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1.
Medicine (Baltimore) ; 99(35): e21997, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871953

RESUMO

BACKGROUND: Ulcerative colitis (UC) was a type of inflammatory bowel diseases, which was difficult to cure and even would malignant turn into colon cancer. The specific etiology and molecular mechanism of UC were unclear to date. The purpose of this study was to search for new targets for the diagnosis and treatment of UC. METHODS: Firstly, we downloaded the gene expression data of UC from the gene expression omnibus database database (GSE107499), and used multiple bioinformatics methods to find differently expressed genes (DEGs) in UC. Subsequently, we evaluated the lymphocyte infiltration in UC inflamed colon tissue by using the cell type identification by estimating relative subset of known RNA transcripts method. RESULTS: We obtained 1175 DEGs and 8 hub genes (IL6, TNF, PTPRC, CXCL8, FN1, CD44, IL1B, and MMP9) in this study. Among them, 903 DEGs were up-regulated and 272 DEGs were down-regulated. Compared with non-inflamed colon tissues, the inflamed colon tissues had higher levels of memory B cells, activated memory CD4 T cells, follicular helper T cells, M1 macrophages, resting dendritic cells, activated dendritic cells, activated mast cells, and neutrophils, whereas the proportions of plasma cells, resting memory CD4 T cells, gamma delta T cells, activated NK cells, M2 macrophages and resting mast cells were relatively lower. CONCLUSIONS: The DEGs, hub genes and different lymphatic infiltration conditions can provide new targets for diagnosis and treatment of UC. However, these were just predictions through some theoretical methods, and more basic experiments will be needed to prove in the future.


Assuntos
Colite Ulcerativa/metabolismo , Linfócitos/fisiologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Biologia Computacional , Humanos , Mapas de Interação de Proteínas , Transcriptoma
2.
Life Sci ; 259: 118356, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861798

RESUMO

Curculigoside (CUR) is natural ingredient from Curculigo orchioides Gaertn with multiple biological activities. However, whether CUR protects from ulcerative colitis (UC) and underlying mechanisms are unclear. Herein, mice challenged with dextran sulfate sodium (DSS) were established and administrated with CUR for 7 days. Then histological pathologies and ferroptosis regulators were determined in vivo. The ferroptotic IEC-6 cells were prepared to investigate the underlying mechanism of CUR. Results showed that CUR inhibited the disease activity index, histological damage and cell death in mice with colitis. We also found that ferroptosis was induced in mice with colitis, as evidenced by iron overload, GSH depletion, ROS and MDA production, accompanied by decreased expression of SOD and GPX4. CUR treatment significantly reversed these alterations of ferroptotic features in DSS-induced mice. Furthermore, similar effects of CUR on ferroptosis were observed in IEC-6 cells under the combined treatment of H2O2 and iron chloride hexahydrate. Interestingly, we found that CUR could increase the selenium sensitivity and promote GPX4 transcription level in IEC-6 cells. Knockdown of GPX4 significantly blocked the protective effects of CUR on cell death, GSH and MDA contents as well as LDH activity in ferroptotic IEC-6 cells. Taken together, these findings suggest that CUR protects against ferroptosis in UC by the induction of GPX4, which presents a potential agent for UC treatment.


Assuntos
Benzoatos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Glucosídeos/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Western Blotting , Linhagem Celular , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/química , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ferro/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Reação em Cadeia da Polimerase em Tempo Real
3.
J Chromatogr A ; 1629: 461503, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-32858455

RESUMO

Colorectal cancer (CRC) is one of the most serious complications of ulcerative colitis (UC). Altered gut microbiota is implicated in the development of CRC and metabolic perturbations are often associated with changes in the gut microbiome composition. Given the links between gut microbiome and the metabolic profiles in the body, an approach involving ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) metabolomics and 16S rDNA sequencing technology was applied to trace the development UC into CRC in rats. The study identified 11 differential metabolites related to both UC and CRC, which mainly referred to the linoleic acid metabolism. Among these, linoleic acid and 12­hydroxy­8,10-octadecadienoic acid could serve as key biomarkers for the development of UC into CRC. Besides, a significant change was observed in the microflora structure during the development from UC to CRC; this mainly involved a gradual increase in Escherichia-Shigella and a gradual decrease in Lactobacillus. In addition, Pearson's correlation analysis revealed strong correlations between intestinal microflora-related metabolites and specific intestinal microflora, which indicated both of them can promote the transition of UC to CRC. The results of the present study provided positive support for the involvement of intestinal microflora and host metabolism in the pathophysiological mechanism that is responsible for the development of UC into CRC. This information can help understand the risk for CRC that accompanies a diagnosis of UC and also provide different means of targeting these differential metabolites and intestinal microbiota to avoid UC-induced CRC.


Assuntos
Colite Ulcerativa/patologia , Neoplasias Colorretais/patologia , Microbioma Gastrointestinal , Ácido Linoleico/metabolismo , Metabolômica/métodos , Animais , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/metabolismo , Neoplasias Colorretais/metabolismo , Análise Discriminante , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Fezes/microbiologia , Análise dos Mínimos Quadrados , Ácido Linoleico/análise , Masculino , Análise de Componente Principal , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Ratos , Ratos Sprague-Dawley , Shigella/genética , Shigella/isolamento & purificação , Espectrometria de Massas em Tandem
4.
DNA Cell Biol ; 39(9): 1573-1582, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32678986

RESUMO

Many immune cells participate in the pathogenesis of ulcerative colitis (UC), and fatty acid metabolism (FAM) is reported to supporting their cell-specific functions and proliferation, but the underlying mechanism is unclear. This study aimed to investigate the relationship between FAM and inflammation in colon tissues and identify potential therapeutic targets for regulating immune response. A total of 870 different expression genes (DEGs), 304 immunity-related DEGs, and 11 FAM-related DEGs were obtained, gene ontology analysis results showed that immune DEGs were significantly enriched in neutrophil migration, positive regulation of T cell activation. Fifteen types of immune cells were identified in inflamed colon tissues. Five FAM-related DEGs (ACOX1, ACSL4, ELOVL5, FADS2, and SCD) were highly correlated with immunity-related DEGs, and ACSL4, ELOVL5, and FADS2 were significantly upregulated in immune cells, while SCD is downregulated. Five FAM-related DEGs were highly correlated with immune cells. The study promotes the understanding of the pathogenesis of FAM in UC immune cells.


Assuntos
Colite Ulcerativa/genética , Ácidos Graxos/metabolismo , Redes Reguladoras de Genes , Transcriptoma , Acil-CoA Oxidase/genética , Acil-CoA Oxidase/metabolismo , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Colite Ulcerativa/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Linfócitos/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
5.
Life Sci ; 256: 117927, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32526285

RESUMO

AIMS: Ulcerative colitis (UC) has many complications, from colonic damage to colorectal cancer. The mystery of both etiology and effective treatment of UC still challenging process. The role of gut microbiota in UC is still unclear. In the current study we compare the difference in gut microbiota abundance in both UC and normal colon besides the therapeutic effect of Lactobacillus spp. in treating UC versus the standard drug. MATERIALS AND METHODS: The experimental panel included five group of rats; normal control, UC diseased rats, sterilizing rats, ASA treated and Lactobacillus treated. The change in the microbiota abundance was investigated using conventional and real time PCR. In parallel, clinical evaluation of UC and macroscopic examination scoring was also done. Colonic oxidants/antioxidant stress biomarkers; MDA, GSH, catalase, myeloperoxidase activity, and SOD activity were assessed. Colon Nrf2, HO-1 contents and TNF-α was evaluated. KEY FINDINGS: The current study revealed a significant difference in the relative abundance of microbiota where, UC is associated with massive increase of E. coli and Fusobacterium spp., while enormous decrease in Bifidobacteria spp. in contrast with negative control. Both 5-ASA and Lactobacillus show a significant amelioration of all antioxidant enzymes and marked decline of inflammatory and oxidative stress markers. Both Lactobacillus and 5-ASA show significant increase of NrF2 and HO-1 and marked decrease of TNF-α. SIGNIFICANCE: Lactobacillus spp. exerted a beneficial effect on the inflammation, oxidative stress and the symbiosis of gut microbiota that improve structural intestinal defect and promote healing in UC.


Assuntos
Colite Ulcerativa/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Lactobacillus/efeitos dos fármacos , Mesalamina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/farmacologia , Escherichia coli , Fusobacterium , Humanos , Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
6.
J Pharmacol Exp Ther ; 374(3): 420-427, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546529

RESUMO

Inflammatory bowel diseases are caused by inflammation of the gastrointestinal tract, which may or may not have a specific cause or pathogen. They affect millions of people around the world and there are still few effective treatments. The aim of this work is to investigate the anti-inflammatory effect of the IKK-ß inhibitor LASSBio-1524 and its three analogs, LASSBio-1760, LASSBio-1763, and LASSBio-1764, on mediator production and expression of inflammatory enzymes using experimental animal models of intestinal inflammatory diseases. Colitis was performed using two different models, which mimic Crohn disease (induced by dinitrobenzene acid) and ulcerative colitis (induced by sodium dextran sulfate) in mice. In both models, a therapeutic protocol with a daily dose of 1, 3, or 30 µmol/kg was performed. LASSBio-1524 and its three analogs reduced the secretion of tumor necrosis factor-α, IL-1ß, IL-6, IL-12, and IFN-γ and increased secretion of IL-10, protecting gastrointestinal homeostasis. All compounds reduced macro- and microscopic colonic damage caused by experimental colitis and p38 mitogen-activated protein kinase expression in the colon, as well as leukocytosis and anemia resulting from the disease. Our data may suggest LASSBio-1524 and its analogs (LASSBio-1760, LASSBio-1763, and LASSBio-1764) as promising candidates for new prototypes designed to treat inflammatory bowel diseases. SIGNIFICANCE STATEMENT: Three new N-acylhydrazones were synthetized as analogs of LASSBio-1524. All new substances were evaluated in dextran sulfate- and dinitrobenzene acid-induced colitis, with LASSBio-1760, LASSBio-1762, and LASSBio-1763 presenting a significant effect in both models of colitis without toxic effects. The new substances could be considered as a new prototype for the development of new anti-inflammatory treatments of colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
7.
Am J Gastroenterol ; 115(6): 885-894, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384283

RESUMO

INTRODUCTION: We applied the Grading of Recommendations, Assessment, Development, and Evaluation framework to evaluate the performance of fecal calprotectin (FC) as an alternative to endoscopy in patients with moderate-to-severe ulcerative colitis (UC) treated with a biologic agent or tofacitinib. METHODS: Individual participant data from the trials of infliximab, golimumab, vedolizumab, and tofacitinib for UC were pooled to generate prevalence of endoscopic activity (Mayo endoscopy score) across different combinations of the rectal bleeding score (RBS) and stool frequency score (SFS). These estimates were then combined with the data from an updated systematic review of the operating properties of FC to generate clinical scenario-specific assessments of the performance of FC as a predictor of endoscopic disease activity. A prespecified threshold of acceptability for false-negative (FN) and false-positive (FP) test results was set at 5%. RESULTS: For patients with UC achieving RBS 0 + SFS 0/1, FC ≤ 50 µg/g may avoid endoscopy in 50% patients with a FN rate <5%. Similarly, for patients with RBS 2/3 + SFS 2/3, FC ≥ 250 µg/g potentially avoids endoscopy in approximately 50% patients with an FP rate <5%. The greatest uncertainty in the diagnostic performance for FC was observed in patients with UC achieving RBS 0 but having SFS 2/3, where FN and FP rates were consistently >10%, and endoscopic evaluation may be warranted. DISCUSSION: Two clinical scenarios were identified where FC can be used with confidence for monitoring treatment response to biologics or tofacitinib in patients with UC without the requirement for endoscopy.


Assuntos
Produtos Biológicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colonoscopia , Fármacos Gastrointestinais/uso terapêutico , Complexo Antígeno L1 Leucocitário/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Fezes/química , Humanos , Infliximab/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Medidas de Resultados Relatados pelo Paciente , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Life Sci ; 250: 117553, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32194081

RESUMO

AIMS: Enhancer of zeste homolog 2 (EZH2) is associated with ulcerative colitis development. However, the mechanism of EZH2 in ulcerative colitis progression remains unclear. MAIN METHODS: Lipopolysaccharide (LPS)-treated Caco-2 cells and dextran sodium sulfate (DSS)-treated mice were used as model of ulcerative colitis. The levels of EZH2, angiopoietin-like 4 (ANGPTL4) and cyclic adenosine monophosphate response element-binding protein 1 (CREB1) were tested via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell viability and apoptosis was measured via 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide or flow cytometry. The abundances of inflammatory cytokines were examined via qRT-PCR and enzyme-linked immunosorbent assay. The association between EZH2 and ANGPTL4 was explored via chromatin immunoprecipitation. The colon damage in DSS-treated mice was investigated by colon length, histological analysis, inflammatory response and apoptosis. KEY FINDINGS: LPS induced viability inhibition, inflammatory response and apoptosis in Caco-2 cells. EZH2 expression was increased but ANGPTL4 and CREB1 levels were decreased in LPS-challenged Caco-2 cells. Overexpression of ANGPTL4 or CREB1 suppressed LPS-induced damage in Caco-2 cells. EZH2 could target ANGPTL4 to mediate CREB1 expression. Inhibition of EZH2 suppressed LPS-caused injury. Moreover, knockdown of ANNGPTL4 or CREB1 attenuated the role of EZH2 inhibition. DSS caused the reduced colon length and increased inflammatory response as well as apoptosis. EZH2 expression was up-regulated but ANGPTL4 and CREB1 expression were down-regulated in DSS-treated mice. SIGNIFICANCE: Inhibition of EZH2 declined LPS-induced injury in Caco-2 cells by mediating ANGPTL4 and CREB1, indicating the potential of EZH2 in treatment of ulcerative colitis.


Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Colite Ulcerativa/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Animais , Apoptose , Células CACO-2 , Sobrevivência Celular , Progressão da Doença , Humanos , Inflamação , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
10.
Phytomedicine ; 68: 153182, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32065953

RESUMO

BACKGROUND: Gegen Qinlian decoction (GQ) is a well-known traditional Chinese medicine that has been clinically proven to be effective in treating ulcerative colitis (UC). However, its therapeutic mechanism has not been fully elucidated. Notch signaling plays an essential role in the regeneration of the intestinal epithelium. PURPOSE: This study was designed to ascertain the mechanism by which GQ participates in the recovery of the colonic mucosa by regulating Notch signaling in acute and chronic UC models. METHODS: Acute and chronic UC mice (C57BL/6) were established with 3 and 2% dextran sulfate sodium (DSS), respectively, and treated with oral administration of GQ. The expression of the Notch target gene Hes1 and the Notch-related proteins RBP-J, MAML and Math1 was analyzed by western blotting. PTEN mRNA levels were detected by qRT-PCR. Mucin production that is characteristic of goblet cells was determined by Alcian blue/periodic acid-Schiff staining and verified by examining MUC2 mRNA levels by qRT-PCR. Cell proliferation was assayed by immunohistochemistry analysis of Ki67. HT-29 and FHC cells and Toll-like receptor 4 knockout (TLR4-/-) acute UC mice were also used in this study. RESULTS: GQ restored the injured colonic mucosa in both acute and chronic UC models. We found that Notch signaling was hyperactive in acute UC mice and hypoactive in chronic UC mice. GQ downregulated Hes1, RBP-J and MAML proteins and augmented goblet cells in the acute UC models, whereas GQ upregulated Hes1, RBP-J and MAML proteins in chronic UC mice, reducing goblet cell differentiation and promoting crypt base columnar (CBC) stem cell proliferation. Hes1 mRNA was suppressed in TLR4-/- UC mice, and GQ treatment reversed this effect. In vitro, GQ reduced Hes1 protein in Notch-activated HT29 and FHC cells but increased Hes1 protein in Notch-inhibited cells. CONCLUSIONS: GQ restored the colonic epithelium by maintaining mucosal homeostasis via bidirectional regulation of Notch signaling in acute/chronic UC models.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Receptores Notch/metabolismo , Doença Aguda , Animais , Diferenciação Celular/fisiologia , Proliferação de Células , Doença Crônica , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Sulfato de Dextrana/toxicidade , Feminino , Mucosa Gástrica/patologia , Células Caliciformes/efeitos dos fármacos , Células HT29 , Homeostase/efeitos dos fármacos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo
11.
Aliment Pharmacol Ther ; 51(7): 689-698, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32048751

RESUMO

BACKGROUND: Histologic healing is emerging as a new therapeutic goal in both routine practice and clinical trials in ulcerative colitis (UC). However, it requires repeated endoscopies and biopsies. Faecal calprotectin is a non-invasive marker of mucosal healing (endoscopic and histologic healing). AIM: To conduct a systematic review to clarify the correlation between faecal calprotectin levels and histologic activity in UC patients. METHODS: We searched PubMed/MEDLINE, EMBASE and Web of Science through September 2019 to identify studies in patients with confirmed diagnosis of UC, reporting the correlation between faecal calprotectin levels and histologic analysis. RESULTS: Twelve studies enrolling 1168 patients were included in the final review. Histologic remission was defined according to nonvalidated scores in five articles and using partially validated scores in seven articles. Faecal calprotectin values were measured in 6 of 12 studies (50%) with the same kit, while the remaining six studies adopted individually different kits. A clear correlation between faecal calprotectin levels and histology was showed in all included studies. Eleven different faecal calprotectin cut-off points were identified to distinguish histological remission from histological activity, ranging from 40.5 to 250 µg/g. CONCLUSIONS: Faecal calprotectin can be used to predict histologic remission in patients with UC, but the cut-off level varies across studies, according to the test used to measure this biomarker and according to the definition of histologic remission. Larger prospective studies using validated histologic indexes are needed to identify a globally accepted faecal calprotectin cut-off level to discriminate between histologic remission and histologically active disease.


Assuntos
Colite Ulcerativa/patologia , Fezes/química , Complexo Antígeno L1 Leucocitário/análise , Adulto , Biomarcadores/análise , Biópsia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Feminino , Humanos , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Cicatrização/fisiologia
12.
Talanta ; 211: 120710, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070601

RESUMO

Screening diagnostic biomarkers can be challenging due to the complexity of traditional Chinese medicine (TCM) and ambiguous pharmacological mechanisms. In this study, we reported an integrated strategy for accurately screening diagnostic biomarkers based on metabolomics coupled with network pharmacology. First, a feasible pharmacological model was established through systems pharmacology and based on metabolomics-based techniques to explore diagnostic biomarkers. While the components satisfying the q-value < 0.05, fold change (FC) ≥ 1.2 or FC ≤ 0.8, coefficient of variance (CV) ≤ 30%(QC) and the variable importance in the project (VIP) value > 1 are considered to be diagnostic biomarkers. Second, the ingredients were retained only when oral bioavailability (OB), Caco-2 permeability, drug half-life, TPSA and drug likeness (DL) satisfied the criteria (OB ≥ 40%; Caco-2 ≥ -0.4; HL ≥ 4 h; TPSA˂140; DL ≥ 0.18) suggested by the TCMSP database. Moreover, ingredients that exhibit extensive biological activity in TCM are also retained. Third, the effect targets of TCM were screened using the TCMSP database, Swiss Target Prediction and STICH online software. Disease targets were gathered from the therapeutic target database (TTD), PharmGkb and TCMSP database. Hub genes were screened by potential protein-protein interaction (PPI) network pharmacology analysis. Finally, a metabolic network pathway is established between the diagnostic biomarker and the hub gene. In the network analysis of metabolic pathways, most of the genes involved in this pathway are the second-step-obtained hub genes, which can explain the accuracy of the identified biomarkers. The proposed integrated strategy was successfully applied to explore the mechanism of action of Pulsatilla decoction (PD) in the treatment of acute ulcerative colitis (UC). Based on this integrated strategy, 23 potential biomarkers of acute UC treated with PD were identified. In conclusion, the integrated strategy provides novel insights into network pharmacology and metabolomics as effective tools to illuminate the mechanism of action of TCM.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Coptis , Fraxinus , Phellodendron , Preparações de Plantas/uso terapêutico , Pulsatilla , Animais , Biomarcadores/metabolismo , Células CACO-2 , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Fezes/química , Humanos , Masculino , Medicina Tradicional Chinesa , Metabolômica , Camundongos Endogâmicos BALB C , Farmacologia/métodos , Fitoterapia , Preparações de Plantas/farmacologia
13.
Biopharm Drug Dispos ; 41(3): 91-100, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32043274

RESUMO

In the colon of patients with ulcerative colitis (UC), decreased function of the paracellular barrier, especially hypofunction of the tight junction, is associated with pathological conditions. However, there has been no report to date on the function of tight junctions in the small intestine. Here, we focused on the barrier function of the small intestine, especially in tight junctions, and compared it with that of the colon. Dextran sulfate sodium (DSS) was used to induce ulcerative colitis in rats in order to evaluate the function of the paracellular barrier in the jejunum, ileum, and colon. An in vitro diffusion chamber method was used to evaluate membrane resistance, which is an index of tight junction function and mucosal permeability, using 6-carboxyfluorescein (6-CF), a paracellular marker. In the jejunum and colon, with decrease of membrane resistance in the DSS group, mucosal permeability increased, whereas no marked difference was observed in the ileum. In the in situ closed-loop method, absorption of 6-CF from the jejunum was higher than that from the ileum. Immunohistochemical staining of claudin-4 showed heterogeneous attenuation of claudin-4 in the jejunum. Pharmacokinetic parameters were calculated from the blood concentration after intravenous injection and oral administration of 6-CF. In the DSS group, there was a delay in the elimination phase, suggesting a decrease in renal function, and an increase in maximum blood concentration, associated with an increased absorption rate constant. The increased absorption and decreased renal function due to decreased paracellular barrier function in the small intestine and colon may cause fluctuations in drug efficacy and side effects.


Assuntos
Colite Ulcerativa/metabolismo , Colo/metabolismo , Fluoresceínas/farmacocinética , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Administração Intravenosa , Administração Oral , Animais , Permeabilidade da Membrana Celular , Colite Ulcerativa/sangue , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Intestino Delgado/patologia , Masculino , Ratos Wistar , Junções Íntimas/metabolismo
14.
Clin Ther ; 42(1): 157-174.e4, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982148

RESUMO

PURPOSE: Golimumab is a fully human monoclonal antibody to tumor necrosis factor-α and is indicated for the treatment of moderately to severely active ulcerative colitis (UC). This study analyzed the population pharmacokinetic (PK) properties of golimumab and exposure-response for efficacy and safety, using data from combined Phase II/III UC studies. METHODS: Data on serum golimumab concentration following IV and subcutaneous (SC) administration were fitted simultaneously using nonlinear mixed-effects modeling for the development of a population PK model. Logistic regression models were used for assessing relationships between serum golimumab concentrations and clinical efficacy outcomes in SC induction and maintenance studies. The percentages of patients developing infections, serious infections, and serious adverse events were assessed by golimumab exposure metric quartiles. FINDINGS: The PK properties of golimumab are well described by a 2-compartment model with first-order absorption and elimination. Typical values of PK parameters in a 70-kg patient were clearance, 0.544 L/d; central and peripheral compartment Vd, 3.43 and 2.27 L, respectively; and intercompartmental clearance, 0.291 L/d. Golimumab t1/2 was 10.5 days; bioavailability following SC administration was 52.2%. Body weight, anti-golimumab antibodies, serum albumin, C-reactive protein, and alkaline phosphatase affected golimumab disposition. A positive exposure-response relationship was established between golimumab concentration and efficacy outcomes. No apparent correlation between golimumab exposure and rate of infections, serious infections, or serious adverse events was observed in patients receiving golimumab 50 or 100 mg SC every 4 weeks through 1 year. IMPLICATIONS: Body weight, serum albumin, and anti-golimumab antibodies explain some of the variability observed in the PK properties of golimumab, and exposure-response findings support the recommended posology of golimumab in UC. ClinicalTrials.gov identifiers: NCT00488774, NCT00487539, and NCT00488631.


Assuntos
Anticorpos Monoclonais/farmacocinética , Colite Ulcerativa , Modelos Biológicos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Fosfatase Alcalina/sangue , Anticorpos/sangue , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Peso Corporal , Proteína C-Reativa/análise , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Infecções/sangue , Infecções/metabolismo , Masculino , Pessoa de Meia-Idade , Albumina Sérica/análise , Resultado do Tratamento , Adulto Jovem
15.
Anticancer Res ; 40(1): 101-107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892558

RESUMO

BACKGROUND: Mitochondria are energy-producing organelles, and dysfunction in these organelles causes various types of disease. Although several studies have identified mutations in nuclear DNA that are associated with the etiology of ulcerative colitis (UC), information regarding mitochondrial DNA (mtDNA) in UC is limited. This study aimed to investigate the mitochondrial DNA polymorphism underlying the etiology of UC and UC-associated colorectal cancer. MATERIALS AND METHODS: Next-generation sequencing was performed to assess mitochondrial DNA mutations in 12 patients with UC-associated cancer. The mtDNA mutations in the non-neoplastic mucosa, tumor tissues, and healthy controls were compared. RESULTS: The incidence of mutations of nicotinamide adenine dinucleotide phosphate ubiquinone oxidase subunit, ATP synthetase, and tRNA was higher in non-neoplastic mucosa in those with UC compared with the healthy controls. However, no statistically significant differences were observed in mutations between the tumor tissues and non-neoplastic mucosa in UC. CONCLUSION: Significant mutations in mtDNA were observed in the non-neoplastic mucosa of patients with UC-associated cancer.


Assuntos
Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Neoplasias Colorretais/etiologia , Genes Mitocondriais , Polimorfismo Genético , Transformação Celular Neoplásica/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Suscetibilidade a Doenças , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Mutação
16.
Exp Cell Res ; 388(1): 111820, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31923427

RESUMO

Butyrate-induced autophagy and anti-inflammatory effects of IECs plays an important role in UC. HSP has been proved to be associated with autophagy. HSF2, as an important regulator of HSP, has been determined to be highly expressed in UC. This study was designed to elucidate the relationship between HSF2, butyrate and epithelial autophagy and the potential mechanism of HSF2-related autophagy in UC. The autophagy levels and HSF2 expression in intestinal mucosa were increased in UC patients compared to controls. In DSS colitis models, hsf2-/- mice exhibited more severe intestinal inflammation and lower autophagy levels than wild-type mice. HSF2 expression could be induced by sodium butyrate and LPS as a dose-response relationship in HT-29 cells, epigenetically via increasing histone acetylation levels at the promoter region by sodium butyrate. Autophagy induced by sodium butyrate was promoted by overexpression HSF2 in HT-29 cells. Moreover, overexpression HSF2 decreased the expression and phosphorylation levels of PI3K, Akt and mTOR induced by sodium butyrate. HSF2 might induced by sodium butyrate and inflammation and played protective roles in UC by enhancing autophagy of IECs. This indicated that HSF2 may be a critical target for autophagy modulation and a new potential therapeutic target in UC.


Assuntos
Autofagia , Colite Ulcerativa/metabolismo , Proteínas de Choque Térmico/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Animais , Ácido Butírico/farmacologia , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Feminino , Células HT29 , Proteínas de Choque Térmico/genética , Humanos , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética
17.
Food Funct ; 11(2): 1279-1291, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31984399

RESUMO

Lactobacillus plantarum is a probiotic that is widely used to prevent ulcerative colitis (UC). However, the effects of this species are strain-specific. We believe that the physiological characteristics of L. plantarum strains may affect their UC-alleviating function. Therefore, this study investigated the relationship between the alleviating effect of L. plantarum strains on UC and their physiological characteristics in vitro. The physiological characteristics of 14 L. plantarum strains were assayed in vitro, including gastrointestinal transit tolerance, oligosaccharide fermentation, HT-29 cell adhesion, generation time, exopolysaccharide production, acetic acid production, and conjugated linoleic acid (CLA) synthesis. To create animal models, colitis was established in C57BL/6 mice by adding 3.5% dextran sulfate sodium to drinking water for 7 days. L. plantarum strains with significantly different physiological characteristics were orally administered to the mice at a dose of 3 × 109 CFU. The results indicated that among the tested L. plantarum strains, L. plantarum N13 and L. plantarum CCFM8610 significantly alleviated colitis in the mice, as observed from the restoration of the body weight and disease activity index (DAI) score, recovery of the gut microbiota composition, reduced expression of pro-inflammatory cytokines, and significantly inhibited expression of p65. Correlation analysis indicated that four of the measured physiological characteristics (gastrointestinal transit tolerance, HT-29 cell adhesion, generation time, and CLA synthesis) were related to the UC-alleviating effects to different degrees. The strongest correlation was observed between the CLA synthesis ability and UC-alleviating effects (with Pearson correlation coefficients for IL-1ß, IL-6, IL-17F, TNF-α, myeloperoxidase, and the DAI all below -0.95). The ability to synthesize CLA may be the key physiological characteristic of L. plantarum in UC alleviation. Our findings may contribute to the rapid screening of lactic acid bacterial strains with UC-alleviating effects.


Assuntos
Colite Ulcerativa , Lactobacillus plantarum , Probióticos/farmacologia , Animais , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/química , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Células HT29 , Humanos , Lactobacillus plantarum/metabolismo , Lactobacillus plantarum/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
FASEB J ; 34(2): 3289-3304, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31916636

RESUMO

The enzyme glutathione S-transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Here, we provide a significant insight into the role of GSTT1 in inflammatory bowel disease (IBD). We identified decreased expression of GSTT1 in inflamed colons from IBD patients compared to controls. We intrarectally or intraperitoneally delivered Gstt1 gene to mice with dextran sodium sulfate (DSS)-induced colitis and noted attenuation of colitis through gene transfer of Gstt1 via an IL-22 dependent pathway. Downregulation of GSTT1 by pathogen-associated molecular patterns (PAMPs) of microbes reduced innate defense responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells (IECs) and IBD patients decreased its dimerization, which was connected to insufficient phosphorylation of signal transducer and activator of transcription-3 and p38/mitogen-activated protein kinase by their common activator, IL-22. GSTT1 ameliorated colitis and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerization. Our results provide new insights into GSTT1 mutations that are linked to chronic intestinal inflammation due to its insufficient dimerization and their functional consequences in IBDs.


Assuntos
Diferenciação Celular , Colite Ulcerativa/metabolismo , Glutationa Transferase/metabolismo , Células Caliciformes/metabolismo , Interleucinas/metabolismo , Animais , Células Cultivadas , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Enterócitos/citologia , Enterócitos/metabolismo , Feminino , Glutationa Transferase/genética , Células Caliciformes/citologia , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Multimerização Proteica , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células THP-1 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Eur J Clin Pharmacol ; 76(3): 409-418, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982922

RESUMO

PURPOSE: The partial ineffectiveness and side effects of inflammatory bowel disease (IBD) current therapies drive basic research to look for new therapeutic target in order to develop new drug lead. Considering the pivotal role played by toll-like receptors (TLRs) in gut inflammation, we evaluate here the therapeutic effect of the synthetic glycolipid TLR4 antagonist FP7. METHODS: The anti-inflammatory effect of FP7, active as TLR4 antagonist, was evaluated on peripheral blood mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) isolated from IBD patients, and in a mouse model of ulcerative colitis. RESULTS: FP7 strongly reduced the inflammatory responses induced by lipopolysaccharide (LPS) in vitro, due to its capacity to compete with LPS for the binding of TLR4/MD-2 receptor complex thus inhibiting both the MyD88- and TRIF-dependent inflammatory pathways. Colitic mice treated with FP7 exhibit reduced colonic inflammation and decreased levels of pro-inflammatory cytokines. CONCLUSIONS: This study suggests that TLR4 chemical modulation can be an effective therapeutic approach to IBD. The selectivity of FP7 on TLR4 makes this molecule a promising drug lead for new small molecules-based treatments.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Glicolipídeos/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Adulto , Animais , Células Cultivadas , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
20.
Clin Transl Gastroenterol ; 11(1): e00112, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972611

RESUMO

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder that is frequently associated with ulcerative colitis (UC). Patients with PSC and UC (PSC-UC) have a higher risk of colorectal neoplasia compared with patients with UC. The oncogenic properties of microRNA-346 (miR-346) have been recently reported. We investigated the expression of miR-346 and its 2 target genes, the receptor of vitamin D (VDR), and the tumor necrosis factor-α (TNF-α), which are known to modulate carcinogenesis. METHODS: Ascending and sigmoid colon biopsies were obtained from patients with PSC, PSC and UC (PSC-UC), UC, and healthy controls (n = 10 in each group). Expressions of VDR, TNF-α, 18S RNA, p27, miR-346, and reference microRNA, miR-191, were evaluated by real-time PCR using human TaqMan Gene Expression and TaqMan MicroRNA Assays. Functional studies with miR-346 mimic and inhibitor were conducted in HepG2 and Caco-2 cells. The effect of ursodeoxycholic acid on miR-346 expression was examined in Caco-2 cells. RESULTS: An increased expression of miR-346 in the ascending colon of PSC-UC was observed (P < 0.001 vs all groups). In patients with UC, an exceptionally low colonic expression of miRNA-346 was accompanied by the extensive upregulation of VDR and TNF-α genes. A functional in vitro analysis demonstrated that inhibition of miR-346 resulted in the upregulation of VDR and TNF-α, whereas the induction of miR-346 activity suppressed VDR, TNF-α, and p27. DISCUSSION: The upregulation of miRNA-346 in the colon of patients with PSC may be responsible for the disturbance of VDR and TNF-α signaling pathway, which could result in an inadequate suppression of neoplasia.


Assuntos
Colangite Esclerosante/genética , Colite Ulcerativa/genética , Colo/metabolismo , Neoplasias Colorretais/genética , MicroRNAs/genética , Adulto , Células CACO-2 , Estudos de Casos e Controles , Colagogos e Coleréticos/farmacologia , Colangite Esclerosante/complicações , Colangite Esclerosante/metabolismo , Colite Ulcerativa/complicações , Colite Ulcerativa/metabolismo , Colo Ascendente , Colo Sigmoide , Inibidor de Quinase Dependente de Ciclina p27/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/genética , Feminino , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Masculino , MicroRNAs/efeitos dos fármacos , Pessoa de Meia-Idade , RNA Ribossômico 18S/genética , Receptores de Calcitriol/efeitos dos fármacos , Receptores de Calcitriol/genética , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Regulação para Cima , Ácido Ursodesoxicólico/farmacologia , Adulto Jovem
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