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1.
Am J Hum Genet ; 108(3): 431-445, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33600772

RESUMO

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.


Assuntos
Calbindina 2/genética , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Negro ou Afro-Americano/genética , Idoso , Idoso de 80 Anos ou mais , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Doença de Crohn/genética , Doença de Crohn/patologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Sequenciamento Completo do Genoma
2.
Small ; 20(20): e2308680, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38225709

RESUMO

Gut microbiota function has numerous effects on humans and the diet humans consume has emerged as a pivotal determinant of gut microbiota function. Here, a new concept that gut microbiota can be trained by diet-derived exosome-like nanoparticles (ELNs) to release healthy outer membrane vesicles (OMVs) is introduced. Specifically, OMVs released from garlic ELN (GaELNs) trained human gut Akkermansia muciniphila (A. muciniphila) can reverse high-fat diet-induced type 2 diabetes (T2DM) in mice. Oral administration of OMVs released from GaELNs trained A. muciniphila can traffick to the brain where they are taken up by microglial cells, resulting in inhibition of high-fat diet-induced brain inflammation. GaELNs treatment increases the levels of OMV Amuc-1100, P9, and phosphatidylcholines. Increasing the levels of Amuc-1100 and P9 leads to increasing the GLP-1 plasma level. Increasing the levels of phosphatidylcholines is required for inhibition of cGas and STING-mediated inflammation and GLP-1R crosstalk with the insulin pathway that leads to increasing expression of Insulin Receptor Substrate (IRS1 and IRS2) on OMV targeted cells. These findings reveal a molecular mechanism whereby OMVs from plant nanoparticle-trained gut bacteria regulate genes expressed in the brain, and have implications for the treatment of brain dysfunction caused by a metabolic syndrome.


Assuntos
Eixo Encéfalo-Intestino , Diabetes Mellitus Tipo 2 , Exossomos , Alho , Microbioma Gastrointestinal , Nanopartículas , Diabetes Mellitus Tipo 2/metabolismo , Alho/química , Animais , Nanopartículas/química , Exossomos/metabolismo , Camundongos , Akkermansia , Humanos , Masculino , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Encéfalo/metabolismo , Encéfalo/patologia
3.
EMBO Rep ; 23(3): e53365, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34994476

RESUMO

Bark protects the tree against environmental insults. Here, we analyzed whether this defensive strategy could be utilized to broadly enhance protection against colitis. As a proof of concept, we show that exosome-like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)-mediated activation of the AhR signaling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium-specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti-microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter-kingdom communication in the mammalian intestine through an AhR-COPS8-mediated anti-inflammatory pathway. These data suggest that inflammatory pathways in a microbiota-enriched intestinal environment are regulated by COPS8 and that edible plant-derived ELNs may hold the potential as new agents for the prevention and treatment of gut-related inflammatory disease.


Assuntos
Colite , Exossomos , Morus , Nanopartículas , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/prevenção & controle , Modelos Animais de Doenças , Exossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Casca de Planta/metabolismo
4.
Gastroenterology ; 152(1): 206-217.e2, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693347

RESUMO

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.


Assuntos
Negro ou Afro-Americano/genética , Moléculas de Adesão Celular Neuronais/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Predisposição Genética para Doença/genética , Cadeias HLA-DRB1/genética , Proteínas Repressoras/genética , Ubiquitina Tiolesterase/genética , Adenilil Ciclases/genética , Estudos de Casos e Controles , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Cadeias alfa de HLA-DQ/genética , Humanos , Subunidade p40 da Interleucina-12/genética , Canal de Potássio KCNQ2/genética , Polimorfismo de Nucleotídeo Único , Receptores CXCR6 , Receptores de Quimiocinas/genética , Receptores de Interleucina/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores Virais/genética , Nexinas de Classificação/genética , Tenascina/genética , População Branca/genética
5.
BMJ Open ; 13(9): e073735, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37699630

RESUMO

OBJECTIVES: Patient experiences are critical when determining the acceptability of novel interventional pharmaceuticals. Here, we report the development and validation of a product acceptability questionnaire (SPRAY PAL) assessing feasibility, acceptability and tolerability of an intranasal Q-Griffithsin (Q-GRFT) drug product designed for COVID-19 prophylaxis. DESIGN: SPRAY PAL validation was undertaken as part of an ongoing phase 1 clinical trial designed to test the safety, pharmacokinetics and tolerability of intranasally administered Q-GRFT for the prevention of SARS-CoV-2 infection. SETTING: The phase 1 clinical trial took place at a University Outpatient Clinical Trials Unit from November 2021 to September 2023. PARTICIPANTS: The initial SPRAY PAL questionnaire was piloted among healthy volunteers ages 25 to 55 in phase 1a of the clinical trial (N=18) and revised for administration in phase 1b for participants ages 24-59 (N=22). RESULTS: Spearman correlations tested convergent and discriminant validity. Internal consistency was assessed using Cronbach's alpha, and test-retest reliability was assessed using intraclass correlation coefficients of responses collected from three repeated questionnaire administrations. The initial version demonstrated excellent internal consistency. The revised version demonstrated very good internal consistency after removal of one item (alpha=0.739). Excellent test-retest reliability (intraclass coefficient=0.927) and adequate convergent (r's=0.208-0.774) and discriminant (r's=0.123-0.392) validity were achieved. Subscales adequately distinguished between the constructs of acceptability, feasibility and tolerability. CONCLUSIONS: The SPRAY PAL product acceptability questionnaire is a valid and reliable patient-reported outcomes measure that can be considered a credible tool for assessing patient-reported information about product acceptability, feasibility of use, tolerability of product and side effects and cost of product for novel intranasal drug formulations. The SPRAY PAL is generalisable, and items may be readily adapted to assess other intranasal formulations. TRIAL REGISTRATION NUMBERS: NCT05122260 and NCT05437029.


Assuntos
COVID-19 , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , COVID-19/prevenção & controle , Reprodutibilidade dos Testes , SARS-CoV-2
6.
J Extracell Vesicles ; 12(2): e12307, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36754903

RESUMO

Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an 'organiser' of protein networks to generate a new or different biological effect from that identified in EV-producing cells has never been demonstrated. Here, as a proof-of-concept, we demonstrate that EV-G12D-mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL-17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D-mutant KRAS complex from EVs-producing cells, EV-G12D-mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin-1 (Fn1), which drives the activation of the IL-17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV-Fn1 leads to a reduction of a number of inflammatory cytokines including IL-17A; (ii) induction of IL-17A promotes lung inflammation, which in turn leads to IL-17A mediated induction of FGF21 in the lung; and (iii) EV-G12D-mutant KRAS complex mediated lung inflammation is abrogated in IL-17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV-mediated disease processes.


Assuntos
Vesículas Extracelulares , Neoplasias Pulmonares , Pneumonia , Camundongos , Animais , Interleucina-17/metabolismo , Interleucina-17/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Mutantes/metabolismo , Proteínas Mutantes/uso terapêutico , Vesículas Extracelulares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/genética
7.
Theranostics ; 12(3): 1220-1246, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154484

RESUMO

Background: Obesity is becoming a global epidemic and reversing the pathological processes underlying obesity and metabolic co-morbidities is challenging. Obesity induced chronic inflammation including brain inflammation is a hallmark of obesity via the gut-brain axis. The objective of this study was to develop garlic exosome-like nanoparticles (GaELNs) that inhibit systemic as well as brain inflammatory activity and reverse a HFD induced obesity in mice. Methods: GELNs were isolated and administrated orally into HFD fed mice. GaELNs were fluorescent labeled for monitoring their in vivo trafficking route after oral administration and quantified the number particles in several tissues. The brain inflammation was determined by measuring inflammatory cytokines by ELISA and real-time PCR. Mitochondrial membrane permeability of microglial cells was determined using JC-10 fluorescence dye. The in vivo apoptotic cell death was quantified by TUNEL assay. The brain metabolites were identified and quantified by LC-MS analysis. Memory function of the mice was determined by several memory functional analysis. The effect of GaELNs on glucose and insulin response of the mice was determined by glucose and insulin tolerance tests. c-Myc localization and interaction with BASP1 and calmodulin was determined by confocal microscopy. Results: Our results show that GaELNs is preferentially taken up microglial cells and inhibits the brain inflammation in HFD mice. GaELN phosphatidic acid (PA) (36:4) is required for the uptake of GaELNs via interaction with microglial BASP1. Formation of the GaELNs/BASP1 complex is required for inhibition of c-Myc mediated expression of STING. GaELN PA binds to BASP1, leading to inhibition of c-Myc expression and activity through competitively binding to CaM with c-Myc transcription factor. Inhibition of STING activity leads to reducing the expression of an array of inflammatory cytokines including IFN-γ and TNF-α. IFN-γ induces the expression of IDO1, which in turn the metabolites generated as IDO1 dependent manner activate the AHR pathway that contributes to developing obesity. The metabolites derived from the GaELNs treated microglial cells promote neuronal differentiation and inhibit mitochondrial mediated neuronal cell death. GaELNs treated HFD mice showed improved memory function and increased glucose tolerance and insulin sensitivity in these mice. Conclusion: Collectively, these results demonstrate how nanoparticles from a healthy diet can inhibit unhealthy high-fat diet induced brain inflammation and reveal a link between brain microglia/diet to brain inflammatory disease outcomes via diet-derived exosome-like nanoparticles.


Assuntos
Encefalite , Alho , Nanopartículas , Animais , Antioxidantes , Encéfalo/metabolismo , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Alho/metabolismo , Glucose , Inflamação/metabolismo , Insulina , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
8.
Theranostics ; 11(9): 4061-4077, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754048

RESUMO

Background: Diet manipulation is the basis for prevention of obesity and diabetes. The molecular mechanisms that mediate the diet-based prevention of insulin resistance are not well understood. Here, as proof-of-concept, ginger-derived nanoparticles (GDNP) were used for studying molecular mechanisms underlying GDNP mediated prevention of high-fat diet induced insulin resistance. Methods: Ginger-derived nanoparticles (GDNP) were isolated from ginger roots and administered orally to C57BL/6 high-fat diet mice. Fecal exosomes released from intestinal epithelial cells (IECs) of PBS or GDNP treated high-fat diet (HFD) fed mice were isolated by differential centrifugation. A micro-RNA (miRNA) polymerase chain reaction (PCR) array was used to profile the exosomal miRs and miRs of interest were further analyzed by quantitative real time (RT) PCR. miR-375 or antisense-miR375 was packed into nanoparticles made from the lipids extracted from GDNP. Nanoparticles was fluorescent labeled for monitoring their in vivo trafficking route after oral administration. The effect of these nanoparticles on glucose and insulin response of mice was determined by glucose and insulin tolerance tests. Results: We report that HFD feeding increased the expression of AhR and inhibited the expression of miR-375 and VAMP7. Treatment with orally administered ginger-derived nanoparticles (GDNP) resulted in reversing HFD mediated inhibition of the expression of miR-375 and VAMP7. miR-375 knockout mice exhibited impaired glucose homeostasis and insulin resistance. Induction of intracellular miR-375 led to inhibition of the expression of AhR and VAMP7 mediated exporting of miR-375 into intestinal epithelial exosomes where they were taken up by gut bacteria and inhibited the production of the AhR ligand indole. Intestinal exosomes can also traffic to the liver and be taken up by hepatocytes, leading to miR-375 mediated inhibition of hepatic AhR over-expression and inducing the expression of genes associated with the hepatic insulin response. Altogether, GDNP prevents high-fat diet-induced insulin resistance by miR-375 mediated inhibition of the aryl hydrocarbon receptor mediated pathways over activated by HFD feeding. Conclusion: Collectively our findings reveal that oral administration of GDNP to HFD mice improves host glucose tolerance and insulin response via regulating AhR expression by GDNP induced miR-375 and VAMP7.


Assuntos
Bactérias/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/genética , Insulina/genética , MicroRNAs/genética , Receptores de Hidrocarboneto Arílico/genética , Triptofanase/genética , Adulto , Animais , Células Cultivadas , Zingiber officinale/química , Hepatócitos/efeitos dos fármacos , Humanos , Lipídeos/genética , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Obesidade/genética , Proteínas R-SNARE/genética
9.
Nat Commun ; 12(1): 213, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431899

RESUMO

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.


Assuntos
Dieta Hiperlipídica , Exossomos/metabolismo , Resistência à Insulina/genética , Fosfatidilcolinas/metabolismo , Regulação para Cima/genética , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/complicações , Dislipidemias/genética , Dislipidemias/patologia , Células Epiteliais/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Fezes , Regulação da Expressão Gênica , Intolerância à Glucose , Proteínas de Fluorescência Verde/metabolismo , Humanos , Insulina/metabolismo , Interleucina-6/sangue , Intestinos/citologia , Lipídeos/química , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Tetraspanina 30/metabolismo , Fator de Necrose Tumoral alfa/sangue
10.
Nat Commun ; 10(1): 89, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626868

RESUMO

The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.


Assuntos
Cumarínicos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células CACO-2 , Cumarínicos/química , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Mucosa Intestinal/metabolismo , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Organismos Livres de Patógenos Específicos , Proteínas de Junções Íntimas/genética
11.
Inflamm Bowel Dis ; 23(11): 1962-1971, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28945635

RESUMO

BACKGROUND: Anorectal fistulas (ARFs) are a common, devastating, event in the life of a patient with Crohn's disease. ARFs occur in up to 50% of patients with Crohn's disease. Treatment begins with surgical drainage of the initial abscess, followed by antibiotic therapy, then anti-inflammatory medications. If medical therapy fails to close the fistula tract, surgical intervention is often pursued. Surgery incurs risk of incontinence because of sphincter injury. Increasingly, the role of cell-based therapy is being investigated in ARFs. We evaluated the role a bioabsorbable scaffold plays in delivering cell-based therapy using a porcine model of AFR. METHODS: ARFs were mechanically created and matured by setons. After 28 days, setons were removed; periaortic fat was harvested and processed for stromal vascular fraction (SVF). The cells were labeled with a membrane stain for later identification, then injected into the fistula or implanted through scaffold. Fistulas not treated with cells were injected with fibrin glue. Animals were monitored visually for healing at weeks 2 and 4, then euthanized to evaluate fistulas for histologic healing. RESULTS: All fistulas (6/6) treated with SVF + scaffolds healed by week 2, compared with only 4/6 with just SVF and 0/5 treated with fibrin glue. Scaffolds retained SVF within the fistula tract more readily than injection method and SVF+scaffold treatment accelerated the healing process. Robust neovascularization was also seen in fistulas treated with SVF+scaffold. No adverse events occurred. CONCLUSIONS: Scaffold technology may improve cell-based therapy healing rates for Crohn's ARFs. This advance should be investigated by human trials.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Adesivo Tecidual de Fibrina/uso terapêutico , Fístula Retal/terapia , Alicerces Teciduais , Cicatrização , Implantes Absorvíveis , Animais , Doença de Crohn/complicações , Feminino , Suínos
12.
J Nucl Med ; 58(6): 1009-1012, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27908970

RESUMO

Currently, several noninvasive modalities, including MRI and PET, are being investigated to identify early intestinal inflammation, longitudinally monitor disease status, or detect dysplastic changes in patients with inflammatory bowel disease. Here, we assess the applicability and utility of multispectral optoacoustic tomography (MSOT) in evaluating the presence and severity of colitis. Methods: C57B/6 mice were untreated or treated with Bacteroides fragilis and antibiotic-mediated depletion of intestinal flora to initiate colitis. Mice were imaged using MSOT to detect intestinal inflammation. Intestinal inflammation identified with MSOT was also confirmed using both colonoscopy and histology. Results: Mice with bacterial colitis demonstrated a temporally associated increase in mesenteric and colonic vascularity with an increase in mean signal intensity of oxygenated hemoglobin (P = 0.004) by MSOT 2 d after inoculation. These findings were significantly more prominent 7 d after inoculation, with increased mean signal intensity of oxygenated hemoglobin (P = 0.0002) and the development of punctate vascular lesions on the colonic surface, which corresponded to changes observed on colonoscopy as well as histology. Conclusion: With improvements in depth of tissue penetration, MSOT may hold potential as a sensitive, accurate, noninvasive imaging tool in the evaluation of patients with inflammatory bowel disease.


Assuntos
Infecções Bacterianas/diagnóstico por imagem , Colite/diagnóstico por imagem , Tomografia/métodos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Técnicas Fotoacústicas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
Inflamm Bowel Dis ; 24(1): 159-165, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29272478

RESUMO

Background: Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. Methods: Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. Results: Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). Conclusions: We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions.


Assuntos
Biomarcadores/sangue , Colite Ulcerativa/sangue , Doença de Crohn/sangue , MicroRNAs/sangue , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Nutr Clin Pract ; 18(6): 461-82, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16215082

RESUMO

Animal and human research has established the beneficial effects of enteral nutrition on the gut. Both the innate and acquired immune systems are bolstered by enteral alimentation. Emerging clinical concepts tie these beneficial effects to a significant influence on the host immune response to stressors during critical illness. In this article, we examine how enteral nutrition impacts gastrointestinal immunity and demonstrate how these changes may affect the body's systemic immune response to nongastrointestinal challenges. This modulatory effect occurs because of changes in the pattern of cytokine secretion and alterations in lymphocyte and neutrophil recruitment. Imbalances in these regulatory mechanisms may be the engine driving hyperresponsiveness to subsequent challenges in the critically ill patient.

15.
FEBS Lett ; 588(22): 4195-206, 2014 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-24681103

RESUMO

The interplay between the immune response and the gut microbiota is complex. Although it is well-established that the gut microbiota is essential for the proper development of the immune system, recent evidence indicates that the cells of the immune system also influence the composition of the gut microbiota. This interaction can have important consequences for the development of inflammatory diseases, including autoimmune diseases and allergy, and the specific mechanisms by which the gut commensals drive the development of different types of immune responses are beginning to be understood. Furthermore, sex hormones are now thought to play a novel role in this complex relationship, and collaborate with both the gut microbiota and immune system to influence the development of autoimmune disease. In this review, we will focus on recent studies that have transformed our understanding of the importance of the gut microbiota in inflammatory responses.


Assuntos
Doença , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Microbiota , Linfócitos T , Animais , Humanos , Imunidade , Linfócitos T/imunologia
17.
Inflamm Bowel Dis ; 19(9): 1904-12, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23846486

RESUMO

BACKGROUND: Green tea and its main polyphenolic component, (-)-epigallocatechin-3-gallate (EGCG), exert powerful anti-inflammatory effects that are protective against both inflammatory diseases and cancer. Research with animal and human cell lines provide plausible support for these claims. Poor absorption results in low systemic bioavailability of EGCG after oral administration but high colonic mucosal exposure. METHODS: Patients with mild to moderate ulcerative colitis (UC) were randomized to daily doses of oral Polyphenon E (400 mg or 800 mg of total EGCG daily, administered in split doses) or placebo in a double-blinded, placebo-controlled pilot study. Response was measured by the UC disease activity index and the inflammatory bowel disease questionnaire on day 56. RESULTS: Twenty patients were randomized to active therapy or placebo in a 4:1 ratio. Nineteen subjects received >1 dose of study medication (15 Polyphenon E, 4 placebo). The mean UC disease activity index score at study entry was 6.5 ± 1.9 in the treatment group and 7.3 ± 1.7 in the placebo group. After 56 days of therapy, the response rate was 66.7% (10 of 15) in the Polyphenon E group and 0% (0 of 4) in the placebo group (P = 0.03). The active treatment remission rate was 53.3% (8 of 15) compared with 0% (0 of 4) for placebo (P = 0.10). Polyphenon E treatment resulted in only minor side effects. CONCLUSIONS: Administration of Polyphenon E resulted in a therapeutic benefit for patients who were refractory to 5-aminosalicylic and/or azathioprine. This agent holds promise as a novel option for the treatment of patients with UC with mild to moderately active disease.


Assuntos
Catequina/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Chá/química , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Catequina/administração & dosagem , Catequina/química , Catequina/farmacologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Qualidade de Vida , Indução de Remissão , Adulto Jovem
18.
Int J Nanomedicine ; 8: 2153-61, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23818775

RESUMO

Gold nanoparticles and near infrared-absorbing light are each innocuous to tissue but when combined can destroy malignant tissue while leaving healthy tissue unharmed. This study investigated the feasibility of photothermal ablation therapy for esophageal adenocarcinoma using chitosan-coated gold/gold sulfide (CS-GGS) nanoparticles. A rat esophagoduodenal anastomosis model was used for the in vivo ablation study, and three human esophageal cell lines were used to study the response of cancer cells and benign cells to near infrared light after treatment with CS-GGS. The results indicate that both cancerous tissue and cancer cells took up more gold nanoparticles and were completely ablated after exposure to near infrared light. The benign tissue and noncancerous cells showed less uptake of these nanoparticles, and remained viable after exposure to near infrared light. CS-GGS nanoparticles could provide an optimal endoluminal therapeutic option for near infrared light ablation of esophageal cancer.


Assuntos
Adenocarcinoma , Antineoplásicos/farmacologia , Morte Celular , Neoplasias Esofágicas , Ouro/farmacologia , Nanopartículas Metálicas/química , Técnicas de Ablação , Animais , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ouro/química , Humanos , Raios Infravermelhos , Ratos , Ratos Sprague-Dawley
20.
Expert Opin Biol Ther ; 9(8): 967-74, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19591627

RESUMO

Therapy for Crohn's disease (CD) is evolving at breakneck speed. Biologic therapies are assuming ever more important roles in treating this unrelenting, life-long disorder. New evidence suggests that earlier, more aggressive use of biological therapies for CD may improve overall efficacy rates, as well as reduce long-term complications. In addition to optimizing the use of older biologic therapies (antibodies against TNF-alpha), recent and ongoing clinical trials are evaluating the clinical efficacy of a large number of other biologic therapies, honing in on a wide array of immunological targets. The promise of biologic therapies stems from their ability to induce complete and long-lasting remission of symptoms in a way that 'standard' therapies have not been able to accomplish. In this review of biologic therapies for CD, we examine the latest clinical trial data and evidence for mechanism of action of a variety of current and future therapies.


Assuntos
Terapia Biológica/métodos , Doença de Crohn/terapia , Abatacepte , Adalimumab , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Certolizumab Pegol , Ensaios Clínicos como Assunto , Doença de Crohn/imunologia , Humanos , Imunoconjugados/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Infliximab , Natalizumab , Polietilenoglicóis/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo , Ustekinumab
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