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1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445577

RESUMO

Infections by the zoonotic foodborne bacterium Campylobacter jejuni (C. jejuni) are among the most frequent causes of bacterial gastroenteritis worldwide. The aim was to evaluate the relationship between epithelial barrier disruption, mucosal immune activation, and vitamin D (VD) treatment during C. jejuni infection, using intestinal epithelial cells and mouse models focused on the interaction of C. jejuni with the VD signaling pathway and VD treatment to improve C. jejuni-induced barrier dysfunction. Our RNA-Seq data from campylobacteriosis patients demonstrate inhibition of VD receptor (VDR) downstream targets, consistent with suppression of immune function. Barrier-preserving effects of VD addition were identified in C. jejuni-infected epithelial cells and IL-10-/- mice. Furthermore, interference of C. jejuni with the VDR pathway was shown via VDR/retinoid X receptor (RXR) interaction. Paracellular leakiness of infected epithelia correlated with tight junction (TJ) protein redistribution off the TJ domain and apoptosis induction. Supplementation with VD reversed barrier impairment and prevented inhibition of the VDR pathway, as shown by restoration of transepithelial electrical resistance and fluorescein (332 Da) permeability. We conclude that VD treatment restores gut epithelial barrier functionality and decreases bacterial transmigration and might, therefore, be a promising compound for C. jejuni treatment in humans and animals.


Assuntos
Infecções por Campylobacter/complicações , Permeabilidade da Membrana Celular , Células Epiteliais/efeitos dos fármacos , Interleucina-10/fisiologia , Mucosa Intestinal/efeitos dos fármacos , Vitamina D/farmacologia , Animais , Infecções por Campylobacter/microbiologia , Campylobacter jejuni/isolamento & purificação , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Junções Íntimas/metabolismo , Vitaminas/farmacologia
2.
FASEB J ; 35(9): e21667, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34405442

RESUMO

Long noncoding RNAs (lncRNAs) are central regulators of the inflammatory response and play an important role in inflammatory diseases. PINT has been reported to be involved in embryonic development and tumorigenesis. However, the potential functions of PINT in the innate immune system are largely unknown. Here, we revealed the transcriptional regulation of inflammatory genes by PINT, whose expression is primarily dependent on the NF-κB signaling pathway in human and mouse macrophage and intestinal epithelial cell lines. Functionally, PINT selectively regulates the expression of TNF-α in basal and LPS-stimulated cells. Mechanistically, PINT acts as a modular scaffold of p65 and EZH2 to coordinate their localization and specify their binding to the target genes. Further, a high expression level of PINT was detected in intestinal mucosal tissues from patients with ulcerative colitis (UC). Together, these findings demonstrate that PINT acts as an activator of inflammatory responses, highlighting the importance of this lncRNA as a potential therapeutic target in infectious diseases and inflammatory diseases.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Fator de Transcrição RelA/metabolismo , Transcrição Genética , Fator de Necrose Tumoral alfa/genética , Animais , Linhagem Celular , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Citocinas/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transcrição Genética/genética
3.
Front Immunol ; 12: 708149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335624

RESUMO

Microbial translocation (MT) and intestinal damage (ID) are poorly explored in COVID-19. Aims were to assess whether alteration of gut permeability and cell integrity characterize COVID-19 patients, whether it is more pronounced in severe infections and whether it influences the development of subsequent bloodstream infection (BSI). Furthermore, we looked at the potential predictive role of TM and ID markers on Intensive Care Unit (ICU) admission and in-hospital mortality. Over March-July 2020, 45 COVID-19 patients were enrolled. Markers of MT [LPB (Lipopolysacharide Binding Protein) and EndoCab IgM] and ID [I-FABP (Intestinal Fatty Acid Binding Protein)] were evaluated at COVID-19 diagnosis and after 7 days. As a control group, age- and gender-matched healthy donors (HDs) enrolled during the same study period were included. Median age was 66 (56-71) years. Twenty-one (46.6%) were admitted to ICU and mortality was 22% (10/45). Compared to HD, a high degree of MT and ID was observed. ICU patients had higher levels of MT, but not of ID, than non-ICU ones. Likewise, patients with BSI had lower EndoCab IgM than non-BSI. Interestingly, patients with high degree of MT and low ID were likely to be admitted to ICU (AUC 0.822). Patients with COVID-19 exhibited high level of MT, especially subjects admitted to ICU. COVID-19 is associated with gut permeability.


Assuntos
COVID-19/metabolismo , Mucosa Intestinal/metabolismo , SARS-CoV-2/fisiologia , Proteínas de Fase Aguda/metabolismo , Idoso , Biomarcadores/metabolismo , COVID-19/diagnóstico , COVID-19/mortalidade , COVID-19/patologia , Proteínas de Transporte/metabolismo , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Unidades de Terapia Intensiva , Mucosa Intestinal/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Junções Íntimas/metabolismo
4.
J Virol ; 95(18): e0085321, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34232065

RESUMO

Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus causing acute intestinal infection in pigs, with high mortality often seen in neonatal pigs. The newborns rely on innate immune responses against invading pathogens because of lacking adaptive immunity. However, how PEDV disables the innate immunity of newborns toward severe infection remains unknown. We found that PEDV infection led to reduced expression of histone deacetylases (HDACs), especially HDAC1, in porcine IPEC-J2 cells. HDACs are considered important regulators of innate immunity. We hypothesized that PEDV interacts with certain host factors to regulate HDAC1 expression in favor of its replication. We show that HDAC1 acted as a negative regulator of PEDV replication in IPEC-J2 cells, as shown by chemical inhibition, gene knockout, and overexpression. A GC-box (GCCCCACCCCC) within the HDAC1 promoter region was identified for Sp1 binding in IPEC-J2 cells. Treatment of the cells with Sp1 inhibitor mithramycin A inhibited HDAC1 expression, indicating direct regulation of HDAC1 expression by Sp1. Of the viral proteins that were overexpressed in IPEC-J2 cells, the N protein was found to be present in the nuclei and more inhibitory to HDAC1 transcription. The putative nuclear localization sequence 261PKKNKSR267 contributed to its nuclear localization. The N protein interacted with Sp1 and interfered with its binding to the promoter region, thereby inhibiting its transcriptional activity for HDAC1 expression. Our findings reveal a novel mechanism of PEDV evasion of the host responses, offering implications for studying the infection processes of other coronaviruses. IMPORTANCE The enteric coronavirus porcine epidemic diarrhea virus (PEDV) causes fatal acute intestinal infection in neonatal pigs that rely on innate immune responses. Histone deacetylases (HDACs) play important roles in innate immune regulation. Our study found PEDV suppresses HDAC1 expression via the interaction of its N protein and porcine Sp1, which identified a novel mechanism of PEDV evasion of the host responses to benefit its replication. This study suggests that other coronaviruses, including SARS-CoV and SARS-CoV-2, also make use of their N proteins to intercept the host immune responses in favor of their infection.


Assuntos
Infecções por Coronavirus/veterinária , Células Epiteliais/virologia , Histona Desacetilase 1/antagonistas & inibidores , Mucosa Intestinal/virologia , Fator de Transcrição Sp1/metabolismo , Doenças dos Suínos/virologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral , Animais , Células Cultivadas , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Vírus da Diarreia Epidêmica Suína/patogenicidade , Fator de Transcrição Sp1/genética , Suínos , Doenças dos Suínos/metabolismo , Doenças dos Suínos/patologia , Proteínas não Estruturais Virais/genética
5.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298894

RESUMO

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body's health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Adiponectina/metabolismo , Animais , Comportamento Alimentar/fisiologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Receptores para Leptina/metabolismo
7.
Anticancer Res ; 41(7): 3511-3517, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230146

RESUMO

BACKGROUND/AIM: We previously found crypts in symmetric fission (CSF) and in asymmetric fission (CAF) in colectomy-specimens with ulcerative colitis. We now analyzed CSF and CAF (CSAF) in biopsies from 80 patients with inflammatory bowel disease (IBD) without dysplasia or carcinoma. PATIENTS AND METHODS: One unselected double-biopsy from affected endoscopic areas was investigated in the 80 cases. RESULTS: A total of 353 crypts in fission were found. The median number of CAF/biopsy was 3.7 and for CSF/biopsy, 0.7 (p<0.00001). CONCLUSION: CSAF often occur in unselected biopsies from patients with IBD. Whereas the increased frequency of CSF might mirror a compensatory mechanism of crypt production in areas occupied by inflammation, CAF reflects a pathological aberration of cryptogenesis, probably generated by somatic mutations. The biological significance of CAF in IBD without dysplasia or carcinoma, deserves to be further investigated.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Biópsia/métodos , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias do Colo/patologia , Feminino , Humanos , Inflamação/patologia , Mucosa Intestinal/patologia , Masculino , Suécia
8.
Anticancer Res ; 41(7): 3689-3698, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230168

RESUMO

BACKGROUND/AIM: SPARC-related modular calcium-binding protein 2 (SMOC2), a secreted matricellular protein, is reported to be involved in cancer progression such as cell cycle, angiogenesis, and invasion. In this study, we aimed to investigate the expression of SMOC2 in various gastric lesions and assessed its prognostic value in a large cohort of gastric cancer (GC) patients. PATIENTS AND METHODS: SMOC2 mRNA levels were measured by quantitative real-time PCR using 26 matched fresh-frozen GC samples. SMOC2 protein expression was determined by immunohistochemistry on tissue microarrays including 734 GC specimens and its correlations with clinicopathological features and survival were evaluated. RESULTS: The transcription level of SMOC2 was higher in GC samples compared to normal mucosa (p=0.006). Its expression levels were associated with the intestinal stem cell (ISC) marker, LGR5, but there were no correlations with EPHB2 and OLFM4 or the candidate cancer stem cell markers CD133 and CD44. SMOC2 expression was significantly increased in the intestinal metaplasia and was further increased in gastric adenomas and early gastric cancers (EGC). In total, 34% of GCs were positive for SMOC2, and SMOC2 positivity was higher in old (p=0.001) and male (p<0.001) patients, and in well-differentiated GC (p<0.001). SMOC2 expression had a negative association with perineural invasion (p<0.001) and tumor stage (p<0.001). In survival analysis, SMOC2-positive GC patients had much better clinical outcomes in overall survival rates (p<0.001) compared to SMOC2-negative GC patients. The prognostic impact of SMOC2 remained significant both in intestinal (p<0.001) and diffuse-type GC (p<0.001). Remarkably, a multivariate analysis demonstrated SMOC2 as an independent prognostic marker [hazard ratio (HR)=0.732, p=0.045] along with venous invasion (p=0.012), tumor stage (p<0.001) and CDX2 (p=0.028). CONCLUSION: Our results suggest that SMOC2 can be a prognostic marker for better clinical outcomes in GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Feminino , Humanos , Mucosa Intestinal/patologia , Masculino , Estadiamento de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
9.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199463

RESUMO

Little is known about the ability for epithelial regeneration and wound healing in patients with inflammatory bowel diseases. We evaluated the epithelial proliferation and wound healing ability of patients with Crohn's disease (CD) using patient-derived intestinal organoids. Human intestinal organoids were constructed in a three-dimensional intestinal crypt culture of enteroscopic biopsy samples from controls and CD patients. The organoid-forming efficiency of ileal crypts derived from CD patients was reduced compared with those from control subjects (p < 0.001). Long-term cultured organoids (≥6 passages) derived from controls and CD patients showed an indistinguishable microscopic appearance and culturing behavior. Under TNFα-enriched conditions (30 ng/mL), the organoid reconstitution rate and cell viability of CD patient-derived organoids were significantly lower than those of the control organoids (p < 0.05 for each). The number of EdU+ cells was significantly lower in TNFα-treated organoids derived from CD patients than in TNFα-treated control organoids (p < 0.05). In a wound healing assay, the unhealed area in TNFα-treated CD patient-derived organoids was significantly larger than that of TNFα-treated control organoids (p < 0.001). The wound healing ability of CD patient-derived organoids is reduced in TNFα-enriched conditions, due to reduced cell proliferation. Epithelial regeneration ability may be impaired in patients with CD.


Assuntos
Proliferação de Células/genética , Doença de Crohn/terapia , Células Epiteliais/metabolismo , Organoides/crescimento & desenvolvimento , Adulto , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Células Epiteliais/patologia , Feminino , Humanos , Íleo/crescimento & desenvolvimento , Íleo/lesões , Íleo/patologia , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/patologia , Intestinos/diagnóstico por imagem , Intestinos/lesões , Masculino , Pessoa de Meia-Idade , Organoides/metabolismo , Regeneração/genética , Transdução de Sinais/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Fator de Necrose Tumoral alfa/genética , Cicatrização/genética
10.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201918

RESUMO

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Mice lacking PTPN2 in dendritic cells (DCs) develop skin and liver inflammation by the age of 22 weeks due to a generalized loss of tolerance leading to uncontrolled immune responses. The effect of DC-specific PTPN2 loss on intestinal health, however, is unknown. The aim of this study was to investigate the DC-specific role of PTPN2 in the intestine during colitis development. PTPN2fl/flxCD11cCre mice were subjected to acute and chronic DSS colitis as well as T cell transfer colitis. Lamina propria immune cell populations were analyzed using flow cytometry. DC-specific PTPN2 deletion promoted infiltration of B and T lymphocytes, macrophages, and DCs into the lamina propria of unchallenged mice and elevated Th1 abundance during acute DSS colitis, suggesting an important role for PTPN2 in DCs in maintaining intestinal immune cell homeostasis. Surprisingly, those immune cell alterations did not translate into increased colitis susceptibility in acute and chronic DSS-induced colitis or T cell transfer colitis models. However, macrophage depletion by clodronate caused enhanced colitis severity in mice with a DC-specific loss of PTPN2. Loss of PTPN2 in DCs affects the composition of lamina propria lymphocytes, resulting in increased infiltration of innate and adaptive immune cells. However, this did not result in an elevated colitis phenotype, likely because increased infiltration of macrophages in the intestine upon loss of PTPN2 loss in DCs can compensate for the inflammatory effect of PTPN2-deficient DCs.


Assuntos
Colite/etiologia , Colite/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Animais , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Transgênicos , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Fator de Transcrição STAT1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
11.
Nat Commun ; 12(1): 4246, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253728

RESUMO

Modeling human diseases as networks simplify complex multi-cellular processes, helps understand patterns in noisy data that humans cannot find, and thereby improves precision in prediction. Using Inflammatory Bowel Disease (IBD) as an example, here we outline an unbiased AI-assisted approach for target identification and validation. A network was built in which clusters of genes are connected by directed edges that highlight asymmetric Boolean relationships. Using machine-learning, a path of continuum states was pinpointed, which most effectively predicted disease outcome. This path was enriched in gene-clusters that maintain the integrity of the gut epithelial barrier. We exploit this insight to prioritize one target, choose appropriate pre-clinical murine models for target validation and design patient-derived organoid models. Potential for treatment efficacy is confirmed in patient-derived organoids using multivariate analyses. This AI-assisted approach identifies a first-in-class gut barrier-protective agent in IBD and predicted Phase-III success of candidate agents.


Assuntos
Inteligência Artificial , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/patologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Estudos de Coortes , Colite/genética , Sulfato de Dextrana , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Funções Verossimilhança , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Família Multigênica , Organoides/patologia , Reprodutibilidade dos Testes , Resultado do Tratamento
12.
Anticancer Res ; 41(7): 3261-3270, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230120

RESUMO

BACKGROUND/AIM: Chronic inflammation generates large quantities of reactive oxygen and nitrogen species that damage DNA. DNA repair is important for cellular viability and genome integrity. MATERIALS AND METHODS: Expression levels of the DNA repair proteins OGG1, XPA, MLH1, PARP1, and XRCC6, which function in base excision repair, nucleotide excision repair, mismatch repair, single-strand break repair and double-strand break repair, respectively, were assessed using immunohistochemistry in ulcerative colitis and sporadic colorectal cancer biopsies. Levels of oxidative/ nitrosative stress biomarkers were also assessed. RESULTS: Ulcerative colitis and colorectal cancer lesions expressed significantly higher levels of all DNA repair proteins and oxidative/ nitrosative stress biomarkers compared to normal colonic mucosa. Ulcerative colitis had the highest XPA and XRCC6 expression. CONCLUSION: Oxidative/nitrosative stress is prevalent in the colon of both diseases. Nucleotide excision repair and non-homologous end-joining double-strand break repair may be compromised in colorectal cancer, but not in ulcerative colitis.


Assuntos
Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , DNA/genética , Estresse Nitrosativo/genética , Estresse Oxidativo/genética , Biomarcadores Tumorais/genética , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Humanos , Mucosa Intestinal/patologia , Oxirredução
13.
N Engl J Med ; 385(1): 35-45, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192430

RESUMO

BACKGROUND: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).


Assuntos
Doença Celíaca/tratamento farmacológico , Duodeno/patologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Imidazóis/administração & dosagem , Mucosa Intestinal/patologia , Piridinas/administração & dosagem , Transglutaminases/antagonistas & inibidores , Administração Oral , Adulto , Doença Celíaca/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Duodeno/imunologia , Feminino , Glutens/administração & dosagem , Glutens/efeitos adversos , Humanos , Imidazóis/efeitos adversos , Mucosa Intestinal/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Piridinas/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença
14.
Am J Pathol ; 191(9): 1537-1549, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139193

RESUMO

Epithelial barrier impairment is a hallmark of several pathologic processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial cells. Herein, we show that in colonocytes, rictor/mammalian target of rapamycin complex 2 (mTORC2) signaling is a prosurvival stimulus. Mechanistically, mTORC2 activates Akt, which, in turn, inhibits apoptosis by phosphorylating B-cell lymphoma 2 (BCL2) associated agonist of cell death (Bad) and preventing caspase-3 activation. Nevertheless, during inflammation, rictor/mTORC2 signaling declines and Akt activity is reduced. Consequently, active caspase-3 increases in surface colonocytes undergoing apoptosis/anoikis and causes epithelial barrier breakdown. Likewise, Rictor ablation in intestinal epithelial cells interrupts mTORC2/Akt signaling and increases apoptosis/anoikis of surface colonocytes without affecting the crypt architecture. The increase in epithelial permeability induced by Rictor ablation produces a mild inflammatory response in the colonic mucosa, but minimally affects the development/establishment of colitis. The data identify a previously unknown mechanism by which rictor/mTORC2 signaling regulates apoptosis/anoikis in intestinal epithelial cells during colitis and clarify its role in the maintenance of the intestinal epithelial barrier.


Assuntos
Apoptose/fisiologia , Colite/patologia , Células Epiteliais/metabolismo , Mucosa Intestinal/patologia , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Animais , Colite/metabolismo , Células Epiteliais/patologia , Mucosa Intestinal/metabolismo , Camundongos , Transdução de Sinais/fisiologia
15.
Nutrients ; 13(5)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064541

RESUMO

An association between celiac disease and IgA nephropathy (IgAN) has been suggested. In celiac disease, in addition to circulating in serum, IgA-class tissue transglutaminase (tTG) autoantibodies are deposited in the small bowel mucosa and extraintestinal organs. In this case series of IgAN patients with or without celiac disease, we studied whether celiac disease-type IgA-tTG deposits occur in kidney biopsies. The study included nine IgAN patients, four of them with celiac disease. At the time of the diagnostic kidney biopsy serum tTG autoantibodies were measured and colocalization of IgA and tTG was investigated in the frozen kidney biopsies. Three IgAN patients with celiac disease had IgA-tTG deposits in the kidney even though in two of these the celiac disease diagnosis had been set years later. These deposits were not found in a patient with already diagnosed celiac disease following a gluten-free diet. Of the five non-celiac IgAN patients, three had IgA-tTG deposits in the kidney. We conclude that tTG-targeted IgA deposits can be found in the kidney biopsies of gluten-consuming IgAN patients but their specificity to celiac disease seems limited.


Assuntos
Autoanticorpos/sangue , Biópsia , Doença Celíaca/diagnóstico , Doença Celíaca/patologia , Proteínas de Ligação ao GTP/imunologia , Glomerulonefrite por IGA/patologia , Rim/patologia , Transglutaminases/imunologia , Adulto , Dieta Livre de Glúten , Feminino , Glutens , Humanos , Imunoglobulina A/sangue , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
16.
Am J Clin Oncol ; 44(8): 395-401, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34091476

RESUMO

BACKGROUND: Eosinophilic colitis (EoC) is a rare form of eosinophilic gastrointestinal disease characterized by diffuse eosinophilic infiltration in the deep lamina propria of colonic mucosa. The pathophysiology is unclear, but EoC has been associated with multiple known risk factors. AIM: The aim of this study was to characterize the clinical characteristics and disease course of patients with EoC at a major cancer center. MATERIAL AND METHODS: We retrospectively reviewed colonic samples obtained between January 2000 and December 2018 from our institutional database and included cases with significant colonic eosinophilia. Baseline clinical data and EoC-related clinical course and outcomes were documented. RESULTS: Forty-one patients were included. One fourth had coexisting autoimmune conditions. Seventy-eight percent had a cancer diagnosis. Half the patients received chemotherapy, with a median duration of 180 days between chemotherapy and EoC onset. Symptoms were present in 76% of patients. Diarrhea was more prevalent in patients who received chemotherapy (85% vs. 42%). Median duration of EoC symptoms was 30 days in patients with cancer and 240 days in those without cancer (P=0.03). Most patients (88%) had normal colonoscopy findings. Fifteen percent of patients required hospitalization. All-cause mortality was 37%, mostly related to underlying malignancy and organ failure. CONCLUSIONS: EoC in cancer patients appears to have more diarrhea-predominant symptoms, particularly in patients receiving chemotherapy, but a shorter disease duration compared with patients without cancer. Hospitalization can be required for serious cases. Treatment may be reserved for patients requiring symptom management, as most patients with EoC have good clinical outcomes regardless of treatment.


Assuntos
Colite/etiologia , Colite/patologia , Colite/terapia , Eosinofilia/etiologia , Neoplasias/fisiopatologia , Idoso , Colite/mortalidade , Colonoscopia , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Diarreia/etiologia , Eosinofilia/mortalidade , Eosinofilia/terapia , Feminino , Hospitalização , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco
17.
Life Sci ; 279: 119672, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34097971

RESUMO

AIMS: Intestinal nutrient absorption plays a vital role in developing obesity, and nutrient transporters expressed in the enterocytes facilitate this process. Moreover, previous studies have shown that specific foods and diets can affect their cell levels. Herein, we investigated the effects of pequi oil (PO), which is high in several bioactive compounds, on intestinal nutrient transporter levels as well as on intestinal morphology and metabolic biomarkers. MAIN METHODS: Groups of male C57BL/6 mice were fed either a standard (C) or a high-fat diet (HFD) and pequi oil (CP and HFDP with PO by gavage at 150 mg/day) for eight weeks. Food intake and body weight were monitored, serum metabolic biomarkers, intestinal transporter levels and histological analyses were performed. KEY FINDINGS: PO increased caloric intake without increasing body or fat mass regardless of diet. The HFD group treated with PO reduced fasting blood glucose and villus width. PO did not affect GLUT2, L-FABP, FATP4, NPC1L1, NHE3 or PEPT1 content in CP or HFDP groups. GLUT5 and FAT/CD36 levels were reduced in both CP and HFDP. SIGNIFICANCE: Our data suggest that PO attenuated monosaccharide and fatty acid absorption, contributing to lower fasting glycemia and higher food intake without affecting body weight or visceral fat of high-fat feed mice.


Assuntos
Glicemia/metabolismo , Antígenos CD36/metabolismo , Carotenoides/farmacologia , Transportador de Glucose Tipo 5/metabolismo , Hiperglicemia/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Óleos Vegetais/farmacologia , Animais , Biomarcadores/metabolismo , Caderinas/metabolismo , Dieta Hiperlipídica , Ingestão de Energia , Ericales/química , Ácidos Graxos/metabolismo , Controle Glicêmico , Hiperglicemia/etiologia , Hiperglicemia/patologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações
18.
Molecules ; 26(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066903

RESUMO

The effect of effective microorganisms (EM) on internal organ morphology, intestinal morphometry, and serum biochemical activity in Japanese quails under Clostridium perfringens challenge was determined. After 30 days of EM addition, one group of quails was orally inoculated with Clostridium perfringens. The second group did not receive EM and was inoculated with C. perfringens. In the gut, EM supplementation reduced the number of lesions, enhanced gut health, and protected the mucosa from pathogenic bacteria. EM showed an anti-inflammatory effect and fewer necrotic lesions in villi. In the internal organs, EM showed a protective effect against a typical lesion of C. perfringens infection. Necrosis and degeneration of the hepatocytes, necrosis of bile ducts, and bile duct proliferation were more severe in the infected group without EM. Morphometric evaluation showed significantly higher villi in the jejunum after EM addition. A greater crypt depth was observed in the C. perfringens group. Biochemical analysis of the blood indicated lower cholesterol on the 12th day of the experiment and between-group differences in total protein, lactate dehydrogenase (LDH), and albumin levels in the EM group. Further studies are needed to improve EM activity against pathologic bacteria as a potential alternative to antibiotics and to develop future natural production systems.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças das Aves/sangue , Doenças das Aves/dietoterapia , Infecções por Clostridium/sangue , Infecções por Clostridium/dietoterapia , Clostridium perfringens , Enterite/sangue , Enterite/dietoterapia , Mucosa Intestinal/microbiologia , Probióticos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Codorniz/sangue , Codorniz/microbiologia , Ração Animal/microbiologia , Animais , Ductos Biliares/patologia , Doenças das Aves/microbiologia , Colesterol/sangue , Infecções por Clostridium/microbiologia , Enterite/microbiologia , Feminino , Hepatócitos/patologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , L-Lactato Desidrogenase/sangue , Necrose , Albumina Sérica/análise , Resultado do Tratamento
19.
Hum Genet ; 140(8): 1143-1156, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33974130

RESUMO

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.


Assuntos
Oftalmopatias Hereditárias/genética , Mucosa Intestinal/metabolismo , Síndromes de Malabsorção/genética , Microvilosidades/patologia , Mucolipidoses/genética , Polimorfismo de Nucleotídeo Único , Proteínas Qa-SNARE/genética , Células Fotorreceptoras Retinianas Cones/metabolismo , Distrofias Retinianas/genética , Idoso , Idoso de 80 Anos ou mais , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Animais , Autopsia , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Feminino , Regulação da Expressão Gênica , Homozigoto , Humanos , Mucosa Intestinal/patologia , Síndromes de Malabsorção/metabolismo , Síndromes de Malabsorção/patologia , Camundongos , Camundongos Knockout , Microvilosidades/genética , Microvilosidades/metabolismo , Mucolipidoses/metabolismo , Mucolipidoses/patologia , Fenótipo , Proteínas Qa-SNARE/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Fotorreceptoras Retinianas Cones/patologia , Distrofias Retinianas/metabolismo , Distrofias Retinianas/patologia , Rodopsinas Sensoriais/genética , Rodopsinas Sensoriais/metabolismo , Sequenciamento Completo do Exoma
20.
NPJ Biofilms Microbiomes ; 7(1): 41, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958592

RESUMO

The importance of sun exposure on human health is well recognized, and a recent trend in the avoidance of sun exposure has led to the risk of missing the beneficial effects such as vitamin D3 biogenesis. Vitamin D3 insufficiency is one of the risk factors for the development of food allergies (FAs), and vitamin D3 status controls gut homeostasis by modulating the microbiota. This study aimed to explore the impact of daily full spectrum light exposure (phototherapy) on the pathogenesis of FAs. Phototherapy ameliorated allergic diarrhea and improved FA-associated vitamin D3 insufficiency and dysbiosis. Fecal microbiota transplantation (FMT) of FA donor feces induced allergic diarrhea with OVA-specific IgE elevation in naïve mice. In contrast, FMT of naïve donor feces ameliorated allergic diarrhea in established FA mice, suggesting the involvement of the microbiota composition in FA. Phototherapy is an alternative approach for the prevention of FA-like allergic diarrhea through the modulation of vitamin D3 status and microbiota composition.


Assuntos
Colecalciferol/metabolismo , Diarreia/etiologia , Diarreia/prevenção & controle , Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/prevenção & controle , Microbioma Gastrointestinal , Luz Solar , Atividades Cotidianas , Animais , Formação de Anticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Disbiose , Exposição Ambiental , Transplante de Microbiota Fecal/métodos , Feminino , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Estresse Oxidativo , Fototerapia , Linfócitos T/imunologia , Linfócitos T/metabolismo
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