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Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin

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ABSTRACT

Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine‐enzyme, which was described as to play bioactivities both in the intracellular and in the extracellular environment. However, while the functions of intracellular NAMPT (iNAMPT) are well known, much less is known on extracellular NAMPT (eNAMPT), also called visfatin or pre‐B cell colony‐enhancing factor. iNAMPT catalyzes the rate‐limiting step in the NAD+ biosynthesis pathway from nicotinamide. Its inhibition severely reduces intracellular NAD+ levels, achieving anti‐inflammatory and anti‐cancer effects. eNAMPT can be detected in the human circulation and in many extracellular environments. Studies show that eNAMPT can act as a growth factor, as an enzyme, and as a cytokine, but its true mechanism of secretion and its physiological functions are still debated. Increased levels of eNAMPT have been associated with different metabolic disorders and cancers. eNAMPT was demonstrated to modulate the pathways involved in the pathophysiology of obesity, diabetes, atherosclerosis, and cardiovascular events by regulating the oxidative stress response, apoptosis, and inflammation. In cancer, eNAMPT was shown to play a pivotal role in modulating cancer cell metabolism, in promoting epithelial‐to‐mesenchymal transition and in shaping the tumor microenvironment. In line with these functions, circulating eNAMPT levels are frequently increased in cancer patients. Given these pleiotropic roles of eNAMPT in human disease, this protein has attracted attention as a therapeutic target. In this narrative review, we will discuss recent evidence on eNAMPT‐driven signalling, highlighting the emerging pathophysiological roles of this protein in different disorders and the potential therapeutic opportunities linked to its targeting. © 2017 American Physiological Society. Compr Physiol 7:603‐621, 2017.

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Figure 1. Figure 1. Physiological activity of intracellular nicotinamide phosphoribosyltransferase (iNAMPT). iNAMPT catalyses the rate‐limiting reaction of the nicotinamide dinucleotide (NAD+) salvage pathway. NAMPT recycles nicotinamide (NAM), generating nicotinamide mononucleotide (NMN), which is the converted to NAD+ by the NMN adenylyltransferases (NMNAT1‐3). NAMPT expression is dependent on the circadian regulators CLOCK:BMAL1 in complex with SIRT1. iNAMPT modulates the activity of PARPs and of sirtuins located in the nucleus (SIRT1, SIRT6, and SIRT7), in the mitochondria (SIRT3, SIRT4, and SIRT5) and in the cytoplasm (SIRT1 and SIRT2). Some of the nucleotides produced by PARP, sirtuins, as well by other NAD+‐degrading enzymes (e.g., CD38) act as second messengers with calcium‐mobilizing effects. These include cADPR, ADPR, and NAADP.
Figure 2. Figure 2. Autocrine/paracrine effects of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT acts as a cytokine in a wide range of extracellular environments. Although its receptor has not been identified yet, eNAMPT may activate different intracellular cascades and then promote gene transcription. eNAMPT‐mediated cellular responses include the release of other cytokines and the activation of physiological/pathological intracellular pathways. NF‐κB: nuclear factor kappa‐light‐chain‐enhancer of activated B cells; IL: interleukin; ERK: extracellular signal‐regulated kinases; CD: cluster of differentiation; TNF: tumour necrosis factor; iNOS: inducible nitric oxide synthase; NO: nitric oxide; G‐CSF: granulocyte colony stimulating factor; MMP: matrix metalloproteinase; PI3K: phosphatidylinositol‐4,5‐bisphosphate 3‐kinase; CCL: chemokine (C‐C motif) ligand; CCR: C‐C chemokine receptor; CXCL: chemokine (C‐X‐C motif) ligand; AMPK: 5' AMP‐activated protein kinase; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion molecule; SOD: superoxide dismutase; GSH: glutathione.


Figure 1. Physiological activity of intracellular nicotinamide phosphoribosyltransferase (iNAMPT). iNAMPT catalyses the rate‐limiting reaction of the nicotinamide dinucleotide (NAD+) salvage pathway. NAMPT recycles nicotinamide (NAM), generating nicotinamide mononucleotide (NMN), which is the converted to NAD+ by the NMN adenylyltransferases (NMNAT1‐3). NAMPT expression is dependent on the circadian regulators CLOCK:BMAL1 in complex with SIRT1. iNAMPT modulates the activity of PARPs and of sirtuins located in the nucleus (SIRT1, SIRT6, and SIRT7), in the mitochondria (SIRT3, SIRT4, and SIRT5) and in the cytoplasm (SIRT1 and SIRT2). Some of the nucleotides produced by PARP, sirtuins, as well by other NAD+‐degrading enzymes (e.g., CD38) act as second messengers with calcium‐mobilizing effects. These include cADPR, ADPR, and NAADP.


Figure 2. Autocrine/paracrine effects of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT acts as a cytokine in a wide range of extracellular environments. Although its receptor has not been identified yet, eNAMPT may activate different intracellular cascades and then promote gene transcription. eNAMPT‐mediated cellular responses include the release of other cytokines and the activation of physiological/pathological intracellular pathways. NF‐κB: nuclear factor kappa‐light‐chain‐enhancer of activated B cells; IL: interleukin; ERK: extracellular signal‐regulated kinases; CD: cluster of differentiation; TNF: tumour necrosis factor; iNOS: inducible nitric oxide synthase; NO: nitric oxide; G‐CSF: granulocyte colony stimulating factor; MMP: matrix metalloproteinase; PI3K: phosphatidylinositol‐4,5‐bisphosphate 3‐kinase; CCL: chemokine (C‐C motif) ligand; CCR: C‐C chemokine receptor; CXCL: chemokine (C‐X‐C motif) ligand; AMPK: 5' AMP‐activated protein kinase; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; ICAM: intracellular adhesion molecule; VCAM: vascular cell adhesion molecule; SOD: superoxide dismutase; GSH: glutathione.
References
 1.Adeghate E. Visfatin: structure, function and relation to diabetes mellitus and other dysfunctions. Curr Med Chem 15: 1851‐1862, 2008.
 2.Adya R, Tan BK, Chen J, Randeva HS. Pre‐B cell colony enhancing factor (PBEF)/visfatin induces secretion of MCP‐1 in human endothelial cells: Role in visfatin‐induced angiogenesis. Atherosclerosis 205: 113‐119, 2009.
 3.Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin induces human endothelial VEGF and MMP‐2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin‐induced angiogenesis. Cardiovasc Res 78: 356‐365, 2008.
 4.Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J. Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res 95: 971‐980, 2004.
 5.Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423: 181‐185, 2003.
 6.Audrito V, Serra S, Brusa D, Mazzola F, Arruga F, Vaisitti T, Coscia M, Maffei R, Rossi D, Wang T, Inghirami G, Rizzi M, Gaidano G, Garcia JG, Wolberger C, Raffaelli N, Deaglio S. Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia. Blood 125: 111‐123, 2015.
 7.Auguet T, Aragones G, Guiu‐Jurado E, Berlanga A, Curriu M, Martinez S, Alibalic A, Aguilar C, Camara ML, Hernandez E, Ruyra X, Martin‐Paredero V, Richart C. Adipo/cytokines in atherosclerotic secretomes: Increased visfatin levels in unstable carotid plaque. BMC Cardiovasc Disord 16: 149, 2016.
 8.Auguet T, Terra X, Hernandez M, Sabench F, Porras JA, Orellana‐Gavalda JM, Llutart J, Guiu‐Jurado E, Berlanga A, Martinez S, Aguilar C, Castillo DD, Richart C. Clinical and adipocytokine changes after bariatric surgery in morbidly obese women. Obesity (Silver Spring) 22: 188‐194, 2014.
 9.Auguet T, Terra X, Porras JA, Orellana‐Gavalda JM, Martinez S, Aguilar C, Lucas A, Pellitero S, Hernandez M, Del Castillo D, Richart C. Plasma visfatin levels and gene expression in morbidly obese women with associated fatty liver disease. Clin Biochem 46: 202‐208, 2013.
 10.Aust G, Uptaite‐Patapoviene M, Scholz M, Richter O, Rohm S, Bluher M. Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA). Clin Chim Acta 412: 1195‐1200, 2011.
 11.Bae YH, Bae MK, Kim SR, Lee JH, Wee HJ, Bae SK. Upregulation of fibroblast growth factor‐2 by visfatin that promotes endothelial angiogenesis. Biochem Biophys Res Commun 379: 206‐211, 2009.
 12.Barth S, Klein P, Horbach T, Dotsch J, Rauh M, Rascher W, Knerr I. Expression of neuropeptide Y, omentin and visfatin in visceral and subcutaneous adipose tissues in humans: Relation to endocrine and clinical parameters. Obes Facts 3: 245‐251, 2010.
 13.Bauer I, Grozio A, Lasiglie D, Basile G, Sturla L, Magnone M, Sociali G, Soncini D, Caffa I, Poggi A, Zoppoli G, Cea M, Feldmann G, Mostoslavsky R, Ballestrero A, Patrone F, Bruzzone S, Nencioni A. The NAD+‐dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem 287: 40924‐40937, 2012.
 14.Benedict C, Shostak A, Lange T, Brooks SJ, Schioth HB, Schultes B, Born J, Oster H, Hallschmid M. Diurnal rhythm of circulating nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF): Impact of sleep loss and relation to glucose metabolism. J Clin Endocrinol Metab 97: E218‐E222, 2012.
 15.Berndt J, Kloting N, Kralisch S, Kovacs P, Fasshauer M, Schon MR, Stumvoll M, Bluher M. Plasma visfatin concentrations and fat depot‐specific mRNA expression in humans. Diabetes 54: 2911‐2916, 2005.
 16.Bi J, Li H, Ye SQ, Ding S. Pre‐B‐cell colony‐enhancing factor exerts a neuronal protection through its enzymatic activity and the reduction of mitochondrial dysfunction in in vitro ischemic models. J Neurochem 120: 334‐346, 2012.
 17.Billington RA, Bruzzone S, De Flora A, Genazzani AA, Koch‐Nolte F, Ziegler M, Zocchi E. Emerging functions of extracellular pyridine nucleotides. Mol Med 12: 324‐327, 2006.
 18.Billington RA, Genazzani AA, Travelli C, Condorelli F. NAD depletion by FK866 induces autophagy. Autophagy 4: 385‐387, 2008.
 19.Blakemore AI, Meyre D, Delplanque J, Vatin V, Lecoeur C, Marre M, Tichet J, Balkau B, Froguel P, Walley AJ. A rare variant in the visfatin gene (NAMPT/PBEF1) is associated with protection from obesity. Obesity (Silver Spring) 17: 1549‐1553, 2009.
 20.Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: A molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr 28: 115‐130, 2008.
 21.Boini KM, Zhang C, Xia M, Han WQ, Brimson C, Poklis JL, Li PL. Visfatin‐induced lipid raft redox signaling platforms and dysfunction in glomerular endothelial cells. Biochim Biophys Acta 1801: 1294‐1304, 2010.
 22.Brunetti L, Recinella L, Di Nisio C, Chiavaroli A, Leone S, Ferrante C, Orlando G, Vacca M. Effects of visfatin/PBEF/NAMPT on feeding behaviour and hypothalamic neuromodulators in the rat. J Biol Regul Homeost Agents 26: 295‐302, 2012.
 23.Bruzzone S, Fruscione F, Morando S, Ferrando T, Poggi A, Garuti A, D'Urso A, Selmo M, Benvenuto F, Cea M, Zoppoli G, Moran E, Soncini D, Ballestrero A, Sordat B, Patrone F, Mostoslavsky R, Uccelli A, Nencioni A. Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PLoS One 4: e7897, 2009.
 24.Buldak RJ, Buldak L, Polaniak R, Kukla M, Birkner E, Kubina R, Kabala‐Dzik A, Dulawa‐Buldak A, Zwirska‐Korczala K. Visfatin affects redox adaptative responses and proliferation in Me45 human malignant melanoma cells: An in vitro study. Oncol Rep 29: 771‐778, 2013.
 25.Burgos ES, Vetticatt MJ, Schramm VL. Recycling nicotinamide. The transition‐state structure of human nicotinamide phosphoribosyltransferase. J Am Chem Soc 135: 3485‐3493, 2013.
 26.Busso N, Karababa M, Nobile M, Rolaz A, Van Gool F, Galli M, Leo O, So A, De Smedt T. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS One 3: e2267, 2008.
 27.Cabia B, Andrade S, Carreira MC, Casanueva FF, Crujeiras AB. A role for novel adipose tissue‐secreted factors in obesity‐related carcinogenesis. Obes Rev 17: 361‐376, 2016.
 28.Cagnetta A, Caffa I, Acharya C, Soncini D, Acharya P, Adamia S, Pierri I, Bergamaschi M, Garuti A, Fraternali G, Mastracci L, Provenzani A, Zucal C, Damonte G, Salis A, Montecucco F, Patrone F, Ballestrero A, Bruzzone S, Gobbi M, Nencioni A, Cea M. APO866 increases antitumor activity of cyclosporin‐A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells. Clin Cancer Res 21: 3934‐3945, 2015.
 29.Cakmak HA, Aslan S, Yalcin AA, Akturk IF, Yalcin B, Uzun F, Ozturk D, Erturk M, Gul M. Relationship between serum visfatin levels and coronary slow‐flow phenomenon. Herz 40: 921‐928, 2015.
 30.Camp SM, Ceco E, Evenoski CL, Danilov SM, Zhou T, Chiang ET, Moreno‐Vinasco L, Mapes B, Zhao J, Gursoy G, Brown ME, Adyshev DM, Siddiqui SS, Quijada H, Sammani S, Letsiou E, Saadat L, Yousef M, Wang T, Liang J, Garcia JG. Unique toll‐like receptor 4 activation by NAMPT/PBEF induces NFkappaB signaling and inflammatory lung injury. Sci Rep 5: 13135, 2015.
 31.Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez‐Marcos PJ, Yamamoto H, Andreux PA, Cettour‐Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high‐fat diet‐induced obesity. Cell metabolism 15: 838‐847, 2012.
 32.Catalan V, Gomez‐Ambrosi J, Rodriguez A, Ramirez B, Silva C, Rotellar F, Cienfuegos JA, Salvador J, Fruhbeck G. Association of increased visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity. Nutr Metab Cardiovasc Dis 21: 245‐253, 2011.
 33.Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro‐inflammatory cytokine‐mediated impairment of mouse islet function. Diabetologia 54: 3083‐3092, 2011.
 34.Cea M, Cagnetta A, Acharya C, Acharya P, Tai YT, Yang G, Lovera D, Soncini D, Miglino M, Fraternali‐Orcioni G, Mastracci L, Nencioni A, Montecucco F, Monacelli F, Ballestrero A, Hideshima T, Chauhan D, Gobbi M, Lemoli RM, Munshi NC, Treon SP, Anderson KC. Dual Nampt and Btk targeting leads to synergistic killing of Waldenstrom'S macroglobulinemia cells regardless of Myd88 and Cxcr4 somatic mutations status. Clin Cancer Res 2016.
 35.Cea M, Cagnetta A, Fulciniti M, Tai YT, Hideshima T, Chauhan D, Roccaro A, Sacco A, Calimeri T, Cottini F, Jakubikova J, Kong SY, Patrone F, Nencioni A, Gobbi M, Richardson P, Munshi N, Anderson KC. Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal‐regulated kinase (ERK1/2) inhibition. Blood 120: 3519‐3529, 2012.
 36.Chan TF, Chen YL, Chen HH, Lee CH, Jong SB, Tsai EM. Increased plasma visfatin concentrations in women with polycystic ovary syndrome. Fertil Steril 88: 401‐405, 2007.
 37.Chang YH, Chang DM, Lin KC, Shin SJ, Lee YJ. Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: A meta‐analysis and systemic review. Diabetes Metab Res Rev 27: 515‐527, 2011.
 38.Chen MP, Chung FM, Chang DM, Tsai JC, Huang HF, Shin SJ, Lee YJ. Elevated plasma level of visfatin/pre‐B cell colony‐enhancing factor in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 91: 295‐299, 2006.
 39.Chen Y, Chen M, Wu Z, Zhao S. Ox‐LDL induces ER stress and promotes the adipokines secretion in 3T3‐L1 adipocytes. PLoS One 8: e81379, 2013.
 40.Cheng G, Liu C, Sun X, Zhang L, Liu L, Ouyang J, Li B. Visfatin promotes osteosarcoma cell migration and invasion via induction of epithelial‐mesenchymal transition. Oncol Rep 34: 987‐994, 2015.
 41.Cline MA, Nandar W, Prall BC, Bowden CN, Denbow DM. Central visfatin causes orexigenic effects in chicks. Behav Brain Res 186: 293‐297, 2008.
 42.Costford SR, Bajpeyi S, Pasarica M, Albarado DC, Thomas SC, Xie H, Church TS, Jubrias SA, Conley KE, Smith SR. Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab 298: E117‐E126, 2010.
 43.Curat CA, Wegner V, Sengenes C, Miranville A, Tonus C, Busse R, Bouloumie A. Macrophages in human visceral adipose tissue: Increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 49: 744‐747, 2006.
 44.Dahl TB, Yndestad A, Skjelland M, Oie E, Dahl A, Michelsen A, Damas JK, Tunheim SH, Ueland T, Smith C, Bendz B, Tonstad S, Gullestad L, Froland SS, Krohg‐Sorensen K, Russell D, Aukrust P, Halvorsen B. Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: Possible role in inflammation and plaque destabilization. Circulation 115: 972‐980, 2007.
 45.Dalamaga M, Karmaniolas K, Papadavid E, Pelekanos N, Sotiropoulos G, Lekka A. Elevated serum visfatin/nicotinamide phosphoribosyl‐transferase levels are associated with risk of postmenopausal breast cancer independently from adiponectin, leptin, and anthropometric and metabolic parameters. Menopause 18: 1198‐1204, 2011.
 46.de Boer JF, Bahr MJ, Boker KH, Manns MP, Tietge UJ. Plasma levels of PBEF/Nampt/visfatin are decreased in patients with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 296: G196‐G201, 2009.
 47.De Flora A, Zocchi E, Guida L, Franco L, Bruzzone S. Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP‐ribose system. Ann N Y Acad Sci 1028: 176‐191, 2004.
 48.Degtyarev M, De Maziere A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, Davis DP, Stern HM, Murray LJ, Hoeflich KP, Klumperman J, Friedman LS, Lin K. Akt inhibition promotes autophagy and sensitizes PTEN‐null tumors to lysosomotropic agents. J Cell Biol 183: 101‐116, 2008.
 49.El‐Mesallamy HO, Kassem DH, El‐Demerdash E, Amin AI. Vaspin and visfatin/Nampt are interesting interrelated adipokines playing a role in the pathogenesis of type 2 diabetes mellitus. Metabolism 60: 63‐70, 2011.
 50.El‐Shishtawy SH, Mosbah O, Sherif N, Metwaly A, Hanafy A, Kamel L. Association between serum visfatin and carotid atherosclerosis in diabetic and non‐diabetic patients on maintenance hemodialysis. Electron Physician 8: 1966‐1972, 2016.
 51.Erfani S, Khaksari M, Oryan S, Shamsaei N, Aboutaleb N, Nikbakht F. Nampt/PBEF/visfatin exerts neuroprotective effects against ischemia/reperfusion injury via modulation of Bax/Bcl‐2 ratio and prevention of caspase‐3 activation. J Mol Neurosci 56: 237‐243, 2015.
 52.Erfani S, Khaksari M, Oryan S, Shamsaei N, Aboutaleb N, Nikbakht F, Jamali‐Raeufy N, Gorjipour F. Visfatin reduces hippocampal CA1 cells death and improves learning and memory deficits after transient global ischemia/reperfusion. Neuropeptides 49: 63‐68, 2015.
 53.Ernst IM, Fliegert R, Guse AH. Adenine dinucleotide second messengers and T‐lymphocyte calcium signaling. Front Immunol 4: 259, 2013.
 54.Ersoy C, Sadikoglu G, Orhan H, Guclu M, Sarandol E, Akgun MD, Ozcakir A, Imamoglu S. Body fat distribution has no effect on serum visfatin levels in healthy female subjects. Cytokine 49: 275‐278, 2010.
 55.Esposito E, Impellizzeri D, Mazzon E, Fakhfouri G, Rahimian R, Travelli C, Tron GC, Genazzani AA, Cuzzocrea S. The NAMPT inhibitor FK866 reverts the damage in spinal cord injury. J Neuroinflammation 9: 66, 2012.
 56.Evans L, Williams AS, Hayes AJ, Jones SA, Nowell M. Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre‐B cell colony‐enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866‐mediated therapy in human fibroblasts and murine collagen‐induced arthritis. Arthritis Rheum 63: 1866‐1877, 2011.
 57.Fan Y, Meng S, Wang Y, Cao J, Wang C. Visfatin/PBEF/Nampt induces EMMPRIN and MMP‐9 production in macrophages via the NAMPT‐MAPK (p38, ERK1/2)‐NF‐kappaB signaling pathway. Int J Mol Med 27: 607‐615, 2011.
 58.Fazeli MS, Dashti H, Akbarzadeh S, Assadi M, Aminian A, Keramati MR, Nabipour I. Circulating levels of novel adipocytokines in patients with colorectal cancer. Cytokine 62: 81‐85, 2013.
 59.Fazeli MS, Keramati MR, Rahimi A, Kazemeini A, Banoei MM, Dashti H, Fazeli AR. Visfatin level in patients with colorectal adenoma. Med J Islam Repub Iran 30: 320, 2016.
 60.Formentini L, Moroni F, Chiarugi A. Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo. Biochem Pharmacol 77: 1612‐1620, 2009.
 61.Friebe D, Loffler D, Schonberg M, Bernhard F, Buttner P, Landgraf K, Kiess W, Korner A. Impact of metabolic regulators on the expression of the obesity associated genes FTO and NAMPT in human preadipocytes and adipocytes. PLoS One 6: e19526, 2011.
 62.Friebe D, Neef M, Kratzsch J, Erbs S, Dittrich K, Garten A, Petzold‐Quinque S, Bluher S, Reinehr T, Stumvoll M, Bluher M, Kiess W, Korner A. Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre‐B cell colony (PBEF)/visfatin linking obesity and inflammation in humans. Diabetologia 54: 1200‐1211, 2011.
 63.Fruscione F, Scarfi S, Ferraris C, Bruzzone S, Benvenuto F, Guida L, Uccelli A, Salis A, Usai C, Jacchetti E, Ilengo C, Scaglione S, Quarto R, Zocchi E, De Flora A. Regulation of human mesenchymal stem cell functions by an autocrine loop involving NAD+ release and P2Y11‐mediated signaling. Stem Cells Dev 20: 1183‐1198, 2011.
 64.Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Visfatin: A protein secreted by visceral fat that mimics the effects of insulin. Science 307: 426‐430, 2005.
 65.Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Retraction. Science 318: 565, 2007.
 66.Galli U, Travelli C, Massarotti A, Fakhfouri G, Rahimian R, Tron GC, Genazzani AA. Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. J Med Chem 56: 6279‐6296, 2013.
 67.Garavaglia S, Bruzzone S, Cassani C, Canella L, Allegrone G, Sturla L, Mannino E, Millo E, De Flora A, Rizzi M. The high‐resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem J 441: 131‐141, 2012.
 68.Garten A, Petzold S, Barnikol‐Oettler A, Korner A, Thasler WE, Kratzsch J, Kiess W, Gebhardt R. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes. Biochem Biophys Res Commun 391: 376‐381, 2010.
 69.Garten A, Petzold S, Korner A, Imai S, Kiess W. Nampt: Linking NAD biology, metabolism and cancer. Trends Endocrinol Metab 20: 130‐138, 2009.
 70.Garten A, Schuster S, Penke M, Gorski T, de Giorgis T, Kiess W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol 11: 535‐546, 2015.
 71.Gorgian Mohammadi M, Hedayati M, Zarghami N, Ghaemmaghami S, Mohaddes M. Adipocyte derived hormones gene expression, resistin and visfatin, in AGS gastric cancer cell line. Iran J Cancer Prev 6: 165‐169, 2013.
 72.Grolla AA, Torretta S, Gnemmi I, Amoruso A, Orsomando G, Gatti M, Caldarelli A, Lim D, Penengo L, Brunelleschi S, Genazzani AA, Travelli C. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is a tumoural cytokine released from melanoma. Pigment Cell Melanoma Res 28: 718‐729, 2015.
 73.Grozio A, Sociali G, Sturla L, Caffa I, Soncini D, Salis A, Raffaelli N, De Flora A, Nencioni A, Bruzzone S. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866‐treated tumor cells. J Biol Chem 288: 25938‐25949, 2013.
 74.Grzywocz P, Mizia‐Stec K, Wybraniec M, Chudek J. Adipokines and endothelial dysfunction in acute myocardial infarction and the risk of recurrent cardiovascular events. J Cardiovasc Med (Hagerstown) 16: 37‐44, 2015.
 75.Haider DG, Schaller G, Kapiotis S, Maier C, Luger A, Wolzt M. The release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia 49: 1909‐1914, 2006.
 76.Hajianfar H, Bahonar A, Entezari MH, Askari G, Yazdani M. Lipid profiles and serum visfatin concentrations in patients with type II diabetes in comparison with healthy controls. Int J Prev Med 3: 326‐331, 2012.
 77.Hara N, Yamada K, Shibata T, Osago H, Tsuchiya M. Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS One 6: e22781, 2011.
 78.Hasmann M, Schemainda I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res 63: 7436‐7442, 2003.
 79.Hassan SB, Lovborg H, Lindhagen E, Karlsson MO, Larsson R. CHS 828 kill tumour cells by inhibiting the nuclear factor‐kappaB translocation but unlikely through down‐regulation of proteasome. Anticancer Res 26: 4431‐4436, 2006.
 80.Hong SB, Huang Y, Moreno‐Vinasco L, Sammani S, Moitra J, Barnard JW, Ma SF, Mirzapoiazova T, Evenoski C, Reeves RR, Chiang ET, Lang GD, Husain AN, Dudek SM, Jacobson JR, Ye SQ, Lussier YA, Garcia JG. Essential role of pre‐B‐cell colony enhancing factor in ventilator‐induced lung injury. Am J Respir Crit Care Med 178: 605‐617, 2008.
 81.Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901‐911, 2007.
 82.Hosseinzadeh‐Attar MJ, Golpaie A, Janani L, Derakhshanian H. Effect of weight reduction following bariatric surgery on serum visfatin and adiponectin levels in morbidly obese subjects. Obes Facts 6: 193‐202, 2013.
 83.Hsu CP, Hariharan N, Alcendor RR, Oka S, Sadoshima J. Nicotinamide phosphoribosyltransferase regulates cell survival through autophagy in cardiomyocytes. Autophagy 5: 1229‐1231, 2009.
 84.Hsu CP, Oka S, Shao D, Hariharan N, Sadoshima J. Nicotinamide phosphoribosyltransferase regulates cell survival through NAD+ synthesis in cardiac myocytes. Circ Res 105: 481‐491, 2009.
 85.Hsu CP, Yamamoto T, Oka S, Sadoshima J. The function of nicotinamide phosphoribosyltransferase in the heart. DNA Repair (Amst) 23: 64‐68, 2014.
 86.Hsu CP, Zhai P, Yamamoto T, Maejima Y, Matsushima S, Hariharan N, Shao D, Takagi H, Oka S, Sadoshima J. Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation 122: 2170‐2182, 2010.
 87.Huang WS, Chen CN, Sze CI, Teng CC. Visfatin induces stromal cell‐derived factor‐1 expression by beta1 integrin signaling in colorectal cancer cells. J Cell Physiol 228: 1017‐1024, 2013.
 88.Huang Q, Liu D, Majewski P, Schulte LC, Korn JM, Young RA, Lander ES, Hacohen N. The plasticity of dendritic cell responses to pathogens and their components. Science 294: 870‐875, 2001.
 89.Huang P, Riordan SM, Heruth DP, Grigoryev DN, Zhang LQ, Ye SQ. A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells. Oncotarget 6: 10812‐10824, 2015.
 90.Hung WC, Yu TH, Hsu CC, Lu LF, Chung FM, Tsai IT, Lu YC, Houng JY, Lee YJ, Wang CP. Plasma visfatin levels are associated with major adverse cardiovascular events in patients with acute ST‐elevation myocardial infarction. Clin Invest Med 38: E100‐E109, 2015.
 91.Jing Z, Xing J, Chen X, Stetler RA, Weng Z, Gan Y, Zhang F, Gao Y, Chen J, Leak RK, Cao G. Neuronal NAMPT is released after cerebral ischemia and protects against white matter injury. J Cereb Blood Flow Metab 34: 1613‐1621, 2014.
 92.Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Tsanikidis H, Vitta I, Karkos C, Karayannacos PE, Gerasimidis T, Liapis CD. Visfatin (nampt) and ghrelin as novel markers of carotid atherosclerosis in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 118: 75‐80, 2010.
 93.Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444: 840‐846, 2006.
 94.Kaminska A, Kopczynska E, Bronisz A, Zmudzinska M, Bielinski M, Borkowska A, Tyrakowski T, Junik R. An evaluation of visfatin levels in obese subjects. Endokrynol Pol 61: 169‐173, 2010.
 95.Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF. SIRT6 links histone H3 lysine 9 deacetylation to NF‐kappaB‐dependent gene expression and organismal life span. Cell 136: 62‐74, 2009.
 96.Khan JA, Tao X, Tong L. Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents. Nat Struct Mol Biol 13: 582‐588, 2006.
 97.Kim SR, Bae YH, Bae SK, Choi KS, Yoon KH, Koo TH, Jang HO, Yun I, Kim KW, Kwon YG, Yoo MA, Bae MK. Visfatin enhances ICAM‐1 and VCAM‐1 expression through ROS‐dependent NF‐kappaB activation in endothelial cells. Biochim Biophys Acta 1783: 886‐895, 2008.
 98.Kim SR, Bae SK, Choi KS, Park SY, Jun HO, Lee JY, Jang HO, Yun I, Yoon KH, Kim YJ, Yoo MA, Kim KW, Bae MK. Visfatin promotes angiogenesis by activation of extracellular signal‐regulated kinase 1/2. Biochem Biophys Res Commun 357: 150‐156, 2007.
 99.Kim HS, Han SY, Sung HY, Park SH, Kang MK, Han SJ, Kang YH. Blockade of visfatin induction by oleanolic acid via disturbing IL‐6‐TRAF6‐NF‐kappaB signaling of adipocytes. Exp Biol Med (Maywood) 239: 284‐292, 2014.
 100.Klein C, Grahnert A, Abdelrahman A, Muller CE, Hauschildt S. Extracellular NAD(+) induces a rise in [Ca(2+)](i) in activated human monocytes via engagement of P2Y(1) and P2Y(11) receptors. Cell calcium 46: 263‐272, 2009.
 101.Kollmar O, Rupertus K, Scheuer C, Junker B, Tilton B, Schilling MK, Menger MD. Stromal cell‐derived factor‐1 promotes cell migration and tumor growth of colorectal metastasis. Neoplasia 9: 862‐870, 2007.
 102.Konior A, Schramm A, Czesnikiewicz‐Guzik M, Guzik TJ. NADPH oxidases in vascular pathology. Antioxid Redox Signal 20: 2794‐2814, 2014.
 103.Korner A, Garten A, Bluher M, Tauscher R, Kratzsch J, Kiess W. Molecular characteristics of serum visfatin and differential detection by immunoassays. J Clin Endocrinol Metab 92: 4783‐4791, 2007.
 104.Kovacs D, Lovaszi M, Poliska S, Olah A, Biro T, Veres I, Zouboulis CC, Stahle M, Ruhl R, Remenyik E, Torocsik D. Sebocytes differentially express and secrete adipokines. Exp Dermatol 25: 194‐199, 2016.
 105.Kralisch S, Klein J, Lossner U, Bluher M, Paschke R, Stumvoll M, Fasshauer M. Hormonal regulation of the novel adipocytokine visfatin in 3T3‐L1 adipocytes. J Endocrinol 185: R1‐R8, 2005.
 106.Krzystek‐Korpacka M, Patryn E, Bednarz‐Misa I, Hotowy K, Noczynska A. Visfatin in juvenile obesity—the effect of obesity intervention and sex. Eur J Clin Invest 41: 1284‐1291, 2011.
 107.Leander K, Gigante B, Silveira A, Vikstrom M, Hamsten A, Hogberg J. NAMPT (visfatin) and AKT1 genetic variants associate with myocardial infarction. Clin Chim Acta 413: 727‐732, 2012.
 108.Lee KA, Gong MN. Pre‐B‐cell colony‐enhancing factor and its clinical correlates with acute lung injury and sepsis. Chest 140: 382‐390, 2011.
 109.Lee WJ, Wu CS, Lin H, Lee IT, Wu CM, Tseng JJ, Chou MM, Sheu WH. Visfatin‐induced expression of inflammatory mediators in human endothelial cells through the NF‐kappaB pathway. Int J Obes (Lond) 33: 465‐472, 2009.
 110.Lee YC, Yang YH, Su JH, Chang HL, Hou MF, Yuan SS. High visfatin expression in breast cancer tissue is associated with poor survival. Cancer Epidemiol Biomarkers Prev 20: 1892‐1901, 2011.
 111.Li RZ, Ma X, Hu XF, Kang SX, Chen SK, Cianflone K, Lu HL. Elevated visfatin levels in obese children are related to proinflammatory factors. J Pediatr Endocrinol Metab 26: 111‐118, 2013.
 112.Li S, Wang C, Li K, Li L, Tian M, Xie J, Yang M, Jia Y, He J, Gao L, Boden G, Liu H, Yang G. NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high‐fat‐induced insulin resistance. Sci Rep 6: 26746, 2016.
 113.Li Y, Zhang Y, Dorweiler B, Cui D, Wang T, Woo CW, Brunkan CS, Wolberger C, Imai S, Tabas I. Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin‐6/STAT3 signaling mechanism. J Biol Chem 283: 34833‐34843, 2008.
 114.Lim SY, Davidson SM, Paramanathan AJ, Smith CC, Yellon DM, Hausenloy DJ. The novel adipocytokine visfatin exerts direct cardioprotective effects. J Cell Mol Med 12: 1395‐1403, 2008.
 115.Lin YC, Wu HC, Liao CC, Chou YC, Pan SF, Chiu CM. Secretion of one adipokine Nampt/Visfatin suppresses the inflammatory stress‐induced NF‐kappaB activity and affects Nampt‐dependent cell viability in Huh‐7 cells. Mediators Inflamm 2015: 392471, 2015.
 116.Liu SW, Qiao SB, Yuan JS, Liu DQ. Association of plasma visfatin levels with inflammation, atherosclerosis and acute coronary syndromes (ACS) in humans. Clin Endocrinol (Oxf) 71: 202‐207, 2009.
 117.Lopez‐Bermejo A, Chico‐Julia B, Fernandez‐Balsells M, Recasens M, Esteve E, Casamitjana R, Ricart W, Fernandez‐Real JM. Serum visfatin increases with progressive beta‐cell deterioration. Diabetes 55: 2871‐2875, 2006.
 118.Lovren F, Pan Y, Shukla PC, Quan A, Teoh H, Szmitko PE, Peterson MD, Gupta M, Al‐Omran M, Verma S. Visfatin activates eNOS via Akt and MAP kinases and improves endothelial cell function and angiogenesis in vitro and in vivo: Translational implications for atherosclerosis. Am J Physiol Endocrinol Metab 296: E1440‐E1449, 2009.
 119.Magnone M, Bauer I, Poggi A, Mannino E, Sturla L, Brini M, Zocchi E, De Flora A, Nencioni A, Bruzzone S. NAD+ levels control Ca2+ store replenishment and mitogen‐induced increase of cytosolic Ca2+ by cyclic ADP‐ribose‐dependent TRPM2 channel gating in human T lymphocytes. J Biol Chem 287: 21067‐21081, 2012.
 120.Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88: 841‐886, 2008.
 121.Martin PR, Shea RJ, Mulks MH. Identification of a plasmid‐encoded gene from Haemophilus ducreyi which confers NAD independence. J Bacteriol 183: 1168‐1174, 2001.
 122.Martos‐Moreno GA, Kratzsch J, Korner A, Barrios V, Hawkins F, Kiess W, Argente J. Serum visfatin and vaspin levels in prepubertal children: Effect of obesity and weight loss after behavior modifications on their secretion and relationship with glucose metabolism. Int J Obes (Lond) 35: 1355‐1362, 2011.
 123.Mazaherioun M, Hosseinzadeh‐Attar MJ, Janani L, Vasheghani Farahani A, Rezvan N, Karbaschian Z, Hossein‐Nezhad A. Elevated serum visfatin levels in patients with acute myocardial infarction. Arch Iran Med 15: 688‐692, 2012.
 124.Mohammadi M, Zarghami N, Hedayati M, Ghaemmaghami S, Yamchi RM, Mohaddes M. Visfatin effects on telomerase gene expression in AGS gastric cancer cell line. Indian J Cancer 52: 32‐35, 2015.
 125.Montecucco F, Bauer I, Braunersreuther V, Bruzzone S, Akhmedov A, Luscher TF, Speer T, Poggi A, Mannino E, Pelli G, Galan K, Bertolotto M, Lenglet S, Garuti A, Montessuit C, Lerch R, Pellieux C, Vuilleumier N, Dallegri F, Mage J, Sebastian C, Mostoslavsky R, Gayet‐Ageron A, Patrone F, Mach F, Nencioni A. Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil‐mediated injury in myocardial infarction. Antioxid Redox Signal 18: 630‐641, 2013.
 126.Montecucco F, Cea M, Bauer I, Soncini D, Caffa I, Lasiglie D, Nahimana A, Uccelli A, Bruzzone S, Nencioni A. Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors as therapeutics: Rationales, controversies, clinical experience. Curr Drug Targets 14: 637‐643, 2013.
 127.Moreno‐Vinasco L, Quijada H, Sammani S, Siegler J, Letsiou E, Deaton R, Saadat L, Zaidi RS, Messana J, Gann PH, Machado RF, Ma W, Camp SM, Wang T, Garcia JG. Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in murine models of inflammatory lung injury. Am J Respir Cell Mol Biol 51: 223‐228, 2014.
 128.Moreschi I, Bruzzone S, Nicholas RA, Fruscione F, Sturla L, Benvenuto F, Usai C, Meis S, Kassack MU, Zocchi E, De Flora A. Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes. J Biol Chem 281: 31419‐31429, 2006.
 129.Moschen AR, Gerner R, Schroll A, Fritz T, Kaser A, Tilg H. A key role for Pre‐B cell colony‐enhancing factor in experimental hepatitis. Hepatology 54: 675‐686, 2011.
 130.Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, Tilg H. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 178: 1748‐1758, 2007.
 131.Motawi TM, Shaker OG, El‐Sawalhi MM, Abdel‐Nasser ZM. Visfatin ‐948G/T and resistin ‐420C/G polymorphisms in Egyptian type 2 diabetic patients with and without cardiovascular diseases. Genome 57: 259‐266, 2014.
 132.Mutafova‐Yambolieva VN, Hwang SJ, Hao X, Chen H, Zhu MX, Wood JD, Ward SM, Sanders KM. Beta‐nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc Natl Acad Sci U S A 104: 16359‐16364, 2007.
 133.Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone‐Corsi P. Circadian control of the NAD+ salvage pathway by CLOCK‐SIRT1. Science 324: 654‐657, 2009.
 134.Nakajima TE, Yamada Y, Hamano T, Furuta K, Gotoda T, Katai H, Kato K, Hamaguchi T, Shimada Y. Adipocytokine levels in gastric cancer patients: Resistin and visfatin as biomarkers of gastric cancer. J Gastroenterol 44: 685‐690, 2009.
 135.Nencioni A, da Silva RF, Fraga‐Silva RA, Steffens S, Fabre M, Bauer I, Caffa I, Magnone M, Sociali G, Quercioli A, Pelli G, Lenglet S, Galan K, Burger F, Vazquez Calvo S, Bertolotto M, Bruzzone S, Ballestrero A, Patrone F, Dallegri F, Santos RA, Stergiopulos N, Mach F, Vuilleumier N, Montecucco F. Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice. Thromb Haemost 111: 308‐322, 2014.
 136.Neubauer K, Misa IB, Diakowska D, Kapturkiewicz B, Gamian A, Krzystek‐Korpacka M. Nampt/PBEF/visfatin upregulation in colorectal tumors, mirrored in normal tissue and whole blood of colorectal cancer patients, is associated with metastasis, hypoxia, IL1beta, and anemia. Biomed Res Int 2015: 523930, 2015.
 137.Nikiforov A, Dolle C, Niere M, Ziegler M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: From entry of extracellular precursors to mitochondrial NAD generation. J Biol Chem 286: 21767‐21778, 2011.
 138.Ninomiya S, Shimizu M, Imai K, Takai K, Shiraki M, Hara T, Tsurumi H, Ishizaki S, Moriwaki H. Possible role of visfatin in hepatoma progression and the effects of branched‐chain amino acids on visfatin‐induced proliferation in human hepatoma cells. Cancer Prev Res (Phila) 4: 2092‐2100, 2011.
 139.Ognjanovic S, Bao S, Yamamoto SY, Garibay‐Tupas J, Samal B, Bryant‐Greenwood GD. Genomic organization of the gene coding for human pre‐B‐cell colony enhancing factor and expression in human fetal membranes. J Mol Endocrinol 26: 107‐117, 2001.
 140.Ognjanovic S, Ku TL, Bryant‐Greenwood GD. Pre‐B‐cell colony‐enhancing factor is a secreted cytokine‐like protein from the human amniotic epithelium. Am J Obstet Gynecol 193: 273‐282, 2005.
 141.Olarescu NC, Ueland T, Lekva T, Dahl TB, Halvorsen B, Aukrust P, Bollerslev J. Adipocytes as a source of increased circulating levels of nicotinamide phosphoribosyltransferase/visfatin in active acromegaly. J Clin Endocrinol Metab 97: 1355‐1362, 2012.
 142.Olesen UH, Hastrup N, Sehested M. Expression patterns of nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase in human malignant lymphomas. APMIS 119: 296‐303, 2011.
 143.Olesen UH, Petersen JG, Garten A, Kiess W, Yoshino J, Imai S, Christensen MK, Fristrup P, Thougaard AV, Bjorkling F, Jensen PB, Nielsen SJ, Sehested M. Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase. BMC Cancer 10: 677, 2010.
 144.Olsen LS, Hjarnaa PJ, Latini S, Holm PK, Larsson R, Bramm E, Binderup L, Madsen MW. Anticancer agent CHS 828 suppresses nuclear factor‐kappa B activity in cancer cells through downregulation of IKK activity. Int J Cancer 111: 198‐205, 2004.
 145.Ozgen M, Koca SS, Aksoy K, Dagli N, Ustundag B, Isik A. Visfatin levels and intima‐media thicknesses in rheumatic diseases. Clin Rheumatol 30: 757‐763, 2011.
 146.Pagano C, Pilon C, Olivieri M, Mason P, Fabris R, Serra R, Milan G, Rossato M, Federspil G, Vettor R. Reduced plasma visfatin/pre‐B cell colony‐enhancing factor in obesity is not related to insulin resistance in humans. J Clin Endocrinol Metab 91: 3165‐3170, 2006.
 147.Park HJ, Kim SR, Kim SS, Wee HJ, Bae MK, Ryu MH, Bae SK. Visfatin promotes cell and tumor growth by upregulating Notch1 in breast cancer. Oncotarget 5: 5087‐5099, 2014.
 148.Patel ST, Mistry T, Brown JE, Digby JE, Adya R, Desai KM, Randeva HS. A novel role for the adipokine visfatin/pre‐B cell colony‐enhancing factor 1 in prostate carcinogenesis. Peptides 31: 51‐57, 2010.
 149.Pillai VB, Sundaresan NR, Kim G, Samant S, Moreno‐Vinasco L, Garcia JG, Gupta MP. Nampt secreted from cardiomyocytes promotes development of cardiac hypertrophy and adverse ventricular remodeling. Am J Physiol Heart Circ Physiol 304: H415‐H426, 2013.
 150.Pittelli M, Formentini L, Faraco G, Lapucci A, Rapizzi E, Cialdai F, Romano G, Moneti G, Moroni F, Chiarugi A. Inhibition of nicotinamide phosphoribosyltransferase: Cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J Biol Chem 285: 34106‐34114, 2010.
 151.Preiss J, Handler P. Enzymatic synthesis of nicotinamide mononucleotide. J Biol Chem 225: 759‐770, 1957.
 152.Presumey J, Courties G, Louis‐Plence P, Escriou V, Scherman D, Pers YM, Yssel H, Pene J, Kyburz D, Gay S, Jorgensen C, Apparailly F. Nicotinamide phosphoribosyltransferase/visfatin expression by inflammatory monocytes mediates arthritis pathogenesis. Ann Rheum Dis 72: 1717‐1724, 2013.
 153.Ramsey KM, Mills KF, Satoh A, Imai S. Age‐associated loss of Sirt1‐mediated enhancement of glucose‐stimulated insulin secretion in beta cell‐specific Sirt1‐overexpressing (BESTO) mice. Aging Cell 7: 78‐88, 2008.
 154.Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J. Circadian clock feedback cycle through NAMPT‐mediated NAD+ biosynthesis. Science 324: 651‐654, 2009.
 155.Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Canto C. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun 7: 13103, 2016.
 156.Reda R, Shehab A, Soliman D, Gabr A, Abbass A. Serum visfatin levels in a group of Egyptian obese individuals. Egypt J Immunol 18: 25‐32, 2011.
 157.Reddy PS, Umesh S, Thota B, Tandon A, Pandey P, Hegde AS, Balasubramaniam A, Chandramouli BA, Santosh V, Rao MR, Kondaiah P, Somasundaram K. PBEF1/NAmPRTase/Visfatin: A potential malignant astrocytoma/glioblastoma serum marker with prognostic value. Cancer Biol Ther 7: 663‐668, 2008.
 158.Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 279: 50754‐50763, 2004.
 159.Revollo JR, Grimm AA, Imai S. The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Curr Opin Gastroenterol 23: 164‐170, 2007.
 160.Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab 6: 363‐375, 2007.
 161.Rissiek B, Haag F, Boyer O, Koch‐Nolte F, Adriouch S. ADP‐ribosylation of P2X7: A matter of life and death for regulatory T cells and natural killer T cells. Curr Top Microbiol Immunol 384: 107‐126, 2015.
 162.Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F. Pre‐B‐cell colony‐enhancing factor, whose expression is up‐regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur J Immunol 32: 3225‐3234, 2002.
 163.Saboori S, Hosseinzadeh‐Attar MJ, Yousefi Rad E, Hosseini M, Mirzaei K, Ahmadivand Z. The comparison of serum vaspin and visfatin concentrations in obese and normal weight women. Diabetes Metab Syndr 9: 320‐323, 2015.
 164.Saddi‐Rosa P, Oliveira C, Crispim F, Giuffrida FM, de Lima V, Vieira J, Doria A, Velho G, Reis A. Association of circulating levels of nicotinamide phosphoribosyltransferase (NAMPT/Visfatin) and of a frequent polymorphism in the promoter of the NAMPT gene with coronary artery disease in diabetic and non‐diabetic subjects. Cardiovasc Diabetol 12: 119, 2013.
 165.Salama HM, Galal A, Motawie AA, Kamel AF, Ibrahim DM, Aly AA, Hassan EA. Adipokines vaspin and visfatin in obese children. Open Access Maced J Med Sci 3: 563‐566, 2015.
 166.Salgado‐Delgado RC, Saderi N, Basualdo Mdel C, Guerrero‐Vargas NN, Escobar C, Buijs RM. Shift work or food intake during the rest phase promotes metabolic disruption and desynchrony of liver genes in male rats. PLoS One 8: e60052, 2013.
 167.Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I. Cloning and characterization of the cDNA encoding a novel human pre‐B‐cell colony‐enhancing factor. Mol Cell Biol 14: 1431‐1437, 1994.
 168.Sampath D, Zabka TS, Misner DL, O'Brien T, Dragovich PS. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer. Pharmacol Ther 151: 16‐31, 2015.
 169.Sandeep S, Velmurugan K, Deepa R, Mohan V. Serum visfatin in relation to visceral fat, obesity, and type 2 diabetes mellitus in Asian Indians. Metabolism 56: 565‐570, 2007.
 170.Segawa K, Fukuhara A, Hosogai N, Morita K, Okuno Y, Tanaka M, Nakagawa Y, Kihara S, Funahashi T, Komuro R, Matsuda M, Shimomura I. Visfatin in adipocytes is upregulated by hypoxia through HIF1alpha‐dependent mechanism. Biochem Biophys Res Commun 349: 875‐882, 2006.
 171.Soncini D, Caffa I, Zoppoli G, Cea M, Cagnetta A, Passalacqua M, Mastracci L, Boero S, Montecucco F, Sociali G, Lasiglie D, Damonte P, Grozio A, Mannino E, Poggi A, D'Agostino VG, Monacelli F, Provenzani A, Odetti P, Ballestrero A, Bruzzone S, Nencioni A. Nicotinamide phosphoribosyltransferase promotes epithelial‐to‐mesenchymal transition as a soluble factor independent of its enzymatic activity. J Biol Chem 289: 34189‐34204, 2014.
 172.Spinnler R, Gorski T, Stolz K, Schuster S, Garten A, Beck‐Sickinger AG, Engelse MA, de Koning EJ, Korner A, Kiess W, Maedler K. The adipocytokine Nampt and its product NMN have no effect on beta‐cell survival but potentiate glucose stimulated insulin secretion. PLoS One 8: e54106, 2013.
 173.Spiroglou SG, Kostopoulos CG, Varakis JN, Papadaki HH. Adipokines in periaortic and epicardial adipose tissue: differential expression and relation to atherosclerosis. J Atheroscler Thromb 17: 115‐130, 2010.
 174.Takahashi R, Nakamura S, Yoshida T, Kobayashi Y, Ohkubo T. Crystallization of human nicotinamide phosphoribosyltransferase. Acta Crystallogr Sect F Struct Biol Cryst Commun 63: 375‐377, 2007.
 175.Tanaka T, Nabeshima Y. Nampt/PBEF/Visfatin: A new player in beta cell physiology and in metabolic diseases? Cell Metab 6: 341‐343, 2007.
 176.Taskesen D, Kirel B, Us T. Serum visfatin levels, adiposity and glucose metabolism in obese adolescents. J Clin Res Pediatr Endocrinol 4: 76‐81, 2012.
 177.Terra X, Auguet T, Quesada I, Aguilar C, Luna AM, Hernandez M, Sabench F, Porras JA, Martinez S, Lucas A, Pellitero S, Llutart J, del Castillo D, Richart C. Increased levels and adipose tissue expression of visfatin in morbidly obese women: The relationship with pro‐inflammatory cytokines. Clin Endocrinol (Oxf) 77: 691‐698, 2012.
 178.Tian W, Zhu Y, Wang Y, Teng F, Zhang H, Liu G, Ma X, Sun D, Rohan T, Xue F. Visfatin, a potential biomarker and prognostic factor for endometrial cancer. Gynecol Oncol 129: 505‐512, 2013.
 179.Unluturk U, Harmanci A, Yildiz BO, Bayraktar M. Dynamics of Nampt/visfatin and high molecular weight adiponectin in response to oral glucose load in obese and lean women. Clin Endocrinol (Oxf) 72: 469‐474, 2010.
 180.Van den Bergh R, Morin S, Sass HJ, Grzesiek S, Vekemans M, Florence E, Tran HT, Imiru RG, Heyndrickx L, Vanham G, De Baetselier P, Raes G. Monocytes contribute to differential immune pressure on R5 versus X4 HIV through the adipocytokine visfatin/NAMPT. PLoS One 7: e35074, 2012.
 181.van der Veer E, Ho C, O'Neil C, Barbosa N, Scott R, Cregan SP, Pickering JG. Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J Biol Chem 282: 10841‐10845, 2007.
 182.Van Gool F, Galli M, Gueydan C, Kruys V, Prevot PP, Bedalov A, Mostoslavsky R, Alt FW, De Smedt T, Leo O. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin‐dependent manner. Nat Med 15: 206‐210, 2009.
 183.Varma V, Yao‐Borengasser A, Rasouli N, Bodles AM, Phanavanh B, Lee MJ, Starks T, Kern LM, Spencer HJ, III, McGehee RE, Jr, Fried SK, Kern PA. Human visfatin expression: Relationship to insulin sensitivity, intramyocellular lipids, and inflammation. J Clin Endocrinol Metab 92: 666‐672, 2007.
 184.von Heideman A, Berglund A, Larsson R, Nygren P. Safety and efficacy of NAD depleting cancer drugs: Results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother Pharmacol 65: 1165‐1172, 2010.
 185.Wang Y, Gao C, Zhang Y, Gao J, Teng F, Tian W, Yang W, Yan Y, Xue F. Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways. Gynecol Oncol 143: 168‐178, 2016.
 186.Wang P, Guan YF, Du H, Zhai QW, Su DF, Miao CY. Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 8: 77‐87, 2012.
 187.Wang G, Tian W, Liu Y, Ju Y, Shen Y, Zhao S, Zhang B, Li Y. Visfatin triggers the cell motility of non‐small cell lung cancer via up‐regulation of matrix metalloproteinases. Basic Clin Pharmacol Toxicol 119: 548‐554, 2016.
 188.Wang P, Xu TY, Guan YF, Su DF, Fan GR, Miao CY. Perivascular adipose tissue‐derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide. Cardiovasc Res 81: 370‐380, 2009.
 189.Wang P, Xu TY, Guan YF, Tian WW, Viollet B, Rui YC, Zhai QW, Su DF, Miao CY. Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1‐dependent adenosine monophosphate‐activated kinase pathway. Ann Neurol 69: 360‐374, 2011.
 190.Wang LS, Yan JJ, Tang NP, Zhu J, Wang YS, Wang QM, Tang JJ, Wang MW, Jia EZ, Yang ZJ, Huang J. A polymorphism in the visfatin gene promoter is related to decreased plasma levels of inflammatory markers in patients with coronary artery disease. Mol Biol Rep 38: 819‐825, 2011.
 191.Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C. Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nat Struct Mol Biol 13: 661‐662, 2006.
 192.Watson M, Roulston A, Belec L, Billot X, Marcellus R, Bedard D, Bernier C, Branchaud S, Chan H, Dairi K, Gilbert K, Goulet D, Gratton MO, Isakau H, Jang A, Khadir A, Koch E, Lavoie M, Lawless M, Nguyen M, Paquette D, Turcotte E, Berger A, Mitchell M, Shore GC, Beauparlant P. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: Strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1‐deficient tumors. Mol Cell Biol 29: 5872‐5888, 2009.
 193.Xiao J, Sun B, Li M, Wu Y, Sun XB. A novel adipocytokine visfatin protects against H(2)O(2)‐induced myocardial apoptosis: A missing link between obesity and cardiovascular disease. J Cell Physiol 228: 495‐501, 2013.
 194.Xiao C, Wang RH, Lahusen TJ, Park O, Bertola A, Maruyama T, Reynolds D, Chen Q, Xu X, Young HA, Chen WJ, Gao B, Deng CX. Progression of chronic liver inflammation and fibrosis driven by activation of c‐JUN signaling in Sirt6 mutant mice. J Biol Chem 287: 41903‐41913, 2012.
 195.Xie H, Tang SY, Luo XH, Huang J, Cui RR, Yuan LQ, Zhou HD, Wu XP, Liao EY. Insulin‐like effects of visfatin on human osteoblasts. Calcif Tissue Int 80: 201‐210, 2007.
 196.Yamamoto T, Sadoshima J. Protection of the heart against ischemia/reperfusion by silent information regulator 1. Trends Cardiovasc Med 21: 27‐32, 2011.
 197.Yang T, Chan NY, Sauve AA. Syntheses of nicotinamide riboside and derivatives: Effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem 50: 6458‐6461, 2007.
 198.Yang Y, Li Z, Tao HF, Qi XY, Wang WL, Yang L, Wang H, Xu P. An elevated plasma level of visfatin increases the risk of myocardial infarction. Genet Mol Res 13: 8586‐8595, 2014.
 199.Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF‐kappaB‐dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23: 2369‐2380, 2004.
 200.Yilmaz MI, Saglam M, Qureshi AR, Carrero JJ, Caglar K, Eyileten T, Sonmez A, Cakir E, Oguz Y, Vural A, Yenicesu M, Stenvinkel P, Lindholm B, Axelsson J. Endothelial dysfunction in type‐2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin. Nephrol Dial Transplant 23: 1621‐1627, 2008.
 201.Yin H, van der Veer E, Frontini MJ, Thibert V, O'Neil C, Watson A, Szasz P, Chu MW, Pickering JG. Intrinsic directionality of migrating vascular smooth muscle cells is regulated by NAD(+) biosynthesis. J Cell Sci 125: 5770‐5780, 2012.
 202.Yoon MJ, Yoshida M, Johnson S, Takikawa A, Usui I, Tobe K, Nakagawa T, Yoshino J, Imai S. SIRT1‐mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD+ and function in mice. Cell Metab 21: 706‐717, 2015.
 203.Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet‐ and age‐induced diabetes in mice. Cell Metab 14: 528‐536, 2011.
 204.Yoshitake N, Fukui H, Yamagishi H, Sekikawa A, Fujii S, Tomita S, Ichikawa K, Imura J, Hiraishi H, Fujimori T. Expression of SDF‐1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer 98: 1682‐1689, 2008.
 205.Yu‐Duan T, Chao‐Ping W, Chih‐Yu C, Li‐Wen L, Tsun‐Mei L, Chia‐Chang H, Fu‐Mei C, Hsien‐Chang L, Hsia‐Fen H, Yau‐Jiunn L, Jer‐Yiing H. Elevated plasma level of visfatin/pre‐b cell colony‐enhancing factor in male oral squamous cell carcinoma patients. Med Oral Patol Oral Cir Bucal 18: e180‐e186, 2013.
 206.Yun MR, Seo JM, Park HY. Visfatin contributes to the differentiation of monocytes into macrophages through the differential regulation of inflammatory cytokines in THP‐1 cells. Cell Signal 26: 705‐715, 2014.
 207.Zabka TS, Singh J, Dhawan P, Liederer BM, Oeh J, Kauss MA, Xiao Y, Zak M, Lin T, McCray B, La N, Nguyen T, Beyer J, Farman C, Uppal H, Dragovich PS, O'Brien T, Sampath D, Misner DL. Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase. Toxicol Sci 144: 163‐172, 2015.
 208.Zak M, Liederer BM, Sampath D, Yuen PW, Bair KW, Baumeister T, Buckmelter AJ, Clodfelter KH, Cheng E, Crocker L, Fu B, Han B, Li G, Ho YC, Lin J, Liu X, Ly J, O'Brien T, Reynolds DJ, Skelton N, Smith CC, Tay S, Wang W, Wang Z, Xiao Y, Zhang L, Zhao G, Zheng X, Dragovich PS. Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time‐dependent inhibition and improved aqueous solubility. Bioorg Med Chem Lett 25: 529‐541, 2015.
 209.Zhai RG, Rizzi M, Garavaglia S. Nicotinamide/nicotinic acid mononucleotide adenylyltransferase, new insights into an ancient enzyme. Cell Mol Life Sci 66: 2805‐2818, 2009.
 210.Zhang J, Lee SM, Shannon S, Gao B, Chen W, Chen A, Divekar R, McBurney MW, Braley‐Mullen H, Zaghouani H, Fang D. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119: 3048‐3058, 2009.
 211.Zhang W, Xie Y, Wang T, Bi J, Li H, Zhang LQ, Ye SQ, Ding S. Neuronal protective role of PBEF in a mouse model of cerebral ischemia. J Cereb Blood Flow Metab 30: 1962‐1971, 2010.
 212.Zhao Y, Liu XZ, Tian WW, Guan YF, Wang P, Miao CY. Extracellular visfatin has nicotinamide phosphoribosyltransferase enzymatic activity and is neuroprotective against ischemic injury. CNS Neurosci Ther 20: 539‐547, 2014.
 213.Zhao B, Zhang M, Han X, Zhang XY, Xing Q, Dong X, Shi QJ, Huang P, Lu YB, Wei EQ, Xia Q, Zhang WP, Tang C. Cerebral ischemia is exacerbated by extracellular nicotinamide phosphoribosyltransferase via a non‐enzymatic mechanism. PLoS One 8: e85403, 2013.
 214.Zhong M, Tan HW, Gong HP, Wang SF, Zhang Y, Zhang W. Increased serum visfatin in patients with metabolic syndrome and carotid atherosclerosis. Clin Endocrinol (Oxf) 69: 878‐884, 2008.
 215.Zoppoli G, Cea M, Soncini D, Fruscione F, Rudner J, Moran E, Caffa I, Bedognetti D, Motta G, Ghio R, Ferrando F, Ballestrero A, Parodi S, Belka C, Patrone F, Bruzzone S, Nencioni A. Potent synergistic interaction between the Nampt inhibitor APO866 and the apoptosis activator TRAIL in human leukemia cells. Exp Hematol 38: 979‐988, 2010.

 

Teaching Material

Carbone F, Liberale L, Bonaventura A, Vecchiè A, Casula M, Cea M, Monacelli F, Caffa I, Bruzzone S, Montecucco F, Nencioni A. Regulation and function of extracellular nicotinamide phosphoribosyltransferase/visfatin. Compr Physiol 2017, 7: 603-621. doi: 10.1002/cphy.c160029

Didactic Synopsis

Major Teaching Points:

              Nicotinamide phosphoribosiltransferase (NAMPT), also known as visfatin, has functions both as an intracellular enzyme (iNAMPT; mediating the synthesis of nicotinamide mononucleotide -NAD+- from nicotinamide) and as a soluble factor secreted into the extracellular space (extracellular NAMPT, eNAMPT).

              eNAMPT has pro-inflammatory, pro-chemotactic, pro-angiogenic and insulin-like effects.

              NAMPT is frequently overexpressed by solid and hematologic malignancies.

              iNAMPT supports cancer cell metabolism and DNA repair (particularly in tumors with defects in their homologous recombination).

              eNAMPT promotes the acquisition of a mesenchymal phenotype in epithelial cells (facilitating metastasis) and of a protumorigenic phenotype in tumor-associated macrophages.

              Inhibitors of NAMPT enzymatic activity hold promise as cancer therapeutics and as anti-inflammatory drugs and so do neutralizing antibodies for eNAMPT.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching Points: intracellular NAMPT (iNAMPT) performs the synthesis of NAD+ starting from nicotinamide (NAM), which is produced intracellularly by many enzymes that actively degrade NAD+ itself during their enzymatic reactions. Such enzymes include the NAD+-dependent deacetylases, sirtuins, the DNA repair enzyme, PARP, as well as CD38. Some of the nucleotides produced by these NAD+-degrading enzymes act as second messengers with calcium-mobilizing effects.

Figure 2. Teaching Points: Once secreted into the extracellular space, extracellular NAMPT (eNAMPT) exerts cytokine-like functions, some of which are seemingly unrelated from its enzymatic activity. These include i) pro-inflammatory effects on immune cells, ii) the ability to stimulate endothelial cells, promoting angiogenesis, ii) the promotion of cardiac and neuronal cell survival, as well as iv) the ability to stimulate the so-named epithelial-to-mesenchymal transition and the secretion of pro-inflammatory and pro-angiogenic factors in cancer cells.

 

 


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How to Cite

Federico Carbone, Luca Liberale, Aldo Bonaventura, Alessandra Vecchiè, Matteo Casula, Michele Cea, Fiammetta Monacelli, Irene Caffa, Santina Bruzzone, Fabrizio Montecucco, Alessio Nencioni. Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin. Compr Physiol 2017, 7: 603-621. doi: 10.1002/cphy.c160029