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1.
PLoS One ; 15(10): e0233938, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33095803

RESUMO

BACKGROUND: Onion is one of the most commonly used plants in the traditional medicine for the treatment of various diseases. We recently demonstrated the anti-inflammatory properties of onion bulb extract (OBE) in reducing colitis severity in mice when administered at the same time of colitis induction. However, whether onion can reverse established colitis or even prevent its development has not been investigated. HYPOTHESIS: To test 1. whether OBE can reduce colitis severity when given either before (preventative approach) or after (treatment approach) colitis induction and if so, 2. what are the mechanisms by which onion can achieve these effects. METHODS: Colitis was induced by dextran sulfate sodium (DSS) administration using treatment and preventative approaches. The severity of the inflammation was determined by the gross and histological assessments. The colonic level/activity of pro-inflammatory molecules and immune cell markers was assessed by immunofluorescence and western blotting analysis. In vitro neutrophil superoxide release and survival was assessed by chemilumenecense and Annexin-V/7AAD assays respectively. RESULTS: OBE treatment significantly reduced colitis severity in both approaches, the colonic expression/activity profile of pro-inflammatory molecules, inhibited WKYMVm-induced superoxide release, and increased spontaneous apoptosis of neutrophils in vitro. CONCLUSIONS: OBE can be used as an effective option in the prevention and/or the treatment of established colitis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Colite/tratamento farmacológico , Cebolas/química , Extratos Vegetais/administração & dosagem , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Índice de Gravidade de Doença , Resultado do Tratamento
2.
Anim Sci J ; 91(1): e13468, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33025687

RESUMO

Here, we investigated the effect of prophylactic oral treatment with carbonate apatite-based particles (ID35caps) containing Lactobacillus rhamnosus GG-derived immunostimulatory oligodeoxynucleotides (ID35) when used in mice with acute colitis. Mice were administered orally with control particles (carbonate apatite particles, Caps), ID35, or ID35caps for 2 days, and then were given free access to drinking water containing 3% (w/v) dextran sodium sulfate (DSS) for 5 days (Days 0-5) to induce acute colitis. Body weight change, fecal bleeding, and stool consistency were monitored and scored as a disease activity index (DAI) to assess symptoms of colitis. On Day 10, animals were euthanized and the colon length was measured to evaluate inflammatory tissue injury. Prophylactic oral treatment with ID35caps significantly suppressed DSS-induced elevation of the DAI score and shortening of the colon compared to the respective parameters in DSS-exposed mice treated with Cap or ID35. We conclude that oral priming with ID35caps attenuates symptoms and inflammatory colonic injury in a mouse model of DSS-induced acute colitis. This finding suggests that ID35caps may be a new oral agent for preventing intestinal inflammation.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Lactobacillus rhamnosus/química , Oligodesoxirribonucleotídeos/administração & dosagem , Doença Aguda , Adjuvantes Imunológicos/isolamento & purificação , Administração Oral , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/isolamento & purificação
3.
Life Sci ; 260: 118437, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32950577

RESUMO

AIMS: There has been an increasing trend towards the ulcerative colitis (UC) incidence worldwide. The present study aimed to explore novel biomarkers and potential therapeutic agents for UC. MATERIALS AND METHODS: Differentially expressed genes (DEGs) among UC and healthy control samples were identified by GEO2R online tool. Functional analysis was performed and protein-protein interaction networks were constructed. The hub genes were explored by Cytoscape, and quantitative real-time-PCR (qRT-PCR) was used to valid their expression in clinical samples. ImmuCellAI was utilized to analyze the fraction of 24 types of immune cells. The L1000 platform was applied to determine potential agents for UC treatment. The dextran sulfate sodium (DSS)-induced colitis model was used to identify the therapeutic effect of meclofenamic acid. KEY FINDINGS: A total of 270 DEGs were identified among UC and healthy control samples. Functional analysis indicated that the DEGs were primarily enriched in several immune response and digestion pathways. A proportion of 18 immune-cell types was found to be significantly altered between UC and healthy control samples. 10 compounds were predicted to have therapeutic potentials for treating UC. Among them, we selected meclofenamic acid to identify its therapeutic effect on UC treatment by animal experiments. SIGNIFICANCE: The current study comprehensively analyzed the DEGs and immune infiltration in UC, as well as screened for potential agents for UC treatment.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Ácido Meclofenâmico/farmacologia , Transcriptoma , Animais , Estudos de Casos e Controles , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/genética , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Marcadores Genéticos/genética , Humanos , Camundongos Endogâmicos C57BL , Mapas de Interação de Proteínas/genética
4.
Ann R Coll Surg Engl ; 102(7): e176-e179, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32803988

RESUMO

Spain has been one of the most affected countries by the COVID-19 outbreak. After the high impact of the pandemic, a wide clinical spectrum of late complications associated with COVID-19 are being observed. We report a case of a severe Clostridium difficile colitis in a post-treatment and recovered COVID-19 patient. A 64-year-woman with a one-month hospital admission for severe bilateral pneumonia associated with COVID-19 and 10 days after discharge presented with diarrhoea and abdominal pain. Severe C. difficile-associated colitis is diagnosed according to clinical features and CT findings. An urgent pancolectomy was performed due to her bad response to conservative treatment. Later evolution slowly improved to recovery. C. difficile-associated colitis is one of the most common hospital-acquired infections. Significant patient-related risk factors for C. difficile infection are antibiotic exposure, older age, and hospitalisation. Initial therapeutic recommendations in our country included administration broad-spectrum antibiotics to all patients with bilateral pneumonia associated with SARS-CoV-2. These antibiotics are strongly associated with C. difficile infection. Our patient developed a serious complication of C. difficile due to the use of broad-spectrum antibiotics. The appearance of late digestive symptoms in patients diagnosed and treated for COVID-19 should alert clinicians to the possibility of C. difficile infection. The updated criteria for severe colitis and severe C. difficile infection should be considered to ensure an early effective treatment for the complication.


Assuntos
Antibacterianos/uso terapêutico , Betacoronavirus , Clostridium difficile/isolamento & purificação , Colite/etiologia , Infecções por Coronavirus/complicações , Infecção Hospitalar/etiologia , Pneumonia Viral/complicações , Colite/tratamento farmacológico , Colite/microbiologia , Infecções por Coronavirus/epidemiologia , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X
5.
Arch Biochem Biophys ; 692: 108490, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721434

RESUMO

Ulcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride (Cl-) and thiocyanous (SCN-) anions, respectively. While HOCl indiscriminately oxidises biomolecules, HOSCN primarily targets low-molecular weight protein thiols. Oxidative damage mediated by HOSCN may be reversible, potentially decreasing MPO-associated host tissue destruction. This study investigated the effect of SCN- supplementation in a model of acute colitis. Female mice were supplemented dextran sodium sulphate (DSS, 3% w/v) in the presence of 10 mM Cl- or SCN- in drinking water ad libitum, or with salts (NaCl and NaSCN only) or water only (controls). Behavioural studies showed mice tolerated NaSCN and NaCl-treated water with water-seeking frequency. Ion-exchange chromatography showed increased fecal and plasma SCN- levels in thiocyanate supplemented mice; plasma SCN- reached similar fold-increase for smokers. Overall there was no difference in weight loss and clinical score, mucin levels, crypt integrity and extent of cellular infiltration between DSS/SCN- and DSS/Cl- groups. Neutrophil recruitment remained unchanged in DSS-treated mice, as assessed by fecal calprotectin levels. Total thiol and tyrosine phosphatase activity remained unchanged between DSS/Cl- and DSS/SCN- groups, however, colonic tissue showed a trend in decreased 3-chlorotyrosine (1.5-fold reduction, p < 0.051) and marked increase in colonic GCLC, the rate-limiting enzyme in glutathione synthesis. These data suggest that SCN- administration can modulate MPO activity towards a HOSCN-specific pathway, however, this does not alter the development of colitis within a DSS murine model.


Assuntos
Colite , Colo , Sulfato de Dextrana/toxicidade , Peroxidase/metabolismo , Tiocianatos/farmacologia , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/enzimologia , Colite/patologia , Colo/enzimologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Camundongos
6.
Ulus Travma Acil Cerrahi Derg ; 26(4): 503-508, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32589234

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is an important health problem. The most important hypotheses for the pathogenesis of this disease are the deterioration of immune responses and loss of tolerance against bacteria in the enteric flora. Although IBD has been widely investigated, its treatment remains difficult. This study aims to investigate the effects of garlic oil (GO) on an experimental colitis model. METHODS: Twenty-eight rats were randomly divided into four equal groups as follows: group 1 (sham), group 2 (control), group 3 (topical treatment) and group 4 (topical and systemic treatment). An acetic acid-induced colitis model was produced in groups 2, 3 and 4 and was administered normal saline, topical GO and topical and systemic GO, respectively. RESULTS: Hydroxyproline levels were lower in the treatment groups than in the control group. TNF-α levels were significantly lower in group 3 than in group 2. Macroscopic scores were significantly lower in group 4 than in group 2. Significant differences were observed between the treatment and control groups according to their epithelial loss. CONCLUSION: GO can reduce colonic damage and inflammation in the acetic acid-induced colitis model, with effects on both local and systemic treatments, but with a more pronounced effect in local treatment.


Assuntos
Ácido Acético/efeitos adversos , Compostos Alílicos/uso terapêutico , Colite/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Colite/induzido quimicamente , Modelos Animais de Doenças , Alho , Ratos
8.
Acta Cir Bras ; 35(4): e202000404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555936

RESUMO

PURPOSE: To analyze the effect of calcitriol treatment on acute colitis in an experimental rat model. METHODS: A total of 24 adult Sprague Dawley albino rats were randomly separated into 3 equal groups: control group (n:8), colitis group (n:8), calcitriol administered group (n:8). A single dose of acetic acid (1 ml of 4% solution) was administered intrarectally to induce colitis. Group 1 was given 1 ml/kg 0.9% NaCl intraperitoneally; rats belonging to Group 2 were administered calcitriol 1 µg/kg for 5 days. RESULTS: Plasma tumor necrosis factor alpha, Pentraxin 3, and malondialdehyde levels were significantly lower in the calcitriol administered colitis group than in the standard colitis group (p<0.01). In the Calcitriol group, there was a significant histological improvement in hyperemia, hemorrhage and necrotic areas in the epithelium compared to the placebo group (p <0.000). CONCLUSION: The findings suggest that calcitriol may be an agent that could be used in acute colitis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Calcitriol/uso terapêutico , Colite/tratamento farmacológico , Doença Aguda , Animais , Proteína C-Reativa/análise , Colite/sangue , Colite/patologia , Modelos Animais de Doenças , Peroxidação de Lipídeos , Masculino , Malondialdeído/sangue , Estresse Oxidativo/genética , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Componente Amiloide P Sérico/análise , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
9.
Toxicol Appl Pharmacol ; 400: 115075, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470352

RESUMO

NLRP3, one of the HSP-90 clients, has been defined as a critical component of IBD. In a rat model of DSS-induced colitis, we investigated the anti-inflammatory potential of the combined therapy with CP-456773 (CP), an NLRP3 inhibitor, and celastrol (CSR), an NF-κB inhibitor. Our results revealed that the CSR/CP combined therapy (CCCT) attenuated colon shortening, DAI and MDI in addition to improvement of the colonic histological picture. Moreover, the CCCT increased the antioxidant defense machinery of the colonic tissue and decreased MPO activity. Furthermore, the inflammation markers such as TNF-α and IL-6 were downregulated. These effects might be attributed to the inhibitory effect of CSR on the priming step of the NLRP3 inflammasome activation by interrupting NF-κB signalling and inhibition of HSP-90 (at the protein and mRNA levels) along with inhibitory effect of CP on the expression of the NLRP3. These latter effects resulted in decreased tissue expression and activity of the caspase-1 and repressing the subsequent release of the active forms of IL-1ß and IL-18, hence, the pyroptosis process is restrained. Additionally, the CCCT resulted in inducing autophagy by AMPK/mTOR-dependent mechanisms leading to the accumulation of BECN1 protein and a significant decrease in the levels of p62 SQSTM1. The inhibitory effect on HSP-90 in conjunction with induction of autophagy suggest increased autophagic degradation of NLRP3. This novel approach provides a basis for the clinical application of this combination in IBD treatment and might also be promising for the pharmacological intervention of other NLRP3 inflammasome-dependent inflammatory conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Colite/tratamento farmacológico , Proteínas de Choque Térmico HSP90/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Proteínas de Choque Térmico HSP90/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Masculino , Ratos Sprague-Dawley , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico , Triterpenos/administração & dosagem , Triterpenos/uso terapêutico
10.
Trends Mol Med ; 26(5): 435-437, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32359474

RESUMO

A recent study by Dvorák et al. supports metabolite mimicry as a drug development strategy. A potent agonist of the human pregnane X receptor (hPXR) was designed from two ligands that are products of the microbial catabolism of tryptophan. Its validity was demonstrated in cellular assays and a murine colitis model expressing hPXR by a significant reduction in inflammation biomarkers.


Assuntos
Colite , Microbiota , Receptores de Esteroides , Animais , Colite/tratamento farmacológico , Descoberta de Drogas , Humanos , Camundongos , Receptor de Pregnano X
11.
JAAPA ; 33(5): 28-30, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32345945

RESUMO

Evaluating patients for abdominal pain is common in the ED and can involve many differential diagnoses and treatment options. This case report describes a 35-year-old active duty military man whose abdominal pain evaluation at a military treatment facility led to the diagnosis of epiploic appendagitis.


Assuntos
Abdome Agudo/etiologia , Colite/complicações , Tratamento Conservador/métodos , Manejo da Dor/métodos , Doenças do Colo Sigmoide/complicações , Abdome Agudo/diagnóstico por imagem , Abdome Agudo/tratamento farmacológico , Acetaminofen/uso terapêutico , Adulto , Colite/diagnóstico , Colite/tratamento farmacológico , Humanos , Hidromorfona/uso terapêutico , Cetorolaco/uso terapêutico , Masculino , Naproxeno/uso terapêutico , Doenças do Colo Sigmoide/diagnóstico por imagem , Doenças do Colo Sigmoide/tratamento farmacológico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
J Med Chem ; 63(8): 3881-3895, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223194

RESUMO

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.


Assuntos
Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Sequência de Aminoácidos , Animais , Colite/metabolismo , Colite/patologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química
13.
Adv Exp Med Biol ; 1244: 247-253, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301019

RESUMO

Immune checkpoint inhibitors (ICIs) have shown significant benefit in cancer patients. Their success, however, is associated with immune-related adverse events (irAEs), which commonly affect the gastrointestinal tract, resulting in diarrhea and colitis. IrAEs range from mild self-limiting to severe life-threatening diseases and potentially limit the use of these medications. Diagnosis of ICI-induced enterocolitis is based on clinical symptoms, physical examination, stool tests, endoscopic and histologic evaluation, and/or imaging. Current management strategy is mainly anti-diarrheal agents for mild symptoms and immunosuppressants (e.g., corticosteroids, and infliximab or vedolizumab) for more severe diseases.


Assuntos
Colite/induzido quimicamente , Diarreia/induzido quimicamente , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Colite/tratamento farmacológico , Colite/imunologia , Colite/patologia , Diarreia/tratamento farmacológico , Diarreia/imunologia , Diarreia/patologia , Humanos , Neoplasias/imunologia
14.
Biochem Pharmacol ; 177: 113987, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32330496

RESUMO

The cysteinyl leukotrienes (CysLTs), i.e. LTC4, LTD4 and LTE4, are a family of proinflammatory agents synthesized from the arachidonic acid. In target cells, these lipid mediators bind to the cysteinyl leukotriene receptors (CysLTR), a family of seven transmembrane G-protein coupled receptors. The CysLT1R is a validated target for treatment of pulmonary diseases and several selective antagonists for this receptor, including montelukast, zafirlukast and pranlukast, have shown effective in the management of asthma. Nevertheless, others CysLT1R antagonists, such as the alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol (REV5901), have been extensively characterized without reaching sufficient priority for clinical development. Since drug reposition is an efficient approach for maximizing investment in drug discovery, we have investigated whether CysLT1R antagonists might exert off-target effects. In the report we demonstrate that REV5901 interacts with GPBAR1, a well characterized cell membrane receptor for secondary bile acids. REV5901 transactivates GPBAR1 in GPBAR1-transfected cells with an EC50 of 2.5 µM and accommodates the GPBAR1 binding site as shown by in silico analysis. Exposure of macrophages to REV5901 abrogates the inflammatory response elicited by bacterial endotoxin in a GPBAR1-dependent manner. In vivo, in contrast to montelukast, REV5901 attenuates inflammation and immune dysfunction in rodent models of colitis. The beneficial effects exerted by REV5901 in these models were abrogated by GPBAR1 gene ablation, confirming that REV5901, a shelved CysLT1R antagonist, is a GPBAR1 ligand. These data ground the basis for the development of novel hybrid ligands designed for simultaneous modulation of CysTL1R and GPBAR1.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colite/tratamento farmacológico , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Leucotrienos/metabolismo , Acetatos/farmacologia , Animais , Ácidos e Sais Biliares/farmacologia , Colite/genética , Colite/metabolismo , Colite/patologia , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Células HEK293 , Células Hep G2 , Humanos , Leucotrieno C4/metabolismo , Leucotrieno D4/metabolismo , Leucotrieno E4/metabolismo , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Knockout , Simulação de Acoplamento Molecular , Células RAW 264.7 , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/genética , Receptores de Leucotrienos/química , Receptores de Leucotrienos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
15.
J. coloproctol. (Rio J., Impr.) ; 40(1): 61-66, Jan.-Mar. 2020. tab, ilus
Artigo em Inglês | LILACS | ID: biblio-1090837

RESUMO

Abstract Rationale: Disuse colitis is frequent in our country and the most effective treatment is high cost and there is a need for effective and low cost therapy. Objective: To evaluate the efficacy of Baccharis dracunculifolia (field rosemary) in the treatment of exclusion colitis in rats. Method: Eighteen Wistar rats were anesthetized and submitted to colostomy; they were then distributed into two groups: Control Group, receiving intrarectal saline infusion (n = 8) and Group BD receiving intrarectal infusion ofBaccharis dracunculifolia extract (n = 10); after 21 days of treatment they were euthanized, the intestinal segment excluded from intestinal transit was resected and submitted to histopathological study, classifying the degree of inflammation and degree of vascular congestion from 0 to 3. Results: Mean inflammation was 2.7 in Control Group versus 2.1 in BD Group (p = 0.049), while mean vascular congestion was 2.3 and 2, respectively, in Control and BD groups (p = 0.1642). Conclusion: Intra-rectal infusion ofBaccharis dracunculifolia extract significantly minimized the inflammatory process in the exclusion colitis of rats submitted to colostomy, without altering the degree of vascular congestion.


Resumo Racional A colite de desuso é frequente em nosso meio e o tratamento de maior eficácia é de alto custo, havendo necessidade de se encontrar uma terapêutica eficaz e de baixo custo. Objetivo Avaliar a eficácia da Baccharis dracunculifolia (alecrim-do-campo) no tratamento da colite de exclusão em ratos. Método Utilizou-se 18 ratos Wistar, os quais foram anestesiados e submetidos à colostomia; em seguida distribuídos em 2 grupos: Grupo Controle, recebendo infusão intrarretal de solução salina (n = 8) e Grupo BD, recebendo infusão intrarretal de extrato de Baccharis dracunculifolia (n = 10); após 21 dias de tratamento foram submetidos a eutanásia, o segmento intesinal excluso de trânsito intestinal foi ressecado e submetido a estudo histopatológico classificando-se o grau de inflamação e grau de congestão vascular de 0 a 3. Resultados Verificou-se média de inflamação 2,7 no Grupo Controle vs. 2,1 no Grupo BD (p = 0,049), enquanto as médias de congestão vascular foram 2,3 e 2, respectivamente, nos grupos controle e BD (p = 0,1642). Conclusão A infusão intrarretal do extrato de Baccharis dracunculifolia minimizou significantemente o processo inflamatório na colite de exclusão de ratos submetidos à colostomia, sem alterar o grau de congestão vascular.


Assuntos
Animais , Ratos , Colite , Colite/tratamento farmacológico , Preparações de Plantas , Vernonia , Fitoterapia , Plantas Medicinais , Colostomia , Vernonia/efeitos adversos
16.
Biol Pharm Bull ; 43(3): 450-457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115503

RESUMO

Resveratrol (Res) is a natural active antioxidant that is effective in relieving inflammatory bowel disease (IBD). However, the specific mechanism for its function is unknown. In our study, dextran sodium sulfate (DSS)-induced mouse IBD disease model was constructed. All mice were randomly divided into three groups. The treatment effects of resveratrol on IBD were evaluated by observing the body weight, fecal traits, colon/spleen gross appearance, tissue hematoxylin-eosin (H&E)/immunohistochemistry (IHC) and inflammatory factors. The expression of small ubiquitin-like modifier protein 1 (SUMO1) and its Wnt/ß-catenin pathway-related genes was analyzed by IHC, Western blot, Real-time PCR (RT-PCR) and Immunofluorescence. The outcome indicated that resveratrol treatment significantly relieved the symptoms of IBD. The expression level of anti-inflammatory cytokines was increased while that of pro-inflammatory cytokines was decreased in both colon and spleen tissues of resveratrol-treated mice. SUMO1 expression and Wnt/ß-catenin pathway were suppressed in colon and spleen tissues of IBD mice treated with resveratrol. In addition, we provided evidence that resveratrol inhibited SUMO1 and ß-catenin expression and their nuclear localization in human colonic epithelial cell line (FHC). Moreover, we found that SUMO1 and ß-catenin had higher expression levels in colorectal cancer patients than in health and colitis patients. In conclusions, resveratrol alleviates DSS-induced IBD by modulating SUMO1 through Wnt/ß-catenin pathway.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Resveratrol/farmacologia , Proteína SUMO-1/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Técnicas de Cultura de Células , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Baço/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina
18.
Pharmacol Rep ; 72(1): 135-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016839

RESUMO

BACKGROUND: Inflammatory bowel disease is an intestinal disorder presented by recurrent inflammation in the gastrointestinal tract. It has been reported that modafinil, also known as an awakening drug, has anti-inflammatory characteristics. The objective of this experiment is to investigate the protective effects of modafinil on colitis induced by acetic acid in rat and the involvement of nitric oxide pathway. METHODS: Colitis was induced by intra-rectal instillation of 1 ml acetic acid (4%). After one h of colitis induction (first day), intraperitoneal injection of dexamethasone (1 mg/kg), modafinil (50, 100, and 150 mg/kg), nitric oxide synthase inhibitors (NOS)-N (G)-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg, 7-nitroindazole 40 mg/kg, and aminoguanidine 50 mg/kg-was performed and continued for 2 consecutive days. Ultimately, macroscopic, microscopic, and biochemical assessments were performed. RESULTS: While induction of colitis caused severe macroscopic lesions, administration of dexamethasone and modafinil (100 and 150 mg/kg) significantly improved macroscopic ulcers. Interestingly, the combination of modafinil with NOS inhibitors reversed the beneficial effects of modafinil on macroscopic destructions. In addition, the elevated level of interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) was decreased by modafinil. However, treatment with NOS inhibitors before modafinil neutralized the anti-inflammatory influence of modafinil. Additionally, histological disorders emerged by acetic acid in colon tissue remarkably were disappeared after treatment with modafinil. CONCLUSIONS: In conclusion, modafinil has a protective effect on injuries induced by acetic acid in the colon of rat, which is presumably via the inhibition of inflammatory cascade and mediation of NO pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Modafinila/farmacologia , Óxido Nítrico/metabolismo , Ácido Acético , Animais , Anti-Inflamatórios/administração & dosagem , Colite/tratamento farmacológico , Colite/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Doenças Inflamatórias Intestinais/fisiopatologia , Masculino , Modafinila/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar
19.
Eur J Pharmacol ; 873: 172974, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32027888

RESUMO

Gabapentin is an anticonvulsant drug that is also used for post-herpetic neuralgia and neuropathic pain. Recently, gabapentin showed anti-inflammatory effect. Nuclear factor kappa B (NFκB) is a regulator of the inflammatory process, and Peroxisome Proliferator-activated Receptor gamma (PPAR-gamma) is an important receptor involved in NFκB regulation. The aim of the present work was to study the potential role of PPAR-gamma receptor in gabapentin-mediated anti-inflammatory effects in a colitis experimental model. We induced colitis in rats using trinitrobenzenosulfonic acid and treated them with gabapentin and bisphenol A dicyldidyl ether (PPAR-gamma inhibitor). Macroscopic lesion scores, wet weight, histopathological analysis, mast cell count, myeloperoxidase, malondialdehyde acid, glutathione, nitrate/nitrite, and interleukin levels in the intestinal mucosa were determined. In addition, western blots were performed to determine the expression of Cyclooxygenase-2 (COX-2) and NFκB; Nitric Oxide Inducible Synthase (iNOS) and Interleukin 1 beta (IL-1ß) levels were also determined. Gabapentin was able to decrease all inflammatory parameters macroscopic and microscopic in addition to reducing markers of oxidative stress and cytokines such as IL-1ß and Tumor Necrosis Factor alpha (TNF-α) as well as enzymes inducible nitric oxide synthase and cyclooxygenase 2 and inflammatory genic regulator (NFκB). These effect attributed to gabapentin was observed to be lost in the presence of the specific inhibitor of PPAR-gamma. Gabapentin inhibits bowel inflammation by regulating mast cell signaling. Furthermore, it activates the PPAR-gamma receptor, which in turn inhibits the activation of NFκB, and consequently results in reduced activation of inflammatory genes involved in inflammatory bowel diseases.


Assuntos
Colite/tratamento farmacológico , Gabapentina/uso terapêutico , PPAR gama/efeitos dos fármacos , Animais , Compostos Benzidrílicos/uso terapêutico , Colite/induzido quimicamente , Colite/patologia , Citocinas/metabolismo , Glutationa/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Malondialdeído/metabolismo , Mastócitos/efeitos dos fármacos , NF-kappa B/metabolismo , PPAR gama/antagonistas & inibidores , Peroxidase/metabolismo , Fenóis/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico
20.
Eur J Pharmacol ; 873: 172992, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035144

RESUMO

Hesperetin, a flavonoid from citrus fruits, possess various pharmacological properties, including anti-inflammatory, anti-oxidative, anti-tumor potentials. However, the role and its mechanism in ulcerative colitis (UC) remains unclear. This study aimed to investigate the protective effects and mechanisms of hesperetin on dextran sodium sulfate (DSS) -induced colitis. Our results showed that hesperetin significantly relieved the symptoms of DSS -induced colitis and increased the expressions of zonula occludens-1 (ZO-1), occludin and mucin2 (MUC-2) as well as the decrease of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-18, HMGB1 and IL-6. Of note, results from immunohistochemistry (IHC) and western blotting indicated that hesperetin inhibited the expressions of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), the two key proteins of necroptosis pathway, and inactivated RIPK3/MLKL necroptosis signalling. Meanwhile, in the cell-coculture system between Caco-2 and RAW264.7 cells, hesperetin treatment significantly ameliorated the decrease of trans epithelial electric resistance (TEER) value while HS-173 (necroptosis inducer) could obviously influence the effect of hesperetin. In addition, hesperetin attenuated the LPS-induced increasing in 4-kDa fluorescein isothiocyanate-dextran (FD4) permeability while HS-173 could weaken the protective effect of hesperetin. Meanwhile, HS-173 reduced the changes in the expressions of phosphorylated RIPK3, phosphorylated MLKL, ZO-1, occludin and MUC-2 as well as TNF-α, IL-1ß. These findings demonstrated hesperetin ameliorated DSS-induced colitis by maintaining the epithelial barrier via blocking the intestinal epithelial necroptosis.


Assuntos
Colite/tratamento farmacológico , Epitélio/efeitos dos fármacos , Hesperidina/uso terapêutico , Necroptose , Proteínas Quinases/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colite/induzido quimicamente , Citocinas/biossíntese , Sulfato de Dextrana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7
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