Person: Baffy, Gyorgy
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Baffy
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Baffy, Gyorgy
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Publication Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, and Prevention(XIA & HE Publishing Ltd, 2013) Baffy, GyorgyHepatocellular cancer (HCC) is the fifth most prevalent cancer worldwide and the third leading cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD), a spectrum of hepatic disorders associated with obesity and the metabolic syndrome, is a recognized risk factor for HCC. NAFLD that is advanced to cirrhosis carries the highest risk for HCC, but there is increasing concern that NAFLD-associated HCC may also occur in non-cirrhotic liver. As NAFLD is rapidly becoming the most common liver condition, it has been implicated in the worrisome trend of rising HCC incidence in a number of countries, which may offset successful measures in reducing the effect of virus-related liver cancer. Independently or in synergy with cirrhosis, NAFLD may provide a special oncogenic microenvironment through its pathogenic association with chronic nutrient excess and adipose tissue remodeling, characterized by pro-inflammatory adipokine profiles, lipotoxicity, altered hepatocellular bioenergetics, and insulin resistance. Better understanding of this complex process, and development of reliable biomarkers for HCC will be critical for early recognition and risk prediction. Moreover, correcting deranged lipid metabolism and restoring insulin sensitivity by lifestyle measures and targeted pharmacotherapy holds major promise for effective prevention of NAFLD-associated HCC.Publication MicroRNAs in Nonalcoholic Fatty Liver Disease(2015) Baffy, GyorgyNonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD.Publication Disordered Purinergic Signaling and Abnormal Cellular Metabolism are Associated with Development of Liver Cancer in Cd39/Entpd1 Null Mice(Wiley, 2013-01) Sun, Xiaofeng; Han, Lihui; Seth, Pankaj; Bian, Shu; Li, Linglin; Csizmadia, Eva; Junger, Wolfgang; Schmelzle, Moritz; Usheva, Anny; Tapper, Elliot B.; Baffy, Gyorgy; Sukhatme, Vikas; Wu, Yan; Robson, SimonLiver cancer is associated with chronic inflammation, which is linked to immune dysregulation, disordered metabolism and aberrant cell proliferation. CD39/ENTPD1 is an ectonucleotidase that regulates extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimately generate adenosine. These properties inhibit anti tumor immune responses and promote angiogenesis, being permissive for the growth of transplanted tumors. Here, we show Cd39 deletion promotes development of both induced and spontaneous autochthonous liver cancer in mice. Loss of Cd39 results in higher concentrations of extracellular nucleotides, which stimulate proliferation of hepatocytes, abrogate autophagy and disrupt glycolytic metabolism. Constitutive activation of Ras-MAPK and mTOR-S6K1 pathways occurs in both quiescent Cd39 null hepatocytes in vitro and liver tissues in vivo. Exogenous ATP boosts these signaling pathways, while rapamycin inhibits such aberrant responses in hepatocytes. Conclusions Deletion of Cd39 and resulting changes in disordered purinergic signaling perturb hepatocellular metabolic/proliferative responses, paradoxically resulting in malignant transformation. These findings might impact adjunctive therapies for cancer. Lastly, our studies indicate that the biology of autochthonous and transplanted tumors is quite distinct.Publication The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells(American Association for Cancer Research (AACR), 2008-04-15) Derdak, Zoltan; Mark, Nicholas M.; Beldi, Guido; Robson, Simon; Wands, Jack R.; Baffy, GyorgyCancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis post-exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered N-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer.Publication Uncoupling Protein-2 Modulates the Lipid Metabolic Response to Fasting in Mice(American Physiological Society, 2008-04) Sheets, Anthony; Fülöp, Péter; Derdák, Zoltán; Kassai, Andrea; Sabo, Edmond; Mark, Nicholas M.; Paragh, György; Wands, Jack R.; Baffy, GyorgyUncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in β cells. While UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to β cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2−/− mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates, but culminates in protracted steatosis indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.Publication Eosinophilic Colitis(Baishideng Publishing Group Inc., 2009-06-28) Okpara, Nnenna; Aswad, Bassam; Baffy, GyorgyEosinophilic colitis (EC) is a rare form of primary eosinophilic gastrointestinal disease with a bimodal peak of prevalence in neonates and young adults. EC remains a little understood condition in contrast to the increasingly recognized eosinophilic esophagitis. Clinical presentation of EC is highly variable according to mucosal, transmural, or serosal predominance of inflammation. EC has a broad differential diagnosis because colon tissue eosinophilia often occurs in parasitic infection, drug-induced allergic reactions, inflammatory bowel disease, and various connective tissue disorders, which require thorough searching for secondary causes that may be specifically treated with antibiotics or dietary and drug elimination. Like eosinophilic gastrointestinal disease involving other segments of the gastrointestinal tract, EC responds very well to steroids that may be spared by using antihistamines, leukotriene inhibitors and biologics.Publication Complexity and network dynamics in physiological adaptation: An integrated view(Elsevier BV, 2014) Baffy, Gyorgy; Loscalzo, JosephLiving organisms constantly interact with their surroundings and sustain internal stability against perturbations. This dynamic process follows three fundamental strategies (restore, explore, and abandon) articulated in historical concepts of physiological adaptation such as homeostasis, allostasis, and the general adaptation syndrome. These strategies correspond to elementary forms of behavior (ordered, chaotic, and static) in complex adaptive systems and invite a network-based analysis of the operational characteristics, allowing us to propose an integrated framework of physiological adaptation from a complex network perspective. Applicability of this concept is illustrated by analyzing molecular and cellular mechanisms of adaptation in response to the pervasive challenge of obesity, a chronic condition resulting from sustained nutrient excess that prompts chaotic exploration for system stability associated with tradeoffs and a risk of adverse outcomes such as diabetes, cardiovascular disease, and cancer. Deconstruction of this complexity holds the promise of gaining novel insights into physiological adaptation in health and disease.Publication Novel strategies in the pharmacotherapy of nonalcoholic fatty liver disease(Promenade Publishing House, 2016) Baffy, GyorgyNonalcoholic fatty liver disease (NAFLD) affects an estimated one billion people in the world. NAFLD is a spectrum of disease ranging from steatosis to steatohepatitis with variable outcomes that include cirrhosis and hepatocellular carcinoma. Lifestyle adjustment may be sufficient to manage steatosis, but success is difficult to achieve and sustain. In addition, patients with advanced forms of NAFLD or faster rates of progression need more efficient treatment. There is still no approved pharmacotherapy for NAFLD and current options have been limited to the secondary use of drugs developed for the treatment of obesity or diabetes and to hepatoprotective agents for the effect of which the strength of evidence is variable. However, recent advances in pharmaceutical research may soon change the landscape with several promising drug candidates in the pipeline designed to target specific molecular mechanisms implicated in the pathogenesis of NAFLD.Publication Mitochondrial uncoupling in cancer cells: Liabilities and opportunities(Elsevier BV, 2017) Baffy, GyorgyAcquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochon- dria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the de- velopment of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the ‘contract of endosymbiosis’ represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This impor- tant property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Respiratory complex I, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.Publication Metformin and Hepatocellular Carcinoma(2015) Kilaru, Saikiran Mayi; Baffy, GyorgyThere is ample evidence that type 2 diabetes is an independent risk factor for the development of various cancers including hepatocellular carcinoma (HCC). Metformin, a widely used antidiabetic agent, has been shown to have chemopreventive properties that may reduce the risk of cancer in diabetes. Here we summarize clinical and experimental data concerning the role of metformin in diabetes-associated hepatocarcinogenesis and review the key molecular mechanisms implicated in this action. By modulating mitochondrial function, metformin activates adenosine monophosphateactivated protein kinase (AMPK), a master regulator of energy metabolism that corrects most diabetes-associated derangements and mitigates the impact of insulin resistance on tumor growth. Moreover, metformin acts through additional AMPK targets in various pathways of oncogenesis and tumor suppression. Finally, metformin may also hinder hepatocarcinogenesis through AMPK-independent mechanisms. Controversies about the use of metformin as a chemopreventive agent include an efficacy bias related to duration and severity of diabetes, a lack of convincing impact on nonalcoholic fatty liver disease (NAFLD) representing the liver manifestation of diabetes, and a disputed role in lactic acidosis as a major adverse event. Future research may help develop randomized clinical trials on the impact of HCC by metformin, explore its utility in the non-diabetic and noncirrhotic population, elucidate its precise mechanisms of action to identify new molecular targets, and evaluate safer and more efficient derivatives of this intriguing compound.