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1.
Anticancer Res ; 41(9): 4401-4405, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475060

RESUMO

BACKGROUND/AIM: We previously found in Swedish patients with inflammatory bowel disease (IBD), crypts in symmetric fission (CSF) and in asymmetric fission (CAF). This study aimed to examine CSF and CAF in a cohort of German patients with IBD. PATIENTS AND METHODS: H&E-sections from 106 IBD-patients [59 ulcerative colitis (UC) and 47 Crohn colitis (CCs)] were analysed. RESULTS: A total of 588 crypts in fission (CF) were found; 342 (58.2%) in UC and 246 (41.8%) in CCs. Out of the 505 CAFs found, 304 (60.2%) were recorded in UC, and 201(39.8%) in CCs (p=0.15272). CONCLUSION: Despite that German and Swedish populations reside in disparate geographical regions with different ecological milieus, the proportions of CAF and CSF were similar, thereby suggesting that CAF and CSF develop in IBD independently of the local environmental conditions in the two regions.


Assuntos
Colite Ulcerativa/patologia , Colite/patologia , Doença de Crohn/patologia , Biópsia , Estudos de Coortes , Colite/epidemiologia , Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Alemanha/epidemiologia , Humanos , Fatores de Risco , Suécia/epidemiologia
2.
Cells ; 10(9)2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34571891

RESUMO

Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine-cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from the literature and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated the literature information on cell-cytokine interactions from two systems of immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell-cell communication network connected by cytokines; and a cytokine-cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink, we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify cell types and cytokine interactions following SARS-CoV-2 infection, highlighting important cytokine interactions that might contribute to severe illness in a subgroup of patients. Such findings have the potential to inform the development of novel, cytokine-targeted therapeutic strategies. CytokineLink is freely available for the scientific community through the NDEx platform and the project github repository.


Assuntos
COVID-19/imunologia , Citocinas/metabolismo , Imunidade , Doenças Inflamatórias Intestinais/imunologia , Comunicação Celular , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Bases de Dados Genéticas , Humanos , Doenças Inflamatórias Intestinais/patologia , Transdução de Sinais
3.
Medicine (Baltimore) ; 100(34): e27065, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449501

RESUMO

ABSTRACT: The aim of this study was to assess the appropriate time interval to identify the association between the fecal calprotectin (FC) test and endoscopic activity, and to evaluate whether the time interval affects the therapeutic plan adjustment in patients with ulcerative colitis (UC).This study included 103 patients who underwent FC tests and endoscopic examinations within the past three months. The FC test results classified cases into three groups as follows: moderate to severe (>200, >250, or >300 µg/g), mild (100-200, 100-250, or 100-300 µg/g), and inactive (<100 µg/g) activity. The Mayo endoscopic subscore was used to determine endoscopic activity. Therapeutic plan adjustment included the addition or increased dosage of anti-inflammatory drugs, steroids, immunomodulators, and biologics.Using the cutoff value for FC of 200 µg/g, the appropriate time interval for dividing the association and non-association between Mayo endoscopic subscore and FC was 7 days (sensitivity, 74.4%; specificity, 50.0%; area under the curve [AUC], 0.6032). When using FC 250 or 300 µg/g, the appropriate time interval was 5.5 days, with a sensitivity of 71.7% and specificity of 49.1 (AUC 0.5862) in FC 250 µg/g, a sensitivity of 69.6%, and a specificity of 47.4 (AUC 0.5549) for FC 300 µg/g. Therapeutic plans changed in 29.1% of patients. In patients with shorter intervals (≤7 days) between the FC test and endoscopy, significant therapeutic plan adjustments were observed in patients with UC (36.5% vs. 17.5%, P = .047).Although the need for endoscopy within 7 days after detecting high FC (≥ 200 µg/g) was not statistically supported, endoscopy within a shorter interval (≤7 days) in UC patients with high FC can help determine the therapeutic plan.


Assuntos
Colite Ulcerativa/patologia , Colonoscopia/métodos , Complexo Antígeno L1 Leucocitário/análise , Corticosteroides/uso terapêutico , Adulto , Produtos Biológicos/uso terapêutico , Biomarcadores , Colite Ulcerativa/tratamento farmacológico , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Sulfassalazina/uso terapêutico , Tempo para o Tratamento
4.
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
5.
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
6.
Biomed Res Int ; 2021: 6633442, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327234

RESUMO

Ulcerative colitis (UC) is a common disease with great variability in severity, with a high recurrence rate and heavy disease burden. In recent years, the different biological functions of competing endogenous RNA (ceRNA) networks of long noncoding RNAs (lncRNAs) and microRNAs (miRs) have aroused wide concerns, the ceRNA network of ulcerative colitis (UC) may have potential research value, and these expressed noncoding RNAs may be involved in the molecular basis of inflammation recurrence and progression. This study analyzed 490 colon samples associated with UC from 4 gene expression microarrays from the GEO database and identified gene modules by weighted correlation network analysis (WGCNA). CIBERSORT detected tissue-infiltrating leukocyte profiling by deconvolution of microarray data. LncBase and multiMIR were used to identify lncRNA-miRNA-mRNA interaction. We constructed a ceRNA network which includes 4 lncRNAs (SH3BP5-AS1, MIR4435-2HG, ENTPD1-AS1, and AC007750.1), 5 miRNAs (miR-141-3p, miR-191-5p, miR-192-5p, miR-194-5p, and miR196-5p), and 52 mRNAs. Those genes are involved in interleukin family signals, neutrophil degranulation, adaptive immunity, and cell adhesion pathways. lncRNA MIR4435-2HG is a variable in the decision tree for moderate-to-severe UC diagnostic prediction. Our work identifies potential regulated inflammation-related lncRNA-miRNA-mRNA regulatory axes. The regulatory axes are dysregulated during the deterioration of UC, suggesting that it is a risk factor for UC progression.


Assuntos
Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Progressão da Doença , Redes Reguladoras de Genes , Inflamação/genética , RNA/genética , Colite Ulcerativa/patologia , Bases de Dados Genéticas , Árvores de Decisões , Regulação da Expressão Gênica , Ontologia Genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença
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.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G157-G170, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132111

RESUMO

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.


Assuntos
Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Lipopolissacarídeos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Calgranulina A/metabolismo , Quimiocina CXCL1/metabolismo , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Absorção Intestinal , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Zucker , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Fator de Transcrição STAT3/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Biomed Pharmacother ; 140: 111770, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34119929

RESUMO

Our study has renewed interest in the genus Jasmine for the treatment of chronic inflammatory conditions. Aerial parts of Jasminum grandiflorum L. subsp. floribundum total methanolic extract (JTME) were tested for its therapeutic potential as an anti-inflammatory agent using two experimental models in rats; acetic acid (AA) induced ulcerative colitis and adjuvant induced arthritis. The administration of JTME showed anti-inflammatory activity in a dose dependent manner. JTME, 400 mg/kg was like prednisolone, 2 mg/kg p.o. (the reference drug), since it improved the tissues of the colon clinically, macro and microscopically (ulcer index), and histopathological (scoring). It reduced the intestinal expression of pro-inflammatory cytokines in the colonic mucosa; IFNγ, TNFα, IL-6, IL-1, and MPO. It also preserved tight junctions in intestinal epithelial cells by counter-regulating claudin-5 and occludin levels additionally, it had a potent antioxidant activity. The expressions of NF-κB p65, TNF-α and caspase-3 in rats administered AA (2 mL of 4% solution, once, intrarectally) were significantly increased, where the lowest expression was scored in JTME, 400 mg/kg group. In the adjuvant induced model of rheumatoid arthritis, the TJME, 400 mg/kg reduced the levels of cathepsin D, iNOS, NO, RF, CRP, CPP and elevated the total antioxidant capacity of tissues. Additionally, it maintained bones without histopathological lesions, articular cartilage damage, and inflammation of the synovial membrane and periarticular tissues, in contrast to arthritic rats. Finally, we report a new detailed study to validate the medicinal importance of Jasminum for the chronic inflammatory disorders with immune dysfunction with anti-inflammatory and antioxidant effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Jasminum , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Artrite Experimental/patologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
10.
Eur J Med Chem ; 223: 113604, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34174740

RESUMO

Glucose-regulated protein 94 (Grp94), a member of the Heat shock protein 90 (Hsp90) family, is implicated in many human diseases, including cancer, neurodegeneration, inflammatory, and infectious diseases. Here, we describe our effort to design and develop a new series of Grp94 inhibitors based on Phe199 induced fit mechanism. Using an alkynyl-containing inhibitor as a starting point, we developed compound 4, which showed potent inhibitory activity toward Grp94 in a fluorescence polarization-based assay. With improved physicochemical properties and suitable pharmacokinetic properties, compound 4 was advanced into in vivo bioactivity evaluation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 4 showed anti-inflammatory property and reduced the levels of pro-inflammatory cytokines (TNF-α and IL-6). Together, these findings provide evidence that this approach may be promising for further Grp94 drug development efforts.


Assuntos
Alcinos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzamidas/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , Alcinos/síntese química , Alcinos/metabolismo , Alcinos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Benzamidas/síntese química , Benzamidas/metabolismo , Benzamidas/farmacocinética , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/patologia , Células HCT116 , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
11.
Nat Commun ; 12(1): 3989, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183667

RESUMO

In the search for improved stool biomarkers for inflammatory bowel disease (IBD), an aptamer-based screen of 1129 stool proteins was conducted using stool samples from an IBD cohort. Here we report that of the 20 proteins subsequently validated by ELISA, stool Ferritin, Fibrinogen, Haptoglobin, Hemoglobin, Lipocalin-2, MMP-12, MMP-9, Myeloperoxidase, PGRP-S, Properdin, Resistin, Serpin A4, and TIMP-1 are significantly elevated in both ulcerative colitis (UC) and Crohn's disease (CD) compared to controls. When tested in a longitudinal cohort of 50 UC patients at 4 time-points, fecal Fibrinogen, MMP-8, PGRP-S, and TIMP-2 show the strongest positive correlation with concurrent PUCAI and PGA scores and are superior to fecal calprotectin. Unlike fecal calprotectin, baseline stool Fibrinogen, MMP-12, PGRP-S, TIMP-1, and TIMP-2 can predict clinical remission at Week-4. Here we show that stool proteins identified using the comprehensive aptamer-based screen are superior to fecal calprotectin alone in disease monitoring and prediction in IBD.


Assuntos
Colite Ulcerativa/patologia , Doença de Crohn/patologia , Fezes/química , Proteínas/análise , Adolescente , Aptâmeros de Peptídeos/metabolismo , Biomarcadores/análise , Criança , Pré-Escolar , Humanos , Complexo Antígeno L1 Leucocitário/análise , Proteômica/métodos , Índice de Gravidade de Doença
12.
J Cell Mol Med ; 25(12): 5707-5720, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34002930

RESUMO

To investigate the therapeutic effects of phellodendrine in ulcerative colitis (UC) through the AMPK/mTOR pathway. Volunteers were recruited to observe the therapeutic effects of Compound Cortex Phellodendri Liquid (Huangbai liniment). The main components of Compound Cortex Phellodendri Liquid were analysed via network pharmacology. The target of phellodendrine was further analysed. Caco-2 cells were cultured, and H2 O2 was used to stimulate in vitro cell model. Expression levels of LC3, AMPK, p-AMPK, mTOR and p-mTOR were detected via Western blotting and through immunofluorescence experiments. The therapeutic effects of phellodendrine were analysed via expression spectrum chip sequencing. The sequencing of intestinal flora further elucidated the therapeutic effects of phellodendrine. Compared with the control group, Compound Cortex Phellodendri Liquid could substantially improve the healing of intestinal mucosa. Network pharmacology analysis revealed that phellodendrine is the main component of Compound Cortex Phellodendri Liquid. Moreover, this alkaloid targets the AMPK signalling pathway. Results of animal experiments showed that phellodendrine could reduce the intestinal damage of UC compared with the model group. Findings of cell experiments indicated that phellodendrine treatment could activate the p-AMPK /mTOR signalling pathway, as well as autophagy. Expression spectrum chip sequencing showed that treatment with phellodendrine could promote mucosal healing and reduce inflammatory responses. Results of intestinal flora detection demonstrated that treatment with phellodendrine could increase the abundance of flora and the content of beneficial bacteria. Phellodendrine may promote autophagy by regulating the AMPK-mTOR signalling pathway, thereby reducing intestinal injury due to UC.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Colite Ulcerativa/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Quinolizinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Adulto , Animais , Estudos de Casos e Controles , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
13.
Life Sci ; 278: 119603, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984358

RESUMO

Multidrug resistance gene (MDR1a) and P-glycoprotein (P-gp) play an important role in the development of ulcerative colitis (UC) and influence the therapeutic effect of glucocorticoids, which may lead to drug resistance mechanically. UC may be related to miR-145 to some extent, and the relationship still needs further exploration. In this study we found that the expression of miR-145 was downregulated in the colonic tissues of rats with Dextran sodium sulfate (DSS)-induced UC. Also, the expression of MDR1a in colon tissues of each group negatively correlated with the expression of miR-145 in rats. The change in the plasma peak concentration (Cmax) in each group positively related to the miR-145 level. Mechanistically, miR-145 negatively regulated the expression and function of P-gp via acting directly on the 3'-UTR of MDR1 mRNA. Overall, these results indicated that miR-145 had a protective effect on the colorectal mucosa, and its downregulation may enhance the expression and function of MDR1a and P-gp, promoting the occurrence and development of UC. The downregulation of miR-145 reduced the drug sensitivity of 5-aminosalicylic acid (5-ASA) and glucocorticoids in treating UC, indicating that miR-145 might be a potential therapeutic target for UC.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colite Ulcerativa/genética , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Colite Ulcerativa/patologia , Regulação da Expressão Gênica , Genes MDR , Masculino , RNA Mensageiro/genética , Ratos Sprague-Dawley
14.
Arch Pathol Lab Med ; 145(9): 1062-1068, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961007

RESUMO

CONTEXT.­: Although primarily considered a respiratory illness, coronavirus disease 2019 (COVID-19) can cause gastrointestinal manifestations. OBJECTIVE.­: To evaluate histopathology and in situ hybridization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gastrointestinal samples from patients with recent and remote COVID-19. DESIGN.­: Patients with positive SARS-CoV-2 nasopharyngeal tests and a gastrointestinal tissue specimen were included. SARS-CoV-2 in situ hybridization (ISH) was performed on each sample. A subset had SARS-CoV-2 next-generation sequencing (NGS) performed. RESULTS.­: Twenty-five patients met inclusion criteria. Five had positive SARS-CoV-2 nasopharyngeal tests within 7 days of their gastrointestinal procedure. Two were ulcerative colitis patients on steroid therapy who lacked typical COVID-19 symptoms. Their colectomies showed severe ulcerative colitis; one demonstrated SARS-CoV-2 by NGS but a negative ISH. Another had an ischemic colon resected as a complication of the COVID-19 course; however, both ISH and NGS were negative. A fourth had a normal-appearing terminal ileum but positive ISH and NGS. The fifth patient had ileal ulcers with SARS-CoV-2 negativity by both modalities. The remaining 20 patients had positive nasopharyngeal tests an average of 53 days prior to procedure. None of their samples demonstrated SARS-CoV-2 ISH positivity, but one was positive on NGS despite a negative nasopharyngeal test. CONCLUSIONS.­: Gastrointestinal findings from SARS-CoV-2-infected patients ranged from normal with virus detected by ISH and NGS to bowel ischemia secondary to systemic viral effects without evidence of virus in the tissue. No distinct histologic finding was identified in those with gastrointestinal tissue specimens demonstrating SARS-CoV-2 positivity in this cohort.


Assuntos
COVID-19/patologia , COVID-19/virologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , Teste de Ácido Nucleico para COVID-19 , Estudos de Coortes , Colite Isquêmica/etiologia , Colite Isquêmica/patologia , Colite Isquêmica/virologia , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Colite Ulcerativa/virologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Pandemias , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Adulto Jovem
15.
Nat Commun ; 12(1): 2624, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976143

RESUMO

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.


Assuntos
Colite Ulcerativa/imunologia , Interferons/metabolismo , Mucosa Intestinal/patologia , Reepitelização/imunologia , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos
16.
Anticancer Res ; 41(5): 2681-2688, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952499

RESUMO

BACKGROUND/AIM: The aim of the study was to analyze the postoperative survival of colitis-associated colorectal cancer (CAC) with ulcerative colitis (UC), and the risk factors affecting it. PATIENTS AND METHODS: A questionnaire including postoperative survival was sent to 88 hospitals that reported CAC patients in the literature up until January, 2006 and to members of the Research Group of Intractable Inflammatory Bowel Disease. RESULTS: The 5-year postoperative overall survival (OS) of 170 CAC patients was 74.2% which was similar to sporadic colorectal cancer in Japan (72.1%). Pathologic TNM stage, histological type, type of surgical procedure (proctocolectomy, segmental resection), and preoperative cancer surveillance were statistically significant factors for OS. By Cox regression analysis, pathologic TNM stage and proctocolectomy were statistically significant prognostic factors for OS. CONCLUSION: In CAC with UC, the postoperative OS was similar to sporadic colorectal cancer. Pathologic TNM stage and proctocolectomy were confirmed as important prognostic factors.


Assuntos
Colite Ulcerativa/epidemiologia , Colite/epidemiologia , Neoplasias Colorretais/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colite/complicações , Colite/patologia , Colite/cirurgia , Colite Ulcerativa/complicações , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Proctocolectomia Restauradora , Modelos de Riscos Proporcionais , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
17.
Lancet Gastroenterol Hepatol ; 6(6): 429-437, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887262

RESUMO

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab. METHODS: We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. FINDINGS: Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1-90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0-69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7-44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0-44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI -10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9-90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions. INTERPRETATION: Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. FUNDING: Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Infliximab/efeitos adversos , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Suspensão de Tratamento/estatística & dados numéricos , Administração Intravenosa , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/patologia , Colite Ulcerativa/prevenção & controle , Feminino , Humanos , Infliximab/administração & dosagem , Infliximab/uso terapêutico , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/uso terapêutico
18.
Science ; 372(6539)2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33859001

RESUMO

The intestinal mucus layer, an important element of epithelial protection, is produced by goblet cells. Intestinal goblet cells are assumed to be a homogeneous cell type. In this study, however, we delineated their specific gene and protein expression profiles and identified several distinct goblet cell populations that form two differentiation trajectories. One distinct subtype, the intercrypt goblet cells (icGCs), located at the colonic luminal surface, produced mucus with properties that differed from the mucus secreted by crypt-residing goblet cells. Mice with defective icGCs had increased sensitivity to chemically induced colitis and manifested spontaneous colitis with age. Furthermore, alterations in mucus and reduced numbers of icGCs were observed in patients with both active and remissive ulcerative colitis, which highlights the importance of icGCs in maintaining functional protection of the epithelium.


Assuntos
Colo/citologia , Células Caliciformes/fisiologia , Mucosa Intestinal/citologia , Muco/fisiologia , Animais , Diferenciação Celular , Colite/induzido quimicamente , Colite/fisiopatologia , Colite Ulcerativa/patologia , Colite Ulcerativa/fisiopatologia , Colo/fisiologia , Células Caliciformes/citologia , Humanos , Mucosa Intestinal/fisiologia , Intestino Delgado/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-ets/genética , Transcriptoma
19.
Biomed Pharmacother ; 139: 111580, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33857914

RESUMO

Qing-Chang-Hua-Shi (QCHS) is a Chinese herbal formula, which is composed of 11 herbs. Studies have also shown that QCHS granules can alleviate colitis in animal models by preventing inflammatory responses and suppressing apoptosis through the MEK/ERK signaling pathway. To determine the efficacy and safety of QCHS granules in patients with moderately active UC. We performed a multicenter, randomized, placebo-controlled, double-blind study of patients with moderately active UC who did not respond to 4 weeks of mesalazine therapy at the maximum dose. Patients were randomly assigned to groups and administered QCHS granules (125 g/day, n = 59) or an identical placebo, which was similar to the QCHS granules in color and taste (125 g/day, n = 60), with continued 5-ASA 4 g/d therapy for 12 weeks. The primary outcome was the rate of clinical response and clinical remission at week 12. The secondary outcomes were health-related quality of life, endoscopic response rate, and mucosal healing rate. Any changes in mucus/bloody stool and diarrhea were recorded. Out of the 119 enrolled patients at 10 different centers in China, 102 patients completed the trial. Clinical remission and clinical response were seen in 31.48% and 92.59% of QCHS-treated patients, and 12.50% and 72.92% of placebo-treated patients, respectively. There was a significant difference between the two treatment groups. More patients receiving QCHS granules vs. placebo achieved remission of mucus/bloody stool (70.37% vs. 47.92%, P = 0.0361). Adverse event rates were similar (QCHS granules 38.33%; placebo 25.42%). In conclusion, QCHS granules were superior to the placebo in introducing clinical remission and mucosal healing, as well as in relieving mucus/blood stool in patients with moderately active and 5-ASA-refractory UC.


Assuntos
Antiulcerosos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Adulto , Antiulcerosos/efeitos adversos , Colite Ulcerativa/patologia , Colite Ulcerativa/psicologia , Método Duplo-Cego , Feminino , Humanos , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Sulfassalazina/uso terapêutico , Resultado do Tratamento
20.
PLoS One ; 16(4): e0250597, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886687

RESUMO

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Citocromo P-450 CYP3A/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Tacrolimo/administração & dosagem , Adulto , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Citocromo P-450 CYP2C19/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Genótipo , Humanos , Inativação Metabólica/genética , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética
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