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1.
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
2.
Life Sci ; 236: 116833, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491456

RESUMO

AIMS: Inflammatory bowel disease is a chronic relapsing inflammation that affects the gastrointestinal tract, causing changes in colonic motility. The evolution of these changes is not completely understood and possibly related to symptoms that appear in different degrees of the intestinal inflammation. Therefore, our aim is evaluate during 14 days of assessment aspects of colonic contractility using 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammation in rats and associate the inflammatory process with colonic motility. METHODS: Contractility and inflammatory parameters were assessed in the same animal in six different moments: before intestinal inflammation induction, 2, 5, 8, 11, and 14 days after induction. The mechanical activity was determined by alternating current biosusceptometry (ACB) and subdivided into rhythmic propagating ripples (RPR) and rhythmic propulsive motor complexes (RPMC). We assessed inflammation by determining myeloperoxidase activity in feces. RESULTS: Transient and permanent changes were observed in colonic motility as a function of the inflammatory process evaluated through myeloperoxidase activity. We identified two contraction profiles: RPR and RPMC. The microscopic analysis demonstrated a depth of damage caused by an injury that was associated with changes in motility. CONCLUSIONS: We implemented a robust and adequate (specific) signal processing to quantify two measured colonic frequency patterns. Thus, we performed a detailed temporal analysis of the consequences of TNBS-induced inflammation on colonic motility in rats. Our approach enables further long-term assessments in the same animal with different mechanisms and duration of injury, remission, treatments and their motor consequences.


Assuntos
Colite/patologia , Modelos Animais de Doenças , Inflamação/patologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mucosa Intestinal/fisiopatologia , Contração Muscular , Ácido Trinitrobenzenossulfônico/toxicidade , Animais , Colite/induzido quimicamente , Inflamação/induzido quimicamente , Masculino , Ratos , Ratos Wistar
3.
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
4.
Zhonghua Nei Ke Za Zhi ; 58(8): 584-591, 2019 Aug 01.
Artigo em Chinês | MEDLINE | ID: mdl-31365980

RESUMO

Objective: To investigate the effects of probiotics and synbiotics on inflammation and microbiota of acute colitis in mice. Methods: C57BL/6J mice were divided into 4 groups randomly. Each group had 10 mice and was given 2.5% dextran sulfate sodium (DSS) drinking water for 5 days other than the blank control group. Except for model control group, other two groups were administrated with probiotics and synbiotics, respectively. Probiotics was composed of Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium lactis, while synbiotics was composed of the aforementioned probiotics, inulin and galactooligosaccharide. Feces of different periods and mucosa samples were collected to analyze the differences of enteric flora by 16s rDNA sequencing. Results: (1) Pathological scores in probiotics group and synbiotics group were 5.40±2.79 and 7.25±2.87, respectively, which were significantly lower than those in the model control group with scores 27.00±7.94. Model control group, probiotics group and synbiotics group showed lower flora diversity, increased Bacteroides and decreased Faecalibacterium than blank control group. The mucosal microbiota was different from fecal flora in abundance and species for each group, and Mucispirillum was more common in mucosa. Conclusions: Probiotics and synbiotics alleviate the inflammation of acute colitis in mice. Imbalance of beneficial genera to harmful genera is the characteristic of acute colitis. Supplementation of probiotics and synbiotics contributes to regulating the balance of intestinal microbiota.


Assuntos
Colite/tratamento farmacológico , Colo/microbiologia , Fármacos Gastrointestinais/administração & dosagem , Microbiota/efeitos dos fármacos , Probióticos/administração & dosagem , Simbióticos/administração & dosagem , Animais , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Modelos Animais de Doenças , Fezes/microbiologia , Fármacos Gastrointestinais/uso terapêutico , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/uso terapêutico
5.
J Agric Food Chem ; 67(34): 9522-9531, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31379161

RESUMO

The imbalance of T lymphocyte subsets substantially conduces to disturbed intestinal immune system and succeeding colonic tissue damage in inflammatory bowel diseases. It is considered that regulation of phytochemicals on cytokine production potentially provides a broad prospect for the exploitation of immunomodulatory agents. Here, we reported that oral administration of feruloylated oligosaccharides (FOs) effectively alleviated mice colitis disease induced by dextran sulfate sodium (DSS). FOs decreased the percentage of T helper (Th)17 cells and downregulated the production of Th17-specific cytokines. In contrast, FOs increased the percentage of regulatory T (Treg) cells and elevated the production of Treg-specific cytokines in colons of DSS-challenged mice. These results indicated that FOs restored the immunologic equilibrium of Th17 and Treg subsets, hereby ameliorating the deterioration of colitis. Furthermore, FOs diminished the secretion of interleukin (IL)-23 and IL-6 but enhanced the transforming growth factor-ß1 (TGF-ß1) in dendritic cells in vitro and in vivo, which contributed to the restoration of Th17 and Treg cells immune balance. The mechanistic analysis showed that the regulation of FOs on IL-23 and IL-6 was associated with the nuclear factor-κ-gene binding signaling pathway and TGF-ß1 with mitogen-activated protein kinase-activator protein 1 signaling pathway. Taken together, oral administration of FOs exerted potent immunomodulatory effects against mice colitis via restoring the immune balance of Th17 and Treg cells.


Assuntos
Colite/tratamento farmacológico , Oligossacarídeos/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Humanos , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligossacarídeos/química , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
6.
Eur J Med Chem ; 180: 154-170, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31302448

RESUMO

The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d]thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with Kis in the picomolar or low nanomolar range, and selectivity indices (Ki hCB1/Ki hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC50s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzotiazóis/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Colite/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Tiazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Benzotiazóis/síntese química , Benzotiazóis/química , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
7.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(7): 778-783, 2019 Jul 30.
Artigo em Chinês | MEDLINE | ID: mdl-31340909

RESUMO

OBJECTIVE: To investigate the protective effect of procyanidin B2 (PCB2) on the intestinal barrier and against enteritis in mice with trinitrobenzene sulphonic acid (TNBS)-induced colitis and explore the possible mechanism. METHODS: A mouse model of TNBS-induced colitis was established in male Balb/c mice aged 6-8 weeks. The successfully established mouse models were randomly divided into PCB2 treatment group (n=10) and model group (n=10) and were treated with daily intragastric administration of PCB2 (100 mg/kg, 0.2 mL) and 0.2 mL normal saline, respectively. After 4 weeks, the disease symptoms, intestinal inflammation, intestinal mucosal cell barrier function and the changes in PI3K/AKT signaling were evaluated using HE staining, immunofluorescence assay and Western blotting. RESULTS: The disease activity index of the mice was significantly lower and the mean body weight was significantly greater in PCB2 group than in the model group in the 3rd and 4th weeks of intervention (P < 0.05). The levels of colonic inflammation and intestinal mucosal inflammatory mediators IL-1ß and TNF-α were significantly lower while IL-10 was significantly higher in PCB2 group than in the model group (P < 0.05). Compared with those in the model group, the mice in PCB2 treatment group showed a significantly lower positive rate of bacterial translocation in the mesenteric lymph nodes and a lower thiocyanate-dextran permeability of the intestinal mucosa (P < 0.05). Western blotting showed that PCB2 treatment significantly increased the expressions of claudin-1 and ZO-1 (P < 0.05) and significantly lowered the expression levels of p-PI3K and p-AKT in the intestinal mucosa as compared with those in the model group (P < 0.05). CONCLUSIONS: PCB2 suppresses intestinal inflammation and protects intestinal mucosal functions and structural integrity by inhibiting intestinal PI3K/AKT signaling pathway, suggesting the potential of PCB2 as a new drug for Crohn's disease.


Assuntos
Colite , Enterite , Animais , Biflavonoides , Catequina , Colite/induzido quimicamente , Colo , Mucosa Intestinal , Masculino , Camundongos , Fosfatidilinositol 3-Quinases , Proantocianidinas , Ácido Trinitrobenzenossulfônico
8.
Life Sci ; 231: 116535, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31175857

RESUMO

Latex proteins from P. pudica (LPPp) have anti-inflammatory activity. In the present study, LPPp was evaluated to protect animals against inflammatory ulcerative colitis (UC). UC was induced by intracolonic instillation of a 6% acetic acid solution and the animals received LPPp (10, 20 or 40 mg/kg) by intraperitoneal route 1 h before and 17 h after acetic acid injection. Eighteen hours after instillation of acetic acid, the mice were euthanized and the colons were excised to determine the wet weight, macroscopic and microscopic lesion scores, myeloperoxidase (MPO) activity, IL1-ß levels, glutathione (GSH) and malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity. The results revealed that LPPp treatment (40 mg/kg) had a protective effect on acetic acid-induced colitis by reducing the wet weight, macroscopic and microscopic scores of intestinal lesions and colonic MPO activity. Additionally, LPPp inhibited tissue oxidative stress, since decreases in GSH consumption, MDA concentration and SOD activity were observed. The treatment with LPPp reduced the levels of cytokine IL-1ß, contributing to the reduction of colon inflammation. Biochemical investigation showed that LPPp comprises a mixture of proteins containing proteinases, chitinases and proteinase inhibitors. These data suggest that LPPp has a protective effect against intestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration, cytokine release and oxidative stress.


Assuntos
Apocynaceae/química , Colite/tratamento farmacológico , Látex/farmacologia , Proteínas de Plantas/farmacologia , Ácido Acético , Animais , Apocynaceae/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Citocinas/metabolismo , Glutationa/metabolismo , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Intestinos/patologia , Látex/isolamento & purificação , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Plantas/isolamento & purificação , Substâncias Protetoras/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Life Sci ; 231: 116536, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176785

RESUMO

AIMS: TL1A was reported to contribute to the susceptibility to ulcerative colitis (UC). However, the molecular mechanisms of TL1A in UC development are poorly understood. We aimed to investigate the role of TL1A in colitis, and reveal the regulatory mechanism of TL1A in chronic colitis development. MAIN METHODS: Wild-type mice and transgenic mice with overexpressing TL1A in lymphocytes were used to construct chronic DSS colitis models. To investigate the molecular mechanism in vitro, CD4+ T cells were sorted from spleens and mesenteric lymph node cells to induce Th9 cells. Biopsy specimens from ulcerative colitis patients were collected for in vivo validation. KEY FINDINGS: The elevated TL1A expression in chronic DSS colitis models exacerbated intestinal inflammation. The differentiation of Th9 cells, IL-9 secretion and production of TGF-ß, IL-4 and PU.1 was significantly enhanced in transgenic mice with TL1A overexpression. In vitro results showed that TL1A enhanced the Th9 cells, IL-9 and PU.1 production, while TL1A antibodies inhibited their production. In human translational studies, patients with ulcerative colitis with elevated TL1A expression also exhibited more serious inflammation with higher levels of Th9 cells, IL-9 and PU.1 expression. SIGNIFICANCE: We presented a possible mechanism of TL1A in UC development that TL1A may promote the differentiation of Th9 cells and enhanced IL-9 secretion by up-regulating the expression of TGF-ß, IL-4 and PU.1, which provided a novel perspective to study the UC pathogenesis, and indicated that targeting of TL1A signal pathway may by a likely strategy for the treatment of chronic colitis.


Assuntos
Colite/imunologia , Interleucina-9/imunologia , Linfócitos T/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Colite/induzido quimicamente , Colite/patologia , Citocinas/imunologia , Citocinas/metabolismo , Glutationa/metabolismo , Interleucina-17/imunologia , Interleucina-1beta/metabolismo , Interleucina-9/metabolismo , Mucosa Intestinal/imunologia , Intestinos/imunologia , Intestinos/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
10.
Carbohydr Polym ; 219: 269-279, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151525

RESUMO

The protective mechanism of chitosan oligosaccharide (COS) against lipopolysaccharides (LPS) -induced inflammatory responses in IPEC-J2 and in mice with DSS dextran sulfate sodium (DSS) -induced colitis is reported. Upon exposure to LPS, the proliferation rate of IPEC-J2 cells markedly decreased, and epithelial cell integrity was compromised. However, COS pretreatment significantly reduced these changes. Low-concentration (200 µg/mL) COS up-regulated Toll-like receptor 4 (TLR4) and nuclear p65 expression, but inhibited LPS-induced expression of nuclear p65, IL-6, and IL-8. Addition of the TLR4 inhibitor reduced nuclear p65, IL-6, and IL-8 expression in IPEC-J2 cells exposed to COS or LPS alone, and a slight up-regulation in nuclear p65 was observed in COS and LPS co-treated cells. Medium-dose COS (600 mg/kg/d) protected against DSS-induced colitis, in which TLR4 and nuclear p65 expression levels were decreased. We postulate that the prevention of both LPS- and DSS -induced inflammatory responses in IPEC-J2 cells and mice by COS are related to the inhibition of the TLR4/NF-κB signaling pathway.


Assuntos
Quitosana/farmacologia , Colite/tratamento farmacológico , Inflamação/tratamento farmacológico , Oligossacarídeos/farmacologia , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colite/induzido quimicamente , Sulfato de Dextrana/química , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
11.
Food Chem Toxicol ; 131: 110596, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226429

RESUMO

This study investigated the effects of chlorpyrifos (CPF) on immune-cell populations and intestinal inflammation using a mouse model of inflammatory bowel disease induced by dextran sulfate sodium (DSS). C57BL/6 mice were randomly assigned to five groups with one normal control (NC) and four DSS-treated groups. Mice in the NC group were given distilled water, whereas the DSS-treated groups received distilled water containing 3% DSS for 6 days to induce colitis. The NC and disease control (DC) groups were fed a control semipurified diet, while the remaining groups were exposed to CPF in the AIN-93 diet at doses of 1, 2.5, or 5 mg/kg/day throughout the study. Results showed that dietary exposure to CPF in colitic mice significantly increased circulating classical monocytes and upregulated gene expressions of chemokines in the colon compared to the NC group. Meanwhile, CPF exposure groups had lower plasma cholinesterase activities and higher percentages of circulating neutrophils than those of the DC group. A shorten length, tissue edema, and lipid peroxidation of the colon were also observed in all CPF-exposed mice. These findings suggest that dietary exposure to CPF affected immune-cell populations and inflammatory responses, which led to more severe tissue injury in mice with DSS-induced colitis.


Assuntos
Clorpirifos/toxicidade , Colite/imunologia , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana , Exposição Dietética , Leucócitos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Nat Commun ; 10(1): 2892, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253778

RESUMO

Clinical manifestations and response to therapies in ulcerative colitis (UC) are heterogeneous, yet patient classification criteria for tailored therapies are currently lacking. Here, we present an unsupervised molecular classification of UC patients, concordant with response to therapy in independent retrospective cohorts. We show that classical clustering of UC patient tissue transcriptomic data sets does not identify clinically relevant profiles, likely due to associated covariates. To overcome this, we compare cross-sectional human data sets with a newly generated longitudinal transcriptome profile of murine DSS-induced colitis. We show that the majority of colitis risk-associated gene expression peaks during the inflammatory rather than the recovery phase. Moreover, we achieve UC patient clustering into two distinct transcriptomic profiles, differing in neutrophil-related gene activation. Notably, 87% of patients in UC1 cluster are unresponsive to two most widely used biological therapies. These results demonstrate that cross-species comparison enables stratification of patients undistinguishable by other molecular approaches.


Assuntos
Mapeamento Cromossômico , Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Transcriptoma , Animais , Colite/induzido quimicamente , Colite/genética , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Camundongos , Membrana Mucosa/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
J Dairy Sci ; 102(8): 6718-6725, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155246

RESUMO

This study aimed to screen lactic acid bacteria (LAB) for their anti-inflammatory activity by using RAW264.7 cells and dextran sulfate sodium (DSS)-induced colitis. In all, 192 LAB strains were isolated from healthy human feces, of which 8 strains showed excellent nitric oxide (NO) inhibitory activity. Peptidoglycan extracts of these 8 LAB strains were subjected to NO assay, Western blot, and ELISA. Among the 8 tested strains, extracts of 4 strains significantly inhibited the production of NO, related enzyme activities such as inducible nitric oxide synthase and cyclooxygenase 2, and key cytokines such as tumor necrosis factor-α and IL-6 in RAW264.7 cells. The 4 strains belonged to Lactobacillus (CAU1054, CAU1055, CAU1064, and CAU1301). Oral administration of the 4 strains inhibited DSS-induced body weight loss, colon shortening, and colon damage in ICR mice. The colon tissue of the mice treated with Lactobacillus plantarum strain CAU1055 had significantly reduced levels of inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor-α, and IL-6. We found that strain CAU1055 could be used as a candidate probiotic strain for the prevention and treatment of inflammatory bowel disease. Further studies are warranted to confirm the mechanisms of interaction between peptidoglycan of L. plantarum strain CAU1055 and upstream cellular signaling mediators.


Assuntos
Colite/prevenção & controle , Sulfato de Dextrana/farmacologia , Inflamação/prevenção & controle , Lactobacillus plantarum/fisiologia , Lipopolissacarídeos/farmacologia , Animais , Colite/induzido quimicamente , Colite/terapia , Inibidores de Ciclo-Oxigenase 2 , Citocinas/antagonistas & inibidores , Modelos Animais de Doenças , Fezes/microbiologia , Humanos , Inflamação/terapia , Lactobacillus plantarum/isolamento & purificação , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Probióticos/administração & dosagem , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
14.
AAPS PharmSciTech ; 20(6): 237, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243601

RESUMO

Nanoparticles for colon-drug delivery were designed and evaluated to solve many discrepancy issues as insufficient drug amount at diseased regions, high adverse effects of released drugs, and unintentionally premature drug release to noninflamed gastrointestinal regions. Herein, the prepared budesonide-loaded Eudragit S 100/Capryol 90 nanocapsules for the treatment of inflammatory bowel disease. Nanocapsules were prepared efficiently by nanoprecipitation technique and composed mainly of the pH-sensitive Eudragit S 100 polymeric coat with a semisynthetic Capryol 90 oily core. Full 31 × 21 factorial design was applied to obtain optimized nanocapsules. Optimal nanocapsules showed mean particle size of 171 nm with lower polydispersity index indicating the production of monodispersed system and negative zeta-potential of - 37.6 mV. Optimized nanocapsules showed high encapsulation efficiency of 83.4% with lower initial rapid release of 10% for first 2 h and higher rapid cumulative release of 72% after 6 h. The therapeutic activity of the prepared budesonide-loaded nanocapsules was evaluated using a rat colitis model. Disease activity score, macroscopical examination, blood glucose level, and histopathological assessment showed marked improvements over that free drug suspension. Obtained results demonstrate that the budesonide-loaded Eudragit S 100 nanocapsules are an effective colon-targeting nanosystem for the treatment of inflammatory bowel disease. Capryol 90 was found to be a successful, and even preferred, alternative to benzyl benzoate, which is commonly employed as the oil core of such nanocapsules.


Assuntos
Ácido Acético/toxicidade , Budesonida/uso terapêutico , Colite/tratamento farmacológico , Glucocorticoides/uso terapêutico , Nanocápsulas , Ácidos Polimetacrílicos/administração & dosagem , Animais , Budesonida/administração & dosagem , Colite/induzido quimicamente , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Glucocorticoides/administração & dosagem , Concentração de Íons de Hidrogênio , Ratos , Ratos Wistar
15.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
16.
Psychopharmacology (Berl) ; 236(5): 1653-1670, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31119329

RESUMO

RATIONALE: Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known. OBJECTIVES: Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659. METHODS: We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages. RESULTS: The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice. CONCLUSION: Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.


Assuntos
Anti-Inflamatórios/imunologia , Anti-Inflamatórios/isolamento & purificação , Mycobacterium/imunologia , Mycobacterium/isolamento & purificação , Estresse Psicológico/imunologia , Estresse Psicológico/prevenção & controle , Animais , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/prevenção & controle , Colite/induzido quimicamente , Colite/imunologia , Colite/prevenção & controle , Medo/efeitos dos fármacos , Medo/fisiologia , Inflamação/imunologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Microbiologia do Solo , Estresse Psicológico/induzido quimicamente
17.
Benef Microbes ; 10(5): 543-553, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31122042

RESUMO

Human inflammatory bowel disease (IBD) and experimental colitis models in mice are associated with shifts in gut microbiota composition, and several probiotics are widely used to improve gastrointestinal health. Here, we investigated whether the probiotic Bacillus licheniformis Zhengchangsheng® (BL) ameliorates dextran sulphate sodium (DSS)-induced colitis through alteration of the gut microbiota. Experimental colitis was induced in BALB/C mice by dissolving 3% DSS in their drinking water for 7 days, which were gavaged with 0.2 ml phosphate-buffered saline or BL (3×107 cfu/ml) once a day. Administration of BL attenuated several effects of DSS-induced colitis, including weight loss, increased disease activity index, and disrupted intestinal barrier integrity. In addition, BL mitigated the reduction in faecal microbiota richness in DSS treated mice. Interestingly, BL was found to reduce the elevated circulating endotoxin level in mice with colitis by modulating the microbial composition of the microbiota, and this was highly associated with a proportional decrease in gut Bacteroidetes. Our results demonstrate that BL can attenuate DSS-induced colitis and provide valuable insight into microbiota interactions during IBD.


Assuntos
Bacillus licheniformis/crescimento & desenvolvimento , Colite/patologia , Colite/terapia , Fármacos Gastrointestinais/administração & dosagem , Microbioma Gastrointestinal , Probióticos/administração & dosagem , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Resultado do Tratamento
18.
BMC Cancer ; 19(1): 428, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072353

RESUMO

BACKGROUND: Colorectal cancer remains the second leading cause of cancer death in the United States, and increased risk in patients with ulcerative colitis (a subset of inflammatory bowel disease) has motivated studies into early markers of dysplasia. The development of clinically translatable multiphoton imaging systems has allowed for the potential of in vivo label-free imaging of epithelial crypt structures via autofluorescence and/or second harmonic generation (SHG). SHG has been used to investigate collagen structures in various types of cancer, though the changes that colorectal epithelial collagen structures undergo during tumor development, specifically colitis-associated tumors, have not been fully investigated. METHODS: This study used two murine models, using A/J mice, one for spontaneous carcinoma and one for colitis-associated carcinoma, to investigate and quantify SHG image features that could potentially inform future study designs of endoscopic multiphoton imaging systems. The spontaneous tumor model comprised a series of six weekly injections of azoxymethane (AOM model). The colitis-associated tumor model comprised a single injection of AOM, followed by cycles of drinking water with dissolved dextran sodium sulfate salt (AOM-DSS model). SHG images of freshly resected murine colon were acquired with a multiphoton imaging system, and image features, such as crypt size, shape and distribution, were quantified using an automated algorithm. RESULTS: The comparison of quantified features of crypt morphology demonstrated the ability of our quantitative image feature algorithms to detect differences between spontaneous (AOM model) and colitis-associated (AOM-DSS model) murine colorectal tissue specimens. There were statistically significant differences in the mean and standard deviation of nearest neighbor (distance between crypts) and circularity between the Control cohort, AOM and AOM-DSS cohorts. We also saw significance between AOM and AOM-DSS cohorts when calculating nearest neighbor in images acquired at fixed depths. CONCLUSION: The results provide insight into the ability of SHG imaging to yield relevant data about the crypt microstructure in colorectal epithelium, specifically the potential to distinguish between spontaneous and colitis-associated murine models using quantification of crypt shape and distribution, informing future design of translational multiphoton imaging systems and protocols.


Assuntos
Colite/patologia , Colo/patologia , Neoplasias do Colo/diagnóstico por imagem , Mucosa Intestinal/patologia , Microscopia de Geração do Segundo Harmônico , Animais , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mucosa Intestinal/diagnóstico por imagem , Camundongos
19.
Anticancer Res ; 39(5): 2443-2446, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092437

RESUMO

BACKGROUND/AIM: TLR-4 Knock-out (KO) mice are protected from colitis-associated cancer in the established AOM/DSS mouse model. The aim of this study was to assess whether the TLR4 KO mice would still be protected from carcinogenesis after platelet depletion and transfusion with TLR4 wild-type platelets. MATERIALS AND METHODS: Thirty-two female C57BL6 mice were divided into 6 groups. Among the three groups that received Azoxymethane/Dextran Sulfate Sodium (AOM/DSS), one group included TLR4KO mice, which were depleted of their platelets and were then transfused with platelets from TLR4 wild-type mice. The other two groups included wild-type and TLR-4KO mice that only received AOM/DSS. RESULTS: All 6 animals in the KO group that underwent platelet depletion/transfusion succumbed. Three of them died before the administration of DSS and three in the week following DSS administration. In contrast, mice in the other two groups experienced less weight loss and only 1 mouse died in each of them. CONCLUSION: Platelet depletion/transfusion was detrimental in TLR-4 transgenic mice that received AOM/DSS.


Assuntos
Plaquetas/metabolismo , Colite/sangue , Neoplasias do Colo/sangue , Transfusão de Plaquetas/efeitos adversos , Receptor 4 Toll-Like/genética , Animais , Azoximetano/toxicidade , Plaquetas/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Colite/induzido quimicamente , Colite/complicações , Colite/genética , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout
20.
Talanta ; 200: 537-546, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036220

RESUMO

Liquid chromatography-mass spectrometry based profiling of microbial metabolites has been a challenging task due to their diverse physicochemical properties and wide concentration ranges. This study is aimed to develop a systematic platform for the broad-scale profiling of microbial metabolites by integrating aqueous-lipophilic biphasic extractions and chemical derivatizations with a data-dependent automatable metabolite annotation algorithm. This complementary strategy of detection will not only largely expand the metabolite coverage, but also facilitate the drawing out of interested submetabolome using designed chemical derivatizations. Then, the data-dependent metabolite annotation algorithm is able to automatically match the raw MS/MS data with those of compounds in the self-collected databases. The performance of this platform is illustrated through the analysis of two representative bacteria (Escherichia coli and Pseudomonas aeruginosa) and intestinal contents samples from experimental colitis mice. As a result, 292 metabolites corresponding to 875 annotated features distributing over 25 chemical families were putatively annotated in a short time. Of these metabolites, 197 and 218 are respectively from the bacteria and intestinal contents, and 107 are identified in all three biological samples. This systematic platform could be used to accomplete high-coverage detection and high-quality data processing of microbial metabolites. At the same time, chemical derivatization design and the establishment of self-collected databases will facilitate self-driven untargeted analysis.


Assuntos
Colite/metabolismo , Escherichia coli/metabolismo , Pseudomonas aeruginosa/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana , Espectrometria de Massas , Camundongos
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