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1.
J Hepatol ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34555423

RESUMO

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to nonalcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing a liver proteomic analysis from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples of patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the liver of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and NASH) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoiltransferase I (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. LAY SUMMARY: We show that autophagy-related gene 3 (ATG3) contributes to the progression of NAFLD in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD, by stimulating SIRT1, CPT1a and mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis.

2.
Rev Esp Enferm Dig ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34470450

RESUMO

BACKGROUND: The impact of the COVID-19 outbreak and lockdown in liver transplant (LT) patients remains unknown. The aim of this cross-sectional study was to assess the consequences of the COVID-19 pandemic on the physical and mental health of LT patients during the lockdown period. METHODS: Between August and October 2020 a Web-based questionnaire was emailed to 238 LT patients undergoing regular follow-up at our unit. This pseudonymized survey explored demographic and lifestyle variables (i.e. eating and physical habits), disruptions in routine medical care, and different dimensions of mental health, COVID-19-related mood and coping (worries/anxiety, depression, insomnia, fear of Covid, resilience, etc.), and health perception using different validated instruments. RESULTS: 48.7% (116 of 238) LT recipients accepted to participate, 104 of whom gave their consent to publish the data. The median age was 63 years. Up to 39.4% presented worrying scores indicating moderate/severe generalized anxiety disorder (GAD), whereas 25.5% exhibited moderate/severe insomnia and only 10.5% moderate/severe depression. Forty patients (38.5%) gained weight, 24% experienced a worsening in their eating habits and 63.4% referred to practice less or much less exercise during the lockdown. Only 25% perceived a worsening in the control of their chronic comorbidities. Missed medical appointments (0.9%) or worsening adherence to therapy (1.9%) were exceptional. CONCLUSIONS: COVID-19 lockdown has negatively impacted the mental and physical health of LT patients. Long-term consequences remain unclear.

3.
Environ Res ; 203: 111788, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34339692

RESUMO

This work investigates the impact of COVID-19 restrictive measures on the mass concentrations of PM1 and PM10, and their chemical components (water-soluble ions, organic and elemental carbon, and major and trace metals) at an urban site in the western Mediterranean. The evolution of gaseous pollutants (NOx, O3 and some volatile organic compounds) was also analyzed. The concentrations measured during the lockdown in 2020 were compared to those obtained during the same period over the preceding five years. The average decrease in the levels of NOx and traffic-related volatile organic compounds was higher than 50 %, while O3 concentrations did not exhibit significant variations during the study period. Our results show that temporal variations in PM1 and PM10 concentrations were strongly affected by the frequency of Saharan dust events. When these episodes were excluded from the analysis period, a 35 % decrease in PM1 and PM10 levels was observed. Traffic restrictions during the lockdown led to important reductions in the concentrations of elemental carbon and metals derived from road dust (e.g. Ca and Fe) and break wear (e.g. Cu). Regarding secondary inorganic aerosols, nitrate showed the largest reductions as a consequence of the drop in local emissions of NOx.

4.
Hepatol Res ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34324766

RESUMO

AIM: Non-malignant portal vein thrombosis (PVT) is a complication of liver cirrhosis. The aim of this study was to evaluate the annual incidence of PVT and related risk factors. METHODS: We retrospectively reviewed clinical, laboratory, and radiological data collected prospectively from September 2016 to September 2017. A follow-up of 36 months was performed in a subset of patients to determine the cumulative incidence of PVT and related complications. RESULTS: The study included 567 patients. The incidence of PVT at 12, 24, and 36 months was 3.7%, 0.8%, and 1.4%, respectively. Patients with PVT were compared with patients without PVT, and showed differences in albumin (p = 0.04), aspartate aminotransferase (p = 0.04), hemoglobin (p = 0.01), and prothrombin activity (p = 0.01). The presence of hydropic decompensation (57.1% vs. 30.1%; p 0.004), gastroesophageal varices (76.2% vs. 39.5%; p = 0.05), variceal bleeding (52.4% vs. 22.7%; p < 0.001), hepatic encephalopathy (38.1% vs. 9.9%; p = 0.01), spontaneous bacterial peritonitis (9.5% vs. 1.7%; p < 0.001), and use of beta-blockers (71.4% vs. 27.7%; p < 0.001) were significantly associated. In the multivariate analysis, use of beta-blockers and hepatic encephalopathy appeared as risk factors, and high albumin levels a protective factor. CONCLUSIONS: The incidence of PVT was 3.7%. Beta-blockers and hepatic encephalopathy were risks factors. High albumin levels were a protective factor.

5.
J Cell Mol Med ; 25(16): 7935-7947, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34288375

RESUMO

Microvesicles (MV) contribute to cell-to-cell communication through their transported proteins and nucleic acids. MV, released into the extracellular space, exert paracrine regulation by modulating cellular responses after interaction with near and far target cells. MV are released at high concentrations by activated inflammatory cells. Different subtypes of human macrophages have been characterized based on surface epitopes being CD16+ macrophages associated with anti-inflammatory phenotypes. We have previously shown that low-density lipoprotein receptor-related protein 5 (LRP5), a member of the LDLR family that participates in lipid homeostasis, is expressed in macrophage CD16+ with repair and survival functions. The goal of our study was to characterize the cargo and tentative function of macrophage-derived MV, whether LRP5 is delivered into MV and whether these MV are able to induce inflammatory cell differentiation to a specific CD16- or CD16+ phenotype. We show, for the first time, that lipid-loaded macrophages release MV containing LRP5. LDL loading induces increased expression of macrophage pro-inflammatory markers and increased release of MV containing pro-inflammatory markers. Conditioning of fresh macrophages with MV released by Lrp5-silenced macrophages induced the transcription of inflammatory genes and reduced the transcription of anti-inflammatory genes. Thus, MV containing LRP5 induce anti-inflammatory phenotypes in macrophages.

7.
Mol Metab ; 53: 101275, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34153521

RESUMO

OBJECTIVE: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. METHODS: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. RESULTS: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models CONCLUSIONS: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.

8.
United European Gastroenterol J ; 9(8): 892-902, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34077628

RESUMO

BACKGROUND AND AIMS: Transient elastography (TE) to estimate liver stiffness has proved to be very useful in the diagnosis of chronic liver disease. Here, we intend to evaluate its use in a large Spanish cohort. METHOD: Nested study within the PREVHEP-ETHON (Epidemiological sTudy of Hepatic infectiONs; NCT02749864) population-based, cross-sectional study performed between July 2015 and April 2017. An epidemiological questionnaire, laboratory tests and TE and anthropometric measurements were obtained. RESULTS: Data from 11,440 subjects were analyzed. Mean age was 50.3 (SD 12.4), of which 58.1% were women. 15.4% showed metabolic syndrome (NCEP ATP-III), 1.3% were positive for hepatitis C antibodies, 0.8% positive for HBsAg, 9.1% reported harmful use of alcohol. The prevalence of significant fibrosis (LSM > 8 kPa), suggestive compensated advanced chronic liver disease (cACLD) (LSM ≥ 10 kPa) and highly suggestive cACLD (LSM > 15 kPa) was 5.6%, 2.9%, and 1.2% respectively. Risk factors associated with significant fibrosis were age (OR 1.03 [1.02-1.04; p < 0.001]), sex (OR 0.8 [0.6-0.95; p = 0.02]), AST (OR 1.01 [1.01-1.02; p < 0.001]), GGT (OR 1.005 [1.003-1.006; p < 0.001]) and metabolic syndrome (OR 2.1 [1.7-2.6; p < 0.001]); risk factors associated with suggestive cACLD were age (OR 1.04 [1.02-1.05; p < 0.001]), AST (OR 1.01 [1.01-1.02; p < 0.001]), GGT (OR 1.006 [1.004-1.008; p < 0.001]), low platelets (OR 0.997 [0.994-0.999; p = 0.02]) and metabolic syndrome (OR 2.2 [1.6-2.9; p < 0.001]); and risk factors associated with highly suggestive cACLD were age (OR 1.04 [1.02-1.06; p = 0.001]), AST (OR 1.02 [1.01-1.03; p < 0.001]), GGT (OR 1.005 [1.003-1.007; p < 0.001]), low platelets (OR 0.993 [0.989-0.997; p < 0.001]), metabolic syndrome (OR 2.1 [1.4-3.3; p = 0.001]) and alcohol consumption (OR 1.8 [1.05-3.1; p = 0.03]). A non-negligible proportion of patients with normal transaminase levels, even with healthy transaminase levels, showed significant fibrosis and suggestive and highly suggestive cACLD 4.6% (95% CI 2.4-3.0), 2.1% (95% CI 1.9-2.5) and 1% (95% CI 0.7-1.1), respectively. CONCLUSION: We found high proportion of significant fibrosis and cACLD measured by TE. The most relevant factor associated with significant fibrosis was metabolic syndrome, however TE is still an imperfect method since it overestimated the fibrosis stage in 50% of the histologically analyzed subjects.

9.
Sci Rep ; 11(1): 9819, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972607

RESUMO

The simplicity and low cost of rapid point-of-care tests greatly facilitate large-scale population testing, which can contribute to controlling the spread of the COVID-19 virus. We evaluated the applicability of a self-testing strategy for SARS-CoV2 in a population-based, cross-sectional study in Cantabria, Spain, between April and May 2020. For the self-testing strategy, participants received the necessary material for the self-collection of blood and performance of a rapid antibody test using lateral flow immunoassay at home without the supervision of healthcare personnel. A total of 1,022 participants were enrolled. Most participants correctly performed the COVID-19 self-test the first time (91.3% [95% CI 89.4-92.9]). Only a minority of the participants (0.7%) needed the help of healthcare personnel, while 6.9% required a second kit delivery, for a total valid test result in 96.9% of the participants. Incorrect use of the self-test was not associated with the educational level, age over 65, or housing area. Prevalence of IgG antibodies against SARS-CoV2 for subjects with a valid rapid test result was 3.1% (95% CI 2.2-4.4), similar to the seroprevalence result obtained using a conventional approach carried out by healthcare professionals. In conclusion, COVID-19 self-testing should be considered as a screening tool.


Assuntos
COVID-19/diagnóstico , SARS-CoV-2/isolamento & purificação , Autoteste , Adolescente , Adulto , Idoso , COVID-19/virologia , Estudos de Coortes , Estudos Transversais , Estudos de Viabilidade , Feminino , Humanos , Imunoglobulina G , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Espanha , Adulto Jovem
11.
Viruses ; 13(4)2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917265

RESUMO

Chronic hepatitis C infection (HCV) activates a systemic cell-mediated immune response characterized by the production of IFNγ and an innate immune response addressed by the activation of TLR signaling. We aimed to investigate whether HCV eradication by direct acting antivirals (DAA) leads to a recovery in cell-mediated immune response and TLR expression and functionality. Blood samples were obtained in HCV infected patients before DAA treatment and at week +48 after the end of treatment. Results were compared to healthy controls. Cell surface expression of TLR8 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated PBMCs were cultured with specific TLR8 agonists and intracellular production of cytokines was determined by flow-cytometry after ex vivo TLR8 activation with ssRNA 40. Production of IFNγ, IL2 and IL17 was assessed by flow cytometry in T cells after polyclonal activation. Included were 50 HCV-infected patients and 15 controls. TLR8 expression in PBMCs was significantly increased before treatment and recovered normal levels at week +48. Production of IL1b, IL6 and TNFα dependent on the activation of TLR8 in PBMCs was also increased in patients before DAA treatment, with a significant reduction at week +48. Combined expression of IFNγ and IL2 in CD4+ T cells in HCV-infected patients was significantly increased compared to controls and recovered normal levels at week +48. DAA-mediated clearance of HCV is associated with a decreased expression and activation of TLR8 in PBMCs until healthy control levels which is accompanied by a reduction in the Th1 response.


Assuntos
Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Interferon gama/análise , Interleucina-2/análise , Receptor 8 Toll-Like/genética , Adulto , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Imunidade Inata , Interferon gama/imunologia , Interleucina-2/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Células Th1/imunologia , Receptor 8 Toll-Like/imunologia
12.
Liver Int ; 41(9): 2076-2086, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33896100

RESUMO

BACKGROUND AND AIM: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). METHODS: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). RESULTS: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. CONCLUSIONS: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Biópsia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Estudos Longitudinais , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia
13.
Front Immunol ; 12: 651728, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859644

RESUMO

The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, medical care, economies and our society as a whole. Furthermore, COVID-19 pandemic joins the increasing prevalence of metabolic syndrome in western countries. Patients suffering from obesity, type II diabetes mellitus, cardiac involvement and metabolic associated fatty liver disease (MAFLD) have enhanced risk of suffering severe COVID-19 and mortality. Importantly, up to 25% of the population in western countries is susceptible of suffering from both MAFLD and COVID-19, while none approved treatment is currently available for any of them. Moreover, it is well known that exacerbated innate immune responses are key in the development of the most severe stages of MAFLD and COVID-19. In this review, we focus on the role of the immune system in the establishment and progression of MAFLD and discuss its potential implication in the development of severe COVID-19 in MAFLD patients. As a result, we hope to clarify their common pathology, but also uncover new potential therapeutic targets and prognostic biomarkers for further research.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/imunologia , COVID-19/patologia , Fígado Gorduroso/imunologia , Imunidade Inata/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/patologia , Humanos , Fígado/imunologia , Fígado/patologia , Obesidade/patologia , Fatores de Risco , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
14.
Atherosclerosis ; 324: 91-101, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33857761

RESUMO

BACKGROUND AND AIMS: Silybum marianum (SM) is an herbal product with cytoprotective and antioxidant properties. We have previously demonstrated that SM ameliorates ventricular remodeling and improves cardiac performance. Here, we evaluated whether SM could exert beneficial effects against cardiac lipotoxicity in a pig model of closed-chest myocardial infarction (MI). METHODS: Study 1 investigated the effect of SM administration on lipid profile and any potential SM-related adverse effects. Animals received SM or placebo during 10 days and were afterward sacrificed. Study 2 evaluated the effectiveness of SM daily administration in reducing cardiac lipotoxicity in animals subjected to a 1.5h myocardial infarction (MI), who were subsequently reperfused for 2.5h and euthanized or kept under study for three weeks and then sacrificed. RESULTS: Animals administered a 10-day SM regime presented a sharp decline in plasma triglyceride levels vs. controls, with no other modifications in lipid profile. The decrease in triglyceride concentration was accompanied by a marked reduction in triglyceride intestinal absorption and glycoprotein-P expression. Three weeks post-MI the triglyceride content in the ischemic myocardium of the SM-treated animals was significantly lower than in the ischemic myocardium of placebo-controls. This effect was associated with an enhanced cardiac expression of PPARγ and triglyceride clearance receptors. This long-term SM-administration induced a lower expression of lipid receptors in subcutaneous adipose tissue. No SM-related side-effects were registered. CONCLUSION: SM administration reduces plasma triglyceride levels through attenuation of triglyceride intestinal absorption and modulates cardiac lipotoxicity in the ischemic myocardium, likely contributing to improve ventricular remodeling.


Assuntos
Cardo-Mariano , Infarto do Miocárdio , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Infarto do Miocárdio/tratamento farmacológico , Miocárdio , Suínos , Triglicerídeos , Remodelação Ventricular
15.
Eur J Public Health ; 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33872348

RESUMO

BACKGROUND: Spain was initially one of the countries most affected by the COVID-19 pandemic. In June 2020, the COVID-SCORE-10 study reported that the Spanish public's perception of their government's response to the pandemic was low. This study examines these perceptions in greater detail. METHODS: We employed an ordered logistic regression analysis using COVID-SCORE-10 data to examine the Spanish public's perception of ten key aspects of their government's COVID-19 control measures. These included support for daily needs, mental and general health services, communication, information and coordination, which were examined by gender, age, education level, having been affected by COVID-19, and trust in government´s success in addressing unexpected health threats. RESULTS: ´Trust in the government´ showed the greatest odds of positive perception for the ten measures studied. Odds of positive perception of communication significantly varied by gender, education level, and having been affected by COVID-19, whereas for information and coordination of disease control, odds significantly varied by gender and having been affected by COVID-19. Odds of positive perception for access to mental health services significantly varied by gender and education level. Age was not significant. CONCLUSION: Public perception of the government's pandemic response in Spain varied by socio-demographic and individual variables, particularly by reported trust in the government. Fostering public trust during health threats may improve perception of response efforts. Future efforts should tailor interventions that consider gender, education level, and whether people have been affected by COVID-19.

16.
Cancer Res ; 81(11): 2874-2887, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33771899

RESUMO

Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1 -/- and E2f2 -/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1 -/- and E2f2 -/- mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis. SIGNIFICANCE: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2874/F1.large.jpg.

17.
Gut ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741640

RESUMO

OBJECTIVE: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. DESIGN: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. RESULTS: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). CONCLUSION: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

18.
Adv Exp Med Biol ; 1261: 165-174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33783738

RESUMO

Haloarchaea are halophilic microorganisms belonging to the Archaea domain that inhabit salty environments (mainly soils and water) all around the world. Most of the genera included in this group are able to produce carotenoids at significant concentrations (even wild-type strains). The major carotenoid produced by the cells is bacterioruberin (and its derivatives), which is only produced by this kind of microbes. Nevertheless, the understanding of carotenoid metabolism in haloarchaea, its regulation, and the roles of carotenoid derivatives in this group of extreme microorganisms remains mostly unrevealed. Besides, potential biotechnological uses of haloarchaeal pigments are poorly explored. This work summarizes what it has been described so far about carotenoid production by haloarchaea, haloarchaeal carotenoid production at large scale, as well as the potential uses of haloarchaeal pigments in biotechnology and biomedicine.


Assuntos
Archaea , Carotenoides , Archaea/genética , Biotecnologia , Pigmentação
20.
J Hepatol ; 75(1): 34-45, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33571553

RESUMO

BACKGROUND & AIMS: Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). METHODS: Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. RESULTS: Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. CONCLUSIONS: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. LAY SUMMARY: Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.

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