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1.
J Biochem Mol Toxicol ; 37(4): e23302, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36636782

RESUMO

Alcohol-induced pancreas damage remains as one of the main risk factors for pancreatitis development. This disorder is poorly understood, particularly the effect of acetaldehyde, the primary alcohol metabolite, in the endocrine pancreas. Hepatocyte growth factor (HGF) is a protective protein in many tissues, displaying antioxidant, antiapoptotic, and proliferative responses. In the present work, we were focused on characterizing the response induced by HGF and its protective mechanism in the RINm5F pancreatic cell line treated with ethanol and acetaldehyde. RINm5F cells were treated with ethanol or acetaldehyde for 12 h in the presence or not of HGF (50 ng/ml). Cells under HGF treatment decreased the content of reactive oxygen species and lipid peroxidation induced by both toxics, improving cell viability. This effect was correlated to an improvement in insulin expression impaired by ethanol and acetaldehyde. Using a specific inhibitor of Erk1/2 abrogated the effects elicited by the growth factor. In conclusion, the work provides mechanistic evidence of the HGF-induced-protective response to the alcohol-induced damage in the main cellular component of the endocrine pancreas.


Assuntos
Acetaldeído , Etanol , Acetaldeído/toxicidade , Acetaldeído/metabolismo , Linhagem Celular , Etanol/toxicidade , Fator de Crescimento de Hepatócito , Pâncreas/metabolismo , Sistema de Sinalização das MAP Quinases
2.
Cancers (Basel) ; 14(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36077755

RESUMO

Pancreatic cancer has a complex tumor microenvironment which engages in extensive crosstalk between cancer cells, cancer-associated fibroblasts, and immune cells. Many of these interactions contribute to tumor resistance to anti-cancer therapies. Here, new therapeutic strategies designed to modulate the cancer-associated fibroblast and immune compartments of pancreatic ductal adenocarcinomas are described and clinical trials of novel therapeutics are discussed. Continued advances in our understanding of the pancreatic cancer tumor microenvironment are generating stromal and immune-modulating therapeutics that may improve patient responses to anti-tumor treatment.

4.
PLoS One ; 13(12): e0209067, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30576355

RESUMO

Ginkgo biloba (EGb761) is a widely used botanical drug. Several reports indicate that EGb761 confers preventive as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate functional effects and molecular alterations induced by EGb761 in hepatoma cells and non-malignant hepatocytes. Hepatoma cell lines, primary human HCC cells and immortalized human hepatocytes (IH) were exposed to various concentrations (0-1000 µg/ml) of EGb761. Apoptosis and proliferation were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects were detected in all cell lines, EGb761 promoted anti-proliferative and pro-apoptotic effects mainly in hepatoma cells. Consistently, EGb761 treatment caused a significant reduction in colony and sphere forming ability in hepatoma cells and no mentionable changes in IH. Transcriptomic changes involved oxidative stress response as well as key oncogenic pathways resembling Nrf2- and mTOR signaling pathway. Taken together, EGb761 induces differential effects in non-transformed and cancer cells. While treatment confers protective effects in non-malignant cells, EGb761 significantly impairs tumorigenic properties in cancer cells by affecting key oncogenic pathways. Results provide the rational for clinical testing of EGb761 in preventive and therapeutic strategies in human liver diseases.


Assuntos
Carcinogênese/efeitos dos fármacos , Ginkgo biloba/química , Extratos Vegetais/farmacologia , Transcriptoma/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ginkgo biloba/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
5.
J Cell Physiol ; 233(12): 9354-9364, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29341114

RESUMO

Acute pancreatitis is a multifactorial disease associated with profound changes of the pancreas induced by release of digestive enzymes that lead to increase in proinflammatory cytokine production, excessive tissue necrosis, edema, and bleeding. Elevated levels of hepatocyte growth factor (HGF) and its receptor c-Met have been observed in different chronic and acute pancreatic diseases including experimental models of acute pancreatitis. In the present study, we investigated the protective effects induced by the recombinant human HGF in a mouse model of cerulein-induced acute pancreatitis. Pancreatitis was induced by 8 hourly administrations of supramaximal cerulein injections (50 µg/kg, ip). HGF treatment (20 µg/kg, iv), significantly attenuated lipase content and amylase activity in serum as well as the degree inflammation and edema overall leading to less severe histologic changes such as necrosis, induced by cerulein. Protective effects of HGF were associated with activation of pro-survival pathways such as Akt, Erk1/2, and Nrf2 and increase in executor survival-related proteins and decrease in pro-apoptotic proteins. In addition, ROS content and lipid peroxidation were diminished, and glutathione synthesis increased in pancreas. Systemic protection was observed by lung histology. In conclusion, our data indicate that HGF exerts an Nrf2 and glutathione-mediated protective effect on acute pancreatitis reflected by a reduction in inflammation, edema, and oxidative stress.


Assuntos
Fator de Crescimento de Hepatócito/uso terapêutico , Pancreatite/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Ceruletídeo , Modelos Animais de Doenças , Glutationa/biossíntese , Fator de Crescimento de Hepatócito/sangue , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/patologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida
6.
Oxid Med Cell Longev ; 2016: 9209825, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26788255

RESUMO

Obesity and alcohol consumption are risk factors for hepatic steatosis, and both commonly coexist. Our objective was to evaluate the effect of ethanol and acetaldehyde on primary hepatocytes obtained from mice fed for two days with a high cholesterol (HC) diet. HC hepatocytes increased lipid and cholesterol content. HC diet sensitized hepatocytes to the toxic effect of ethanol and acetaldehyde. Cyp2E1 content increased with HC diet, as well as in those treated with ethanol or acetaldehyde, while the activity of this enzyme determined in microsomes increased in the HC and in all ethanol treated hepatocytes, HC and CW. Oxidized proteins were increased in the HC cultures treated or not with the toxins. Transmission electron microscopy showed endoplasmic reticulum (ER) stress and megamitochondria in hepatocytes treated with ethanol as in HC and the ethanol HC treated hepatocytes. ER stress determined by PERK content was increased in ethanol treated hepatocytes from HC mice and CW. Nuclear translocation of ATF6 was observed in HC hepatocytes treated with ethanol, results that indicate that lipids overload and ethanol treatment favor ER stress. Oxidative stress, ER stress, and mitochondrial damage underlie potential mechanisms for increased damage in steatotic hepatocyte treated with ethanol.


Assuntos
Acetaldeído/toxicidade , Colesterol/farmacologia , Etanol/toxicidade , Hepatócitos/patologia , Animais , Forma Celular/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP2E1/metabolismo , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Lipídeos/química , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
7.
Gac Med Mex ; 151(4): 456-64, 2015.
Artigo em Espanhol | MEDLINE | ID: mdl-26290021

RESUMO

The increment in the prevalence of obesity incidence in Mexico is leading to the increase in many chronic maladies, including liver diseases. It is well known that lipid-induced liver sensitization is related to the kind of lipid rather than the amount of them in the organ. Cholesterol overload in the liver aggravates the toxic effects of canonical liver insults. However, the status on the repair and survival response elicited by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the hepatocyte growth factor (HGF) is not completely understood. In the present, work we aimed to figure out the HGF/NADPH oxidase-induced cellular protection in the hepatocyte with a cholesterol overload. Our results show that a hypercholesterolemic diet induced liver damage and steatosis in mice. The hepatocytes isolated from these animals exhibited an increase in basal NADPH oxidase activity, although transcriptional levels of some of its components were decreased. No effect on the oxidase activity was observed in HGF treatments. The protective effect of HGF was abrogated as a result of cholesterol cellular overload, calculated by a survival assay. In conclusion, the cholesterol overload in hepatocytes impairs the HGF/NADPH oxidase-induced cellular protection.


Assuntos
Colesterol/metabolismo , Fator de Crescimento de Hepatócito/fisiologia , Hepatócitos/metabolismo , NADPH Oxidases/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Food Chem Toxicol ; 69: 102-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24746671

RESUMO

Alcohol is undoubtedly, the main toxic agent that people consume by recreation and the abuse is associated with liver damage, mainly by the overproduction of reactive oxygen species and the toxic effects of its first metabolite acetaldehyde. It is known that acetaldehyde targets mitochondria inducing redox imbalance and oxidative stress. Mitochondrial superoxide dismutase transforms superoxide radical into hydrogen peroxide, which in addition, is transformed in water by other enzymes. In the present study we demonstrate that acetaldehyde transiently impairs SOD2 activity in HepG2 cells, the decrease in the enzyme activity was associated to a reduction in the protein content, which was rapidly recovered, to basal values, by synthesis de novo in a mechanism mediated by NF-κB and PKC. The SOD2 impairment was not associated with adduct formation. The recovery on SOD2 activity in HepG2 cells can represent survival advantage for cancer cells, the results shown that SOD2 could be considered a therapeutic target in liver cancer.


Assuntos
Acetaldeído/farmacologia , Células Hep G2/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Células Hep G2/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1
9.
Toxicol Sci ; 135(1): 26-36, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23764483

RESUMO

The worldwide increment of multidrug- and extensively drug-resistant tuberculosis has emphasized the importance of looking for new options in therapeutics. Long-time usage or higher doses of isoniazid and rifampicin have been considered for the treatment of multidrug-resistant tuberculosis; however, the risk of liver failure is proportionally increased. Hepatocyte growth factor (HGF) is a multitask growth factor that stimulates both antiapoptotic and antioxidant responses that counteract the toxic effects of drug metabolism in the liver. The present work was focused to address the antioxidant and antiapoptotic effects of HGF on isoniazid- and rifampicin-induced hepatotoxicity. BALB/c mice were subjected to rifampicin (150mg/kg, intragavage [ig]) plus isoniazid (75mg/kg, ig) for 7 days. Increments in alanine aminotransferase activity, steatosis, apoptosis, and oxidative stress markers were found in animals. Recombinant HGF (iv) prevented all the harmful effects by increasing the activation of Erk1/2 and PKCδ signaling pathways and glutathione (GSH) synthesis. Furthermore, inhibition of endogenous HGF with anti-HGF antibody (iv) enhanced the isoniazid- and rifampicin-induced oxidative stress damage and decreased the GSH content, aggravating liver damage. In conclusion, HGF demonstrated to be a good protective factor against antituberculosis drug-induced hepatotoxicity and could be considered a good adjuvant factor for the use of high doses of or the reintroduction of these antituberculosis drugs.


Assuntos
Antituberculosos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fator de Crescimento de Hepatócito/farmacologia , Isoniazida/toxicidade , Rifampina/toxicidade , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
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