Liver Research Unit

Mexico City, Mexico

Liver Research Unit

Mexico City, Mexico
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Wu S.-M.,Chang Gung University | Huang Y.-H.,Chang Gung Memorial Hospital | Yeh C.-T.,Liver Research Unit | Tsai M.-M.,Chang Gung University | And 5 more authors.
Oncogene | Year: 2011

Thyroid hormone, 3, 3′, 5-triiodo-L-thyronine (T 3), mediates cell growth, development and differentiation by binding to its nuclear receptors (TRs). The role of TRs in cancer is still undefined. Notably, hyperthyroxinemia has been reported to influence the rate of colon cancer in an experimental model of carcinogenesis in rats. Previous microarray analysis revealed that cathepsin H (CTSH) is upregulated by T 3 in HepG2-TR cells. We verified that mRNA and protein expression of CTSH are induced by T 3 in HepG2-TR cells and in thyroidectomized rats following administration of T 3. The possible thyroid hormone-responsive elements of the CTSH promoter localized to the nucleotides-2038 to-1966 and-1565 to-1501 regions. An in vitro functional assay showed that CTSH can increase metastasis. J7 cells overexpressing CTSH were inoculated into severe combined immune-deficient mice and these J7-CTSH mice displayed a greater metastatic potential than did J7-control mice. The clinicopathologic significance of CTSH expression in hepatocellular carcinoma (HCC) was also investigated. The CTSH overexpressing in HCC was associated with the presence of microvascular invasion (P0.037). The microvascular invasion characteristic is closely related to our in vitro characterization of CTSH function. Our results show that T 3-mediated upregulation of CTSH led to matrix metallopeptidase or extracellular signal-regulated kinase activation and increased cell migration. This study demonstrated that CTSH overexpression in a subset hepatoma may be TR dependent and suggests that this overexpression has an important role in hepatoma progression. © 2011 Macmillan Publishers Limited All rights reserved.

Chen Y.-C.,Liver Research Unit | Hsu C.-W.,Liver Research Unit | Chang M.-Y.,Chang Gung University | Yeh C.-T.,Liver Research Unit | Yeh C.-T.,Chang Gung Memorial Hospital
BMC Research Notes | Year: 2013

Background: Severe acute exacerbation in chronic hepatitis B could lead to mortality in some patients unless timely liver transplantation is performed. The baseline bilirubin level has been reported to be an important prognostic factor for mortality. Here we conducted a prospective observational study to examine the clinical performance of this predictor. Method. Twenty-one consecutive chronic hepatitis B patients experiencing severe acute exacerbation were treated with either telbivudine or entecavir. The clinical characteristics at baseline and week-2 were documented and correlated with mortality. Results: Of the 21 patients included, 9 had baseline bilirubin >10 mg/dL. Four of these 9 patients (44.4%) eventually died, whereas all other patients survived. During the initial 2-week period, the change of bilirubin was -1.2 mg/dl in the survivors, but was +8.05 mg/dl in the mortalities (P = 0.009). When this on-treatment factor was combined, 5 of the 21 patients had baseline bilirubin > 10 mg/dL plus an increase of bilirubin level at week-2. Of these 5 patients, 4 (80%) died. Thus, by combining the baseline and on-treatment bilirubin levels, a positive predictive value of 80% and a negative predictive value of 100% could be achieved. Other significant on-treatment mortality predictors (at week-2) included higher international normalized ratio of prothrombin time (2.75 vs. 1.3, P = 0.004), higher model for end-stage liver disease score (30 vs. 17, P = 0.006), lower alpha-fetoprotein level (36.3 vs. 459.6 ng/mL, P = 0.039), and more rapid deterioration of the estimated glomerular filtration rate (eGFR) (P = 0.008). Interestingly, during the course, deterioration of eGFR was statistically significant in entecavir-treated (P = 0.028), but not in telbivudine-treated patients. Additionally, the patients treated with telbivudine had significant increase in serum alpha-fetoprotein (27.9 to 191.9 ng/ml, P = 0.046) in the first 2 weeks, whereas the corresponding feature was not found in those treated with entecavir (P = 0.139). Conclusions: In this prospective observational study, we discovered that the baseline and on-treatment bilirubin levels should be combined to achieve a better predictive value. Telbivudine might have a renoprotective effect in addition to its efficacy in viral suppression in patients with severe acute exacerbation. © 2013 Chen et al.; licensee BioMed Central Ltd.

Manzano-Robleda M.C.,Obesity and Gastrointestinal Diseases Unit | Ornelas-Arroyo V.,Obesity and Gastrointestinal Diseases Unit | Barrientos-Gutierrez T.,National Institute of Public Health | Mendez-Sanchez N.,Liver Research Unit | And 2 more authors.
Annals of Hepatology | Year: 2015

Background: Treatment of hepatitis C virus (HCV) infection with newer direct-acting antivirals is unrealistic in some countries because of the lack of availability. Aim: Assess benefits and harms of boceprevir (BOC) and telaprevir (TLV) in treatment of genotype 1 HCV infection, and identifying subgroups with most benefit. Material and methods: Search from 2009-2013 in PubMed, EMBASE, and “gray literature” of published and unpublished randomized trials reporting sustained viral response (SVR) or adverse events (AE) with BOC or TLV + pegylated interferon and ribavirin (PR) in HCV-infected patients; cohorts or case reports for comparison protease inhibitors (PI), evaluation of predictors of SVR, and resistant variants. Cochrane guidelines were applied. Comparisons between PI + PR vs. PR were performed. Main outcomes were expressed as risk-ratios with 95% CIs. Meta-regression and trial sequential analysis were performed. Results: 33 studies (10,525 patients) were analyzed. SVR was higher for PI + PR (RR, 2.05; 95% CI 1.70-2.48). In meta-regression, previously treated patients exhibited greater benefit from PI + PR (RR, 3.47; 95% CI, 2.78-4.33). AE were higher with PI + PR (RR, 1.01; 95% CI, 1-1.03; NNH 77.59), also the discontinuation rate (RR, 1.69; 95% CI, 1.36-2.10, NNH, 18). Predictors of SVR were IL-28 TT, nonblack race, low viral load, age, no cirrhosis, statin use, undetectable viral load at the first anemia episode and at week 2 of treatment, and low IL-6 levels. In conclusion SVR was higher in patients treated with PIs, patients previously exposed to PR showed superior response rates. Specific predictors will determine the best candidates for treatments that will offer real-life therapeutic alternatives. © 2014 Annals of Hepatology. All rights reserved.

Chinchilla-Lopez P.,Liver Research Unit | Qi X.,General Hospital of Shenyang Military Command | Yoshida E.M.,University of British Columbia | Mendez-Sanchez N.,Liver Research Unit
Annals of Hepatology | Year: 2017

The increase of incidences of Hepatocellular Carcinoma (HCC) will continue in the next decades. The therapies about hepatitis C infection has been questioned as a risk factor. Some authors emphasized that sustained virologic response (SVR) with interferonbased therapy reduced the risk of developing HCC. In contrast, some publications that to suggest an increasing risk of HCC in patients treated with Direct-Acting Antivirals (DAA). Whether these therapies are associated with an increased risk of HCC remains to be studied and continued long-term observational studies will be needed. The goal in HCV care needs to go beyond merely achieving an SVR. © 2017, Fundacion Clinica Medica Sur. All Rights Reserved.

Buque X.,University of the Basque Country | Martinez M.J.,University of the Basque Country | Cano A.,University of the Basque Country | Miquilena-Colina M.E.,Liver Research Unit | And 5 more authors.
Journal of Lipid Research | Year: 2010

We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulinresistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (∼ 70%); detoxification, steroid, and sulfur metabolism (∼ 65%) as well as cell growth/ proliferation and protein synthesis/transformation (∼ 70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-tocell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7 ∼ hydroxylase, cadherin 17, and peroxisome proliferatoractivated receptor ∼ significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.

Mucino-Bermejo J.,Intensive Care Unit | Carrillo-Esper R.,Intensive Care Unit | Uribe M.,Liver Research Unit | Mendez-Sanchez N.,Liver Research Unit
Annals of Hepatology | Year: 2013

The clotting process is a dynamic array of multiple processes which can be described in four phases: platelet plug initiation and formation, clotting process propagation by the coagulation cascade, clotting termination by antithrombotic mechanisms and clot removal by fibrinolysis. The liver plays a central role in each of these phases of clotting process, as it synthesizes the majority of coagulation factors and proteins involved in fibrinolysis as well as thrombopoeitin, which is responsible for platelet production from megakaryocytes. Many pathological processes associated with cirrhosis, such as portal hypertension and endothelial dysfunction, as well as co-morbid conditions, may also alter the coagulation process. Consequently, patients with liver disease have a disturbed balance of procoagulant and anti-coagulant factors which deviates from the normal coagulation cascade. This situation poses an additional problem in the diagnostic and therapeutic approach to this group of patients, since traditional coagulation test may not be reliable for assessing bleeding or thrombotic risk and traditional transfusional strategies may not be applicable in cirrhotic patients. In this article, we review the pathophysiological bases of coagulation abnormalities, in cirrhotic patients, the diagnostic therapeutic strategies to be followed and its impact on the clinical outcome in the cirrhotic patient.

Sanchez-Valle V.,Liver Research Unit | Chavez-Tapia N.C.,Liver Research Unit | Uribe M.,Liver Research Unit | Mendez-Sanchez N.,Liver Research Unit
Current Medicinal Chemistry | Year: 2012

Liver fibrosis represents a health problem with significant morbidity and mortality that affects 100 million people worldwide. It is a final pathway to several chronic liver diseases and is characterized by excess collagen and accumulation of extracellular matrix in response to chronic hepatocellular damage. Clinical and experimental data suggest that oxidative stress (OS) mediates the progression of fibrosis, and that OS-related molecules may act as mediators of molecular and cellular events implicated in liver fibrosis. The generation of reactive oxygen species (ROS) plays an important role in producing liver damage and initiating hepatic fibrogenesis. OS disrupts lipids, proteins and DNA, induces necrosis and apoptosis of hepatocytes and amplifies the inflammatory response. ROS also stimulate the production of profibrogenic mediators from Kupffer cells and circulating inflammatory cells and directly activate hepatic stellate cells, resulting in the initiation of fibrosis. Advances in understanding the mechanisms involved in fibrosis have identified new molecular targets with therapeutic potential for more targeted and personalized control of this disease. This review will highlight recent concepts in OS, antioxidants and the molecular pathways involved in hepatic fibrosis. © 2012 Bentham Science Publishers.

Almeda-Valdes P.,Instituto Nacional Of Ciencias Medicas Y Nutricion Salvador Zubiran | Aguilar-Olivos N.,Liver Research Unit | Uribe M.,Liver Research Unit | Mendez-Sanchez N.,Liver Research Unit
Reviews on Recent Clinical Trials | Year: 2014

Nonalcoholic fatty liver disease (NAFLD) is an important cause of chronic liver disease; including simple steatosis, steatohepatitis, fibrosis, or cirrhosis. The metabolic syndrome (MS) is the existence of metabolic alterations that confer an increased risk for developing cardiovascular disease and diabetes. NAFLD and MS frequently coexist and 90% of NAFLD patients have more than one manifestation of the MS. In addition, both entities are related to other comorbid conditions. Scientific advances in the understanding of the association between NAFLD and the MS have identified insulin resistance as a key aspect in the pathophysiology of both diseases. Knowledge gained from these advances can be applied clinically in the management and prevention of NAFLD, the MS, and associated metabolic alterations. Cardiovascular disease is the leading cause of death in patients with NAFLD and the MS, therefore adequate diagnosis and effective treatment are critical. This review analyzes current evidence of the association between NAFLD and the MS. The growing prevalence of both entities is highlighted. Next, the common mechanisms leading to insulin resistance are discussed. Manifestations and diagnosis of the MS and NAFLD are reviewed, pointing out the associated comorbid conditions shared by both diseases. Finally, a brief overview regarding NAFLD treatment is presented. © 2014 Bentham Science Publishers.

Lopez-Velazquez J.A.,Liver Research Unit | Silva-Vidal K.V.,Liver Research Unit | Ponciano-Rodriguez G.,National Autonomous University of Mexico | Chavez-Tapia N.C.,Liver Research Unit | And 3 more authors.
Annals of Hepatology | Year: 2014

Nonalcoholic fatty liver disease (NAFLD) is an alarming public health problem. The disease is one of the main causes of chronic liver disease worldwide and is directly linked to the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) in the general population. The worldwide prevalence of NAFLD has been estimated at 20-30%, but the prevalence is unknown in the Americas because of a lack of epidemiological studies. However, given the trends in the prevalence of diabetes and obesity, the prevalence of NAFLD and its consequences are expected to increase in the near future. The aim of the present study is to present the current data on the prevalence of NAFLD in the Americas. We performed an electronic search of the main databases from January 2000 to September 2013 and identified 356 reports that were reviewed. We focused on the epidemiology and prevalence of known NAFLD risk factors including obesity, T2DM, and the metabolic syndrome (MS). The prevalence of the MS was highest in the United States, Mexico, Costa Rica, Puerto Rico, Chile, and Venezuela. In addition, Puerto Rico, Guyana, and Mexico have the highest prevalence of T2DM in the Americas, while USA has the most people with T2DM. In conclusion, the prevalence rates of NAFLD and obesity were highest in the United States, Belize, Barbados, and Mexico. © 2013 Annals of Hepatology. All rights reserved.

Manzano-Robleda M.C.,Liver Research Unit | Barranco-Fragoso B.,National Medical Center | Uribe M.,Liver Research Unit | Mendez-Sanchez N.,Liver Research Unit
Annals of Hepatology | Year: 2015

Portal vein thrombosis (PVT) is one of the most common vascular disorders of the liver with significant morbidity and mortality. Large cohort studies have reported a global prevalence of 1%, but in some risk groups it can be up to 26%. Causes of PVT are cirrhosis, hepatobiliary malignancy, abdominal infectious or inflammatory diseases, and myeloproliferative disorders. Most patients with PVT have a general risk factor. The natural history of PVT results in portal hypertension leading to splenomegaly and the formation of portosystemic collateral blood vessels and esophageal, gastric, duodenal, and jejunal varices. Diagnosis of PVT is made by imaging, mainly Doppler ultrasonography. According to its time of development, localization, pathophysiology, and evolution, PVT should be classified in every patient. Some clinical features such as cirrhosis, hepatocellular carcinoma, and hepatic transplantation are areas of special interest and are discussed in this review. The goal of treatment of acute PVT is to reconstruct the blocked veins. Endoscopic variceal ligation is safe and highly effective in patients with variceal bleeding caused by chronic PVT. In conclusion, PVT is the most common cause of vascular disease of the liver and its prevalence has being increasing, especially among patients with an underlying liver disease. All patients should be investigated for thrombophilic conditions, and in those with cirrhosis, anticoagulation prophylaxis should be considered. © 2014 Annals of Hepatology. All rights reserved.

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