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1.
Biomed Pharmacother ; 153: 113520, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076515

RESUMO

Oxaliplatin, a third-generation platinum derivative, has become one of the main chemotherapeutic treatments for esophagus, gastric and colorectal cancer; however, it is still unclear the potential effectiveness for pancreatic ductal adenocarcinoma (PDAC) with gemcitabine resistance. Here, we observed that PDAC tumors have low level of organic cation transporter 2 (OCT2, also known as SLC22A2) compared with non-tumor tissues and identified that OCT2 expression is positively correlated with oxaliplatin sensitivity in PDAC cells. Treatment of OCT2 inhibitors or knockdown of OCT2 expression significantly decreased the sensitivity to oxaliplatin in PANC-1 cells. In addition, bisulfite sequencing polymerase chain reaction analysis revealed that higher methylation frequency represses OCT2 expression in gemcitabine-resistant PANC-1 (PANC-1/GR) cells. Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Transportador 2 de Cátion Orgânico/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas
2.
Hum Exp Toxicol ; 40(4): 622-633, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32924602

RESUMO

Bacteroides fragilis (BF) plays a critical role in developing and maintaining the mammalian immune system. We previously found that BF colonization could prevent inflammation and tumor formation in a germ-free (GF) colitis-associated colorectal cancer (CAC) mouse model. The role of Toll-like receptor 4 (TLR4) in CAC development has not been clearly elucidated in BF mono-colonized gnotobiotic mice. The wild-type (WT) and TLR4 knockout (T4K) germ-free mice were raised with or without BF colonization for 28 days (GF/WT, GF/T4K, BF/WT, and BF/T4K) and then CAC was induced under azoxymethane (AOM)/dextran sulfate sodium (DSS) administration. The results showed that tumor formation and tumor incidence were significantly inhibited in the BF/WT group compared to those observed in the GF/WT group. However, the tumor prevention effect was not observed in the BF/T4K group unlike in the BF/WT group. Moreover, the CAC histological severity of the BF/WT group was ameliorated, but more severe lesions were found in the GF/WT, GF/T4K, and BF/T4K groups. Immunohistochemistry showed decreased cell proliferation (PCNA, ß-catenin) and inflammatory markers (iNOS) in the BF/WT group compared to those in the BF/T4K group. Taken together, BF mono-colonization of GF mice might prevent CAC via the TLR4 signal pathway.


Assuntos
Bacteroides fragilis , Neoplasias Associadas a Colite , Colite , Neoplasias Colorretais , Receptor 4 Toll-Like/genética , Animais , Azoximetano , Colite/induzido quimicamente , Colite/metabolismo , Colite/microbiologia , Colite/patologia , Neoplasias Associadas a Colite/metabolismo , Neoplasias Associadas a Colite/microbiologia , Neoplasias Associadas a Colite/patologia , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Vida Livre de Germes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , beta Catenina/metabolismo
3.
Biomed Pharmacother ; 128: 110309, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32505820

RESUMO

OBJECTIVE: Breast cancer is the second leading cause of cancer deaths in women worldwide and represents a highly aggressive nature with limited therapeutic options; thus, investigating novel therapeutic agents for breast cancer is much needed. In this study, we investigated the anticancer effects of a novel camptothecin derivative, CPT211, against human breast cancer. METHODS: We used hormone receptor-positive MCF-7, triple-negative (TNBC) MDA-MB-231, and HER2-positive BT-474 human breast cancer cells to examine cytotoxicity of CPT211. We measured cell viability with dose dependence of CPT211 treatments by an MTT assay and investigated the potential underlying mechanism through flow cytometric and Western blot methods. Furthermore, we evaluated the efficacy of the treatment combination of CPT211 and doxorubicin in a mouse model bearing MDA-MB-231 xenografts. RESULTS: CPT211 treatment led to dose-dependent decreases in cell viability of both MCF-7 and MDA-MB-231 cells, but not BT-474 cells. Analysis of the underlying molecular mechanism revealed that CPT211 activated p53-mediated apoptosis, by triggering intrinsic and extrinsic apoptotic pathways in MCF-7 cells. Additionally, CPT211 induced apoptosis and cell cycle arrest of MDA-MB-231 cells by activating Fas/FADD/caspase-8 signaling, suggesting that CPT211-mediated MDA-MB-231 cell apoptosis may occur through an extrinsic apoptosis pathway. CPT211 treatment with doxorubicin in mice bearing MDA-MB-231 xenografts was shown to enhance caspase-8 and caspase-7 activation, resulting in significant inhibition of tumor growth. CONCLUSIONS: These results indicate that Fas/FADD/caspase-8 activation plays an important role in CPT211-mediated tumor growth suppression in TNBC, and the novel camptothecin derivative, CPT211, can be exploited for specific targeted therapies and potentially improve approaches to combination treatments for human breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Camptotecina/análogos & derivados , Caspase 8/metabolismo , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor fas/metabolismo
4.
Drug Des Devel Ther ; 13: 1609-1621, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190740

RESUMO

BACKGROUND: Colorectal cancer is the third leading cause of cancer-related deaths worldwide, and therefore, the development of novel drugs for its prevention and therapy are urgently required. This study aimed to determine the molecular mechanism of 6,7-dihydroxy-2-(4'-hydroxyphenyl) naphthalene (PNAP-6)-induced cytotoxicity in human colorectal cancer (HCT116) cells. METHODS: The effects of 2-phenylnaphthalene derivatives on HCT116 cell growth and viability were assessed by MTT assays. The mechanisms involved in the regulation of the extrinsic apoptosis and endoplasmic reticulum (ER) stress pathways by PNAP-6 were analyzed by annexin-V/propidium iodide flow cytometric analysis, Hoechst 33342 fluorescent staining, and Western blotting. RESULTS: PNAP-6 was shown to have an IC50 value 15.20 µM. It induced G2/M phase arrest in HCT116 cells, associated with a marked decrease in cyclin B and CDK1 protein expression and increased caspase activation, PARP cleavage, chromatin condensation, and sub-G1 apoptosis. Moreover, we found that the apoptotic effects of PNAP-6 proceeded through extrinsic apoptosis and ER stress pathways, by increasing the expression of Fas protein and ER stress markers, including PERK, ATF4, CHOP, p-IRE1α, and XBP-1s. CONCLUSION: These results suggest that 2-phenylnaphthalene derivatives, such as PNAP-6, have potential as new treatments for colorectal cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Naftóis/farmacologia , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Naftóis/química , Relação Estrutura-Atividade
5.
Immunopharmacol Immunotoxicol ; 41(2): 207-213, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706742

RESUMO

Objective: Inflammatory bowel disease (IBD) is generally considered as a major risk factor in the progression of colitis-associated colorectal cancer (CAC). Previous studies have indicated that the composition of gut microflora may be involved in CAC induction and progress. Bacteroides fragilis (BF) is a Gram-negative anaerobe belonging to colonic symbiotic bacteria of the host. This study was aimed to investigate the protective role of BF in a colorectal cancer (CRC) model induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in germ-free (GF) mice. Materials and methods: Total 22 GF mice were divided into two groups: GF and BF group. Half of the GF mice were colonized with BF for 28 days before CRC induction by AOM/DSS. Results: BF colonization increased animal survival (100%). Cecum weight and cecum/body weight ratio significantly decreased in BF/AOM/DSS group. Interestingly, there was a significant decrease in tumor number and tumor incidence in the BF/AOM/DSS group as compared to the GF/AOM/DSS group. The adenocarcinoma/adenoma incidence and histologic score were also decreased in the BF/AOM/DSS group. In addition, immunohistochemistry staining found decreased numbers of cell proliferation (PCNA) and inflammatory cell (granulocytes) infiltration in the colon mucosa of the BF group. The ß-catenin staining in the BF/AOM/DSS group had fewer and weaker positive signal expressions. Taking together, the BF colonization significantly ameliorated AOM/DSS-induced CRC by suppressing the activity of cell proliferation-related molecules and reducing the number of inflammatory cells. Conclusions: Symbiotic BF may play a pivotal role in maintaining the gastrointestinal immunophysiologic balance and regulating anti-tumorigenesis responses.


Assuntos
Azoximetano/toxicidade , Bacteroides fragilis/imunologia , Colite , Neoplasias Colorretais , Sulfato de Dextrana/toxicidade , Vida Livre de Germes , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Masculino , Camundongos
6.
Nutrients ; 10(10)2018 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-30249003

RESUMO

The comprehensive studies done on resveratrol (RES) support that this polyphenol has multiple bioactivities and is widely accepted for dietary supplementation. Furthermore, regular exercise is known to have benefits on health and is considered as a form of preventive medicine. Although the vast majority of prior studies emphasize the efficacy of aerobic exercise in promoting physiological adaptions, other types of exercise, such as resistance exercise and high-intensity interval training (HIIT), may achieve similar or different physiological outcomes. Few studies have looked into the effectiveness of a combinational, synergistic approach to exercise using a weight-loading ladder climbing animal platform. In this study, ICR mice were allocated randomly to the RES and training groups using a two-way ANOVA (RES × Training) design. Exercise capacities, including grip strength, aerobic performance, and anaerobic performance, were assessed and the physiological adaptions were evaluated using fatigue-associated indexes that were implemented immediately after the exercise intervention. In addition, glycogen levels, muscular characteristics, and safety issues, including body composition, histopathology, and biochemistry, were further elucidated. Synergistic effects were observed on grip strength, anaerobic capacities, and exercise lactate, with significant interaction effects. Moreover, the training or RES may have contributed significantly to elevating aerobic capacity, tissue glycogen, and muscle hypertrophy. Toxic and other deleterious effects were also considered to evaluate the safety of the intervention. Resistance exercise in combination with resveratrol supplementation may be applied in the general population to achieve better physiological benefits, promote overall health, and promote participation in regular physical activities.


Assuntos
Adaptação Fisiológica , Substâncias para Melhoria do Desempenho/farmacologia , Condicionamento Físico Animal/fisiologia , Extratos Vegetais/farmacologia , Treinamento Resistido , Resveratrol/farmacologia , Adaptação Fisiológica/efeitos dos fármacos , Limiar Anaeróbio , Análise de Variância , Animais , Composição Corporal , Fadiga , Glicogênio/metabolismo , Força da Mão , Hipertrofia , Ácido Láctico/sangue , Masculino , Camundongos Endogâmicos ICR , Músculo Esquelético/efeitos dos fármacos , Distribuição Aleatória
7.
Nutrients ; 9(11)2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-29113135

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a serious liver disorder associated with the accumulation of fat and inflammation. The objective of this study was to determine the gut microbiota composition that might influence the progression of NAFLD. Germ-free mice were inoculated with feces from patients with nonalcoholic steatohepatitis (NASH) or from healthy persons (HL) and then fed a standard diet (STD) or high-fat diet (HFD). We found that the epididymal fat weight, hepatic steatosis, multifocal necrosis, and inflammatory cell infiltration significantly increased in the NASH-HFD group. These findings were consistent with markedly elevated serum levels of alanine transaminase, aspartate transaminase, endotoxin, interleukin 6 (IL-6), monocyte chemotactic protein 1 (Mcp1), and hepatic triglycerides. In addition, the mRNA expression levels of Toll-like receptor 2 (Tlr2), Toll-like receptor 4 (Tlr4), tumor necrosis factor alpha (Tnf-α), Mcp1, and peroxisome proliferator-activated receptor gamma (Ppar-γ) significantly increased. Only abundant lipid accumulation and a few inflammatory reactions were observed in group HL-HFD. Relative abundance of Bacteroidetes and Firmicutes shifted in the HFD-fed mice. Furthermore, the relative abundance of Streptococcaceae was the highest in group NASH-HFD. Nevertheless, obesity-related Lactobacillaceae were significantly upregulated in HL-HFD mice. Our results revealed that the gut microbiota from NASH Patients aggravated hepatic steatosis and inflammation. These findings might partially explain the NAFLD progress distinctly was related to different compositions of gut microbiota.


Assuntos
Dieta Hiperlipídica , Microbioma Gastrointestinal , Vida Livre de Germes , Hepatopatia Gordurosa não Alcoólica/microbiologia , Tecido Adiposo , Animais , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Biochem Biophys Res Commun ; 493(2): 1075-1081, 2017 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-28923247

RESUMO

Different edible oils such as lard and soybean oil have been reported to interact with the gut microbiota, affecting host lipid metabolism. However, whether bacteria derived from the environment influence host lipid metabolism remains unclear. This study aimed to clarify the roles of environmental bacteria in host lipid storage and distribution with various edible oils. Gnotobiotic C57BL/6JNarl mice were inoculated with Lysinibacillus xylanilyticus and Paenibacillus azoreducens and then fed either a normal diet (LabDiet 5010, control group) or a diet containing 60% lard (L-group) or soybean oil (S-group) for 18 months. Interestingly, the S-group accumulated massive amounts of white adipose tissue compared to the L- and control groups, while the L-group displayed more hepatic steatosis and fatty droplets than the other groups. The expression of fatty acid synthase (FAS), hydroxymethylglutaryl-coenzyme A reductase (HMGCR), sterol regulatory element-binding protein 2 (SREBP2), and peroxisome proliferator-activated receptor gamma (PPARγ) in the livers of the L-group were markedly elevated compared to the S-group. FAS and PPARγ protein levels were also markedly elevated. However, there were no differences in the expression of the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α between the groups. Our results suggest that environmental bacteria may affect host hepatic inflammation and lipid distribution in the presence of high-fat diets, with different effects depending on the fat type consumed.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/microbiologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/microbiologia , Animais , Bacillaceae/fisiologia , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/metabolismo , Fígado Gorduroso/patologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Paenibacillus/fisiologia , Óleo de Soja/efeitos adversos , Óleo de Soja/metabolismo
9.
Invest Ophthalmol Vis Sci ; 58(10): 4332­4343, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28806447

RESUMO

Purpose: To investigate the effects of homocysteine on choroidal angiogenesis, we established an ex vivo choroidal sprouting explant model and examined the potential growth factors for angiogenesis. Methods: Choroid fragments with retinal pigment epithelium were isolated from mouse and embedded in Matrigel. Homocysteine at different concentrations were added to the culture mediums. The choroidal explants were observed at different time points, and the total area of choroidal sprouting was measured and analyzed. Results: Homocysteine evoked choroidal capillary sprouting by inducing capillary endothelial cell proliferation with pericyte formation and by facilitating polygonal angiogenetic networks. In some cases, vascular lumens were observed in the newly forming capillaries facilitated by homocysteine. The choroidal sprouting effect of homocysteine can only be observed at a certain range of homocysteine concentration, with 1-mM homocysteine exhibiting the most significantly increased choroidal sprouting areas. Isolectin overexpression was noted in the homocysteine-treated group. Possible growth factors for angiogenesis were detected through immunofluorescent staining, which demonstrated the overexpression of platelet-derived growth factor C and angiopoietin 1 in the homocysteine-treated preparations only. In these preparations, platelet-derived growth factor C was highly expressed in the tip cells of sprouting capillaries. Conclusions: We therefore conclude that platelet-derived growth factor C and angiopoietin 1 may play key roles in the choroid angiogenesis evoked by homocysteine.


Assuntos
Indutores da Angiogênese/farmacologia , Proliferação de Células/fisiologia , Corioide/irrigação sanguínea , Endotélio Vascular/citologia , Homocisteína/farmacologia , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Angiopoietina-1/metabolismo , Animais , Capilares/fisiologia , Colágeno , Combinação de Medicamentos , Endotélio Vascular/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Laminina , Linfocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteoglicanas , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
PLoS One ; 12(7): e0180025, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28683149

RESUMO

BACKGROUND AND AIMS: Bacteroides fragilis (BF) are Gram-negative anaerobe symbionts present in the colon. Recent studies have reported the beneficial role of BF in maintaining intestinal homeostasis, stimulating host immunologic development, and preventing infectious colitis caused by pathogenic bacteria. Our previous studies showed that monocolonization of germ-free mice with BF significantly reduced colon inflammations and damage. METHODS: In order to investigate the Toll-like receptor-2 (TLR2), TLR4, and interleukin 10 (IL-10) molecular signaling pathways involved in BF-mediated prevention of dextran sulfate sodium (DSS)-induced colitis. The wild-type (WT), TLR4, TLR2, and IL-10 knockout (-/-) germ-free mice grown were with or without BF colonization for 28 days, and then administered 1% DSS in drinking water for 7 day to induce acute ulcerative colitis. RESULTS: We compared phenotypes such as weight loss, disease activity, intestinal histological scores, and immunohistochemistry for inflammatory cells. Unlike WT and TLR4-/- mice, the severity of DSS-colitis did not improve in TLR2-/- animals after BF colonization. The BF enhanced anti-inflammatory cytokines IL-10 expression and inhibited pro-inflammatory-related tumor necrosis factor (TNF-α) and IL-6 mRNA expression in both WT and TLR4-/- mice. In contrast, the failed to up-regulated IL-10 and down-regulated the TNF-α and IL-6 in BF colonization TLR2-/- mice. In addition, we further perform IL-10-/- mice to clarify whether the BF through TLR2 /IL-10 pathway to alleviate DSS-colitis. There were no significant differences in colitis severity and pro-inflammatory related genes expression in the IL-10-/- mice with or without BF colonization. CONCLUSIONS: These results indicate the disease-preventing effects of BF in acute DSS-induced colitis may occur through the TLR2/IL-10 signal pathway.


Assuntos
Bacteroides fragilis/imunologia , Colite/imunologia , Interleucina-10/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Sulfato de Dextrana , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Vida Livre de Germes , Interleucina-10/deficiência , Interleucina-10/genética , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais , Simbiose/imunologia , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
Nutrients ; 8(10)2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27775591

RESUMO

Chili pepper is used as a food, seasoning and has been revered for its medicinal and health claims. It is very popular and is the most common spice worldwide. Capsaicin (CAP) is a major pungent and bioactive phytochemical in chili peppers. CAP has been shown to improve mitochondrial biogenesis and adenosine triphosphate (ATP) production. However, there is limited evidence around the effects of CAP on physical fatigue and exercise performance. The purpose of this study was to evaluate the potential beneficial effects of CAP on anti-fatigue and ergogenic functions following physiological challenge. Female Institute of Cancer Research (ICR) mice from four groups (n = 8 per group) were orally administered CAP for 4 weeks at 0, 205, 410, and 1025 mg/kg/day, which were respectively designated the vehicle, CAP-1X, CAP-2X, and CAP-5X groups. The anti-fatigue activity and exercise performance was evaluated using forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, BUN (blood urea nitrogen) and creatine kinase (CK) after a 15-min swimming exercise. The grip strength and exhaustive swimming time of the CAP-5X group were significantly higher than other groups. CAP supplementation dose-dependently reduced serum lactate, ammonia, BUN and CK levels, and increased glucose concentration after the 15-min swimming test. In addition, CAP also increased hepatic glycogen content, an important energy source for exercise. The possible mechanism was relevant to energy homeostasis and the physiological modulations by CAP supplementation. Therefore, our results suggest that CAP supplementation may have a wide spectrum of bioactivities for promoting health, performance improvement and fatigue amelioration.


Assuntos
Capsaicina/administração & dosagem , Suplementos Nutricionais , Exercício Físico/fisiologia , Fadiga Muscular/efeitos dos fármacos , Resistência Física/efeitos dos fármacos , Fármacos do Sistema Sensorial/administração & dosagem , Amônia/sangue , Animais , Glicemia/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Capsaicina/farmacologia , Capsicum/química , Creatina Quinase/sangue , Feminino , Glicogênio/metabolismo , Humanos , Ácido Láctico/sangue , Fígado/metabolismo , Camundongos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Condicionamento Físico Animal/métodos , Fármacos do Sistema Sensorial/farmacologia , Natação/fisiologia
12.
Biomed Res Int ; 2014: 675786, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24971344

RESUMO

Ulcerative colitis is inflammatory conditions of the colon caused by interplay of genetic and environmental factors. Previous studies indicated that the gut microflora may be involved in the colonic inflammation. Bacteroides fragilis (BF) is a Gram-negative anaerobe belonging to the colonic symbiotic. We aimed to investigate the protective role of BF in a colitis model induced in germ-free (GF) mice by dextran sulfate sodium (DSS). GF C57BL/6JNarl mice were colonized with BF for 28 days before acute colitis was induced by DSS. BF colonization significantly increased animal survival by 40%, with less reduction in colon length, and decreased infiltration of inflammatory cells (macrophages and neutrophils) in colon mucosa following challenge with DSS. In addition, BF could enhance the mRNA expression of anti-inflammatory-related cytokine such as interleukin 10 (IL-10) with polymorphism cytokine IL-17 and diminish that of proinflammatory-related tumor necrosis factor α with inducible nitric oxide synthase in the ulcerated colon. Myeloperoxidase activity was also decreased in BF-DSS mice. Taking these together, the BF colonization significantly ameliorated DSS-induced colitis by suppressing the activity of inflammatory-related molecules and inducing the production of anti-inflammatory cytokines. BF may play an important role in maintaining intestinal immune system homeostasis and regulate inflammatory responses.


Assuntos
Bacteroides fragilis/crescimento & desenvolvimento , Colite/microbiologia , Colite/prevenção & controle , Vida Livre de Germes , Doença Aguda , Animais , Contagem de Células Sanguíneas , Colite/sangue , Colite/patologia , Colo/metabolismo , Colo/patologia , Contagem de Colônia Microbiana , Sulfato de Dextrana , Regulação da Expressão Gênica , Inflamação/patologia , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
13.
Med Sci Sports Exerc ; 46(8): 1517-24, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24504433

RESUMO

PURPOSE: The objective of this study is to verify the beneficial effects of whey protein (WP) supplementation on health promotion and enhance exercise performance in an aerobic-exercise training protocol. METHODS: In total, 40 male Institute of Cancer Research mice (4 wk old) were divided into four groups (n = 10 per group): sedentary control with vehicle (SC) or WP supplementation (4.1 g·kg, SC + WP), and exercise training with vehicle (ET) or WP supplementation (4.1 g·kg, ET + WP). Animals in the ET and ET + WP groups underwent swimming endurance training for 6 wk, 5 d·wk. Exercise performance was evaluated by forelimb grip strength and exhaustive swimming time as well as by changes in body composition and biochemical parameters at the end of the experiment. RESULTS: ET significantly decreased final body and muscle weight and levels of albumin, total protein, blood urea nitrogen, creatinine, total cholesterol, and triacylglycerol. ET significantly increased grip strength; relative weight (%) of liver, heart, and brown adipose tissue (BAT); and levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase, and total bilirubin. WP supplementation significantly decreased final body, muscle, liver, BAT, and kidney weight and relative weight (%) of muscle, liver, and BAT as well as levels of aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and uric acid. In addition, WP supplementation slightly increased endurance time and significantly increased grip strength and levels of albumin and total protein. CONCLUSION: WP supplementation improved exercise performance, body composition, and biochemical assessments in mice and may be an effective ergogenic aid in aerobic exercise training.


Assuntos
Suplementos Nutricionais , Proteínas do Leite/administração & dosagem , Condicionamento Físico Animal/fisiologia , Resistência Física/fisiologia , Animais , Biomarcadores/sangue , Composição Corporal , Peso Corporal , Masculino , Camundongos , Força Muscular/fisiologia , Tamanho do Órgão , Distribuição Aleatória , Natação/fisiologia , Proteínas do Soro do Leite
14.
Immunopharmacol Immunotoxicol ; 35(2): 296-303, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23384342

RESUMO

CONTEXT: Liver injury can be induced by various hepatotoxicants, including Pseudomonas aeruginosa exotoxin A (PEA). Our previous study indicated that PEA-induced rat hepatotoxicity was T cells and Kupffer cells dependent. Several reports have demonstrated that non-toxic doses of bacterial lipopolysaccharide (LPS) can protect liver against the chemicals-induced toxicity such as acetaminophen and concanavalin-A. OBJECTIVE: This study aimed to investigate the protecting mechanisms of LPS on PEA-induced hepatotoxicity. RESULTS: Rats pretreated with LPS (40 µg/kg, 12 h before PEA admission) significantly decreased animal mortality, serum enzyme (ALT, AST and T-bil) activities, histopathological changes and hepatocytes apoptosis following challenge with PEA. The concentrations of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-2 (IL-2) were reduced, but IL-6 and IL-10 were increased in the serum. In addition, prior treatment of these LPS-pretreated rats with gadolinium chloride (GdCl3), a selective Kupffer cell depletion agent, markedly enhanced liver injury after PEA administration. In contrast, the pretreatment of LPS to T-cell deficient athymic nude rats still display significant attenuation of PEA-induced liver injury. This observation further confirmed our hypothesis that LPS ameliorate PEA-hepatotoxicity was through Kupffer cells but not T cells. Moreover, LPS-induced hepatoprotection ability was neutralized by co-treatment with anti-TNF-α antibodies, but not with anti-IFN-γ antibodies. Finally, replacement of LPS with RS-LPS (Rhodobacter sphaeroides LPS), a Toll like receptor-4 (TLR-4) antagonist, resulted in severe hepatotoxicity. CONCLUSION: These results suggested that Kupffer cells, TNF-α and TLR-4 play central mediator roles during the hepatoprotection against PEA-induced hepatotoxicity conferred by LPS.


Assuntos
ADP Ribose Transferases/antagonistas & inibidores , ADP Ribose Transferases/toxicidade , Toxinas Bacterianas/antagonistas & inibidores , Toxinas Bacterianas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Exotoxinas/antagonistas & inibidores , Exotoxinas/toxicidade , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fatores de Virulência/antagonistas & inibidores , Fatores de Virulência/toxicidade , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Interações Medicamentosas , Gadolínio/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Interferon gama/metabolismo , Interleucinas/metabolismo , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Fígado/enzimologia , Masculino , Pseudomonas/metabolismo , Ratos , Ratos Nus , Ratos Wistar , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Exotoxina A de Pseudomonas aeruginosa
15.
J Vet Med Sci ; 71(2): 163-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19262026

RESUMO

Epidemiological investigations suggest that increased age is associated with susceptibility to infection. Pseudomonas aeruginosa (P. aeruginosa) infection and associated exotoxin A (PEA) toxicity have been reported in hospitalized elderly patients and young children with cystic fibrosis. The present study investigated age-related differences in PEA-induced hepatotoxicity in post weaning (PW, 3 weeks), young adult (YA, 12 weeks), and mature adult (MA, 60-64 weeks) rats. PEA (20 microg/kg) was injected intraveneously and mortality, clinical chemistry, hepatic histopathology, TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling) and PCNA (Proliferating cell nuclear antigen) staining, and serum cytokine levels were assessed at specific time points, up to 72 hr post-exposure (HPE). Mortality in MA rats was 100% at less than 48 HPE. Serum ALT levels in MA rats were approximately 5-fold greater than levels in PW and YA rats at 36 HPE. MA rat liver histological sections showed diffuse hepatocellular necrosis. In contrast, hepatocellular apoptosis, demonstrable by the TUNEL method, was noted simply in the periportal and midzonal regions from 36 to 48 HPE. Increased morphological mitoses and PCNA-positive hepatocytes were seen in PW and YA rats at 72 HPE. These parameters were correlated with age-dependent significant increases in TNF-alpha, IL-2, IL-6, and IL-18 levels. These data suggest that inflammatory cytokines play an important role in age-related differences in PEA-induced hepatotoxicity. Moreover, these cytokines might correlate with different patterns histopathologic features at various ages.


Assuntos
ADP Ribose Transferases/toxicidade , Toxinas Bacterianas/toxicidade , Citocinas/análise , Exotoxinas/toxicidade , Marcação In Situ das Extremidades Cortadas/métodos , Fígado/efeitos dos fármacos , Fatores de Virulência/toxicidade , ADP Ribose Transferases/administração & dosagem , ADP Ribose Transferases/metabolismo , Fatores Etários , Análise de Variância , Animais , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/metabolismo , Modelos Animais de Doenças , Exotoxinas/administração & dosagem , Exotoxinas/metabolismo , Marcação In Situ das Extremidades Cortadas/veterinária , Injeções Intravenosas , Estimativa de Kaplan-Meier , Fígado/patologia , Masculino , Antígeno Nuclear de Célula em Proliferação , Infecções por Pseudomonas/metabolismo , Ratos , Ratos Long-Evans , Fatores de Virulência/administração & dosagem , Fatores de Virulência/metabolismo , Exotoxina A de Pseudomonas aeruginosa
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