Je was op zoek naar: inflammasome (Engels - Portugees)

cias1/nlrp3 encodes for cryopyrin, a component of the inflammasome.
o cias1/nlrp3 codifica para a criopirina, um componente do inflamassoma.

under normal circumstances, pyrin limits the activation of the nlrp3-inflammasome.
sob circunstâncias normais, a pirina limita a ativação do nlrp3-inflamassoma.

in addition, recent reports revealed a major role for inflammasome activity in the development of gout attacks.
além disso, achados recentes revelaram um papel relevante da atividade do inflamassoma no desenvolvimento das crises de gota.

it is presumed that the mutated pyrin protein in fmf is theoretically not able to suppress the inflammasome, and thus the inflammatory response develops.
presume-se que a proteína pirina que sofreu mutação na ffm teoricamente não é capaz de suprimir o inflamassoma e, assim, a resposta inflamatória se desenvolve.

the activated inflammasome results in proteolytic maturation and secretion of il-1β, which has a broad range of effects including systemic inflammation.
o inflamassoma ativado resulta em maturação proteolítica e secreção de il-1β, a qual tem uma ampla gama de efeitos, incluindo inflamação sistémica.

it interacts with another card domain containing protein called pycard (or asc) and is involved in inflammasome formation and activation of inflammatory processes.
interage com uma proteína que contém um domínio card, denominada pycard (ou asc) e está envolvida na activação de processos inflamatórios.

in its full form, the inflammasome appositions together many p45 pro-caspase-1 molecules, inducing their autocatalytic cleavage into p20 and p10 subunits.
em sua forma completa, o inflamassoma se liga a diversas moléculas de pró-caspase 1 e induz a clivagem automática nas subunidades p20 e p10.

both gouty arthritis and fmf share some clinical and pathogenic mechanisms such as short-lived and intermittent arthritis, association with inflammasome and response to colchicine and anti-il-1 therapies.
tanto a artrite gotosa quanto a ffm compartilham alguns mecanismos clínicos e patogênicos, como a artrite intermitente e de curta duração, a associação com o inflamassoma e a resposta ao tratamento com colchicina e anti-il-1.

artificial sweeteners induce glucose intolerance by altering the gut microbiota non-caloric artificial sweeteners (nas) are among the most widely used food additives worldwide, regularly consumed byleanandobeseindividualsalike.nasconsumptionisconsideredsafeandbeneficialowingtotheirlowcaloriccontent, yetsupportingscientificdataremainsparseandcontroversial.herewedemonstratethatconsumptionofcommonlyused nasformulationsdrivesthedevelopmentofglucoseintolerancethroughinductionofcompositionalandfunctionalalter- ationstotheintestinalmicrobiota.thesenas-mediateddeleteriousmetaboliceffectsareabrogatedbyantibiotictreatment, andarefullytransferrabletogerm-freemiceuponfaecaltransplantationofmicrobiotaconfigurationsfromnas-consuming mice, orof microbiota anaerobically incubated in the presence of nas. we identify nas-altered microbial metabolic path- waysthatarelinkedtohostsusceptibilitytometabolicdisease,anddemonstratesimilarnas-induceddysbiosisandglucose intolerance in healthy human subjects. collectively, our results link nas consumption, dysbiosis and metabolic abnor- malities, thereby calling for a reassessment of massive nas usage. non-caloricartificialsweeteners(nas)wereintroducedoveracentury ago as means for providing sweet taste to foods without the associated high energy content of caloricsugars. nasconsumptiongained much popularity owing to their reduced costs, low caloric intake and per- ceivedhealthbenefitsforweightreductionandnormalizationofblood sugar levels1. for these reasons, nas are increasingly introduced into commonly consumed foods such as diet sodas, cereals and sugar-free desserts, and are being recommended for weight loss and for indivi- duals suffering from glucose intolerance and type 2 diabetes mellitus1. somestudiesshowedbenefitsfornasconsumption2andlittleinduc- tionofaglycaemicresponse3,whereasothersdemonstratedassociations betweennasconsumptionandweightgain4,andincreasedtype2dia- betesrisk5.however,interpretationiscomplicatedbythefactthatnas aretypicallyconsumedbyindividualsalreadysufferingfrommetabolic syndromemanifestations.despitethesecontroversialdata,theusfood anddrugadministration(fda)approvedsixnasproductsforusein the united states. most nas pass through the human gastrointestinal tract without being digested by the host6,7 and thus directly encounter the intestinal microbiota, which plays central roles in regulating multiple physiolo- gicalprocesses8.microbiotacomposition9andfunction10aremodulated by diet in the healthy/lean state as well as in obesity11,12 and diabetes mellitus13,andinturnmicrobiotaalterationshavebeenassociatedwith propensity to metabolic syndrome14. here, we study nas-mediated modulationofmicrobiotacompositionandfunction,andtheresultant effects on host glucose metabolism. chronic nas consumption exacerbates glucose intolerance to determine the effects of nas on glucose homeostasis, we added commercial formulations of saccharin, sucralose or aspartame to the drinkingwateroflean10-week-oldc57bl/6mice(extendeddatafig.1a). since all three commercial nas comprise ,5% sweetener and ,95% glucose,weusedascontrolsmicedrinkingonlywaterorwatersupple- mented with either glucose or sucrose. notably, at week 11, the three mousegroupsthatconsumedwater,glucoseandsucrosefeaturedcom- parableglucosetolerancecurves,whereasallthreenas-consumingmouse groups developed marked glucose intolerance (p,0.001, fig. 1a, b). assaccharinexertedthemostpronouncedeffect,wefurtherstudied its role as a prototypical artificial sweetener. to corroborate the find- ings in the obesity setup, we fed c57bl/6 mice a high-fat diet (hfd, 60% kcal from fat) while consuming either commercial saccharin or pure glucose as a control (extended data fig. 1b). as in the lean state, micefedhfdandcommercialsaccharindevelopedglucoseintolerance, compared to the control mouse group (p,0.03, fig. 1c and extended datafig.2a).toexaminetheeffectsofpuresaccharinonglucoseintol- erance,wefollowedacohortof10-week-oldc57bl/6micefedonhfd and supplemented with 0.1mgml21 of pure saccharin added to their drinking water (extended data fig. 1c). this dose corresponds to the fdaacceptabledailyintake(adi)inhumans(5mgperkg(bodyweight), adjustedtomouseweights,seemethods).aswithcommercialsaccharin, thislowerdoseofpuresaccharinwasassociatedwithimpairedglucose tolerance (p,0.0002, fig. 1d and extended data fig. 2b) starting as earlyas5weeksafterhfdinitiation.similarly,hfd-fedoutbredswiss webster mice supplemented with or without 0.1mgml21 of pure sac- charin(extended data fig.1d) showedsignificant glucose intolerance after5weeksofsaccharinexposureascomparedtocontrols(p,0.03, extended data fig. 2c, d). metabolicprofilingofnormal-chow-orhfd-fedmiceinmetabolic cages,includingliquidsandchowconsumption,oxygenconsumption, walkingdistanceandenergyexpenditure,showedsimilarmeasuresbe- tween nas- and control-drinking mice (extended data fig. 3 and 4). *these authors contributed equally to this work. 1departmentofimmunology,weizmanninstituteofscience,rehovot76100,israel. 2departmentofcomputerscienceandappliedmathematics,weizmanninstituteofscience,rehovot76100,israel. 3day care unit and the laboratory of imaging and brain stimulation, kfar shaul hospital, jerusalem center for mental health, jerusalem 91060, israel. 4internal medicine department, tel aviv sourasky medical center,telaviv64239,israel.5researchcenterfordigestivetractandliverdiseases,telavivsouraskymedicalcenter,sacklerfacultyofmedicine,telavivuniversity,telaviv69978,israel.6digestivecenter, tel aviv sourasky medical center, tel aviv 64239, israel. 7the nancy and stephen grand israel national center for personalized medicine (incpm), weizmann institute of science, rehovot 76100, israel. 8department of veterinary resources, weizmann institute of science, rehovot 76100, israel. 9department of molecular genetics, weizmann institute of science, rehovot 76100, israel. 0 0 m o n t h 2 0 1 4 | v o l 0 0 0 | n a t u r e | 1 macmillan publishers limited. all rights reserved©2014 fasting serum insulin levels and insulin tolerance were also similar in all mouse groups consuming nas or caloric sweeteners, in both the normal-chowandhfdsettings(extendeddatafig.5).takentogether, these results suggest that nas promote metabolic derangements in a rangeofformulations,doses,mousestrainsanddietsparallelinghuman conditions, in both the lean and the obese state. gut microbiota mediates nas-induced glucose intolerance since diet modulates the gut microbiota15, and microbiota alterations exert profound effects on host physiology and metabolism, we tested whetherthemicrobiotamayregulatetheobservednaseffects.tothis end, we treated mouse groups consuming commercial or pure nas in theleanandhfdstates(extendeddatafig.1a,c)withagram-negative- targeting broad-spectrum antibiotics regimen (designated ‘antibiotics a’)ofciprofloxacin(0.2gl21)andmetronidazole(1gl21),whilemain- taining mice on their diet and sweetener supplementation regimens. notably,after4weeksofantibiotictreatment,differencesinglucosein- tolerance between nas-drinking mice and controls were abolished both in the lean (fig. 1a, b) and the obese (fig. 1d and extended data fig. 2b) states. similar effects were observed with the gram-positive- targeting antibiotic vancomycin (‘antibiotics b’, 0.5gl21, fig. 1a, b). theseresultssuggestthatnas-inducedglucoseintoleranceismediated through alterations to the commensal microbiota, with contributions from diverse bacterial taxa. to test whether the microbiota role is causal, we performed faecal transplantationexperiments,bytransferringthemicrobiotaconfigura- tion from mice on normal-chow diet drinking commercial saccharin or glucose (control) into normal-chow-consuming germ-free mice (extended data fig. 1e). notably, recipients of microbiota from mice consumingcommercialsaccharinexhibitedimpairedglucosetolerance ascomparedtocontrol(glucose)microbiotarecipients,determined6days followingtransfer(p,0.03,fig.1eandextendeddatafig.2e).trans- ferringthemicrobiotacompositionofhfd-consumingmicedrinking water or pure saccharin replicated the glucose intolerance phenotype (p,0.004, fig. 1f and extended data fig. 2f). together, these results establish that the metabolic derangements induced by nas consump- tion are mediated by the intestinal microbiota. nas mediate distinct functional alterations to the microbiota we next examined the faecal microbiota composition of our various mousegroupsbysequencingtheir16sribosomalrnagene.micedrink- ingsaccharinhadadistinctmicrobiotacompositionthatclusteredsepa- ratelyfromboththeirstartingmicrobiomeconfigurationsandfromall control groups at week 11 (fig. 1g). likewise, microbiota in germ-free recipientsofstoolsfromsaccharin-consumingdonormiceclusteredsepa- ratelyfromthatofgerm-freerecipientsofglucose-drinkingdonorstools (fig.1h).comparedtoallcontrolgroups,themicrobiotaofsaccharin- consuming mice displayed considerable dysbiosis, with more than 40 operationaltaxonomicunits(otus)significantlyalteredinabundance (falsediscoveryrate(fdr)correctedpvalue,0.05foreachotu;ex- tendeddatafig.6,supplementarytable1).manyofthetaxathatincreased inrelativeabundancebelongedtothebacteroidesgenusandclostridiales order,withothermembersoftheclostridialesordercomprisingthemajor- ityofunder-representedtaxa,alongwithlactobacillusreuteri,andwere water pure saccharin –a antibiotics: * ** ** *** *** *** *** *** ** ab c blood glucose (mg dl–1) 0 90120 6015 30 time (min) 50 150 250 350 0 90120 6015 30 time (min) 150 250 450 350 aspartame sucralose saccharin glucose sucrose water – a b antibiotics: f 0 90120 6015 30 time (min) 50 150 250 200 100 g 0 90120 6015 30 time (min) 50 150 250 200 100 pure saccharin water ** * * * * * ** commercial saccharin glucose donors drinking: donors drinking: blood glucose (mg dl–1) 0 90120 6015 30 time (min) 50 150 250 450 350 saccharin glucose ** * ** * * de *** *** aspartame sucralose saccharin glucose sucrose water – a b antibiotics: glycaemic response (auc, ×103) 20 40 50 30 0 10 pc2 - 19.4% pc1 - 30.3% 0.20 0.15 0.10 0.05 0.00 –0.05 –0.10 –0.15 –0.20 –0.2 – 0.1 0.0 0.1 0.2 0.3 0.4 saccharin w11 controls, saccharin w0 h pc2 - 19.1% pc1 - 39.6% 0.20 0.15 0.10 0.05 0.00 –0.05 –0.10 –0.15 –0.20 –0.2 –0.1 0.0 0.1 0.2 0.3 0.4 saccharin glucose donors drinking: blood glucose (mg dl–1) blood glucose (mg dl–1) blood glucose (mg dl–1) figure 1 | artificial sweeteners induce glucose intolerance transferable to germ-freemice. a,b,oralglucosetolerancetest(ogtt,a)andareaunderthe two-hour blood glucose response curve (auc, b) in normal-chow-fed mice drinking commercial nas for 11weeks before (n520) and after antibiotics: ciprofloxacin and metronidazole (‘antibiotics a’, n510); or vancomycin (‘antibiotics b’, n55). c, ogtt in mice fed hfd and commercial saccharin (n510) or glucose (n59). d, ogtt of hfd-fed mice drinking 0.1mgml21 saccharin or water for 5weeks (n520), followed by ‘antibiotics a’ (n510). e, f, ogtt of germ-free mice 6days following transplant of microbiota from commercial saccharin- (n512) and glucose-fed mice (n511) (e), or pure saccharin- (n516) and water-fed (n516) donors (f). symbols (ogtt) or horizontal lines (auc), mean; error bars, s.e.m. *p,0.05, **p,0.01, ***p,0.001. ogtt, analysis of variance (anova) and bonferroni; auc, anova and tukey post hoc analysis. each experiment was repeated twice. g, principal coordinates analysis (pcoa) of weighted unifrac distances based on 16s rrna analysis from saccharin-consuming mice at baseline (w0, black hexagons; w11, blue triangles);water controls(blackcircles forw11andw0); glucose (black squares for w11 and w0); or sucrose (black triangles for w11 and w0). n55 in each group. h, pcoa of taxa in germ-free recipients according to donor identity in e. research article 2 | n a t u r e | v o l 0 0 0 | 0 0 m o n t h 2 0 1 4 macmillan publishers limited. all rights reserved©2014 mirrored in germ-free recipients of stools from saccharin-consuming donors (extended data fig. 6, right column). likewise, dysbiosis was observedinmiceconsumingpuresaccharinandhfd(supplementary table1).together,theseresultsdemonstratethatsaccharinconsump- tioninvariousformulations,dosesanddietsinducesdysbiosiswithover- all similar configurations. tostudythefunctionalconsequencesofnasconsumption,weper- formedshotgunmetagenomicsequencingoffaecalsamplesfrombefore and after 11weeks of commercial saccharin consumption, compared tocontrolmiceconsumingeitherglucoseorwater.tocomparerelative speciesabundance,wemappedsequencingreadstothehumanmicro- biomeprojectreferencegenomedatabase16.inagreementwiththe16s rrnaanalysis,saccharintreatmentinducedthelargestchangesinmicro- bial relative species abundance (fig. 2a, supplementary table 2; f-test p value,10210). these changes are unlikely to be an artefact of hori- zontal gene transfer or poorly covered genomes, because changes in relativeabundancewereobservedacrossmuchofthelengthofthebacterial genomes,asexemplifiedbyoneoverrepresented(bacteroidesvulgatus, extendeddatafig.7a)andoneunderrepresentedspecies(akkermansia muciniphila, extended data fig. 7b). wenextmappedthemetagenomicreadstoagutmicrobialgenecata- logue,evenlydividing readsmapping tomore thanonegene,andthen groupinggenesintokegg(kyotoencyclopediaofgenesandgenomes) pathways.examiningpathwayswithgenecoverageabove0.2(115path- ways),changesinpathwayabundancewereinverselycorrelatedbetween commercial saccharin- andglucose-consuming mice (r520.45,p, 1026, fig. 2b). since commercial saccharin consists of 95% glucose, theseresultssuggestthatsaccharingreatlyaffectsmicrobiotafunction. notably, pathways overrepresented in saccharin-consuming mice in- clude a strong increase in glycan degradation pathways (fig. 2c, d), in whichglycansarefermentedtoformvariouscompoundsincludingshort- chainfattyacids(scfas)17.thesepathwaysmark enhancedenergyhar- vestandtheirenrichmentwaspreviouslyassociatedwithobesityinmice11 andhumans18,withscfapossiblyservingasprecursorsand/orsignal- lingmoleculesforde novoglucoseand lipidsynthesis bythehost19. to identifythe underlyingbacteria, weannotatedeveryread that mapped to glycan degradation pathways by its originating bacteria. much of theincreaseinthesepathwaysisattributabletoreadsoriginatingfrom five gram-negative and -positive species, of which two belong to the bacteroides genus (fig. 2e). this is consistent with the sharp increase intheabundanceofthisgenusinsaccharin-consumingmiceobserved inthe 16srrnaanalysis(extended datafig.6). consequently,levels ofthescfaspropionateandacetatemeasuredinstoolweremarkedly higherincommercialsaccharin-consumingmicecomparedtocontrol glucose-consumingmice(fig.2f,g),reflectiveofthedifferentialeffects mediatedbychronicglucoseconsumptionwithandwithoutnasexpo- sure.butyratelevelsweresimilarbetweenthegroups(datanotshown). in addition to glycan degradation, and similar to previous studies on humans with type 2 diabetes13,20, other pathways were enriched in microbiomesofsaccharin-consumingmice,includingstarchandsuc- rose metabolism, fructose and mannose metabolism, and folate, gly- cerolipid and fatty acid biosynthesis (supplementary tables 3 and 4), whereasglucosetransportpathwayswereunderrepresentedinsaccharin- consumingmice(extendeddatafig.7c).miceconsuminghfdandpure saccharinfeaturedseveralenrichedpathways(extendeddatafig.7d), including ascorbate and aldarate metabolism (previously reported to be enriched in leptin-receptor-deficient diabetic mice21), lipopolysac- charidebiosynthesis(linkedtometabolicendotoxemia22)andbacterial chemotaxis (previously reported to be enriched in obese mice11). altogether,saccharinconsumptionresultsindistinctdiet-dependent functionalalterationsinthemicrobiota,includingnormal-chow-related expansioninglycandegradationcontributedbyseveraloftheincreased taxa, ultimatelyresulting in elevated stool scfa levels, characteristicof increased microbial energy harvest11. nas directly modulate the microbiota to induce glucose intolerance todeterminewhethersaccharindirectlyaffectsthegutmicrobiota,we culturedfaecalmatterfromnaivemiceunderstrictanaerobicconditions (75%n2,20%co2,5%h2)inthepresenceofsaccharin(5mgml21)or control growth media. cultures from day 9 of incubation were admi- nistered by gavage to germ-free mice (extended data fig. 8a). in vitro stool culture with saccharin induced an increase of the bacteroidetes phylum and reduction in firmicutes (bacteroidetes 89% versus 70%, firmicutes6%versus22%,extendeddatafig.8b).transferringthisin vitro saccharin-treated microbiota configuration into germ-free mice resultedinsignificantlyhigherglucoseintolerance(p,0.002)compared withgerm-freemicereceivingthecontrolculture(fig.3aandextended ab c saccharin water glucose abundance fold change (week 11/week 0) 100 101 102 103 10–3 10–2 10–1 bacteria growth conditions growth conditions water water glucose saccharin 0.31 –0.45 –0.69 pearson correlation p value (n = 115) 110 –2010 –10 water glucose saccharin definition n-acetylgalactosamine-6-sulphatase iduronate 2-sulphatase heparan-α-glucosaminide n-acetyltransferase α-n-acetylglucosaminidase hyaluronoglucosaminidase n-acetylglucosamine-6-sulphatase β-glucuronidase fold change (week 11/week 0) 0.7 1 4 e f mm acetate/mg faeces 0.0 1.0 1.5 2.0 glucose commercial saccharin 0.5 g mm propionate/mg faeces 0 20 30 40 10 ** bacteroides vulgatus akkermansia muciniphila 0 11 water glucose saccharin week 0 11 0 11 per cent of sample 0.0 0.5 1.0 1.5 other unknown parabacteroides distasonis staphylococcus aureus providencia rettgeri bacteroides vulgatus bacteroides fragilis glucose commercial saccharin β-galactosidase sialidase-1 β-mannosidase α-mannosidase glucosylceramidase endoglycosidase h α-l-fucosidase d figure 2 | functional characterization of saccharin-modulated microbiota. a, species alterations in mice consuming commercial saccharin, water or glucose for 11weeks (n54) shown by shotgun sequencing. b, pairwise correlations between changes in 115 kegg pathways across mice receiving different treatments. c, d, fold change in relative abundance of glycosaminoglycan (c) or other glycan (d) degradation pathway genes. e,higherglycandegradationattributedtofivetaxainthecommercialsaccharin setting. f, g, levels of faecal acetate and propionate at w11 in mice drinking commercial saccharin or glucose (n55). horizontal lines, means; error bars, s.e.m. **p,0.01, two-sided unpaired student t-test. scfa measurements were performed on two independent cohorts. article research 0 0 m o n t h 2 0 1 4 | v o l 0 0 0 | n a t u r e | 3 macmillan publishers limited. all rights reserved©2014 datafig.8c).similartothecompositionofthesaccharin-supplemented anaerobic culture, germ-free recipients of this cultured configuration featuredover-representationofmembersofthebacteroidesgenus,and under-representation of several clostridiales (fig. 3b and supplemen- tary table 5). shotgun metagenomic sequencing analysis revealed that in vitro saccharin treatment induced similar functional alterations to those found in mice consuming commercial saccharin (fig. 4c, p,1024), with glycan degradation pathways being highly enriched in both set- tings. other pathways highly enriched in both settings included those involved in sphingolipid metabolism, previously shown to be over- represented in microbiomes of non-obese diabetic mice23, and com- mon under-represented pathways included glucose transport (fig. 3c and extended data 7c, right column). collectively,theseresultsdemonstratethatsaccharindirectlymod- ulates the composition and function of the microbiome and induces dysbiosis, accounting for the downstream glucose intolerance pheno- type in the mammalian host. nas in humans associate with impaired glucose tolerance to study the effect of nas in humans, we examined the relationship between long-term nas consumption (based on a validated food fre- quency questionnaire, see methods) and various clinical parameters in data collected from 381 non-di
adoçantes artificiais induzem a intolerância à glicose, alterando a microbiota do intestino