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1.
J Infect Public Health ; 16(5): 673-679, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36931143

RESUMO

BACKGROUND: People living with human immunodeficiency virus (PLWH) are at an increased risk of nonalcoholic fatty liver disease (NAFLD) but how these patients react to COVID-19 infection is unclear. We examined the clinical characteristics and outcomes of patients with and without nonalcoholic fatty liver disease (NAFLD) among people living with human immunodeficiency virus (PLWH) diagnosed with COVID-19. METHODS: A multicenter, retrospective cohort study was conducted using TriNetX. Participants diagnosed with COVID-19 between January 20, 2020, and October 31, 2021, in PLWH were identified and divided into cohorts based on preexisting NAFLD. The primary outcome was all-cause mortality, and secondary outcomes were hospitalization, severe disease, critical care, need for mechanical ventilation, and acute kidney injury(AKI). Propensity score matching (PSM) mitigated the imbalance among group covariates. Risk ratios (RR) with 95 % confidence intervals (CI) were calculated. RESULTS: Of the 5012 PLWH identified with confirmed COVID-19 during the study period, 563 had a diagnosis of NAFLD. After PSM, both groups were well-matched with 561 patients. The primary outcome did not differ between the cohorts at 30-days, even after a fully adjusted analysis, and the risk of all-cause mortality did not differ at 60 and 90 days. NAFLD had a significantly higher risk for hospitalization rates (RR 1.32; 95 % CI, 1.06-1.63) and AKI (RR 2.55; 95 % CI 1.42-4.57) than the non-NAFLD group at 30 days. No other differences were detected in other secondary outcome measures. CONCLUSIONS: Preexisting NAFLD is associated with an increased risk for hospitalization and AKI among PLWH infected with COVID-19. The potential role of NAFLD in developing severe COVID-19 among PLWH remains to be elucidated in future studies. Still, this study indicates the need for careful monitoring of this at-risk population.


Assuntos
COVID-19 , Infecções por HIV , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , COVID-19/complicações , COVID-19/terapia , HIV , Estudos Retrospectivos , Infecções por HIV/complicações , Infecções por HIV/epidemiologia
2.
World J Gastroenterol ; 28(5): 570-587, 2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35316959

RESUMO

BACKGROUND: Abnormal liver chemistries are common findings in patients with Coronavirus Disease 2019 (COVID-19). However, the association of these abnormalities with the severity of COVID-19 and clinical outcomes is poorly understood. AIM: We aimed to assess the prevalence of elevated liver chemistries in hospitalized patients with COVID-19 and compare the serum liver chemistries to predict the severity and in-hospital mortality. METHODS: This retrospective, observational study included 3380 patients with COVID-19 who were hospitalized in the Johns Hopkins Health System (Baltimore, MD, United States). Demographic data, clinical characteristics, laboratory findings, treatment measures, and outcome data were collected. Cox regression modeling was used to explore variables associated with abnormal liver chemistries on admission with disease severity and prognosis. RESULTS: A total of 2698 (70.4%) had abnormal alanine aminotransferase (ALT) at the time of admission. Other more prevalent abnormal liver chemistries were aspartate aminotransferase (AST) (44.4%), alkaline phosphatase (ALP) (16.1%), and total bilirubin (T-Bil) (5.9%). Factors associated with liver injury were older age, Asian ethnicity, other race, being overweight, and obesity. Higher ALT, AST, T-Bil, and ALP levels were more commonly associated with disease severity. Multivariable adjusted Cox regression analysis revealed that abnormal AST and T-Bil were associated with the highest mortality risk than other liver injury indicators during hospitalization. Abnormal AST, T-Bil, and ALP were associated with a need for vasopressor drugs, whereas higher levels of AST, T-Bil, and a decreased albumin levels were associated with mechanical ventilation. CONCLUSION: Abnormal liver chemistries are common at the time of hospital admission in COVID-19 patients and can be closely related to the patient's severity and prognosis. Elevated liver chemistries, specifically ALT, AST, ALP, and T-Bil levels, can be used to stratify risk and predict the need for advanced therapies in these patients.


Assuntos
COVID-19 , Fígado/química , Alanina Transaminase , Fosfatase Alcalina , Aspartato Aminotransferases , Baltimore , Bilirrubina , COVID-19/diagnóstico , COVID-19/terapia , Hospitalização , Humanos , Estudos Retrospectivos , Índice de Gravidade de Doença
3.
Nutrients ; 14(6)2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35334967

RESUMO

Background: Malnutrition has been linked to adverse health economic outcomes. There is a paucity of data on malnutrition in patients admitted with COVID-19. Methods: This is a retrospective cohort study consisting of 4311 COVID-19 adult (18 years and older) inpatients at 5 Johns Hopkins-affiliated hospitals between 1 March and 3 December 2020. Malnourishment was identified using the malnutrition universal screening tool (MUST), then confirmed by registered dietitians. Statistics were conducted with SAS v9.4 (Cary, NC, USA) software to examine the effect of malnutrition on mortality and hospital length of stay among COVID-19 inpatient encounters, while accounting for possible covariates in regression analysis predicting mortality or the log-transformed length of stay. Results: COVID-19 patients who were older, male, or had lower BMIs had a higher likelihood of mortality. Patients with malnutrition were 76% more likely to have mortality (p < 0.001) and to have a 105% longer hospital length of stay (p < 0.001). Overall, 12.9% (555/4311) of adult COVID-19 patients were diagnosed with malnutrition and were associated with an 87.9% increase in hospital length of stay (p < 0.001). Conclusions: In a cohort of COVID-19 adult inpatients, malnutrition was associated with a higher likelihood of mortality and increased hospital length of stay.


Assuntos
COVID-19 , Desnutrição , Adulto , Hospitais , Humanos , Pacientes Internados , Tempo de Internação , Masculino , Desnutrição/diagnóstico , Estudos Retrospectivos
4.
Int J Obes (Lond) ; 45(5): 1152-1154, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33637950

RESUMO

COVID-19 is a pandemic disease caused by a coronavirus, designed as SARS CoV-2, whose clinical presentation is widely variable, with most patients having mild or no symptoms, but others developing a malign disease with multi-organ failure and even death. Accumulating data from different populations have shown that obesity is a risk factor for a severe evolution of the disease, however, the mechanisms that explain this association are not clearly understood. An ominous evolution of COVID-19 has been attributed to an exacerbated inflammatory response, designed as "cytokine storm" with augmented production of cytokines/chemokines through the activation of toll-like receptors (TLR) by pathogen-associated molecular patterns, that triggers an inflammatory downstream response, mediated in part by the adaptor molecule, myeloid differentiation factor 88 (MyD88). Previous studies have reported an increased expression of MyD88 and TLRs in people with obesity, mainly in those with metabolic complications. Therefore, we hypothesize, that an underlying increased Myd88/TLR signaling may predispose to patients with obesity to develop an exaggerated and dangerous inflammatory reaction against SARS CoV-2 infection, explaining at least in part, the higher severity of COVID-19. In addition, MyD88/TLR signaling in people with obesity could have a role in the development of several chronic diseases.


Assuntos
COVID-19 , Fator 88 de Diferenciação Mieloide/metabolismo , Obesidade , Receptores Toll-Like/metabolismo , COVID-19/complicações , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Obesidade/complicações , Obesidade/imunologia , Obesidade/fisiopatologia , Pandemias , Fatores de Risco , SARS-CoV-2 , Transdução de Sinais/imunologia
5.
Obes Surg ; 29(10): 3239-3245, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31256356

RESUMO

BACKGROUND: Gut microbiota likely impact obesity and metabolic diseases. We evaluated the changes in gut microbiota after surgical versus medical weight loss in adults with diabetes and obesity. METHODS: We performed 16S rRNA amplicon sequencing to identify the gut microbial composition at baseline and at 10% weight loss in adults with diabetes who were randomized to medical weight loss (MWL, n = 4), adjustable gastric banding (AGB, n = 4), or Roux-en-Y gastric bypass (RYGB, n = 4). RESULTS: All participants were female, 75% reported black race with mean age of 51 years. At similar weight loss amount and glycemic improvement, the RYGB group had the most number of bacterial species (10 increased, 1 decreased) that significantly changed (p < 0.05) in relative abundance. Alpha-diversity at follow-up was significantly lower in AGB group compared to MWL and RYGB (observed species for AGB vs. MWL, p = 0.0093; AGB vs. RYGB, p = 0.0093). The relative abundance of Faecalibacterium prausnitzii increased in 3 participants after RYGB, 1 after AGB, and 1 after MWL. CONCLUSIONS: At similar weight loss and glycemic improvement, the greatest alteration in gut microbiota occurred after RYGB with an increase in the potentially beneficial bacterium, F. prausnitzii. Gut microbial diversity tended to decrease after AGB and increase after RYGB and MWL. Future studies are needed to determine the impact and durability of gut microbial changes over time and their role in long-term metabolic improvement after bariatric surgery in adults with type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCTDK089557- ClinicalTrials.gov.


Assuntos
Cirurgia Bariátrica/métodos , Microbioma Gastrointestinal/fisiologia , Obesidade/cirurgia , Redução de Peso/fisiologia , Adulto , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Técnicas de Tipagem Bacteriana , Biodiversidade , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/cirurgia , Fezes/microbiologia , Feminino , Derivação Gástrica , Gastroplastia , Humanos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/microbiologia , Obesidade Mórbida/sangue , Obesidade Mórbida/microbiologia , Obesidade Mórbida/cirurgia , Projetos Piloto , Período Pós-Operatório , RNA Ribossômico 16S/genética
6.
Obes Surg ; 28(1): 25-30, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28695457

RESUMO

BACKGROUND: It may be difficult to distinguish between adults with type 1 diabetes and type 2 diabetes by clinical assessment. In patients undergoing bariatric surgery, it is critical to correctly classify diabetes subtype to prevent adverse perioperative outcomes including diabetic ketoacidosis. This study aimed to determine whether testing for C-peptide and islet cell antibodies during preoperative evaluation for bariatric surgery could improve the classification of type 1 versus type 2 diabetes compared to clinical assessment alone. METHODS: This is a retrospective analysis of the Improving Diabetes through Lifestyle and Surgery trial, which randomized patients with clinically diagnosed type 2 diabetes and BMI 30-40 kg/m2 to medical weight loss or bariatric surgery; one participant was discovered to have type 1 diabetes after experiencing postoperative diabetic ketoacidosis. Using blood samples collected prior to study interventions, we measured islet cell antibodies and fasting/meal-stimulated C-peptide in all participants. RESULTS: The participant with type 1 diabetes was similar to the 11 participants with type 2 diabetes in age at diagnosis, adiposity, and glycemic control but had the lowest C-peptide levels. Among insulin-treated participants, fasting and stimulated C-peptide correlated strongly with the C-peptide area-under-the-curve on mixed meal tolerance testing (R = 0.86 and 0.88, respectively). Three participants, including the one with type 1 diabetes, were islet cell antibody positive. CONCLUSIONS: Clinical characteristics did not correctly identify type 1 diabetes in this study. Preoperative C-peptide testing may improve diabetes classification in patients undergoing bariatric surgery; further research is needed to define the optimal C-peptide thresholds.


Assuntos
Cirurgia Bariátrica , Técnicas de Laboratório Clínico/métodos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Obesidade/complicações , Obesidade/cirurgia , Adulto , Autoanticorpos/sangue , Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/cirurgia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/cirurgia , Diagnóstico Diferencial , Jejum/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Período Pós-Operatório , Estudos Retrospectivos , Redução de Peso/fisiologia
7.
Biochem Biophys Res Commun ; 469(3): 463-9, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26525850

RESUMO

Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Piruvatos/administração & dosagem , Animais , Linhagem Celular , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Hepatology ; 63(6): 1828-41, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26679751

RESUMO

UNLABELLED: Wilson disease (WD) is a hepatoneurological disorder caused by mutations in the copper-transporter, ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurological symptoms. We demonstrate that in Atp7b(-/-) mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b(-/-) mice identified dysregulation of nuclear receptors (NRs), especially the liver X receptor (LXR)/retinoid X receptor heterodimer, as an important event in WD pathogenesis. Treating Atp7b(-/-) mice with the LXR agonist, T0901317, ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized, and liver function and histology were improved. CONCLUSIONS: The results demonstrate the major role of an altered NR function in the pathogenesis of WD and suggest that modulation of NR activity should be explored as a supplementary approach to improving liver function in WD. (Hepatology 2016;63:1828-1841).


Assuntos
Degeneração Hepatolenticular/tratamento farmacológico , Hidrocarbonetos Fluorados/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/agonistas , Fígado/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Adenosina Trifosfatases/genética , Animais , Proteínas de Transporte de Cátions/genética , Cobre/metabolismo , ATPases Transportadoras de Cobre , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Degeneração Hepatolenticular/genética , Humanos , Hidrocarbonetos Fluorados/farmacologia , Fígado/metabolismo , Testes de Função Hepática , Receptores X do Fígado/metabolismo , Camundongos Knockout , Receptores X de Retinoides/metabolismo , Sulfonamidas/farmacologia
9.
Hum Factors ; 56(7): 1284-95, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25490808

RESUMO

OBJECTIVE: The objective was to study the performance of a manual tracking task with system flexibility and time delays in the input channel and to examine the effects of input shaping the human operator's commands. BACKGROUND: It has long been known that low-frequency, lightly damped vibration hinders performance of a manually controlled system. Recently, input shaping has been shown to improve the performance of such systems in a compensatory-display tracking task. It is unknown if similar improvements are seen with pursuit-display tasks, or how the improvement changes when time delays are added to the system. METHOD: A total of 18 novice participants performed a pursuit-view tracking experiment with a spring-centered joystick. Controlled elements included an integrator, an integrator with a lightly damped flexible mode, and an input-shaped integrator with a flexible mode. The input to these controlled elements was delayed between 0 and 1 s. Tracking performance was quantified by root mean square tracking error, and subjective difficulty was quantified by ratings on a Cooper-Harper scale. RESULTS: Performance was best with the undelayed integrator. Both time delay and flexibility degraded performance. Input shaping improved control of the flexible element, with a diminishing benefit as the time delay increased. Tracking error and subjective rating were significantly related. Some operators used a pulsive control strategy. CONCLUSION: Input shaping can improve the performance of a manually controlled system with flexibility, even when time delays are present. APPLICATION: This study is useful to designers of human-controlled systems, especially those with problematic flexibility and/or time delays.


Assuntos
Análise e Desempenho de Tarefas , Adulto , Feminino , Humanos , Masculino , Vibração , Adulto Jovem
10.
Hepatol Res ; 44(13): 1357-66, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24451003

RESUMO

AIM: Thioredoxin-interacting protein (TXNIP) promotes oxidative stress by inactivating thioredoxin (TXN). This protein is involved in diverse disease processes, including insulin resistance, atherosclerosis and carcinogenesis. The aim of the present study was to measure the expression and function of TXNIP in in vitro models of liver disease, as well as in primary human hepatocellular carcinoma (HCC) tissue specimens. In addition, we wanted to determine the effects of vitamin D3-induced TXNIP stimulation in HCC-derived cell lines. METHODS: TXNIP expression was measured by quantitative reverse transcription polymerase chain reaction and western blots. TXNIP expression was stimulated by vitamin D exposure and by transfection. Cell proliferation, apoptosis and reactive oxygen species were determined by standard assays. RESULTS: TXNIP expression levels were low in HCC cell lines, and vitamin D3 stimulated TXNIP expression in vitro. In HCC cells transfected with a TXNIP expression vector or treated with exogenous vitamin D3, there was a reduction in cell proliferation and an increase in apoptosis. Cells expressing TXNIP were markedly susceptible to oxidative injury induced by cobalt chloride or bacterial lipopolysaccharide. TXNIP expression was reduced or absent in a majority of primary human HCC specimens relative to matching, non-cancerous liver tissue. CONCLUSION: TXNIP expression is low or absent in human HCC specimens and HCC-derived cell lines. Vitamin D3 stimulates TXNIP expression, resulting in diminished proliferation and enhanced apoptosis. Liver cells expressing TXNIP are primed for oxidative injury. These findings suggest that stimulation of TXNIP expression, by factors such as vitamin D3, may attenuate carcinogenesis in patients with chronic liver disease.

11.
Liver Int ; 33(5): 677-86, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23413886

RESUMO

BACKGROUND: Vitamin D deficiency is common in chronic liver disease particularly in those with severe liver fibrosis. AIMS: To determine the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ) on the human α(1) (I) collagen promoter and collagen formation by human stellate LX-2 cells and the mechanism of the effect of the vitamin D receptor (VDR) on the promoter. METHODS: Type I collagen was assessed by measurements of collagen mRNA and collagen protein and by transfection experiments. Binding of VDR to the α(1) (I) collagen promoter was determined by EMSA and ChIP assays. RESULTS: 1,25-(OH)2 D3 decreased human α(1) (I) collagen mRNA and protein and the secretion of type I collagen by stellate cells after exposure to TGFß1. Furthermore, 1,25-(OH)2 D3 inhibited TGFß1-induced activation of the α(1) (I) collagen promoter in transfected LX-2 cells. The effect of 1,25-(OH)2 D3 is mediated by the VDR, which binds at a proximal Sp1 site and also at a newly identified distal site on the collagen promoter. A VDR expression vector reduced the activities of the collagen promoter in transfected LX-2 cells. CONCLUSIONS: 1,25-(OH)2 D3 inhibits type I collagen formation in human stellate cells. The effect of 1,25-(OH)2 D3 is mediated by its receptor which binds at a proximal Sp1.1 site and at a newly identified distal site on the collagen promoter. Correction of vitamin D deficiency in patients with chronic liver disease is a potential therapy to inhibit progression of fibrosis.


Assuntos
Calcitriol/farmacologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Receptores de Calcitriol/metabolismo , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Calcitriol/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Imunoprecipitação da Cromatina , Colágeno Tipo I/biossíntese , Colágeno Tipo I/genética , Drosophila , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Humanos , Luciferases , Oligonucleotídeos/genética , Plasmídeos/genética , Regiões Promotoras Genéticas/genética , Fator de Crescimento Transformador beta1/metabolismo
12.
Hepatol Int ; 7(4): 1040-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26202033

RESUMO

PURPOSE: Evidence indicates a positive association between liver enzymes and the risk of death in Western countries; however, the evidence in Asian populations is scarce. We investigated the association between liver enzymes and total, cardiovascular (CVD), cancer and hepatocellular carcinoma (HCC) mortality in a cohort of Taiwanese male free of cancer at baseline. METHODS: From 1996 to 2003, 54,751 Taiwanese male aged 40-80 years without cancer completed a health screening and were followed through 2005 (5.8 ± 2.5 years of follow-up). A random cohort of 3,961 male was selected to compare to 1,864 male who died. We used Cox proportional hazards regression models to assess the risk of all-cause, cardiovascular and cancer mortality associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT). RESULTS: In this population, higher levels of ALT, AST and GGT were significantly associated with all-cause mortality [hazard ratio (HR) 1.2, 1.8 and 1.6 for ALT, AST and GGT, respectively; all p < 0.05], cancer mortality (HR 1.8-2.8) and HCC mortality (HR 5.5-36.1). GGT was significantly associated with CVD mortality (HR 1.2). CONCLUSIONS: In Taiwanese male free of cancer at baseline, elevations of ALT, AST and GGT were associated with future risk of all-cause death, all cancer and HCC mortality, independent of conventional risk factors, and could be used to identify male who would benefit from HCC screening.

13.
Hepatology ; 56(3): 1097-107, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22886419

RESUMO

UNLABELLED: Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes-associated protein (YAP), the effector of the Hippo tumor-suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver development and hepatocellular carcinogenesis. Therefore, the aim of this study was to examine whether YAP participates in the regenerative response after cholestatic injury. First, we examined human liver tissue from patients with chronic cholestasis. We found more-active nuclear YAP in the bile ductular reactions of primary sclerosing cholangitis and primary biliary cirrhosis patient liver samples. Next, we used the murine bile duct ligation (BDL) model to induce cholestatic liver injury. We found significant changes in YAP activity after BDL in wild-type mice. The function of YAP in the hepatic response after BDL was further evaluated with liver-specific Yap conditional deletion in mice. Ablating Yap in the mouse liver not only compromised bile duct proliferation, but also enhanced hepatocyte necrosis and suppressed hepatocyte proliferation after BDL. Furthermore, primary hepatocytes and cholangiocytes isolated from Yap-deficient livers showed reduced proliferation in response to epidermal growth factor in vitro. Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of Survivin expression. CONCLUSION: Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis-induced human liver disease.


Assuntos
Ductos Biliares/citologia , Colestase/complicações , Hepatócitos/fisiologia , Regeneração Hepática , Proteínas Proto-Oncogênicas c-yes/fisiologia , Animais , Humanos , Ligadura , Masculino , Camundongos
14.
Cell Cycle ; 11(14): 2729-38, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22785131

RESUMO

MicroRNA (miRs) have emerged as salient regulators in cancer homeostasis and, recently, as putative therapeutics. Cholangiocarcinomas (CCA) are aggressive cancers with survival usually measured in months. mRNA arrays followed by pathway analysis revealed that miR-494 is a major modulator of the cell cycle progression from gap 2 (G2) to mitosis (M). We performed fluorescence activated cell sorting (FACS) as well as differential interference contrast (DIC) microscopy, and confirmed that miR-494 induces a significant arrest in G2/M in CCA cells. Furthermore, we verified that miR-494 modulates the protein level of six genes involved in the G2/M transition: Polo-like Kinase 1 (PLK1), pituitary tumor-transforming gene 1 (PTTG1), Cyclin B1 (CCNB1), cell-division cycle 2 (CDC2), cell-division cycle 20 (CDC20) and topoisomerase II α (TOP2A). Next, we identified direct binding of miR-494 to the open reading frame (ORF) and downregulation of PTTG1 and TOP2A. In summary, our findings suggest that miR-494 has a global regulatory role in cell cycle progression, exerted by concerted effects on multiple proteins involved in gap 1 (G1) to synthesis (S), as described previously, as well as G2 to M progression. Therefore, it appears that the simultaneous effects of a single miR species on multiple targets along the same canonical pathway is advantageous for the usage of miRs as therapeutics. In addition, our data suggest that miRs act within a narrow range. miR expression above the upper threshold does not appear to induce further effects, which is reassuring in terms of off-target effects of miR surrounding noncancerous tissue.


Assuntos
MicroRNAs/metabolismo , Antígenos de Neoplasias/metabolismo , Sequência de Bases , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Ciclina B1/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Citometria de Fluxo , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Pontos de Checagem da Fase M do Ciclo Celular , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Securina , Regiões não Traduzidas , Quinase 1 Polo-Like
15.
Alcohol Clin Exp Res ; 35(5): 939-45, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21294757

RESUMO

BACKGROUND: The effects of ethanol and acetaldehyde on uptake of glycerol and on cell size of hepatocytes and a role Aquaporin 9 (AQP9), a glycerol transport channel, were evaluated. METHODS: The studies were done in primary rat and mouse hepatocytes. The uptake of [(14) C] glycerol was determined with hepatocytes in suspension. For determination of cell size, rat hepatocytes on coated dishes were incubated with a lipophilic fluorochrome that is incorporated into the cell membrane and examined by confocal microscopy. A three-dimensional z scan of the cell was performed, and the middle slice of the z scan was used for area measurements. RESULTS: Acute exposure to acetaldehyde, but not to ethanol, causes a rapid increase in the uptake of glycerol and an increase in hepatocyte size, which was inhibited by HgCl(2) , an inhibitor of aquaporins. This was not observed in hepatocytes from AQP9 knockout mice, nor observed by direct application of acetaldehyde to AQP9 expressed in Xenopus Laevis oocytes. Prolonged 24-hour exposure to either acetaldehyde or ethanol did not result in an increase in glycerol uptake by rat hepatocytes. Acetaldehyde decreased AQP9 mRNA and AQP9 protein, while ethanol decreased AQP9 mRNA but not AQP9 protein. Ethanol, but not acetaldehyde, increased the activities of glycerol kinase and phosphoenolpyruvate carboxykinase. CONCLUSIONS: The acute effects of acetaldehyde, while mediated by AQP9, are probably influenced by binding of acetaldehyde to hepatocyte membranes and changes in cell permeability. The effects of ethanol in enhancing glucose kinase, and phosphoenolpyruvate carboxykinase leading to increased formation of glycerol-3-phosphate most likely contribute to alcoholic fatty liver.


Assuntos
Acetaldeído/farmacologia , Aquaporinas/fisiologia , Tamanho Celular/efeitos dos fármacos , Glicerol/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Animais , Aquaporinas/antagonistas & inibidores , Aquaporinas/deficiência , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Etanol/farmacologia , Feminino , Hepatócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Xenopus laevis
16.
Biol Trace Elem Res ; 140(1): 82-94, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20336493

RESUMO

This study investigated the effects of sodium selenite (Se) and of vitamin E (D-α-tochopherol) on the deposition of type I collagen by human LX-2 stellate cells. The cultured cells were treated with or without Se or vitamin E and with or without transforming growth factor ß1 (TGFß1). The combination of Se and vitamin E, but not either alone, protected against hepatic fibrosis by decreasing TGFß1-mediated collagen secretion and accumulation by the stellate cells. This protective effect is due to a combination of decreased formation, decreased stability and increased degradation of the collagen. Effects of Se and vitamin E in decreasing α(1)(I) collagen mRNA and increasing apoptosis of stellate cells indicate decreased formation of collagen, while decreases in transglutaminase 2, which catalyze cross-linking of collagen, lead to decreased stability of the secreted collagen. Effects of Se and vitamin E on reducing tissue inhibitor metalloproteinase 1 (TIMP-1) are associated with increased degradation. The combination of Se and vitamin E decreased lipid peroxidation, while Se alone increased the activity of the antioxidant enzyme thioredoxin reductase. In conclusion, the combination of Se and vitamin E protected against TGFß1-mediated hepatic fibrosis by decreasing TGFß1-mediated type I collagen accumulation by stellate cells. This effect is due to a combination of decreased formation, decreased stability and increased degradation of the collagen.


Assuntos
Colágeno Tipo I/biossíntese , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Selenito de Sódio/farmacologia , Vitamina E/farmacologia , Células Cultivadas , Colágeno Tipo I/antagonistas & inibidores , Células Estreladas do Fígado/citologia , Humanos , Pró-Colágeno/antagonistas & inibidores , Pró-Colágeno/biossíntese , Relação Estrutura-Atividade
17.
Cell ; 143(6): 897-910, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-21145457

RESUMO

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3ß and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3ß signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.


Assuntos
Fosfatos de Inositol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aumento de Peso , Adipogenia , Envelhecimento/metabolismo , Animais , Técnicas de Cultura de Células , Dieta , Difosfatos/metabolismo , Inositol/metabolismo , Insulina/metabolismo , Resistência à Insulina , Camundongos , Obesidade/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Fosfato)/genética
18.
Hepatology ; 52(3): 1033-45, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20564330

RESUMO

UNLABELLED: Transforming growth factor beta1 (TGFbeta1) plays a crucial role in the induction of the epithelial-to-mesenchymal transition (EMT) in hepatocytes, which contributes to the pathogenesis of liver fibrosis. The inhibition of the TGFbeta1 cascade suppresses EMT and the resultant fibrosis. In this study, we focus on EMT-induced fibrosis in hepatocytes and the epigenetic regulation of the type I collagen gene. Histone acetylation is an important, major epigenetic mechanism that modulates gene transcription. We evaluated the epigenetic regulation of type I collagen in alpha mouse liver 12 hepatocytes (an untransformed mouse cell line) that had undergone EMT after treatment with TGFbeta1. The histone deacetylase inhibitor trichostatin A (TSA) inhibited EMT; this was reflected by the preservation of epithelial markers and function (E-cadherin and albumin). Fibrosis, the ultimate outcome of EMT, was abolished by TSA; this was indicated by the inhibition of type I collagen deposition. TSA exerted its anti-EMT effects by deactivating the mothers against decapentaplegic homolog 3 (Smad3)/Smad4 transcription complex and by interfering with p300, a coactivator of the type I collagen promoter, and preventing its binding to Smad3. TSA also restored Friend leukemia virus integration 1, an inhibitor of the type I collagen gene. TGFbeta1-induced EMT and its inhibition by TSA were replicated in human primary hepatocytes. CONCLUSION: Histone deacetylase inhibition abrogates TGFbeta1-induced EMT in hepatocytes and reverses EMT-induced fibrosis by epigenetic modulation of type I collagen.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/patologia , Hepatócitos/patologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Mesoderma/patologia , Fator de Crescimento Transformador beta1/farmacologia , Animais , Linhagem Celular , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Camundongos
19.
J Lipid Res ; 51(7): 1696-703, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20185414

RESUMO

Dietary fatty acids are major contributors to the development and progression of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Dietary fatty acids also alter hepatic NKT cells that are activated by antigens presented by CD1d. In the current study, we examine the mechanism of dietary fatty acid induced hepatic NKT cell deficiency and its causal relationship to insulin resistance and NAFLD. We discover that dietary saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA), but not polyunsaturated fatty acids (PUFA), cause hepatic NKT cell depletion with increased apoptosis. Dietary SFA or MUFA also impair hepatocyte presentation of endogenous, but not exogenous, antigen to NKT cells, indicating alterations of the endogenous antigen processing or presenting pathway. In vitro treatment of normal hepatocytes with fatty acids also demonstrates impaired ability of CD1d to present endogenous antigen by dietary fatty acids. Furthermore, dietary SFA and MUFA activate the NFkappaB signaling pathway and lead to insulin resistance and hepatic steatosis. In conclusion, both dietary SFA and MUFA alter endogenous antigen presentation to hepatic NKT cells and contribute to NKT cell depletion, leading to further activation of inflammatory signaling, insulin resistance, and hepatic steatosis.


Assuntos
Apresentação de Antígeno/imunologia , Gorduras na Dieta/imunologia , Ácidos Graxos/imunologia , Fígado Gorduroso/imunologia , Fígado , Células T Matadoras Naturais/imunologia , Animais , Hepatócitos/citologia , Hepatócitos/imunologia , Humanos , Resistência à Insulina/imunologia , Fígado/citologia , Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/citologia , Transdução de Sinais/fisiologia
20.
Biol Trace Elem Res ; 133(1): 83-97, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19488682

RESUMO

Oxidative stress stimulates fibrogenesis, and selenium (Se) has antioxidant properties. This study determined whether Se supplementation affects CCl(4)-induced liver injury and fibrosis. Mice were administered CCl(4) over 4 weeks, while controls received olive oil. Se was provided as sodium selenite in the drinking water. Se increased liver Se-dependent glutathione peroxidase activity and decreased liver malondialdehyde after CCl(4). Se decreased liver inflammation but not necrosis caused by CCl(4). Se increased hepatocyte apoptosis after CCl(4) and the pro-apoptotic BAX and Bcl Xs/l proteins. Stellate cell apoptosis occurred only after CCl(4) in Se-supplemented mice. Se decreased stellate cell number and fibrosis after CCl(4). Liver matrix metalloproteinase-9 increased after CCl(4) with Se supplementation. In conclusion, Se supplementation decreased hepatic fibrosis after CCl(4) in the setting of decreased inflammation but increased apoptosis. The principal mechanisms for the decreased fibrosis are a lower number of collagen-producing stellate cells and increased collagen degradation.


Assuntos
Intoxicação por Tetracloreto de Carbono , Tetracloreto de Carbono , Suplementos Nutricionais , Fígado/efeitos dos fármacos , Selênio/farmacologia , Animais , Tetracloreto de Carbono/toxicidade , Fígado/lesões , Cirrose Hepática/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Padrões de Referência , Selênio/administração & dosagem
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