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1.
Life Sci ; 240: 117089, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759038

RESUMO

AIMS: Gut microbiota has been closely linked to the mucosal immune and been regarded as a reliable target for intestinal inflammation. This study aimed to explore the therapeutic roles of probiotic mixtures of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis with (quadruple probiotics, P-qua) or without (triple probiotics, P-tri) aerobic Bacillus cereus in colitis, focusing on the multiple barrier functions. MATERIALS AND METHODS: Chronic colitis was induced by dextran sulfate sodium (DSS) in C57BL/6 mice. The probiotic mixtures P-qua or P-tri was gavage administrated respectively, while fecal microbiota transplantation (FMT) as a positive control. The intestinal inflammation and functions of multiple barriers were assessed, including the mucus barrier, epithelial barrier and endothelial barrier known as gut-vascular barrier (GVB). Altered composition and diversity in gut microbiota were observed via sequencing analysis. KEY FINDINGS: Both P-qua and P-tri relieved the intestinal inflammation and improved the functions of multiple barriers with increased integrity of mucous layer, enhanced transepithelial electrical resistance, declined epithelial and endothelial permeability to macromolecules in DSS-colitis. Aerobe-contained P-qua revealed a more active role in barrier recovering relative to P-tri, while FMT as a positive control seemed to get better results than pure probiotics. Indeed, P-qua was effective in rebuilding the structure and diversity of gut flora in DSS-colitis, especially increased abundance of Bifidobacterium, Akkermansia, Lactobacillus and Bacteroides. SIGNIFICANCE: Aerobe-contained P-qua was a powerful adjuvant therapy for chronic colitis, via restoring the intestinal microflora and recovering the multi-barriers in the inflamed gut.


Assuntos
Bactérias Aeróbias , Colite/induzido quimicamente , Colite/tratamento farmacológico , Probióticos/uso terapêutico , Animais , Permeabilidade da Membrana Celular , Doença Crônica , Colite/patologia , Sulfato de Dextrana , Transplante de Microbiota Fecal , Fezes/microbiologia , Microbioma Gastrointestinal , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/administração & dosagem , Junções Íntimas
2.
Life Sci ; 241: 117164, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838135

RESUMO

AIMS: This study was to assess whether andrographolide derivative (AL-1) could restore mucosal homeostasis and regulate tight junctions through MLCK-dependent pathway in DSS-induced colitis mice. MAIN METHODS: Colitis mice model was induced by daily administration of 2.5% DSS for seven days. The therapeutic effect was determined by evaluating the histopathological changes and the pro-inflammatory cytokine level. In addition, the effects of AL-1 on tight junctions were examined by immunohistochemistry and Western blot. The expressions of factors in MLCK-dependent pathway were evaluated by immunofluorescence and Western blot. KEY FINDINGS: AL-1 protected the intestinal barrier function in DSS-induced colitis mice. These protective effects were achieved by maintaining the normal mucus secretion and preserving tight junctions via suppression of the MLCK-dependent pathway. SIGNIFICANCE: AL-1 could prevent the increase in the DSS-induced intestinal permeability. These data indicated that AL-1 could be a promising agent for UC treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Permeabilidade da Membrana Celular/fisiologia , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Diterpenos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Diterpenos/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinase de Cadeia Leve de Miosina/metabolismo , Fosforilação , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia
3.
Life Sci ; 242: 117220, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881230

RESUMO

BACKGROUND/AIMS: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism. MAIN METHODS: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot. KEY FINDINGS: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways. SIGNIFICANCE: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Oligossacarídeos/uso terapêutico , Panteteína/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Panteteína/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
4.
Int J Nanomedicine ; 14: 8361-8378, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749615

RESUMO

Purpose: This study aimed to evaluate the anti-colitis potential of platinum nanoparticles (PtNPs). Materials and methods: 5-, 30- and 70-nm PtNPs were administered to C57BL/6 mice once daily by intragastric gavage for 8 d during and after 5-d dextran sodium sulfate treatment. Results: According to body weight change, stool blood and consistency, and colon length and histopathology, PtNPs size-dependently alleviated DSS-induced murine colitis. PtNPs enhanced gut-barrier function by upregulating the colonic expressions of heat-shock protein 25 and tight junction proteins. Based on colonic myeloperoxidase activity, colonic and peripheral levels of interleukin-6 and tumor necrosis factor-α, and peripheral counts of white blood cells, PtNPs attenuated colonic and systemic inflammation. By suppressing lipopolysaccharide-triggered production of proinflammatory mediators, including nitric oxide, tumor necrosis factor-α and interleukin-6, PtNPs exerted direct anti-inflammatory activities in RAW264.7 macrophages through a mechanism involving intracellular reactive oxygen species scavenging and Toll-like receptor 4/NF-κB signaling suppression. High-throughput 16S rRNA sequencing of fecal samples unveiled that PtNPs induced gut dysbiosis by unfavorably altering α-diversity, Firmicutes/Bacteroidetes ratio, and richness of certain specific bacteria. Conclusion: PtNPs are a promising anti-colitis agent, but may negatively impact gut-microbiota.


Assuntos
Colite/induzido quimicamente , Colite/terapia , Nanopartículas Metálicas/uso terapêutico , Platina/uso terapêutico , Doença Aguda , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Colite/microbiologia , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/patologia , Lipopolissacarídeos , Masculino , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
5.
BMC Complement Altern Med ; 19(1): 329, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752807

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a modern refractory disease, and its etiology has been difficult to discern. Studies have shown that UC is closely associated with the gut microbiota. Garidisan is composed of wild poppy and Artemisia frigida Willd and is commonly used for the treatment of UC in Inner Mongolia, China. In clinical settings, Garidisan has been found to treat UC effectively, with low recurrence. Previous studies have shown that Garidisan has a good therapeutic effect on mice with UC, but the therapeutic mechanism is still unclear. In this study, we investigated the regulatory effect of Garidisan on dysbiosis of the gut microbiota in a UC mouse model and explored the possible mechanism of the therapeutic effect of Garidisan on UC. METHODS: The UC mouse model was established by the dextran sulfate sodium (DSS) circulating free water drinking method, and the luminal contents were sampled under sterile conditions. High-throughput sequencing of the 16S rRNA gene V3 + V4 region of the luminal contents of the control group, model group, and Garidisan group was conducted, and clustering of operational taxonomic units (OTUs) and species annotation were performed. The differences in species composition and microbial community structure between individual groups of samples were analyzed using MetaStat, LefSe, rank sum test, and Bayesian causal network analysis. RESULTS: The UC mouse model was successfully established and the sequencing results were of adequate quality. There were significant differences in the diversity of luminal contents between the control group, model group, and Garidisan group, and the differences between groups were greater than those within any group. The therapeutic effect of Garidisan on UC is attributed to the direct effect on the Lachnospiraceae family of bacteria. CONCLUSION: Garidisan has a good regulatory effect on the gut microbiota, and Lachnospiraceae could be an important direct target of Garidisan for the treatment of UC.


Assuntos
Colite Ulcerativa/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Sulfato de Dextrana , Modelos Animais de Doenças , Masculino , Medicina Tradicional do Leste Asiático , Camundongos , Camundongos Endogâmicos C57BL
6.
J Agric Food Chem ; 67(48): 13299-13306, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31674784

RESUMO

l-Arabinose is a monosaccharide extracted from plants or fibers, which is known to have a variety of functional properties. In this study, we aim to investigate whether l-arabinose could inhibit colitis by modulating gut microbiota. l-Arabinose was administered in mice daily in a dextran sodium sulfate (DSS)-induced colitis model. The histological analysis, disease index, and the expression of inflammatory genes were measured. 16S-rRNA sequence analysis was performed to investigate gut microbiota. Intriguingly, we found that l-arabinose could repress DSS-induced colitis and inhibit p38-/p65-dependent inflammation activation. Besides that, our data revealed that l-arabinose-modulated DSS-induced gut microbiota were disturbed. Additionally, the perturbed gut microbiota was responsible for the suppressive effects of l-arabinose on DSS-induced colitis treated with antibiotics. Lastly, Caco-2 cells were used to confirm the protective effects of l-arabinose in colitis or inflammatory bowel disease. As expected, the protein expression levels in Caco-2 cells of pro-inflammatory genes, which were treated with l-arabinose and incubated with or without tumor necrosis factor alpha. Our work suggested that l-arabinose exerts anti-inflammation effects in DSS-induced colitis. These beneficial effects have correlations with the composition, diversity, and abundance of the gut microbiota regulated by l-arabinose. l-Arabinose could be a remarkable candidate as a functional food or novel therapeutic strategy for intestinal health.


Assuntos
Arabinose/administração & dosagem , Colite/tratamento farmacológico , Colite/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Colite/induzido quimicamente , Colite/imunologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
7.
J Agric Food Chem ; 67(48): 13282-13298, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31690068

RESUMO

Dietary supplementation with conjugated linoleic acid (CLA) has been reported to alleviate the effect of colitis in mice, but the mechanisms involved need further exploration. The study aimed to investigate how orally administered CLA alleviates dextran sulfate sodium (DSS)-induced colitis in mice. CLA was administered in five different doses: 40, 20, 10, 5, and 2.5 mg/day. Doses of CLA at 10 mg/day and higher alleviated colitis symptoms and reduced inflammation induced by DSS, in which 40, 20, and 10 mg/day CLA significantly increased the concentration of mucin2 and goblet cells, but neither 5 mg/day CLA nor 2.5 mg/day CLA had any effects. Meanwhile, 40 and 20 mg/day CLA treatments significantly upregulated the concentration of tight junction proteins (ZO-1, occludin, and claudin-3) and ameliorated epithelial apoptosis caused by DSS. Moreover, oxidative-stress-related enzymes (superoxide dismutase, glutathione peroxidase, and catalase) and inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-10, and IL-6] were modulated by 40 and 20 mg/day CLA. Furthermore, 40 mg/day CLA rebalanced the gut microbiota damaged by DSS, including reducing Bacteroides and increasing Bifidobacterium and Odoribacter. In conclusion, CLA supplementation alleviated DSS-induced colitis in a dose-dependent manner by modulating inflammatory cytokines and oxidation stress, maintaining the mucosal barrier, and reverting microbiota changes.


Assuntos
Colite/tratamento farmacológico , Citocinas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Linoleicos Conjugados/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Colite/induzido quimicamente , Colite/metabolismo , Colite/microbiologia , Citocinas/genética , Sulfato de Dextrana/efeitos adversos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Arkh Patol ; 81(5): 53-63, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626205

RESUMO

OBJECTIVE: To investigate morphological changes in the thymus, the subpopulation composition of lymphocytes and its non-lymphoid cells in dextran-induced experimental acute ulcerative colitis and in different periods of chronic ulcerative colitis. MATERIAL AND METHODS: Acute and chronic ulcerative colitis was simulated in C57BL/6 mice, by replacing drinking water with a 1% aqueous dextran sulfate sodium solution. Thymic changes were morphometrically assessed; the number and absolute area of thymic corpuscles and epithelial cells were calculated; and the subpopulation composition of lymphocytes and thymic stromal cells was determined using flow cytofluorimetry; the Kruskal-Wallis test and the Mann-Whitney test were used to compare the groups. RESULTS: In acute catarrhal and ulcerative colitis, there was acute accidental thymic involution with devastation of the cortical substance and with a decline in its volume fraction, with an increase in the levels of cells dying through the mechanism of apoptosis, and with a decrease in the absolute number of lymphocytes, T-helper cells, cytotoxic T-cells, regulatory T-lymphocytes, B-lymphocytes, and dendritic cells, with a rise in the index of the area of thymic corpuscles and in the content of late-phase corpuscles among them, and with the appearance of thymic corpuscles as cyst-like cavities. In chronic ulcerative colitis, the cortex was expanded and the area of thymic corpuscles and the count of medullary epithelial cells increased. The cyst-like thymic corpuscles formed clusters, the count of dendritic cells increased in early-stage chronic ulcerative colitis, but the levels of macrophages decreased in both periods of its development. CONCLUSION: There is acute accidental involution and thymic hyperplasia with an increase in medullary epithelial cells and thymic corpuscles consisting of cytokeratin 19+ in the epithelial cells in experimental acute and chronic ulcerative colitis, respectively. The more pronounced epithelial cell response found in end-stage experimental chronic ulcerative colitis reflects the enhanced differentiation of regulatory T-lymphocytes and the larger number of which is observed in peripheral blood and in the focus of inflammation in patients with ulcerative colitis, according to the literature.


Assuntos
Colite Ulcerativa/patologia , Linfócitos/citologia , Timo/patologia , Animais , Colite Ulcerativa/induzido quimicamente , Sulfato de Dextrana , Camundongos , Camundongos Endogâmicos C57BL , Timo/citologia
9.
Life Sci ; 238: 116968, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628914

RESUMO

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.


Assuntos
Biomarcadores/metabolismo , Carcinogênese/patologia , Colite/complicações , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Fator 2 Relacionado a NF-E2/fisiologia , Animais , Azoximetano/toxicidade , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinógenos/toxicidade , Colite/induzido quimicamente , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
10.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3435-3440, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602906

RESUMO

The aim of this paper was to investigate the anti-inflammatory effect of Tripterygium wilfordii processed with licorice on DSS-induced ulcerative colitis( UC) mice and its regulation on intestinal immune system. In this study,a DSS-induced animal model of UC mice was established,with mesalazine( Mes) as a positive drug. The pharmacodynamic effects of low( PT1) and high( PT2)doses of T. wilfordii processed with licorice were analyzed by disease activity index( DAI),colon length and colon histopathological score in mice. By detecting the expression levels of TNF-α and IL-6 cytokines in the serum of mice,immunohistochemical CD3+T and Fox P3+Treg staining in the colon of mice,the anti-inflammatory and immunoregulatory effects of T. wilfordii processed with licorice on UC mice were analyzed. The hepatotoxicity of each dose of T. wilfordii processed with licorice was also analyzed by HE staining in liver tissue of mice and ALT and AST levels in serum. The results showed that the colitis symptoms of the mice in the PT1 group and the PT2 group were alleviated,the inflammatory cell infiltration was reduced. And the expression of inflammatory factors was decreased,the difference was statistically significant compared with the model group( P<0. 05). The HE staining and ALT and AST levels in the high dose group and low dose group were not significantly different from those in the normal group. The results showed that T. wilfordii processed with licorice has the anti-inflammatory and immunomodulatory effects on UC mice,and the dose did not show significant hepatotoxicity.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glycyrrhiza/química , Tripterygium/química , Animais , Sulfato de Dextrana , Camundongos , Extratos Vegetais/farmacologia
11.
J Biochem Mol Toxicol ; 33(11): e22400, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31593355

RESUMO

Inflammatory bowel disease (IBD) is a continual ailment condition which engrosses the entire alimentary canal. The IBD can be primarily distinguished into two forms, ulcerative colitis, and Crohn's disease. The major symptoms of IBD include pustules or abscesses, severe abdominal pain, diarrhea, fistula, and stenosis, which may directly affect the patient's quality of life. A variety of mediators can stimulate the circumstances of IBD, some examples include infections by microbes such as bacteria, perturbation of the immune system and the surrounding environment of the intestines. Severe colitis was stimulated in the experimental animals through administering 4% dextran sulfate sodium (DSS) which is mixed in water ad libitum for 6 days. Eriocitrin (30 mg/kg) was then administered to the experimental animals followed by the induction of severe colitis to evaluate the therapeutic prospective of eriocitrin against the colon inflammation stimulated by DSS. In this study, eriocitrin (30 mg/kg) demonstrated significant (P < .05) attenuation activity against the DSS-stimulated severe colitis in experimental animals. Eriocitrin counteracted all of the clinical deleterious effects induced by DSS, such as body-weight loss, colon shortening, histopathological injury, accretion of infiltrated inflammatory cells at the inflamed region and the secretion of inflammatory cytokines. The results clearly showed that eriocitrin effectively attenuated DSS-induced acute colitis in experimental animals.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/farmacologia , Flavanonas/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Citrus/química , Colo/efeitos dos fármacos , Colo/patologia , Ciclo-Oxigenase 2/análise , Citocinas/metabolismo , Modelos Animais de Doenças , Flavanonas/administração & dosagem , Inflamação/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/análise , Peroxidase/metabolismo , Extratos Vegetais/administração & dosagem , Índice de Gravidade de Doença , Perda de Peso/efeitos dos fármacos
12.
J Agric Food Chem ; 67(41): 11408-11419, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31556290

RESUMO

In this study, the effects of 2-O-ß-d-glucopyranosyl-l-ascorbic acid (AA-2ßG), a natural ascorbic acid derivative from the fruits of Lycium barbarum, on treating the dextran sulfate sodium (DSS)-induced colitis in mice were investigated. The results revealed that AA-2ßG had palliating effects on DSS-induced inflammatory bowel disease (IBD) in terms of slowing down the trends of body weight and solid fecal mass loss, reducing colitis disease activity index, improving serum physiological and biochemical indicators, increasing colon length, blocking proinflammatory cytokines, and increasing tight junction proteins. Additionally, AA-2ßG treatment could promote the production of short-chain fatty acids and modulate the composition of the gut microbiota. The key bacteria related to IBD were found to be Porphyromonadaceae, Prevotellaceae, Rikenellaceae, Parasutterella, Parabacteroides, and Clostridium. The results indicated that AA-2ßG might treat IBD through the regulation of gut microbiota, suggesting that AA-2ßG has the potential to be used as a dietary supplement in the treatment of IBD.


Assuntos
Ácido Ascórbico/administração & dosagem , Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Lycium/química , Extratos Vegetais/administração & dosagem , Animais , Ácido Ascórbico/química , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Colite/genética , Colite/imunologia , Colite/microbiologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Frutas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
13.
Nat Commun ; 10(1): 4408, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562318

RESUMO

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.


Assuntos
Colite/imunologia , Receptores ErbB/imunologia , Helmintíase/imunologia , Mucosa Intestinal/imunologia , Proteínas do Tecido Nervoso/imunologia , Fator Trefoil-3/imunologia , Animais , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/metabolismo , Sulfato de Dextrana , Receptores ErbB/genética , Receptores ErbB/metabolismo , Células Caliciformes/imunologia , Células Caliciformes/metabolismo , Células Caliciformes/parasitologia , Células HEK293 , Helmintíase/metabolismo , Helmintíase/parasitologia , Helmintos/imunologia , Helmintos/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fator Trefoil-3/genética , Fator Trefoil-3/metabolismo , Células U937
14.
Nihon Yakurigaku Zasshi ; 154(3): 92-96, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527366

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that responds to mechanical, thermal, and chemical stimuli in addition to various endogenous ligands, such as arachidonic acid metabolites. The present study aimed to elucidate the expression of TRPV4 in the gastrointestinal tract and the pathogenic roles of TRPV4 in dextran sulphate sodium (DSS)-induced colitis. TRPV4-immunoreactivity was detected in epithelial-like cells of the mouse tongue, esophagus, stomach, ileum, and colon; TRPV4 expression in the tongue was higher than other gastrointestinal tracts. TRPV4 colocalized with a type IV cell marker sonic hedgehog in circumvallate papillae. These findings suggest that TRPV4 contributes to sour taste sensing by regulating type III taste cell differentiation in mice. DSS-induced colitis was significantly attenuated in TRPV4-knockout (TRPV4KO) mice when compared to wild-type mice. DSS treatment upregulated TRPV4 expression in vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4KO mice. The activation of TRPV4 decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-α. These findings indicate that the upregulation of TRPV4 in vascular endothelial cells contributes to the progression of colonic inflammation via the activation of vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.


Assuntos
Colite/fisiopatologia , Células Endoteliais/fisiologia , Trato Gastrointestinal/fisiologia , Trato Gastrointestinal/fisiopatologia , Canais de Cátion TRPV/fisiologia , Animais , Colite/induzido quimicamente , Sulfato de Dextrana , Camundongos , Camundongos Knockout , Língua/fisiologia
15.
J Dairy Sci ; 102(11): 9570-9585, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31477303

RESUMO

Colitis severely affects the quality of life of patients, and lactic acid bacteria have been reported to be able to improve or treat colitis. In this study, we selected a strain of Lactobacillus fermentum (CQPC04) with good resistance in vitro to evaluate its effect on improvement in mice with dextran sulfate sodium (DSS)-induced colitis. We analyzed the effects of L. fermentum CQPC04 on mice with colitis macroscopically via colon length and histopathology. We also used conventional biochemical and ELISA kits, real-time quantitative PCR (RT-qPCR), and Western blotting to analyze microscopically the effects of L. fermentum CQPC04 on related oxidant indices and pro- and anti-inflammatory cytokines in serum and colon tissue of mice. The results indicated that L. fermentum CQPC04 notably increased colon length and ameliorated pathological damage of colon tissue in colitic mice. Serum indices showed that L. fermentum CQPC04 increased the enzyme activity of total superoxide dismutase (T-SOD) and catalase (CAT) and decreased the content of malondialdehyde (MDA) and the activity of myeloperoxidase (MPO). In addition, it inhibited the release of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IFN-γ, IL-1ß, IL-6, and IL-12, and increased the release of the anti-inflammatory cytokine IL-10 in serum. The RT-qPCR experiments confirmed that L. fermentum CQPC04 downregulated the expression of pro-inflammatory cytokine nuclear factor-κB-p65 (NF-κBp65), NF-κB inhibitor-α (IκB-α), TNF-α, IFN-γ, IL-1ß, IL-6, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS), and upregulated the expression of IL-10 in colon tissue. Western blot analysis indicated that L. fermentum CQPC04 significantly reduced expression of NF-κBp65, TNF-α, IL-1ß, COX-2, and iNOS in mouse colon tissues, and increased expression of IκB-α and superoxide dismutase 2 (SOD2). Thus, L. fermentum CQPC04 could effectively alleviate the symptoms of DSS-induced colitis mice and is a potential probiotic for human experiments.


Assuntos
Colite/dietoterapia , Lactobacillus fermentum , NF-kappa B/metabolismo , Probióticos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/prevenção & controle , Citocinas/sangue , Sulfato de Dextrana , Feminino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase Tipo II/metabolismo , Substâncias Protetoras , Fator de Necrose Tumoral alfa/metabolismo
16.
Gastroenterology ; 157(5): 1323-1337, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401143

RESUMO

BACKGROUND & AIMS: Epithelial tight junctions are compromised in gastrointestinal disease. Processes that contribute to the resulting barrier loss include endocytic occludin removal from the tight junction and reduced occludin expression. Nevertheless, the relatively-normal basal phenotype of occludin knockout (KO) mice has been taken as evidence that occludin does not contribute to gastrointestinal barrier function. We asked whether stress could unmask occludin functions within intestinal epithelia. METHODS: Wildtype (WT), universal and intestinal epithelial-specific occludin KO, and villin-EGFP-occludin transgenic mice as well as WT and occludin knockdown (KD) Caco-2BBe cell monolayers were challenged with DSS, TNBS, staurosporine, 5-FU, or TNF. Occludin and caspase-3 expression were assessed in patient biopsies. RESULTS: Intestinal epithelial occludin loss limited severity of DSS- and TNBS-induced colitis due to epithelial resistance to apoptosis; activation of both intrinsic and extrinsic apoptotic pathways was blocked in occludin KO epithelia. Promoter analysis revealed that occludin enhances CASP3 transcription and, conversely, that occludin downregulation reduces caspase-3 expression. Analysis of biopsies from Crohn's disease and ulcerative colitis patients and normal controls demonstrated that disease-associated occludin downregulation was accompanied by and correlated with reduced caspase-3 expression. In vitro, cytokine-induced occludin downregulation resulted in reduced caspase-3 expression and resistance to intrinsic and extrinsic pathway apoptosis, demonstrating an overall protective effect of inflammation-induced occludin loss. CONCLUSIONS: The tight junction protein occludin regulates apoptosis by enhancing caspase-3 transcription. These data suggest that reduced epithelial caspase-3 expression downstream of occludin downregulation is a previously-unappreciated anti-apoptotic process that contributes to mucosal homeostasis in inflammatory conditions.


Assuntos
Apoptose , Caspase 3/metabolismo , Colite/enzimologia , Colo/enzimologia , Células Epiteliais/enzimologia , Mucosa Intestinal/enzimologia , Ocludina/metabolismo , Animais , Células CACO-2 , Estudos de Casos e Controles , Caspase 3/deficiência , Caspase 3/genética , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colite Ulcerativa/enzimologia , Colite Ulcerativa/patologia , Colo/patologia , Doença de Crohn/enzimologia , Doença de Crohn/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Células Epiteliais/patologia , Humanos , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ocludina/deficiência , Ocludina/genética , Transdução de Sinais , Ácido Trinitrobenzenossulfônico , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
17.
Appl Microbiol Biotechnol ; 103(19): 7931-7941, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456001

RESUMO

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD) characterized by superficial mucosal inflammation, rectal bleeding, diarrhea, and abdominal pain. Anti-inflammatory and immunosuppressive drugs have been used in the therapy of human UC. Interleukin (IL)-35, which functions as an anti-inflammatory cytokine, has been shown to play a potential therapeutic role in a UC-like mouse colitis induced by dextran sodium sulfate (DSS). However, the contribution of IL-35 via oral administration to colitis prevention has not been determined. In order to explore its preventative potentiality, a dairy Lactococcus lactis NZ9000 strain was engineered to express murine IL-35 (NZ9000/IL-35), and this recombinant bacteria was applied to prevent and limit the development of DSS-induced mouse colitis. We found that oral administration of NZ9000/IL-35 induced the accumulation of IL-35 in the gut lumen of normal mice. When administrated preventatively, NZ9000/IL-35-gavaged mice exhibited decreased weight loss, DAI score, colon shortening as well as colitis-associated histopathological changes in colon, indicating that the oral administration of NZ9000/35 contributed to the suppression of DSS-induced colitis progression. Moreover, much less Th17 cells and higher level of Treg cells in lamina propria, as well as increased colon and serum levels of IL-10 with a concomitant reduced pro-inflammatory cytokines, IL-6, IL-17A, IFN-γ, and TNF-α were apparently regulated by NZ9000/IL-35 in colitis mice. Together, we put forward direct evidence pinpointing the effectiveness of NZ9000/IL-35 in preventing UC-like mouse colitis, implying a potential candidate of this recombinant Lactococcus lactis that prevent the progression of IBD.


Assuntos
Colite Ulcerativa/prevenção & controle , Fatores Imunológicos/metabolismo , Interleucinas/metabolismo , Lactococcus lactis/metabolismo , Administração Oral , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Fatores Imunológicos/genética , Interleucinas/genética , Mucosa Intestinal/patologia , Lactococcus lactis/genética , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Resultado do Tratamento
18.
Immunology ; 158(1): 35-46, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31429085

RESUMO

Chronic inflammation may drive development of cancer as observed in inflammation-induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti-tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein-1 (PD-1)/PD-L1 signalling pathway is currently at the forefront in the development of anti-tumour immunity-based therapies for multiple malignancies. By blocking the immune-checkpoint of activated T-cells, it is possible to rewire the adaptive resistance induced by the PD-1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy-modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T-cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis and colitis-associated CRC. In addition, we examined the expression of PD-1 and its ligands PD-L1 and PD-L2 as well as other molecular targets related to T-cell exhaustion. We found a significant increase in PD-1 expression on all examined mucosal T-cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD-L1 and PD-L2 mRNA expression throughout the AOM/DSS regime. Blocking PD-1 signalling with an anti-PD1 antibody did not affect the tumour burden in the AOM/DSS-treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune-mediated toxicity. This raises a concern for patients with colitis-associated CRCs and should be further investigated.


Assuntos
Azoximetano , Colite/metabolismo , Colo/metabolismo , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana , Mucosa Intestinal/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Animais , Antígeno B7-H1/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Colo/imunologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Mucosa Intestinal/imunologia , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Fenótipo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Linfócitos T/imunologia , Regulação para Cima
19.
Toxicol Lett ; 315: 23-30, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442584

RESUMO

Ulcerative colitis2 (UC) is an inflammatory bowel disease3 (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair function of TLR4 in the intestinal epithelium is still unknown. Here, wild-type4 (WT) mice, TLR4-knockout mice5 (KO; TLR4-/-) and commensal-depleted mice were used as dextran sulfate sodium6 (DSS)-induced or radiation-induced colitis and injury models to explore the role of TLR4 signaling in intestinal injury. Exogenous lipopolysaccharide7 (LPS) promoted DSS-induced inflammatory cytokines and aggravated intestinal damage. TLR4 deficiency and commensal bacterial depletion inhibited the toxic effects of LPS, but these mice were more susceptible to DSS-induced and radiation-induced intestinal damage. Compared with WT mice, neither DSS nor radiation promoted production of more inflammatory cytokines in the guts of TLR4-KO and commensal-depleted mice. Introducing the cytokine repair factors, PGE2 and GM-CSF, increased the cytokine levels in the guts of DSS-induced colitis mice. We hypothesized that TLR4 and its ligands repaired the epithelium after DSS-induced and radiation-induced intestinal damage by upregulating PGE2 and GM-CSF. Transwell migration assays suggested that LPS, IL6, TNF, PGE2 and GM-CSF promoted intestinal cell migration, and cell viability analysis suggested that these factors protected against radiation-induced intestinal damage. Our data underscore the importance of the balancing role of TLR4 in intestinal injury and repair.


Assuntos
Linhagem Celular/efeitos da radiação , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Receptor 4 Toll-Like/efeitos da radiação , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
20.
Mediators Inflamm ; 2019: 5195134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467484

RESUMO

It has been described that the metalloprotease BmooMP-alpha-I purified from Bothrops moojeni snake venom is able to hydrolyze the TNF molecule. However, this observation has been based mainly on in vitro investigation, in addition to molecular modeling and docking approaches. Considering that there is no in vivo study to demonstrate the biological effects of this enzyme, the major aim to the present work was to investigate whether the BmooMP-alpha-I has any anti-inflammatory efficacy by setting up a murine experimental design of colitis induced by dextran sulfate sodium (DSS). For this purpose, C57BL/6 mice were divided into six groups, as follows: (i) animals without intestinal inflammation, (ii) animals without intestinal inflammation treated with BmooMP-alpha-I (50 µg/animal/day), and (iii) animals with intestinal inflammation induced by 3% of DSS, (iv) mice with intestinal inflammation induced by DSS and treated with BmooMP-alpha-I enzyme at the 50, 25, or 12.5 µg/animal/day dosages by intraperitoneal route. Clinical signs of colitis were observed daily for calculating the morbidity scores, cytokine measurements, and histological features. We observed that the animals treated with different doses of the enzyme presented a remarkable improvement of colitis signs, as confirmed by a significant increase of the intestine length in comparison to the DSS group. Also, no difference was observed between the groups treated with the enzyme or vehicle, as the colon length of these animals was slightly lower than that of the group of healthy animals, without induction of intestinal inflammation. The cytokine quantification in supernatants of intestinal tissue homogenates showed a significant reduction of 38% in IFN-gamma levels, when the animals were treated with 50 µg of the BmooMP-alpha-I compared to the animals receiving DSS only. A significant reduction of 39% in TNF levels was also observed in all doses of treatment with BmooMP-alpha-I, in addition to a significant reduction of 35% in the amount of IL-12p40. Histological examinations revealed that the BmooMP-alpha-I 50 µg treated group preserved colon architecture and goblet cells and reduced the ulcer area, when compared with DSS mice, which showed typical inflammatory changes in tissue architecture, such as ulceration, crypt dilation, loss of tissue architecture, and goblet cell depletion, accompanied by a significant cell infiltration. In conclusion, our results suggest that the improvement of clinical scores and histological findings related to BmooMP-alpha-I treatment in this experimental model could be attributed to the metalloprotease ability to modulate cytokine production locally at the inflamed intestine. These findings highlight the potential anti-inflammatory role and effectiveness of this enzyme as a therapeutic alternative in this type of immunopathological condition.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Metaloendopeptidases/uso terapêutico , Animais , Bothrops , Colite/metabolismo , Citocinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
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