tumor-promoting role of obesity is an aberrant secretion of adipokines, a group of hormones secreted from adipose tissue, which have exhibited both oncogenic and tumor-suppressing properties in an adipokine type- and context-dependent manner. Increasing evidence has indicated that these adipose tissue-derived hormones differentially modulate cancer cell-specific metabolism. Some adipokines, such as leptin, resistin, and visfatin, which are overproduced in obesity and widely implicated in different stages of cancer, promote cellular glucose and lipid metabolism. Conversely, adiponectin, an adipokine possessing potent anti-tumor activities, is linked to a more favorable metabolic phenotype. Adipokines may also play a pivotal role under the reciprocal regulation of metabolic rewiring of cancer cells in tumor microenvironment. Given the fact that metabolic reprogramming is one of the major hallmarks of cancer, understanding the modulatory effects of adipokines on alterations in cancer cell metabolism would provide insight into the crosstalk between obesity, adipokines, and tumorigenesis. In this review, we summarize recent insights into putative roles of adipokines as mediators of cellular metabolic rewiring in obesity-associated tumors, which plays a crucial role in determining the fate of tumor cells.


Assuntos
Adipocinas/metabolismo , Progressão da Doença , Neoplasias/complicações , Neoplasias/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adiposidade , Animais , Glucose/metabolismo , Glicólise , Humanos , Inflamação/patologia , Leptina/metabolismo , Metabolismo dos Lipídeos , Camundongos , Mitocôndrias/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Oxirredução , Fenótipo , Espécies Reativas de Oxigênio , Resistina/metabolismo , Microambiente Tumoral
18.
PLoS One ; 16(2): e0241651, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606677

RESUMO

Pancreatic islet ß-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with Type 2 diabetes; however, the mechanism by which it restores ß-cell function is unknown. Here, we show that imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool-potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via ADP ribosyl cyclase/cADPR hydrolase (CD38) is required for imeglimin's effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which-in turn-is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for imeglimin that explains its ability to effectively restore-ß-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Triazinas/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , ADP-Ribose Cíclica/metabolismo , Citocinas/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Masculino , Modelos Biológicos , NAD/metabolismo , Niacinamida/farmacologia , Nicotinamida Fosforribosiltransferase/metabolismo , Ratos Wistar , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Compostos de Sulfonilureia/farmacologia
19.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33597293

RESUMO

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Citocinas/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Interferon Tipo I/metabolismo , NAD/deficiência , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Citocinas/genética , Citocinas/metabolismo , Humanos , Interferon Tipo I/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Aging (Albany NY) ; 13(4): 5150-5163, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535169

RESUMO

The Nicotinamide phosphoribosyltransferase (Nampt)-NAD-Sirt1 pathway modulates processes involved in the pathogenesis of multiple diseases by influencing inflammation. This study aimed to explore the effect of Nampt in osteogenic differentiation and inflammatory response of osteoblastic MC3T3-E1 cells. We developed an in vitro model of lipopolysaccharide (LPS)-induced inflammation and showed that Nampt and Sirt1 were significantly upregulated in LPS-treated MC3T3-E1 cells. LPS induced secretion of the proinflammatory cytokine interleukin-6 (IL-6) and attenuated osteogenic differentiation. Then we transfected cells with adenoviruses to knock down or over express Nampt. Nampt promoted the expression of IL-6, TAK1 and phospho-NF-κB p65 after LPS treatment. Overexpression of Nampt overrode the effect of LPS and rescued LPS-induced inhibition on osteogenic differentiation. FK866, a Nampt inhibitor, had the same inhibitory effect as Nampt knockdown. In addition, Sirt1 suppression by EX527 decreased IL-6 secretion and NF-κB activation without changing the level of Nampt. EX527 also decreased osteogenic differentiation. Incubation with NMN or SRT 1720 also counteract the inhibitory effect of LPS and rescued osteoblast differentiation. Therefore, we demonstrated that Nampt acted both in promoting osteoblast differentiation and in enhancing inflammatory response, mediated by Sirt1 in MC3T3-E1 cells.


Assuntos
Diferenciação Celular/genética , Citocinas/genética , Interleucina-6/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Osteoblastos/metabolismo , Osteogênese/genética , Sirtuína 1/genética , Acrilamidas/farmacologia , Animais , Carbazóis/farmacologia , Linhagem Celular , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Técnicas de Silenciamento de Genes , Inflamação , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinases/efeitos dos fármacos , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Piperidinas/farmacologia , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
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