Serrated adenocarcinoma (SAC) and colorectal carcinomas showing histological and molecular features of high-level of microsatellite instability (hmMSI-H) are both end points of the serrated pathway of colorectal carcinogenesis. Despite common features (right-sided location, CpG island methylation phenotype and BRAF mutation) there are no studies comparing the microRNA (miRNA) expression profiles in SACs and hmMSI-H. The microtranscriptome from 12 SACs and 8 hmMSI-H were analysed using Affymetrix GeneChip miRNA 3.0 arrays and differentially enriched functions involving immune response were observed from this comparison. miR-181a-2* was found significantly more expressed in hmMSI-H than in SAC and higher expression of this miRNA in microsatellite unstable colorectal cancer were corroborated by Real-Time PCR in an extended series (61 SAC, 21 hmMSI-H). An analysis of genes possibly regulated by miR-181a-2* was carried out and, amongst these, an inverse correlation of NAMPT with miR-181a-2* expression was observed, whereas, for TRAF1 and SALL1, additional regulation mechanisms involving CpG island methylation were observed. miR-181a-2* is associated with particular histological and molecular features of colorectal carcinomas within the serrated pathological pathway and might play a role in the immune responses of microsatellite instability carcinomas.

• MeSH
• CpG ostrůvky MeSH
• cytokiny genetika   metabolismus   MeSH
• faktor 1 asociovaný s receptory TNF genetika   metabolismus   MeSH
• genová ontologie MeSH
• karcinom genetika   metabolismus   patofyziologie   MeSH
• kolorektální nádory genetika   metabolismus   patofyziologie   MeSH
• lidé MeSH
• metylace DNA MeSH
• mikro RNA genetika   metabolismus   MeSH
• mikrosatelitní nestabilita * MeSH
• nádorové buněčné linie MeSH
• nikotinamidfosforibosyltransferasa genetika   metabolismus   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• senioři MeSH
• transkripční faktory genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Nicotinamide phosphoribosyltransferase (NAMPT) is located in both the nucleus and cytoplasm and has multiple biological functions including catalyzing the rate-limiting step in NAD synthesis. Moreover, up-regulated NAMPT expression has been observed in many cancers. However, the determinants and regulation of NAMPT's nuclear transport are not known. Here, we constructed a GFP-NAMPT fusion protein to study NAMPT's subcellular trafficking. We observed that in unsynchronized 3T3-L1 preadipocytes, 25% of cells had higher GFP-NAMPT fluorescence in the cytoplasm, and 62% had higher GFP-NAMPT fluorescence in the nucleus. In HepG2 hepatocytes, 6% of cells had higher GFP-NAMPT fluorescence in the cytoplasm, and 84% had higher GFP-NAMPT fluorescence in the nucleus. In both 3T3-L1 and HepG2 cells, GFP-NAMPT was excluded from the nucleus immediately after mitosis and migrated back into it as the cell cycle progressed. In HepG2 cells, endogenous, untagged NAMPT displayed similar changes with the cell cycle, and in nonmitotic cells, GFP-NAMPT accumulated in the nucleus. Similarly, genotoxic, oxidative, or dicarbonyl stress also caused nuclear NAMPT localization. These interventions also increased poly(ADP-ribosyl) polymerase and sirtuin activity, suggesting an increased cellular demand for NAD. We identified a nuclear localization signal in NAMPT and amino acid substitution in this sequence (424RSKK to ASGA), which did not affect its enzymatic activity, blocked nuclear NAMPT transport, slowed cell growth, and increased histone H3 acetylation. These results suggest that NAMPT is transported into the nucleus where it presumably increases NAD synthesis required for cell proliferation. We conclude that specific inhibition of NAMPT transport into the nucleus might be a potential avenue for managing cancer.

• MeSH
• akrylamidy farmakologie   MeSH
• aktivní transport - buněčné jádro MeSH
• buněčné jádro metabolismus   MeSH
• buňky 3T3-L1 MeSH
• buňky Hep G2 MeSH
• cytoplazma metabolismus   MeSH
• histony metabolismus   MeSH
• kontrolní body buněčného cyklu MeSH
• lidé MeSH
• mutageneze cílená MeSH
• myši MeSH
• NAD metabolismus   MeSH
• nikotinamidfosforibosyltransferasa chemie   genetika   metabolismus   MeSH
• oxidační stres MeSH
• piperidiny farmakologie   MeSH
• poly(ADP-ribosa)-polymerasy metabolismus   MeSH
• proliferace buněk MeSH
• rekombinantní fúzní proteiny chemie   genetika   metabolismus   MeSH
• sirtuiny metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Metabolický syndrom, který výrazně zvyšuje kardiovaskulární morbiditu, mortalitu ariziko rozvoje diabetes mellitus 2. typu, vsoučasné době dosahuje epidemických proporcí. Tato komplexní porucha vyžaduje urgentní vývoj nových farmakoterapeutických řešení. Patofyziologické mechanismy vedoucí k rozvoji tohoto syndromu nejsou dosud plně objasněny, nicméně se zdá zřejmé, že k jeho rozvoji přispívá řada metabolických dysregulací. Za potenciálně slibný cíl pro vývoj nových léčiv se považuje dysregulace endokrinních aparakrinních funkcí tukové tkáně. Specifické adipokiny, což jsou proteiny secernované tukovou tkání s jistými pleiotropními účinky, jsou silně asociovány s regulací energetického metabolismu, chuti k jídlu, inzulinové signální dráhy, senzitivity periferních tkání k inzulinu aprozánětlivému stavu spojenému smetabolickým syndromem. Cílem této práce je poskytnout stručný přehled endokrinních aparakrinních funkcí tukové tkáně ve spojitosti s rozvojem metabolického syndromu, jeho patofyziologických podkladů apoukázat na některé adipokiny jako potenciální cíle pro vývoj nových farmakoterapeutických přístupů.

Metabolic syndrome, acondition increasing cardiovascular morbidity, mortality and risk for diabetes mellitus type 2, is currently worldwide reaching epidemic proportions. This complex disorder represents an urgent challenge for new pharmacotherapeutic strategies formulation. Pathophysiological mechanisms underlying metabolic syndrome are not completely understood, nevertheless growing evidence is supporting the hypothesis that multiple metabolic dysregulations do contribute to its development. Apotential target for pharmacological intervention is considered to be dysregulation of adipose tissue endocrine/paracrine function. Specific adipokines, proteins secreted by the adipose tissue, with some pleiotropic effects, have been identified with strong association to regulation of energy metabolism, appetite, insulin signaling, tissue insulin sensitivity and the proinflammatory state related to metabolic syndrome. The aim of this paper is to provide abrief overview of endocrine/paracrine functions of the adipose tissue with regard to metabolic syndrome development and pathophysiology and particular adipokines as potential targets for innovative pharmacotherapeutic approaches.

• Klíčová slova
• omentin, vaspin,
• MeSH
• adipokiny * metabolismus   MeSH
• adiponektin metabolismus   MeSH
• cytokiny metabolismus   MeSH
• GPI-vázané proteiny metabolismus   MeSH
• inzulinová rezistence MeSH
• lektiny metabolismus   MeSH
• leptin metabolismus   MeSH
• lidé MeSH
• metabolický syndrom * etiologie   metabolismus   patofyziologie   MeSH
• nikotinamidfosforibosyltransferasa metabolismus   MeSH
• proteiny vázající mastné kyseliny metabolismus   MeSH
• resistin metabolismus   MeSH
• serpiny metabolismus   MeSH
• tuková tkáň * metabolismus   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Východisko. Visfatin je adipocytokin produkovaný především viscerální tukovou tkání. Vedle účinku na inzulinový receptor je i proinflamačním cytokinem, jehož hladina se může měnit při zánětlivých procesech. Cílem této studie bylo zjistit, jak se mění sérové koncentrace visfatinu v časném údobí po abdominálním chirurgickém výkonu v korelaci s dalšími proinflamačními cytokiny. Metodika a výsledky. Do prospektivní průřezové (cross-sectional) studie bylo zařazeno 20 pacientů, kteří podstoupili elektivní laparotomickou resekci části tlustého střeva. Sledovali jsme hladiny visfatinu, leptinu, rezistinu, adiponektinu, TNF-α, IL-6 a CRP a srovnávali dynamiku změn jednotlivých parametrů za +12, +24, +48 a +72 hodin. Sérové koncentrace visfatinu kulminovaly již za 24 hodin po chirurgickém výkonu a po 72 hodinách se vracely k normě. TNF-α a IL-6 měly maximum o 12–24 hodin později a u CRP hodnoty stoupaly s maximem za 72 hodin. Závěry. V časném pooperačním údobí po abdominálním chirurgickém výkonu byly zachyceny signifikantně zvýšené hladiny sérového visfatinu, které předcházely zvýšení hodnot jiných proinflamačních markerů TNF-α, IL-6 a CRP. Visfatin by proto svojí dynamikou mohl být časným prediktorem rozvoje zánětlivých změn operovaných nemocných především s viscerální obezitou.

Background. Visfatin is a newly recognized adipocytokine produced mainly in visceral fat tissue. Beside its effect on insulin receptor, it serves as proinflammatory cytokine and its level can be changed during inflammatory processes. The aim of the study was to analyze dynamics of serum visfatine level in early period after abdominal surgery and compare it with other proinflammatory markers. Methods and results. In prospective cross-sectional study 20 patients after elective laparotomic abdominal surgery (partial colectomy) were enrolled and dynamics of visfatin, leptin, resistin, adiponectin, TNF-α , IL-6 and CRP in period +12, +24, +48 and + 72 hours was monitored. Serum visfatin was elevated already in +24 hrs period after surgery comparing the culmination of serum level of TNF-α and IL-6 12–24 hrs later and CRP even 48–72 hrs later. Conclusions. Serum visfatin was elevated very early after abdominal surgery and thus its dynamic may be an early predictor of inflammatory processes namely in patients with visceral obesity.

• Klíčová slova
• proinflamační cytokiny, viscerální obezita, visfatin,
• MeSH
• adiponektin krev   MeSH
• biologické markery krev   MeSH
• C-reaktivní protein MeSH
• časná diagnóza MeSH
• index tělesné hmotnosti MeSH
• interleukin-6 krev   MeSH
• kolon chirurgie   MeSH
• laparotomie MeSH
• leptin krev   MeSH
• lidé MeSH
• nikotinamidfosforibosyltransferasa * krev   metabolismus   MeSH
• nitrobřišní tuk metabolismus   MeSH
• obezita MeSH
• pooperační komplikace diagnóza   krev   MeSH
• pooperační období * MeSH
• předoperační období MeSH
• prospektivní studie MeSH
• průřezové studie statistika a číselné údaje   MeSH
• resistin krev   MeSH
• TNF-alfa krev   MeSH
• zánět * komplikace   krev   MeSH
• Check Tag
• lidé MeSH

AIMS: Visfatin (NAMPT/PBEF) is a recently identified adipocytokine which harbors strong insulin-mimetic activity and was reported to be associated with obesity. However, nothing is known about whether visfatin is related to specific nutritional behavior which may result in obesity development. This is the first study focusing on genetic variability of the visfatin gene and its association with circulating visfatin, anthropometric parameters and dietary composition. MATERIALS AND METHODS: We analyzed a total of 11 exons and adjacent non-coding regions of the NAMPT gene in 20 extremely obese Czech individuals (mean BMI 52.2±5.0 SD) using direct sequencing and a frequency of rs2302559 was established in the validation cohort of another 605 individuals with completed 7-day food records and complex anthropometric measurements. Serum levels of visfatin, leptin and leptin-receptor were measured in all sequenced individuals and in part of the validation cohort. RESULTS: Three common polymorphisms were identified, two in non-coding regions (rs78411774 A/C, rs71564769 A/C) and one synonymous SNP in exon 7 (rs2302559 A/G). The rs2302559 showed significant correlation with visfatin serum level throughout the entire study cohort (p<0.001); there was a significant tendency toward higher visfatin levels in G allele carriers with GG homozygotes having the highest visfatin serum levels. Furthermore, a negative correlation was observed between visfatin and leptin serum level (p=0.01). No association between investigated SNPs and anthropometric parameters or native dietary composition was observed. CONCLUSION: This is the first study to demonstrate that the rs2302559 polymorphism in the PBEF gene is related to circulating levels of visfatin. As the SNP is synonymous, we hypothesize it might be linked to another SNP in the PBEF gene which controls visfatin serum levels.

• MeSH
• antropometrie MeSH
• běloši genetika   MeSH
• cytokiny genetika   metabolismus   MeSH
• dieta * MeSH
• dietní záznamy MeSH
• hubenost MeSH
• index tělesné hmotnosti MeSH
• jednonukleotidový polymorfismus * MeSH
• krevní glukóza metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nikotinamidfosforibosyltransferasa genetika   metabolismus   MeSH
• obezita epidemiologie   genetika   metabolismus   MeSH
• sekvenční analýza MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• validační studie MeSH
• Geografické názvy
• Česká republika MeSH

Visfatin, a product of PBEF gene, is an adipocytokine that harbours strong insulin-mimetic activity and it has been reported previously to associate with obesity. Recent reports also provide evidence that Visfatin has also important intracellular effects as it is homologous with nicotinamide phosphoribosyltransferase (NAMPT). In this review, we summarize the main documented effects of Visfatin on metabolism in humans, with special emphasis put on the pathways associated with obesity.

• MeSH
• beta-buňky metabolismus   MeSH
• cytokiny metabolismus   MeSH
• inzulinová rezistence * MeSH
• lidé MeSH
• lipidy krev   MeSH
• nikotinamidfosforibosyltransferasa metabolismus   farmakologie   MeSH
• obezita metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: Visfatin is a recently identified adipokine with numerous metabolic and immunoregulatory properties that has been implicated in the regulation of the white adipose tissue (WAT) and significant changes in visfatin levels were reported during pregnancy. The aim of the study was to investigate dynamics of visfatin levels in maternal serum and human breast milk during a 180-d period after the delivery. MATERIALS AND METHODS: : Breast milk and venous blood samples were obtained from 24 healthy lactating women with uncomplicated, physiological pregnancy and appropriate-for-gestational age neonates and serum-milk sample duos were collected at the time of birth, at the 1-3, 12-14, 28-30, 88-90 and 178-180 postpartum. RESULTS: Our study demonstrates that (1) visfatin is abundantly secreted into breast milk in humans, reaching approx. 100× higher concentrations compared to maternal serum; (2) visfatin concentrations in maternal serum show significant variations after the delivery and (3) visfatin concentration in colostrum could be used for prediction of the subsequent weight development (less/more severe weight loss during first 3 days after the birth) of the infant. DISCUSSION: Our data suggest that visfatin could play an important role in regulation of adiposity of the infant after the birth.

• MeSH
• analýza rozptylu MeSH
• bílá tuková tkáň účinky léků   metabolismus   MeSH
• časové faktory MeSH
• dospělí MeSH
• hmotnostní přírůstek účinky léků   fyziologie   MeSH
• index tělesné hmotnosti MeSH
• kojenec MeSH
• lidé MeSH
• longitudinální studie MeSH
• mateřské mléko účinky léků   metabolismus   MeSH
• nikotinamidfosforibosyltransferasa metabolismus   sekrece   MeSH
• novorozenec MeSH
• porodní hmotnost účinky léků   fyziologie   MeSH
• průzkumy a dotazníky MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• visfatin, TNF-?, interleukin 6,
• MeSH
• adipokiny fyziologie   metabolismus   MeSH
• adiponektin fyziologie   metabolismus   MeSH
• interleukiny fyziologie   metabolismus   MeSH
• leptin fyziologie   metabolismus   MeSH
• lidé MeSH
• nikotinamidfosforibosyltransferasa fyziologie   metabolismus   MeSH
• resistin fyziologie   metabolismus   MeSH
• Check Tag
• lidé MeSH

Adipokines play a significant role in the pathogenesis of a low-grade inflammation associated with obesity and metabolic syndrome, and in chronic inflammatory and autoimmune diseases such as rheumatoid arthritis. Among variety of adipokines, resistin and visfatin are proposed as important pro-inflammatory mediators, which also interfere with the central regulation of insulin sensitivity. Resistin has been initially postulated as a risk factor for insulin resistance, however, the subsequent available data on it have revealed contradictory findings in both humans and rodents. On the other hand, visfatin has been suggested to be a beneficial adipokine with insulin-mimicking/-sensitizing effects, but regulation of visfatin production and its physiological importance in the conditions of obesity and type 2 diabetes mellitus are still not completely understood. Despite the opposing effects of resistin and visfatin on the regulation of insulin sensitivity, both adipokines have pro-inflammatory properties. Clinical and experimental studies have shown that the expression and secretion of resistin and visfatin are up-regulated during inflammation and in response to pro-inflammatory cytokines. It has also become increasingly evident that resistin as well as visfatin itself can contribute to the inflammatory processes by triggering cytokine production and NF-kappaB activation. New insight into the role of adipokines makes them attractive targets for novel therapeutic strategies in chronic inflammatory diseases or subclinical inflammation relating to obesity and various metabolic abnormalities.

• MeSH
• autoimunita MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• nikotinamidfosforibosyltransferasa metabolismus   MeSH
• resistin metabolismus   MeSH
• signální transdukce MeSH
• zánět imunologie   metabolismus   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Visfatin was originally described as an adipokine with insulin mimetic effects. Recently, it was found that visfatin is identical with the Nampt (nicotinamide phosphoribosyltransferase) gene that codes for an intra- and extracellular NAD biosynthetic enzyme and is predominantly expressed outside the adipose tissue. In the current study, we found strong protein and mRNA expression of visfatin in rat heart, liver, kidney, and muscle, while the expression of visfatin in visceral fat was significantly lower and undetectable in subcutaneous fat. The insulin-mimetic effects of visfatin (extracellular form of Nampt or eNampt) are controversial and even less is known about autocrine effects of visfatin (intracellular form of Nampt or iNampt). Since liver plays a major role in glucose metabolism, we studied visfatin effects on insulin-stimulated cellular glucose uptake in Fao rat hepatocytes using RNA interference (RNAi). RNAi-mediated downregulation of visfatin expression in Fao cells was associated with significantly reduced NAD biosynthesis (0.3±0.01 vs. 0.5±0.01 mmol/h/g, P<0.05) and with significantly decreased incremental glucose uptake after stimulation with insulin when compared to controls with normal expression of visfatin (0.6±0.2 vs. 2.2±0.5 nnmol/g/2 h, P=0.02). These results provide evidence that visfatin exhibits important autocrine effects on sensitivity of liver cells to insulin action possibly through its effects on NAD biosynthesis.

• MeSH
• autokrinní signalizace MeSH
• biologický transport MeSH
• buněčné linie MeSH
• cytokiny genetika   metabolismus   MeSH
• financování organizované MeSH
• glukosa metabolismus   MeSH
• hepatocyty enzymologie   MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence MeSH
• krysa rodu rattus MeSH
• messenger RNA metabolismus   MeSH
• NAD metabolismus   MeSH
• nikotinamidfosforibosyltransferasa genetika   metabolismus   MeSH
• potkani inbrední WKY MeSH
• regulace genové exprese enzymů MeSH
• RNA interference MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH