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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.
J Enzyme Inhib Med Chem ; 35(1): 1-20, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619080

RESUMO

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-10, and TGF-ß), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Piridinas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/patologia , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Trinitrobenzenossulfônico , Células U937
4.
Acta Cir Bras ; 34(10): e201901004, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851212

RESUMO

PURPOSE: To evaluate the effects of infliximab on the inflammation of the colonic mucosa devoid from fecal stream. METHODS: Twenty-four rats were submitted to a Hartmann's procedure. They remained for 12 weeks with the fecal derivation to development of diversion colitis on excluded colorectal stump. After this period, they were divided into 3 groups: one group received intervention with saline (2.0 mL / week), other group infliximab at doses of 5 mg/kg/week and the other 10 mg/kg/week for five consecutively weeks. Concluded the intervention period, the animals were euthanized to remove colon segments with and without fecal stream. Colitis was diagnosed by histological analysis and the degree of inflammation by validated score. The neutrophilic infiltrate was evaluated by tissue expression of myeloperoxidase identified by immunohistochemical. The tissue content of myeloperoxidase was measured by computer-assisted image analysis. RESULTS: The inflammatory score was high in colonic segments without fecal stream. The intervention with infliximab reduced the inflammatory score in excluded colonic segments. The content of myeloperoxidase was reduced in colonic segments of animals treated with infliximab mainly in high concentrations. CONCLUSION: Intervention with infliximab reduced the inflammation and the neutrophil infiltrate in colonic segments devoid of the fecal stream.


Assuntos
Colite/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Infliximab/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Fezes , Trânsito Gastrointestinal/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/análise , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
5.
Life Sci ; 239: 117021, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678552

RESUMO

OBJECTIVES: Clematichinenoside AR (AR) is a saponin extracted for traditional Chinese medicine with the effects of improving the expression of tight junction (TJ) proteins and mediating anti-inflammatory activities. However, its effect on Crohn's disease (CD) is still unknown. We aimed to investigate the impact of AR on CD-like colitis and determine the mechanism underlying its effects. METHODS: Interleukin-10 gene knockout (Il-10-/-) mice (male, fifteen weeks old) with spontaneous colitis were allocated to the positive control and AR-treated (32 mg/kg AR administered every other day by gavage for 4 weeks) groups. Wild-type (WT) mice (male, fifteen weeks old) composed the negative control group. The effects of AR on intestinal barrier function and structure and T cell responses as well as the potential mechanisms underlying these effects were investigated. RESULTS: AR treatment significantly improved spontaneous colitis in Il-10-/- mice as demonstrated by reductions in the inflammatory score, disease activity index (DAI) and levels of inflammatory factors. The effects of AR on colitis in Il-10-/- mice were related to protecting intestinal barrier function and maintaining immune system homeostasis (regulatory T cell (Treg)/T helper 17 (Th17) cell balance). The anticolitis effect of AR may partly act by downregulating PI3K/Akt signaling. CONCLUSIONS: AR may have therapeutic potential for treating CD in humans.


Assuntos
Colite/tratamento farmacológico , Colite/genética , Interleucina-10/genética , Intestinos/patologia , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Translocação Bacteriana/efeitos dos fármacos , Colite/patologia , Citocinas/metabolismo , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
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.
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
9.
Appl Microbiol Biotechnol ; 103(21-22): 8937-8945, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520133

RESUMO

Inflammatory bowel diseases are chronic and relapsing-remitting disorders that affect the gastrointestinal tract. Previously, the administration of folate and riboflavin-producing lactic acid bacteria (LAB) or an immune-modulating strain showed beneficial effects as they were able to reduce the acute inflammation in mouse models. The aim of this work was to evaluate a mixture of vitamin-producing and immune-modulating LAB administering together with an anti-inflammatory drug during the remission period of a mouse model of recurrent colitis. BALB/c mice were intrarectally instilled with trinitrobenzene sulfonic acid (TNBS) and those who recovered from this acute challenge were given the LAB mixture, mesalazine, or the combination of both (mesalazine + LAB) during 21 days, followed by a second challenge with TNBS. Control mice instilled with ethanol (vehicle of TNBS) and receiving the different treatments were also evaluated in order to study the effect of chronic anti-inflammatory therapy. The combination of mesalazine and LAB mixture was the most effective to decrease the intestinal damage at macroscopic and histological levels and to reduce pro-inflammatory cytokines (IL-6 and TNF-α) in intestinal fluids. In animals instilled with ethanol, mesalazine produced a loss of body weight and intestinal damages with increased IL-6. These side effects were prevented by the co-administration of mesalazine and the LAB mixture. The LAB blend did not affect the primary anti-inflammatory treatment, was able to improve it, and also prevented the side effects of this therapy.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Colite/tratamento farmacológico , Lactobacillales/metabolismo , Probióticos/administração & dosagem , Vitaminas/metabolismo , Animais , Colite/genética , Colite/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
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
11.
Chem Biol Interact ; 313: 108824, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31542397

RESUMO

Insect-based bioactive components are emerging as novel sources of drugs, effective against various diseases. Inflammation is considered to be an innate immune response developed by different organisms against foreign pathogens and cellular stress. However, repetitive elevated inflammation is considered to be responsible for development of many other diseases including colitis and arthritis. Due to the limited activities and side effects of non-steroidal anti-inflammatory drugs, researchers are continuously looking for alternative sources of drug molecules to alleviate the inflammatory related complications. Recently, insect-based bioactive components, such as venoms, haemocytes, cecropin A, papiliocin, N-acetyldopamine dimers, cecropin-TY1 peptide, cop A3 peptide, glycosaminoglycan, coprisin peptide, silk fibroin microparticles, and silk fibroin nanoparticles have been found to be active against different inflammatory mechanisms and associated diseases. Cancers, are some of the deadliest diseases, which are mainly treated by chemotherapy, radiation therapy and surgery. However, such treatments, mainly chemotherapy, is associated with enormous side effects. Therefore, as an alternative, less hazardous option, compounds from insects with anti-cancerous activity are being explored. Insect-derived compounds, such as cantharidin, norcantharidin, isocoumarin, plancyols A, plancypyrazine A, pancratistatin, narciclasine, and ungeremine, show potential anti-cancerous activity. In this review, we will be discussing the role of different potential drug molecules of insect origin with special emphasis on anti-inflammation and their association with health disorders and cancer.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Inflamação/complicações , Insetos/química , Animais , Artrite/tratamento farmacológico , Artrite/etiologia , Produtos Biológicos/farmacologia , Colite/tratamento farmacológico , Colite/etiologia , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias/etiologia
12.
DNA Cell Biol ; 38(10): 1025-1029, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31532239

RESUMO

Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines. A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury. Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.


Assuntos
Aterosclerose/genética , Colite/genética , Esclerose Múltipla/genética , Neutrófilos/metabolismo , Receptor CB2 de Canabinoide/genética , Traumatismo por Reperfusão/genética , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Citocinas/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Ligantes , Camundongos , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Infiltração de Neutrófilos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/deficiência , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
13.
Nutrients ; 11(8)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394746

RESUMO

Pelargonidins are anthocyanidins thought to be beneficial for the human health, although controversies exist over the doses needed and the unclear mechanism of action, along with poor systemic bioavailability. One putative target of pelargonidins is the aryl hydrocarbon receptor (AhR). A synthetic pelargonidin (Mt-P) was synthesized by the methylation of the pelargonidin (the natural compound indicated as P). Mt-P transactivated the AhR with an EC50 of 1.97 µM and was ~2-fold more potent than the natural compound. In vitro Mt-P attenuated pro-inflammatory activities of Raw264.7 macrophage cells in an AhR-dependent manner. In vivo, administration of the Mt-P in Balb/c mice resulted in a dose-dependent attenuation of signs and symptoms of colitis induced by TNBS. A dose of 5 mg/kg Mt-P, but not the natural compound P, reversed intestinal inflammation and increased expression of Tnf-α, Ifn-Æ´, and Il-6, while promoted the expansion of regulatory T cells and M2 macrophages. In C57BL/6J mice fed a high fat diet (HFD), Mt-P attenuated body weight gain, intestinal and liver inflammation, and ameliorated insulin sensitivity, while worsened liver steatosis by up-regulating the liver expression of Cd36 and Apo100b. These effects were abrogated by AhR gene ablation. Mt-P is a synthetic pelargonidin endowed with robust AhR agonist activity that exerts beneficial effects in murine models of inflammation and metabolic dysfunction.


Assuntos
Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/fisiologia , Animais , Antocianinas/química , Células CACO-2 , Colite/induzido quimicamente , Colite/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Células Hep G2 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/genética
14.
Int J Cancer ; 145(11): 3126-3139, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31407335

RESUMO

Inflammation is currently considered a hallmark of cancer and plays a decisive role in different stages of tumorigenesis, including initiation, promotion, progression, metastasis and resistance to antitumor therapies. Colorectal cancer is a disease widely associated with local chronic inflammation. Additionally, extrinsic factors such as infection may beneficially or detrimentally alter cancer progression. Several reports have noted the ability of various parasitic infections to modulate cancer development, favoring tumor progression in many cases and inhibiting tumorigenesis in others. The aim of our study was to determine the effects of excreted/secreted products of the helminth Taenia crassiceps (TcES) as a treatment in a murine model of colitis-associated colon cancer (CAC). Here, we found that after inducing CAC, treatment with TcES was able to reduce inflammatory cytokines such as IL-1ß, TNF-α, IL-33 and IL-17 and significantly attenuate colon tumorigenesis. This effect was associated with the inhibition of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation. Furthermore, we determined that TcES interfered with LPS-induced NF-κB p65 activation in human colonic epithelial cell lines in a Raf-1 proto-oncogene-dependent manner. Moreover, in three-dimensional cultures, TcES promoted reorganization of the actin cytoskeleton, altering cell morphology and forming colonospheres, features associated with a low grade of aggressiveness. Our study demonstrates a remarkable effect of helminth-derived molecules on suppressing ongoing colorectal cancer by downregulating proinflammatory and protumorigenic signaling pathways.


Assuntos
Anti-Inflamatórios/administração & dosagem , Azoximetano/efeitos adversos , Colite/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Proteínas de Helminto/administração & dosagem , Taenia/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Neoplasias do Colo/etiologia , Modelos Animais de Doenças , Feminino , Proteínas de Helminto/farmacologia , Humanos , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , Camundongos , NF-kappa B/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
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
16.
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
17.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31443089

RESUMO

Crohn's Disease (CD), one of the types of inflammatory bowel disease, poses a significant challenge to modern healthcare. This condition severely impacts patients' quality of life, and its incidence is continuously rising. Despite constant research, current treatment options are limited and largely unsuccessful and result in serious side effects, therefore new therapy alternatives are needed. Liposomal formulation provides a new hope for disease management. In our study, we characterized the anti-inflammatory activity of mesalazine (5-ASA) and chlorogenic acid (CGA) encapsulated in liposomal formulation in the animal model of CD. Liposomes were obtained by thin film hydration method and characterized in terms of suspension stability and particle size and distribution. Colitis was induced in mice by intracolonic (i.c.) administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The effect of treatment with liposomal suspensions of 5-ASA and CGA was evaluated macroscopically and by measuring myeloperoxidase (MPO) activity. We observed that liposome-encapsulated 5-ASA (5 mg/kg), but not CGA (20 mg/kg) attenuated colitis as evidenced by a decreased macroscopic and microscopic scores. It may be hypothesized that the composition of liposomal lipid bilayer as well as the switch in macrophage populations leading to unfavorable accumulation of anti-inflammatory agents in the cells may underly the efficiency of obtained liposomes and need to be taken into consideration in further studies on drug delivery.


Assuntos
Ácido Clorogênico/química , Ácido Clorogênico/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Lipossomos/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Mesalamina/química , Mesalamina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Qualidade de Vida , Ácido Trinitrobenzenossulfônico
18.
DNA Cell Biol ; 38(11): 1338-1345, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31464523

RESUMO

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease, which often affects colon or rectum or both. It is now well recognized that sphingosine kinases-1/sphingosine-1-phosphate (S1P) signaling may have a very significant potential as targets for therapeutic intervention in UC. Compared with the pure dextran sodium sulfate group, administration of PF543 significantly reduced clinical symptoms with less weight loss, diarrhea, and shortening of the colon. The severity of colitis was improved with reduced disease activity index and degree of histological damage in colon. Moreover, treatment with PF543 not only decreased S1P but also inhibited mRNA expression of proinflammatory factors such as interleukin (IL)-1ß and IL-6. This suggests that PF543 might exhibit an anti-inflammatory function against colitis through inhibition of expression of proinflammatory factors.


Assuntos
Colite/patologia , Colo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Metanol/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirrolidinas/farmacologia , Animais , Colite/sangue , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Lisofosfolipídeos/sangue , Masculino , Metanol/farmacologia , Metanol/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Pirrolidinas/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/sangue , Baço/efeitos dos fármacos , Baço/patologia , Especificidade por Substrato
20.
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
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