Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.619
Filtrar
1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 673-679, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958122

RESUMO

Objective To investigate the therapeutic effect and mechanism of paeoniflorin on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) mice. Methods C57BL/6 male mice were randomly divided into control group, model group, 600 mg/(kg.d) mesalazine treatment group, (12.5, 25, 50) mg/(kg.d) paeoniflorin treatment group, with 10 mice in each. All mice were treated with 30 g/L DSS for 5 days except the control group. Meanwhile, the mice in the other groups were orally administrated corresponding drugs for 10 days, while the mice in the control and model groups were given equivalent volumes of distilled water. Body mass, fecal characteristics and hematochezia of the mice were observed and recorded daily, and then disease activity index (DAI) was evaluated and calculated. Pathological changes in the colon were observed by HE staining. The levels of anti-flagellin antibody, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in the serum were measured by ELISA. The expression levels of Toll-like receptor 5 (TLR5), myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-Bp65 (NF-κBp65) in the colon tissues were evaluated by Western blot analysis and the activation of lymphocytes in mesenteric lymph node (MLN) was detected by flow cytometry. Results Compared with the control group, DAI scores in the model group were significantly raised, the colon length was significantly shortened, and the epithelium and intestinal gland disappeared. In addition, the serum levels of anti-flagellin antibody, IL-6, TNF-α and the protein levels of TLR5, MyD88, NF-κBp65 in the colon significantly increased, and the activation of T lymphocytes in MLN went up in the model group. All symptoms above were alleviated in the mesalazine and paeoniflorin groups compared with the model group. Conclusion Paeoniflorin can attenuate UC in mice by inhibiting the expression of flagellin and TLR5, and the activation of T cells.


Assuntos
Colite Ulcerativa , Glucosídeos , Ativação Linfocitária , Monoterpenos , Linfócitos T , Receptor 5 Toll-Like , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos/farmacologia , Monoterpenos/uso terapêutico , Distribuição Aleatória , Linfócitos T/efeitos dos fármacos , Receptor 5 Toll-Like/genética
2.
J Environ Pathol Toxicol Oncol ; 39(3): 235-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865915

RESUMO

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Monoterpenos Cicloexânicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Monoterpenos Cicloexânicos/administração & dosagem , Sulfato de Dextrana , Modelos Animais de Doenças , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
3.
Life Sci ; 259: 118356, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861798

RESUMO

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


Assuntos
Benzoatos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Glucosídeos/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Western Blotting , Linhagem Celular , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/química , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ferro/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Reação em Cadeia da Polimerase em Tempo Real
4.
PLoS One ; 15(8): e0238006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857814

RESUMO

This study aimed to evaluate the effects of two prebiotics in different concentrations on nutrient digestibility, fermentative products and immunological variables in adult dogs. Twenty-four adult dogs were randomly divided into six blocks according to their metabolic body weights (BW0.75); within these groups, dogs were randomized to four treatments: control without prebiotics (CO); inclusion of 0.5% prebiotic blend Yes-Golf (B1); inclusion of 1.0% galactooligosaccharide (GOS); and inclusion of 1.0% prebiotic blend Yes-Golf (B2). The experiment lasted 30 days, with 20 days adaptation and 10 days stool and blood collection. Results were analyzed for normality and means were separated by ANOVA and adjusted by the Tukey test at the significance level of 5.0%. Prebiotic supplementation had no effect on apparent digestibility coefficients (ADC), total stool production and fecal scores (p > 0.05). Prebiotics evaluated also did not alter fecal pH, nor the concentrations of ammonia, lactic acid, short chain fatty acids (SCFA) and most fecal branched chain fatty acids (BCFA) (p > 0.05). The addition of GOS decreased the concentration of iso-valeric acid (p = 0.0423). Regarding immunological variables, concentrations of fecal IgA were not influenced by the treatments. Treatments GOS and B2 increased the total number of polymorphonuclear cells, as well as the oxidative burst in relation to treatments B1 and CO (p < 0.0001). Treatment B2 improved the rate of S. aureus phagocytosis in relation to CO (p = 0.0111), and both the GOS and B2 treatments had a better index for E. coli phagocytosis than the CO treatment (p = 0.0067). In conclusion, there was indication that both prebiotics GOS and B2 at 1.0% inclusion improved the immunity of healthy dogs.


Assuntos
Colo/efeitos dos fármacos , Oligossacarídeos/farmacologia , Prebióticos , Animais , Colo/imunologia , Colo/microbiologia , Dieta/veterinária , Cães , Ácidos Graxos Voláteis/análise , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/fisiologia
5.
PLoS One ; 15(7): e0236106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673362

RESUMO

Alfalfa is a forage legume commonly associated with ruminant livestock production that may be a potential source of health-promoting phytochemicals. Anecdotal evidence from producers suggests that later cuttings of alfalfa may be more beneficial to non-ruminants; however, published literature varies greatly in measured outcomes, supplement form, and cutting. The objective of this study was to measure body weight, average daily feed intake, host immunity, and the colon microbiota composition in mice fed hay, aqueous, and chloroform extracts of early (1st) and late (5th) cutting alfalfa before and after challenge with Citrobacter rodentium. Prior to inoculation, alfalfa supplementation did not have a significant impact on body weight or feed intake, but 5th cutting alfalfa was shown to improve body weight at 5- and 6-days post-infection compared to 1st cutting alfalfa (P = 0.02 and 0.01). Combined with the observation that both chloroform extracts improved mouse body weight compared to control diets in later stages of C. rodentium infection led to detailed analyses of the immune system and colon microbiota in mice fed 1st and 5th cutting chloroform extracts. Immediately following inoculation, 5th cutting chloroform extracts significantly reduced the relative abundance of C. rodentium (P = 0.02) and did not display the early lymphocyte recruitment observed in 1st cutting extract. In later timepoints, both chloroform extracts maintained lower splenic B-cell and macrophage populations while increasing the relative abundance of potentially beneficially genera such as Turicibacter (P = 0.02). At 21dpi, only 5th cutting chloroform extracts increased the relative abundance of beneficial Akkermansia compared to the control diet (P = 0.02). These results suggest that lipid soluble compounds enriched in late-cutting alfalfa modulate pathogen colonization and early immune responses to Citrobacter rodentium, contributing to protective effects on body weight.


Assuntos
Citrobacter rodentium/fisiologia , Colo/efeitos dos fármacos , Infecções por Enterobacteriaceae/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Lipídeos/química , Medicago sativa/química , Extratos Vegetais/farmacologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colo/microbiologia , Citocinas/biossíntese , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/uso terapêutico , Solubilidade
6.
Int J Nanomedicine ; 15: 3965-3980, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606658

RESUMO

Aim: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. Materials and Methods: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. Results: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). Conclusion: E-M14C is a potential system for possible colon targeting of etoricoxib.


Assuntos
Colo/efeitos dos fármacos , Etoricoxib/farmacologia , Etoricoxib/farmacocinética , Voluntários Saudáveis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Administração Oral , Adulto , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Colo/metabolismo , Liberação Controlada de Fármacos , Humanos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Adulto Jovem
7.
J Pharmacol Exp Ther ; 374(3): 420-427, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546529

RESUMO

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


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
8.
Life Sci ; 256: 117960, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534033

RESUMO

BACKGROUND: Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS: 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS: Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION: Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.


Assuntos
Constipação Intestinal/complicações , Constipação Intestinal/fisiopatologia , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/fisiopatologia , Peptídeos/uso terapêutico , Tadalafila/uso terapêutico , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Colo/fisiopatologia , Constipação Intestinal/tratamento farmacológico , GMP Cíclico/metabolismo , Fezes/química , Trânsito Gastrointestinal/efeitos dos fármacos , Hipocampo/metabolismo , Intestino Grosso/metabolismo , Masculino , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Reflexo/efeitos dos fármacos , Natação , Tadalafila/farmacologia , Água
9.
Food Chem ; 331: 127363, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32590269

RESUMO

Rhubarb is a popular food in Europe with laxative properties attributed to anthraquinones. Long term usage of rhubarb anthraquinones has been linked to colonic toxicity, including the formation of melanosis coli, which is associated with increased risk of colon cancer. The major purgative anthraquinone in rhubarb is thought to be sennoside A, which is metabolised by colonic microflora. Here, we sought to identify the toxic metabolite responsible for melanosis coli in rats dosed with rhubarb anthraquinones for up to 90 days. Three metabolites were detected in rat faeces using HPLC. Of these, rhein was identified as the metabolite that accumulated most over time. Fecal flora from treated rats were capable of greater biotransformation of sennoside A to rhein compared to that from control rats. Cell culture experiments suggested that apoptosis and autophagy induced by rhein is the likely mechanism of chronic toxicity of rhubarb anthraquinones.


Assuntos
Antraquinonas/farmacocinética , Antraquinonas/toxicidade , Rheum/química , Animais , Antraquinonas/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biotransformação , Catárticos/química , Catárticos/farmacologia , Cromatografia Líquida de Alta Pressão , Colo/efeitos dos fármacos , Colo/patologia , Diarreia/induzido quimicamente , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Células HT29 , Humanos , Laxantes/farmacocinética , Laxantes/toxicidade , Masculino , Ratos Sprague-Dawley , Senosídeos/farmacocinética , Senosídeos/toxicidade
10.
Chemosphere ; 258: 127255, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554004

RESUMO

Trifluoromethanesulfonic acid (TFMS) is the shortest chain perfluorinated compound. Recently, it has been identified as a persistent and mobile organic chemical with a maximum concentration of 1 µg/L in the environment. However, its toxicological mechanism remains unclear. In this study, to evaluate the liver and intestinal toxicity of TFMS in mammals, male mice were orally exposed to 0, 1, 10 and 100 µg/kg for 12 weeks. Our results showed that TFMS exposure reduced the epididymal fat weight in mice, caused the decrease of serum and liver triglyceride (TG) level and the increase of serum low density lipoprotein (LDL) level. Also, we observed the inflammatory cell infiltration in the liver of mice exposed to 10 µg/kg and 100 µg/kg TFMS, which was coupled with the increased mRNA expression levels of inflammatory factors such as COX2, TNF-α, IL-1ß in the liver. In addition, the mRNA expression levels of lipid metabolism-related genes (PPAR-α, ACOX, SCD1, PPAR-γ, etc.) were significantly decreased in the liver of mice after exposure to both doses of TFMS. We also found TFMS exposure caused the imbalance of cecal gut microbiota and change of cecal microbiota diversity. KEGG pathway predictions showed that the exposure of 100 µg/kg TFMS changed the synthesis and degradation of ketone bodies, benzoate degradation and several other metabolic pathways. Our findings indicated that TFMS exposure disturbed the liver lipid metabolism possibly via altering the gut microbiota.


Assuntos
Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mesilatos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Ceco/efeitos dos fármacos , Ceco/microbiologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Disbiose , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Triglicerídeos/sangue
11.
PLoS One ; 15(5): e0223344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365104

RESUMO

Stilbenes are a group of chemicals characterized with the presence of 1,2-diphenylethylene. Previously, our group has demonstrated that synthesized (E)-N-(2-(3, 5-dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) possesses potential chemopreventive activity specifically inducing NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression and activity. In this study, the cytoprotective effects of BK3C231 on cellular DNA and mitochondria were investigated in normal human colon fibroblast, CCD-18Co cells. The cells were pretreated with BK3C231 prior to exposure to the carcinogen 4-nitroquinoline 1-oxide (4NQO). BK3C231 was able to inhibit 4NQO-induced cytotoxicity. Cells treated with 4NQO alone caused high level of DNA and mitochondrial damages. However, pretreatment with BK3C231 protected against these damages by reducing DNA strand breaks and micronucleus formation as well as decreasing losses of mitochondrial membrane potential (ΔΨm) and cardiolipin. Interestingly, our study has demonstrated that nitrosative stress instead of oxidative stress was involved in 4NQO-induced DNA and mitochondrial damages. Inhibition of 4NQO-induced nitrosative stress by BK3C231 was observed through a decrease in nitric oxide (NO) level and an increase in glutathione (GSH) level. These new findings elucidate the cytoprotective potential of BK3C231 in human colon fibroblast CCD-18Co cell model which warrants further investigation into its chemopreventive role.


Assuntos
4-Nitroquinolina-1-Óxido/toxicidade , Colo/efeitos dos fármacos , Citoproteção , Dano ao DNA/efeitos dos fármacos , Furanos/farmacologia , Mutagênicos/toxicidade , Estilbenos/farmacologia , Linhagem Celular , Colo/citologia , Reparo do DNA/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Furanos/química , Humanos , Mitocôndrias/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estilbenos/química
12.
Toxicol Lett ; 329: 67-79, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387197

RESUMO

This study unveiled the early cellular and molecular events induced by 1,2-dimethylhydrazine (DMH) in the colon and liver and their implications on pre- and neoplastic lesion burden in a late timepoint. Male Wistar rats received four DMH injections (40 mg/kg body weight) for 2 weeks and were sacrificed 24 h (short-term study) or 22 (medium-term study) weeks after the last DMH administration. In the short-term study, DMH led to increased leukocyte (comet assay) and colon (H2AX) genotoxicity, enhanced proliferation (Ki-67) and apoptosis (caspase-3) indexes in both liver and colon. Furthermore, the expression of mRNA (Cat, Gsta1, Gsta2, Gpx1, Gstm1, Sod1, Sod2 and Sod3) and the activity of antioxidant agents were diminished in the colon and liver of DMH-induced rats, eliciting an environment of oxidative stress featuring elevated lipid hydroperoxide levels. Apoptosis effectors were upregulated in the liver (Bax, Casp3 and Fas), and developmental genes were downregulated in both colon and liver (Foxa1, Foxa2, Smad2 and Smad4). In the medium-term study, DMH led to a high number of preneoplastic colonic aberrant crypt foci and tumors (adenomas and invasive adenocarcinomas) but few preneoplastic hepatic glutathione S-transferase (GST-P)-positive foci. Our novel gene expression data highlights overlooked mechanisms in the liver (main metabolizing organ) and colon (main target organ) on toxicity and carcinogenesis induced by repeated doses of DMH, as both organs should be considered in further interventions on the initiation stage of colon carcinogenesis.


Assuntos
1,2-Dimetilidrazina/toxicidade , Carcinógenos/toxicidade , Colo/efeitos dos fármacos , Neoplasias do Colo/induzido quimicamente , Neoplasias Hepáticas/induzido quimicamente , Fígado/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Mutagênicos/toxicidade , Ratos , Ratos Wistar
13.
Chem Biol Interact ; 325: 109132, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437693

RESUMO

BACKGROUND: Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases the risk of multi-organ tissue injury and number of malignancies including CRC. Our prior studies showed that the shift in light-dark cycle exacerbates barrier dysfunction and colonic inflammation in the setting of alcohol treatment, and increases the risk of CRC. Here we studied the interaction of alcohol with an abnormal eating pattern on markers of CD and colonic barrier integrity. METHOD: Mice were subjected to day (rest-phase = wrong-time WT) or night-time (active-phase = right-time RT) access to food in combination with access to water or 15% alcohol for total duration of 10 weeks. The food and liquid intake was measured. The locomotor activity data was recorded throughout the study, using a beam-break system. Mice were euthanized at two time points (ZT2 and ZT14). Time variation in the expression of the molecular marker of circadian clock (per2 gene) was measured in the central (hypothalamus) and intestinal (colon) tissue. Colonic protein expression of barrier markers (Occludin and Claudin-1) was studied. RESULTS: No significant differences were present in the weight gain and alcohol intake among the groups over the study period. We observed an interaction of WT eating with alcohol on behavioral markers of circadian rhythm. Compared to the RT + Water treated animals ("reference group"), combination of WT eating and alcohol consumption (WT + Alcohol) significantly changed the per2 oscillatory pattern, that was different between the colon and hypothalamus, indicative of worsening circadian dyssynchrony. This was associated with an overall impaired expression of barrier integrity markers in the colon. CONCLUSIONS: Alcohol induces circadian dyssynchrony which is worsened by abnormal food timing, associated with impaired barrier integrity in the colon. Future studies on the interaction of alcohol and food timing could provide further insights into alcohol associated CRC pathophysiology.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Ingestão de Alimentos/fisiologia , Etanol/efeitos adversos , Consumo de Bebidas Alcoólicas/patologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Biomarcadores/metabolismo , Colo/lesões , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo
14.
Inflamm Bowel Dis ; 26(6): 797-808, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: covidwho-116826

RESUMO

BACKGROUND: Patients with inflammatory bowel disease (IBD) have intestinal inflammation and are treated with immune-modulating medications. In the face of the coronavirus disease-19 pandemic, we do not know whether patients with IBD will be more susceptible to infection or disease. We hypothesized that the viral entry molecules angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in the intestine. We further hypothesized that their expression could be affected by inflammation or medication usage. METHODS: We examined the expression of Ace2 and Tmprss2 by quantitative polymerase chain reacion in animal models of IBD. Publicly available data from organoids and mucosal biopsies from patients with IBD were examined for expression of ACE2 and TMPRSS2. We conducted RNA sequencing for CD11b-enriched cells and peripheral and lamina propria T-cells from well-annotated patient samples. RESULTS: ACE2 and TMPRSS2 were abundantly expressed in the ileum and colon and had high expression in intestinal epithelial cells. In animal models, inflammation led to downregulation of epithelial Ace2. Expression of ACE2 and TMPRSS2 was not increased in samples from patients with compared with those of control patients. In CD11b-enriched cells but not T-cells, the level of expression of ACE2 and TMPRSS2 in the mucosa was comparable to other functional mucosal genes and was not affected by inflammation. Anti-tumor necrosis factor drugs, vedolizumab, ustekinumab, and steroids were linked to significantly lower expression of ACE2 in CD11b-enriched cells. CONCLUSIONS: The viral entry molecules ACE2 and TMPRSS2 are expressed in the ileum and colon. Patients with IBD do not have higher expression during inflammation; medical therapy is associated with lower levels of ACE2. These data provide reassurance for patients with IBD.


Assuntos
Regulação da Expressão Gênica , Imunossupressores/farmacologia , Síndrome do Intestino Irritável/fisiopatologia , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Adolescente , Adulto , Idoso , Animais , Betacoronavirus/metabolismo , Biópsia , Colo/efeitos dos fármacos , Colo/metabolismo , Biologia Computacional , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Imunossupressores/uso terapêutico , Inflamação/fisiopatologia , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Adulto Jovem
15.
Vet Microbiol ; 243: 108632, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32273011

RESUMO

Zinc treatment is beneficial for infectious diarrhea or colitis. This study aims to characterize the pathomechanisms of the epithelial barrier dysfunction caused by alpha-hemolysin (HlyA)-expressing Escherichia coli in the colon mucosa and the mitigating effects of zinc ions. We performed Ussing chamber experiments on porcine colon epithelium and infected the tissues with HlyA-producing E. coli. Colon mucosa from piglets was obtained from a feeding trial with defined normal or high dose zinc feeding (pre-conditioning). Additional to the zinc feeding, zinc was added to the luminal compartment of the Ussing chamber. Transepithelial electrical resistance (TER) was measured during the infection of the living tissue and subsequently the tissues were immuno-stained for confocal microscopy. Zinc applied to the luminal compartment was effective in preventing from E. coli-induced epithelial barrier dysfunction in Ussing chamber experiments. In contrast, zinc pre-conditioning of colon mucosae when zinc ions were missing subsequently in the luminal compartment was not sufficient to prevent epithelial barrier impairment during E. coli infection. The pathological changes caused by E. coli HlyA were alterations of tight junction proteins claudin-4 and claudin-5, focal leak formation, and cell exfoliation which reflected the paracellular barrier defect measured by a reduced TER. In microscopic analysis of luminal zinc-treated mucosae these changes were absent. In conclusion, continuous presence of unbound zinc ions in the luminal compartment is essential for the protective action of zinc against E. coli HlyA. This suggests the usage of zinc as therapeutic regimen, while prophylactic intervention by high dietary zinc loads may be less useful.


Assuntos
Colo/efeitos dos fármacos , Infecções por Escherichia coli/patologia , Proteínas de Escherichia coli/metabolismo , Proteínas Hemolisinas/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Zinco/farmacologia , Ração Animal , Animais , Colo/citologia , Colo/microbiologia , Escherichia coli/patogenicidade , Infecções por Escherichia coli/prevenção & controle , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Técnicas de Cultura de Órgãos , Suínos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologia
17.
Inflamm Bowel Dis ; 26(6): 797-808, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32333601

RESUMO

BACKGROUND: Patients with inflammatory bowel disease (IBD) have intestinal inflammation and are treated with immune-modulating medications. In the face of the coronavirus disease-19 pandemic, we do not know whether patients with IBD will be more susceptible to infection or disease. We hypothesized that the viral entry molecules angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in the intestine. We further hypothesized that their expression could be affected by inflammation or medication usage. METHODS: We examined the expression of Ace2 and Tmprss2 by quantitative polymerase chain reacion in animal models of IBD. Publicly available data from organoids and mucosal biopsies from patients with IBD were examined for expression of ACE2 and TMPRSS2. We conducted RNA sequencing for CD11b-enriched cells and peripheral and lamina propria T-cells from well-annotated patient samples. RESULTS: ACE2 and TMPRSS2 were abundantly expressed in the ileum and colon and had high expression in intestinal epithelial cells. In animal models, inflammation led to downregulation of epithelial Ace2. Expression of ACE2 and TMPRSS2 was not increased in samples from patients with compared with those of control patients. In CD11b-enriched cells but not T-cells, the level of expression of ACE2 and TMPRSS2 in the mucosa was comparable to other functional mucosal genes and was not affected by inflammation. Anti-tumor necrosis factor drugs, vedolizumab, ustekinumab, and steroids were linked to significantly lower expression of ACE2 in CD11b-enriched cells. CONCLUSIONS: The viral entry molecules ACE2 and TMPRSS2 are expressed in the ileum and colon. Patients with IBD do not have higher expression during inflammation; medical therapy is associated with lower levels of ACE2. These data provide reassurance for patients with IBD.


Assuntos
Regulação da Expressão Gênica , Imunossupressores/farmacologia , Síndrome do Intestino Irritável/fisiopatologia , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Adolescente , Adulto , Idoso , Animais , Betacoronavirus/metabolismo , Biópsia , Colo/efeitos dos fármacos , Colo/metabolismo , Biologia Computacional , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Imunossupressores/uso terapêutico , Inflamação/fisiopatologia , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Adulto Jovem
18.
Mutat Res ; 850-851: 503148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32247557

RESUMO

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of ß-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-ß-carboline derivatives including 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4'- amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)]. Since humans are often simultaneously exposed to ß-carbolines and aniline and o-toluidine, their effects on humans should be clarified. The most potent of these, APNH, induced both point mutations and small deletions in the liver and colon of gpt delta transgenic mice. Major APNH-induced mutations in the liver occurred at a G:C base pair, suggesting that APNH-DNA adducts (dG-C8-APNH) are potentially involved in these mutations. Furthermore, APNH induced hepatic and colon tumors harboring K-ras, ß-catenin, and Apc mutations in F344 rats, with high incidence. Mutations at G:C base pairs were predominant, similar to those in the in vivo mutation assay using gpt delta mice. Moreover, APNH detected in human urine samples obtained from both healthy volunteers on a normal diet and inpatients receiving parenteral alimentation; therefore, APNH can be considered an endogenous carcinogen contributing to tumorigenesis. Exposure levels of these aminophenyl-ß-carboline derivatives may be lower than those of carcinogenic heterocyclic amines (HCAs) including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); however, their health risks in terms of tumorigenesis may be comparable owing to stronger genotoxic effects of APNH rather than HCAs. This review summarized APNH mutagenicity/carcinogenicity, and its in vivo formation. Moreover, the effect on tumorigenesis in humans also discussed.


Assuntos
Carbolinas/química , Indóis/toxicidade , Mutagênese/efeitos dos fármacos , Piridinas/toxicidade , Toluidinas/química , Compostos de Anilina/toxicidade , Animais , Carbolinas/toxicidade , Colo/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mutação Puntual/efeitos dos fármacos , Toluidinas/toxicidade
19.
Mutat Res ; 850-851: 503147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32247562

RESUMO

Bulbus Fritillariacirrhosa D. Don (BFC) has been widely used as an herbal medicament for respiratory diseases in China for over 2000 years. The ethnomedicinal effects of BFC have been scientifically verified, nevertheless its toxicity has not been completely studied. Previously, we have reported that the aqueous extract of BFC induces mitotic aberrations and chromosomal instability (CIN) in human colon epithelial NCM460 cells via dysfunctioning the mitotic checkpoint. Here, we extend this study and specifically focus on the influence of BFC on cytokinesis, the final step of cell division. One remarkable change in NCM460 cells following BFC treatment is the high incidence of binucleated cells (BNCs). More detailed investigation of the ana-telophases reveals that furrow ingression, the first stage of cytokinesis, is inhibited by BFC. Asynchronous cultures treatment demonstrates that furrow ingression defects induced by BFCs are highly associated with the formation of BNCs in ensuing interphase, indicating the BNCs phenotype after BFC treatment was resulted from cytokinesis failure. In line with this, the expression of genes involved in the regulation of furrow ingression is significantly de-regulated by BFC (e.g., LATS-1/2 and Aurora-B are upregulated, and YB-1 is downregulated). Furthermore, long-term treatment of BFC elucidates that the BNCs phenotype is transient and the loss of BNCs is associated with increased frequency of micronuclei and nuclear buds, two biomarkers of CIN. In supporting of these findings, the Nin Jiom Pei Pa Koa and Chuanbei Pipa Gao, two commercially available Chinese traditional medicines containing BFC, are able to induce multinucleation and CIN in NCM460 cells. Altogether, these data provide the first in vitro experimental evidence linking BFC to cytokinesis failure and suggest the resultant BNCs may be intermediates to produce CIN progenies.


Assuntos
Instabilidade Cromossômica/efeitos dos fármacos , Citocinese/efeitos dos fármacos , Fritillaria/química , Extratos Vegetais/farmacologia , Aurora Quinase B/genética , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/genética , Instabilidade Cromossômica/genética , Colo/efeitos dos fármacos , Colo/patologia , Citocinese/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Extratos Vegetais/química , Raízes de Plantas/química , Proteínas Serina-Treonina Quinases/genética , Proteína 1 de Ligação a Y-Box/genética
20.
Am J Physiol Gastrointest Liver Physiol ; 318(5): G980-G987, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308039

RESUMO

Glucagon-like peptide (GLP)-1 and -2-secreting L cells have been shown to express the bile acid receptor Takeda G protein-receptor-5 (TGR5) and increase secretion upon receptor activation. Previous studies have explored GLP-1 secretion following acute TGR5 activation, but chronic activation and GLP-2 responses have not been characterized. In this study, we aimed to investigate the consequences of pharmacological TGR5 receptor activation on L cell hormone production in vivo using the specific TGR5 agonist RO5527239 and the GLP-2 receptor knockout mouse. Here, we show that 1) TGR5 receptor activation led to increased GLP-1 and GLP-2 content in the colon, which 2) was associated with an increased small intestinal weight that 3) was GLP-2 dependent. Additionally, we report that TGR5-mediated gallbladder filling occurred independently of GLP-2 signaling. In conclusion, we demonstrate that pharmacological TGR5 receptor activation stimulates L cells, triggering GLP-2-dependent intestinal adaption in mice.NEW & NOTEWORTHY Using the specific Takeda G protein-receptor-5 (TGR5) agonist RO5527239 and GLP-2 receptor knockout mice, we show that activation of TGR5 led to the increase in colonic GLP-1 and GLP-2 concomitant with a GLP-2 dependent growth response in the proximal portion of the small intestine.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Enteroendócrinas/efeitos dos fármacos , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Intestino Delgado/efeitos dos fármacos , Ácidos Isonipecóticos/farmacologia , Oximas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Colo/efeitos dos fármacos , Colo/crescimento & desenvolvimento , Colo/metabolismo , Células Enteroendócrinas/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Intestino Delgado/crescimento & desenvolvimento , Intestino Delgado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA