RESUMO
Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Neoplasias Hepáticas/patologia , Ácido Fólico/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Microambiente TumoralRESUMO
Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor-suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor-suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma-derived cell lines were exposed to GDF11 (50 ng/ml), RNA-seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum-related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real-time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Carcinoma Hepatocelular/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Lipogênese , Neoplasias Hepáticas/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Glicólise , Humanos , Neoplasias Hepáticas/patologia , Consumo de Oxigênio , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
INTRODUCTION AND AIM: Obesity is a worldwide epidemic problem, described as a risk factor for hepatic diseases, such as non-alcoholic fatty liver disease and other pathologies related to development of cholesterol crystals and cholesterol gallbladder stones. It has been reported that cholesterol overload may cause hepatic damage; however, little is known about the effects of an acute hypercholesterolemic diet on the gallbladder. The aim of this manuscript was to evaluate the impact of a cholesterol-rich diet on the gallbladder. MATERIAL AND METHODS: The study included ten eight-week-old C57BL6 male mice, which were divided into two study groups and fed different diets for 48 h: a hypercholesterolemic diet and a balanced Chow diet. After 48 h, the mice were analyzed by US with a Siemens Acuson Antares equipment. Mice were subsequently sacrificed to carry out a cholesterol analysis with a Refloton System (Roche), a crystal analysis with a Carl Zeiss microscope with polarized light, and a histological analysis with Hematoxylin-eosin staining. RESULTS: The hypercholesterolemic diet induced an increase in gallbladder size and total cholesterol content in the bile, along with important histological changes. CONCLUSION: Cholesterol overloads not only trigger hepatic damage, but also affect the gallbladder significantly.
Assuntos
Colesterol na Dieta , Vesícula Biliar , Cálculos Biliares/etiologia , Hipercolesterolemia/etiologia , Ultrassonografia , Animais , Bile/metabolismo , Colesterol na Dieta/sangue , Cristalização , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/metabolismo , Vesícula Biliar/patologia , Cálculos Biliares/sangue , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/patologia , Hipercolesterolemia/sangue , Masculino , Camundongos Endogâmicos C57BL , Microscopia de Polarização , Fatores de TempoRESUMO
Hepatitis C virus (HCV) replication is associated with the endoplasmic reticulum, where the virus can induce cellular stress. Oxidative cell damage plays an important role in HCV physiopathology. Oxidative stress is triggered when the concentration of oxygen species in the extracellular or intracellular environment exceeds antioxidant defenses. Cells are protected and modulate oxidative stress through the interplay of intracellular antioxidant agents, mainly glutathione system (GSH) and thioredoxin; and antioxidant enzyme systems such as superoxide dismutase, catalase, GSH peroxidase, and heme oxygenase-1. Also, the use of natural and synthetic antioxidants (vitamin C and E, N-acetylcysteine, glycyrrhizin, polyenylphosphatidyl choline, mitoquinone, quercetin, S-adenosylmethionine and silymarin) has already shown promising results as co-adjuvants in HCV therapy. Despite all the available information, it is not known how different agents with antiviral activity can interfere with the modulation of the cell redox state induced by HCV and decrease viral replication. This review describes an evidence-based consensus on molecular mechanisms involved in HCV replication and their relationship with cell damage induced by oxidative stress generated by the virus itself and cell antiviral machinery. It also describes some molecules that modify the levels of oxidative stress in HCV-infected cells.
RESUMO
BACKGROUND: The evolving pattern of HCV genotypes (GTs) and risk factors (RFs) in HCV-infected patients in Mexico is poorly understood. This study aimed to access the temporal trend of HCV GTs and RFs in HCV patients from two care centers. MATERIAL AND METHODS: Chronic HCV patients [177 and 153 patients from the Northeast (NE) and Central West (CW) regions, respectively] were selected. Baseline features were demographics, date of birth (DOB), blood transfusion before 1992 (BTb1992), RFs, sexual promiscuity (SP), dental procedure (DP), injection drug use (IDU), viral load (VL), GTs, cirrhosis status and antiviral therapy (AT). Data were analyzed by Chi-square test for trends, unpaired T-test, and logistic regression. RESULTS: HCV GT distribution was: GT1, 67%; GT2, 16%; GT3, 12% and GT4, 1%. RFs were BTb1992, 56%; surgeries, 56%; tattooing, 18% and IDU, 16%. GT1a mostly prevailed in CW than NE patients. GT1b, surgeries, BTb1992 and cirrhosis were more prevalent in older patients (p < 0.05); GT3, male gender IDU, SP, and tattooing showed an upward trend as younger were the patients in both regions (p < 0.05), contrariwise to the prevalence of GT1b. BTb1992 and surgeries were seen in elder women; BTb1992 was an independent RF for GT1. Age ≥ 50 years old, GT1 and exposure to AT (p < 0.05) were associated with cirrhosis. CONCLUSION: GT1a prevalence in CW Mexico remained stable, whereas GT3 increased and GT1b decreased in younger patients in both regions, along with associated RFs. Further regional molecular epidemiology and RF analyses are required in order to avoid the dissemination of new cases of HCV infection.
Assuntos
Hepacivirus/genética , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/virologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Fatores Etários , Antivirais/uso terapêutico , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/transmissão , Humanos , Cirrose Hepática/epidemiologia , Cirrose Hepática/virologia , Modelos Logísticos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Epidemiologia Molecular , Razão de Chances , Fenótipo , Prevalência , Características de Residência , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Tatuagem/efeitos adversos , Fatores de Tempo , Reação Transfusional , Sexo sem Proteção , Carga ViralRESUMO
Longevity is a complex and dynamic process influenced by a diversity of factors. Amongst other, gestation and lactation contribute to organismal decline because they represent a great energetic investment in mammals. Here we compared the rate of senescence onset observed in primary fibroblast obtained from the lungs of retired female breeder mice (12 months old), with the senescence arrival observed in fibroblasts derived from age-matched nulliparous mice. Two-month-old animals were also used as controls of young, fully-developed adults. Cell proliferation, DNA synthesis, and expression of senescence-associated beta-galactosidase activity were evaluated as senescent parameters. In order to test differences in energetic competence at a systemic level, mitochondrial respiration was also evaluated in mitochondria isolated from the livers of the same animals used for the primary cultures. Our data indicated that the cells derived from female mice subjected to the physiological stress of breeding onset into replicative senescence prior than the cells from female mice age-matched without that particular stress. Thus validating the use of retired breeders as a model to study aging and senescence at the cellular level.
Assuntos
Envelhecimento/fisiologia , Cruzamento , Pulmão/citologia , Pulmão/fisiologia , Animais , Proliferação de Células , Respiração Celular , Senescência Celular , DNA/biossíntese , Feminino , Fibroblastos/fisiologia , Camundongos , Camundongos Endogâmicos , Mitocôndrias Hepáticas/metabolismo , Consumo de Oxigênio , Gravidez , Estresse Fisiológico , Timidina/metabolismo , beta-Galactosidase/metabolismoRESUMO
Senescent phenotype can be attained by diverse agents, thus suggesting that there might be molecular differences between the senescence achieved in vivo and the senescence-like state attained in vitro under culture conditions. In this study we compare the senescent phenotype reached by cells derived from young animals when cultured in vitro with the one associated with the in vivo aging process. Several in vitro senescence parameters, including MTT reduction, proliferation rate, DNA synthesis, SA-beta-gal staining, and both in vivo and in vitro Bcl-2 content, were determined. Alterations in DNA electrophoretic mobility were evaluated to test differences in bulk chromatin structure. Our results indicate that although it is possible to achieve a senescent phenotype with cells derived from young animals aged in culture, this phenotype differs from the one observed in older animals, due to lack of in vivo damage inducers to which cells are being exposed during natural aging.