bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial glutathione: Hepatocellular survival–death switch
Authors: Garcia‐Ruiz Carmen , Fernandez‐Checa José C 
Published: August 2006

AbstractSteatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non‐alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine‐induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol‐mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol‐fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.
Anti‐adipogenic regulation underlies hepatic stellate cell transdifferentiation
Authors: Tsukamoto Hidekazu , She Hongyun , Hazra Saswati , Cheng Jason , Miyahara Takeo 
Published: August 2006

AbstractCirrhosis is the most important consequence of alcoholic liver disease for which liver transplantation is the only treatment option available. Transdifferentiation of hepatic stellate cells (HSC) to myofibroblastic cells (MF) is a central event in liver fibrogenesis, and understanding molecular mechanisms that underlie this cellular event provides pivotal insights into development of new therapeutic modalities for cirrhosis. To this end, the authors proposed several years ago that transdifferentiation of quiescent HSC to MF may be causally associated with transcriptional regulation known for adipocyte–preadipocytic fibroblast dedifferentiation. In support of this notion, the authors showed that adipogenic transcription factors and their downstream adipocyte specific genes are expressed abundantly in quiescent HSC and that this expression profile is lost in HM. Further, gain‐of‐function manipulations for adipogenic transcription factors such as peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) and sterol regulatory element binding protein‐1c have been shown to reverse culture‐induced MF to quiescent HSC. The authors also demonstrated that tumor necrosis factor‐α and Wnt, known mediators of anti‐adipogenesis, also suppress the activity of PPAR‐γ and contribute to HSC‐MF transdifferentiation. These results reinforce the concept of adipogenic regulation essential to the quiescent phenotype and the loss of such regulation underlying HSC‐HM transdifferentiation. They also provide insights into the molecular basis for the use of PPAR‐γ agonists, which has been advocated for treatment of liver fibrosis.
Methionine adenosyltransferase and S‐adenosylmethionine in alcoholic liver disease
Authors: Lu Shelly C , Martínez‐Chantar M Luz , Mato José M 
Published: August 2006

AbstractMethionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the formation of the principal methyl donor S‐adenosylmethionine (SAMe). Studies in the past decade have shown that SAMe is not only a methyl donor, but also a key metabolite that regulates hepatocyte growth, death and differentiation. Abnormalities in MAT and decreased SAMe levels occur in experimental animals and humans with alcoholic liver disease. Chronic hepatic SAMe deficiency can result in the spontaneous development of steatohepatitis and hepatocellular carcinoma. This paper reviews MAT genes and SAMe in relation to alcoholic liver disease and the molecular mechanisms by which SAMe regulates hepatocyte growth and apoptosis.
Role of matrix metalloproteinase‐2 in ethanol‐induced invasion by breast cancer cells
Authors: Luo Jia 
Published: August 2006

AbstractEthanol is a tumor promoter and may enhance the metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Amplification of ErbB2, a receptor tyrosine kinase, is found in 20–30% of breast cancer patients. Ethanol preferably stimulates invasion by breast cancer cells over‐expressing ErbB2 in vitro. Over‐expression of ErbB2 is positively associated with elevated levels of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9. Ethanol at physiologically relevant concentrations activates MMP‐2 without altering its expression level in mammary epithelial cells over‐expressing ErbB2, but not in cells expressing low levels of ErbB2. The activation is dependent on c‐jun N‐terminal kinases (JNK) and reactive oxygen species. Selective inhibitors of MMP‐2 and anti‐oxidants significantly inhibit ethanol‐stimulated cell invasion. Similarly, knocking down MMP‐2 by small interference RNA induces a partial blockage on ethanol‐promoted cell invasion. Matrix metalloproteinase‐2 is predominantly expressed in stromal fibroblasts; ethanol also activates fibroblastic MMP‐2. The conditioned medium collected from ethanol‐exposed fibroblasts dramatically stimulates the invasion of breast cancer cells. The role of MMP‐2 in ethanol‐induced tumor promotion is discussed.
Regulation of Kupffer cell activity during chronic ethanol exposure: Role of adiponectin
Authors: Park Pil‐hoon , Thakur Varsha , Pritchard Michele T , McMullen Megan R , Nagy Laura E 
Published: August 2006

AbstractThere is a growing appreciation that adipose tissue is a multifunctional organ. In addition to its central role in lipid storage, adipose tissue secretes a diverse group of proteins, called adipokines, involved in lipid metabolism, insulin sensitivity, angiogenesis etc. Adipocytes also secrete various inflammatory and anti‐inflammatory mediators. Adiponectin, an adipokine with potent anti‐inflammatory properties, is thought to play an important role in the regulation of inflammation. The development of alcoholic liver disease is thought to involve increased pro‐inflammatory activity, mediated in part by the activation of Kupffer cells. Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of reactive oxygen species (ROS) and tumor necrosis factor‐α (TNF‐α). Recent studies have demonstrated a hepato‐protective effect of adiponectin in the progression of alcoholic liver disease. Herein are summarized recent data demonstrating that adiponectin treatment can normalize LPS‐stimulated ROS production and TNF‐α expression in Kupffer cells after chronic ethanol feeding. These studies suggest that the hepato‐protective activity of adiponectin is due, at least in part, to a direct anti‐inflammatory effect of adiponectin on Kupffer cells.
Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum
Authors: Kaplowitz Neil , Ji Cheng 
Published: August 2006

AbstractIntragastric ethanol feeding in mice induces expression of unfolded protein response/endoplasmic reticulum (UPR/ER) stress response genes. The proximate cause appears to be hyperhomocysteinemia, a well‐known cause of ER stress in other contexts. Hyperhomocysteinemia appears to be due to downregulation of methionine synthase. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol‐induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol‐induced ER stress can activate sterol regulatory element‐binding protein (SREBP)‐1c and SREBP‐2, which contribute to the accumulation of triglyceride and cholesterol. Hyperhomocysteinemia, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNF signaling. At present ER stress as an important factor in the pathogenesis of alcoholic liver disease is an exciting new hypothesis and ongoing research will need to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S‐adenosylhomocysteine, or increased S‐adenosylmethionine.
Alcohol and lipid metabolism
Authors: Crabb David W , Liangpunsakul Suthat 
Published: August 2006

AbstractHepatic lipid metabolism is controlled by several master transcription factors, in particular peroxisome proliferator‐activated receptor‐α (PPAR‐α) and sterol response element binding protein‐1 (SREBP‐1). Peroxisome proliferator‐activated receptor‐α is a receptor for free fatty acids (FFA), and can activate genes involved in transport, oxidation, and export of FFA. Sterol response element binding protein‐1 is a sensor for the level of cholesterol in the liver, and is able to activate genes involved in synthesis of cholesterol and FFA. Chronic ethanol treatment of cells or animals inhibited PPAR‐α function and activated SREBP. In addition, ethanol inhibited adenosine monophosphate‐dependent protein kinase (AMPK). The AMPK controls fatty acid metabolism by inhibiting acetyl‐coenzyme A carboxylase, reducing malonyl‐coenzyme A, and thereby permitting fatty acid transport into and oxidation in the mitochondrion. Adenosine monophosphate‐dependent protein kinase was inhibited in alcohol‐treated animals and cells. The mechanisms by which ethanol affects AMPK and the transcription factors are as yet incompletely understood.
Gene–environment factors that contribute to alcoholic pancreatitis in humans
Authors: Whitcomb David C 
Published: August 2006

AbstractAlcohol‐associated acute and chronic pancreatitis occur in a minority of alcohol users, suggesting that most drinkers are protected from pancreatic diseases while a subset is susceptible. Ongoing studies suggest that the pathophysiology is complex and can involve multiple genetic and environmental pathways and stochastic events. Both rat models and human genetic epidemiology studies have been used to understand susceptibility and modifying factors in humans. Rat studies suggest that different types of altered pancreatic physiology occur depending on dose, they occur rapidly and that alcohol changes the immune response to recurrent pancreatic injury. Human studies suggest that PRSS1 and SPINK1 mutation increase the pancreas’ susceptibility to alcohol‐associated pancreatitis, and that tobacco smoking, and some factors, affect disease progression.
Hepatic stellate cells and the reversal of fibrosis
Authors: Kisseleva Tatiana , Brenner David A 
Published: August 2006

AbstractHepatic fibrosis is an outcome of many chronic liver diseases, such as viral and autoimmune hepatitis, and of alcohol consumption and biliary obstruction. Prolonged liver injury results in hepatocyte damage, which triggers activation of hepatic stellate cells (HSC) and recruitment of inflammatory cells into the liver. The HSC play a critical role in fibrogenesis. They produce collagen type I and secrete pro‐fibrogenic cytokines and inhibitors of matrix‐degrading enzymes (tissue inhibitor of matrix metalloproteinase), causing the production of extracellular matrix deposition over degradation. However, many clinical and experimental studies suggest that this process can be reversed, including the apoptosis of activated HSC. Thus, HSC represent an appealing target for antifibrotic therapy. This review will focus on some aspects of etiology and molecular pathogenesis of liver fibrosis and the reversal of fibrosis.
Transcriptional regulation of stellate cell activation
Authors: Friedman Scott L 
Published: August 2006

AbstractThe identification of activated hepatic stellate cells and related cell types as key fibrogenic effectors during liver injury has led to intense evaluation of transcriptional events underlying their behavior. While initial studies focused on characterizing interactions between transcription factors and regulatory regions within gene promoters, epigenetic mechanisms have emerged as major determinants of gene activation and repression, in particular histone acetylation and promoter methylation, as well as other complex conditional interactions that underlie global changes in gene expression. Three examples are provided that illustrate how stellate cell activation may be controlled by widely divergent regulatory pathways, including alternative splicing of a growth inhibitory transcription factor (Kruppel‐like factor‐6), epigenetic regulation of a factor regulating stellate cell survival (nuclear factor κB), and regulation of a transcription factor whose expression maintains stellate cell quiescence (LIM homeobox gene 2 [Lhx2]). These complex cascades illustrate how clarifying the finely tuned interdependent layers of transcriptional, translational, post‐translational and epigenetic gene regulation in stellate cells is raising new prospects for therapy of hepatic fibrosis.
Matrix metalloproteinases, the pros and cons, in liver fibrosis
Authors: Han Yuan‐Ping 
Published: August 2006

AbstractResiding in the space of Disse within loose extracellular matrix (ECM) resembling that in basement membranes, the hepatic stellate cells (HSC) remain in quiescence as vitamin A storage cells. In response to liver injury HSC undergo morphologic and functional trans‐differentiation, converting from vitamin A‐storing, star‐like cells into contractile myofibroblastic cells, a process called activation. Accompanying cellular activation, the ECM components in the space of Disse switch from matrices rich in type‐IV collagen and laminin, into condensed interstitial ECM, indicating that proteolytic degradation may occur to change the microenvironment in sinusoids as well as the fate of HSC. Indeed, matrix metalloproteinases (MMP), a family of ECM degradative enzymes, are promptly expressed by HSC in response to diverse hepatic toxins. In vitro experiments also demonstrated the role of MMP in activation of HSC cultured in 3‐D ECM. Conversely, MMP may also contribute to regression of liver fibrosis through cleavage of the fibrillar ECM and promotion of apoptosis among the activated HSC. Thus, MMP play dual roles both bad and good in liver fibrosis, depending on the timing.
Battle‐scarred pancreas: Role of alcohol and pancreatic stellate cells in pancreatic fibrosis
Authors: Apte Minoti V , Pirola Romano C , Wilson Jeremy S 
Published: August 2006

AbstractPancreatic stellate cells (PSC) are now recognized as the key mediators of pancreatic fibrosis, a characteristic feature of chronic pancreatitis. The role of PSC in alcoholic pancreatic fibrosis has been examined in vivo (using pancreatic tissue from patients with alcohol‐induced chronic pancreatitis and from animal models of experimental pancreatitis) and in vitro (using PSC in culture). These studies indicate that PSC are activated early in the course of pancreatic injury and are the predominant source of collagen in the fibrotic pancreas. The factors responsible for mediating PSC activation during chronic alcohol exposure include ethanol, its metabolite acetaldehyde, oxidant stress and cytokines (released during episodes of alcohol‐induced pancreatic necroinflammation). Most recently, the intracellular signaling mechanisms regulating ethanol‐induced PSC activation have been identified and include the mitogen‐activated protein kinase (MAPK) pathway, phosphatidylinositol‐3‐kinase (PI3K) and protein kinase C (PKC), and the transcription factor activator protein‐1 (AP‐1).
Evaluation of the role of nuclear factor‐κB signaling in liver injury using genetic animal models
Authors: Luedde Tom , Beraza Naiara , Trautwein Christian 
Published: August 2006

AbstractMost chronic liver diseases are not sufficiently treatable at present and very often progress to liver fibrosis and liver cirrhosis. Several recent studies have suggested that cytokines and cytokine‐activated inflammatory signaling pathways might play an important role in the mediation of liver injury. Although pro‐inflammatory signaling pathways such as nuclear factor (NF)‐κB have evolved primarily for host defense to infections, they appear to be involved in the pathogenesis of inflammatory diseases and may mediate liver injury in response to a variety of agents and pathogens. Herein is summarized briefly some recent findings concerning the role of NF‐κB in different models of liver injury based on transgenic and knockout animal technology.
Alcohol‐induced oxidative stress and cell responses
Authors: Wu Dongmei , Zhai Qiwei , Shi Xianglin 
Published: August 2006

AbstractEpidemiological and animal studies have demonstrated that alcohol abuse is directly associated with the increase of multiple organ diseases, such as liver injury, cardiovascular diseases, and neurological disorders. While the mechanisms of alcohol‐induced cell injury and disease remain to be investigated, recent studies indicate that reactive oxygen species (ROS) may play an important role. Reactive oxygen species are able to cause various cellular injuries, such as DNA damage, lipid peroxidation and protein modification. Cellular systems are protected from ROS‐induced cell injuries by an array of defenses composed of various anti‐oxidants with different functions. When the ROS present in the cellular system overpower the defense systems, they will cause oxidative stress or cell injury, leading to the development of diseases. This article reviews recent literature on alcohol‐induced ROS production, oxidative stress, signal transduction, and cellular responses. The implication of these processes in alcohol‐related diseases is also discussed.
Interactions of cytokines, S‐adenosylmethionine, and S‐adenosylhomocysteine in alcohol‐induced liver disease and immune suppression
Authors: Barve Shirish , Joshi‐Barve Swati , Song Zhenyuan , Hill Daniell , Hote Prachi , Deaciuc Ion , McClain Craig 
Published: August 2006

AbstractAlcoholic liver disease (ALD) remains a leading cause of death in the USA. Defining mechanisms for liver cell death in ALD in order to develop potential new agents for therapeutic intervention is a major focus of the authors’ work. Abnormal cytokine metabolism is a major feature of ALD, and a thorough understanding of both mechanisms and interactions of cytokine overproduction and sensitization are critical to developing a possible treatment for ALD. S‐Adenosylmethionine has been used in a variety of animal studies and clinical trials and has been reported to improve biochemical parameters of liver function. Last, immunosuppression associated with chronic alcohol abuse is an important predisposing factor to opportunistic infections and cancer. It is the authors’ working hypothesis that alcohol consumption leads to chronic activation of the immune system.
Causes and consequences of mitochondrial reactive oxygen species generation in hepatitis C
Authors: Wang Ting , Weinman Steven A 
Published: August 2006

AbstractHepatitis C virus has developed mechanisms to alter the redox state of hepatocytes and this is associated with changes in mitochondrial structure and function. Chronic hepatitis C patients manifest hepatic oxidative stress and this is exacerbated by alcohol consumption and associated with fibrosis progression. Several viral proteins, including core and NS5a appear to contribute to reactive oxygen species (ROS) generation by mechanisms that involve both mitochondria and endoplasmic reticulum (ER). Hepatitis C virus (HCV) core protein localizes to both ER and mitochondria and has effects at both sites. At the mitochondria a chain of events is initiated by core binding, which consists of increased Ca2+ uptake, increased mitochondrial superoxide production, oxidation of the mitochondrial glutathione pool, inhibition of electron transport complex I activity, and sensitization of mitochondria to Ca2+‐ and ROS‐induced membrane permeability transition. These effects have been observed in isolated mitochondria, cells bearing full‐length HCV replicons, and liver mitochondria derived from HCV transgenic mice. In addition to these direct effects on mitochondria, core protein has been shown to causes a state of ER stress and an increase in the efficiency of ER to mitochondria Ca2+ transfer. The resulting oxidized redox state has a number of potential consequences for liver function. It interferes with the antiviral innate immune responses and potentiates fibrosis and carcinogenesis. Alcohol exacerbates these effects by increasing core‐induced ROS production, further oxidizing the mitochondrial glutathione pool. The resulting mitochondrial effects may contribute to liver injury and oxidative stress seen in chronic hepatitis C.
Role of stellate cells in pancreatic fibrogenesis associated with acute and chronic pancreatitis
Authors: Bachem Max G , Zhou Zhengfei , Zhou Shaoxia , Siech Marco 
Published: August 2006

AbstractPancreas fibrosis is the result of a dynamic cascade of mechanisms beginning with acinar cell (AC) injury and necrosis and followed by inflammation, activation of macrophages, aggregation of platelets, release of growth factors and reactive oxygen species (ROS), activation of pancreatic stellate cells (PSC), stimulated synthesis of extracellular matrix and reduced matrix degradation. The result is a net matrix accumulation. Numerous in vivo and in vitro studies have provided strong evidence of a central role for PSC in fibrogenesis associated with acute and chronic pancreatitis. The PSC share homologies with hepatic stellate cells (HSC). In normal pancreas, the fat‐storing phenotype of PSC is found in low numbers (approx. 4% of the cells) in the periacinar and interlobular space. Similar to the stellate cell‐activating mechanisms in the liver, in pancreas injury PSC change their phenotype from the fat‐storing to a highly active matrix‐producing cell type (activated PSC). The induction of the activated phenotype of PSC has been shown to involve a number of diverse extra‐ and intracellular effector molecules, including inflammatory cytokines, growth factors, ethanol, acetaldehyde, and oxidative stress.
Early peristalsis following epidural analgesia during abdominal surgery in an extremely low birth weight infant
Authors: HOEHN THOMAS , JETZEK‐ZADER MARTIN , BLOHM MARTIN , MAYATEPEK ERTAN 
Published: August 2006

SummaryThe inhibiting effect of opioids on intestinal motility is a cause of particular concern in extremely low birth weight (ELBW; birth weight <1000 g) infants with decreased peristalsis. An ELBW infant (birth weight 740 g) born after 26 + 1 week of gestation had an uneventful clinical course during the first few days of life. Sudden deterioration occurred on day 8 with metabolic acidosis, hyperglycemia and frequent apnea with secondary bradycardia. A chest X ray demonstrated the presence of air beneath the diaphragm. Intestinal perforation was suspected and the infant was taken to theater for laparotomy. For pain management, a 22 G epidural catheter was inserted via the caudal approach and threaded to a mid‐thoracic level. Epidural ropivacaine was administered intraoperatively and for 48 h postoperatively. The infant was extubated on the following day. Opioids were not required or given at any stage during or after surgery. Peristalsis was present on auscultation as early as 3 h after surgery, the first stool was passed on the same day. Enteral nutrition was resumed early and tolerated well, full enteral feeding was rapidly achieved. Our case shows that the technique of caudal anesthesia is feasible in ELBW infants. We speculate that intestinal motility and establishment of full enteral feedings may be achieved earlier by epidural ropivacaine in cases of abdominal surgery in ELBW infants.