Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The capacity for the liver to regenerate after injury or resection has long been recognized, as implied by the legend of Prometheus. Resections of up to 70% of the liver are followed by a sequence of events that generally result in complete restitution of hepatic mass and function. Hypertrophy of hepatocytes begins within hours, with accumulation of amino acids and triglycerides and activation of enzymes that are associated with proliferative activity. Increased DNA synthesis is associated initially with hyperplasia of hepatocytes, and then other cells, which begins in the periportal region and spreads in a wave-like fashion to the pericentral region of the lobule. Quiescent hepatocytes are primed to enter the cell cycle and then proceed through the G1/S and G2/M restriction points, under the influence of a variety of proteins, growth factors (especially hepatocyte growth factor) and cycle dependent kinases. At each stage there is interplay between growth promoters and inhibitors, including transforming growth factor-beta and GABA. Factors that initiate hepatic regeneration are unknown, and might include hepatic depolarization, increases in blood flow, destruction of liver matrix (with release of growth factors), and increased production or expression of growth promoters compared to inhibitors. Regenerative activity increases with the amount of resection to a point, and then relatively declines. Uncontrolled proliferation of liver tissue after resection or injury is not necessarily beneficial, because it could lead to a diversion of resources from the maintenance of hepatic function and to an increased risk of neoplasia. Therefore, it is unclear whether clinicians should attempt to enhance hepatocyte regeneration. Since both hepatic regeneration and metabolic function require energy from high-energy nucleotide triphosphates, especially adenosine triphosphate (ATP), a reasonable strategy might be to augment energy delivery and ATP production. Mortality rates after limited (fewer than 70%) resections and mild or moderate injuries of previously normal livers are low, and supportive care is often sufficient. The prognosis is unclear; however, in cases of more massive resection, resections in the setting of underlying liver disease or cirrhosis, and fulminant hepatic failure, and liver transplantation is still an important option.
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PMID:Hepatic regeneration: If it ain't broke, don't fix it. 1291 14

Amino acids can serve as regulatory molecules that modulate numerous cellular functions. Branched chain amino acids (BCAAs) are known to exert influences on cellular metabolism, amino acid transport, protein turn over, and gene expression. However, the mechanisms involved in the specific effect of BCAAs have not been clarified. BCAA supplementation therapy is a current treatment for patients with liver cirrhosis, therefore, specific BCAA activities should be examined. Hepatocyte growth factor (HGF) is considered to be a pleiotropic factor, and is reported to modulate gene expression and to stimulate the proliferation and functions of many cell types, including hepatocytes. A potential application of HGF for several types of diseases has been postulated. Here, we describe the potential of BCAAs as a therapeutic agent that acts through the induction of HGF production in the liver.
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PMID:Significance of branched chain amino acids as possible stimulators of hepatocyte growth factor. 1468 77

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide; the overall survival of patients with HCC is grim because most patients are diagnosed late, when curative treatment is not possible. Cirrhosis is the strongest risk factor for the development of HCC. HCC surveillance with alpha-fetoprotein (AFP) and ultrasonography has been recommended for persons with cirrhosis. However, AFP level is insensitive for the early detection of HCC, and ultrasonography is expensive and operator dependent. Clearly, there is a need for novel strategies for the early detection of HCC. The ideal biomarker assay for HCC would be sensitive, specific, noninvasive, reproducible, inexpensive, and acceptable to patients. The Early Detection Research Network of the National Cancer Institute has proposed 5 phases for biomarker validation: preclinical exploratory studies, clinical assay development for disease, retrospective longitudinal study to detect preclinical disease, prospective screening study, and cancer control studies. Several biomarkers, such as des-gamma carboxyprothrombin, lens culinaris agglutinin-reactive AFP, human hepatocyte growth factor, and insulin-like growth factor-1, are promising, but none of these markers has been validated for clinical use. Limitations of the current literature include inadequate sample size, heterogeneity in biomarker assay methods and result reporting, limited analysis of demographics and cause of liver disease as covariates in the expression of these markers, and a scarcity of longitudinal studies evaluating the ability of biomarkers to detect preclinical disease. There is an urgent need for novel biomarkers for the detection of early HCC; the National Cancer Institute proposal provides a framework for future validation studies.
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PMID:Newer markers for hepatocellular carcinoma. 1550 74

Vocal fold scarring remains a therapeutic challenge. Hepatocyte growth factor (HGF) has strong antifibrotic activity and has proved to have therapeutic potential in restoration of scar tissues such as liver cirrhosis and lung fibrosis. The present study aimed to clarify the effects of HGF injection into scarred vocal folds in a canine model. Canine vocal folds were stripped unilaterally and treated with intracordal injection of saline solution (sham group), HGF (HGF group), or HGF with cultured autologous normal vocal fold fibroblasts (Fb/HGF group) 1 month after injury. The larynges were harvested 6 months after the initial injury and then subjected to vibratory and histologic examination. The results of vibratory examinations in the excised larynx setup revealed that phonation threshold pressure significantly increased and vocal efficiency was significantly reduced in all treated groups as compared to normal data obtained from normal canine larynges. However, the HGF group presented much better results than both the sham and Fb/HGF groups in terms of mucosal wave amplitude and incidence of vocal fold bowing, glottal incompetence, and phase asymmetry. The histologic data indicated a significant increase of collagen in both the sham and Fb/HGF groups, while normal levels of collagen were found in the HGF group. Tissue contraction of the lamina propria was also observed in both the sham and Fb/HGF groups, but was barely detectable in the HGF group. Although the HGF-treated vocal folds appeared to require more driving forces for vibration, HGF might prevent excessive collagen deposition and tissue contraction and thus reduce the effects of scarring on the vibratory properties of the vocal folds. From these data it is concluded that HGF has considerable potential in the treatment of vocal fold scarring.
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PMID:Growth factor therapy for vocal fold scarring in a canine model. 1553 39

Hepatocyte growth factor (HGF) stimulates liver regeneration and has the potential to be a therapeutic agent for fatal liver diseases, including fulminant hepatic failure and liver cirrhosis. In this study, we investigated the pharmacokinetics of recombinant human HGF, which will be soon available for clinical applications. When recombinant human HGF (0.1mg/kg) was administered intravenously to normal rats, serum levels of human HGF increased to 89.7+/-20.6ng/ml 5min after the bolus injection, followed by a decrease with a half-life of 2.4min. Recombinant HGF administered intravenously was distributed primarily to the liver and induced c-Met tyrosine phosphorylation in liver tissues. In comparison, rats given recombinant human HGF via the portal vein exhibited lower serum HGF and an increase in hepatic distribution. Additionally, when compared with normal rats, those with 70% partial hepatectomy or liver cirrhosis showed an increase in serum levels of human HGF with a prolonged half-life. These results suggest that, despite a short half-life, bolus injection of recombinant human HGF may induce therapeutic effect in patients with fatal live disease, and that the dose of this recombinant protein should be modulated according to the degree of liver injury.
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PMID:Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein. 1558 84

Although the functions associated with differentiation are thought to be suppressed when cells proliferate, recent studies have shown that several mitogens can stimulate functions such as protein production under certain physiological conditions. Hepatocyte growth factor (HGF) is now considered to be a pluripotent factor and has been shown to stimulate the differentiated functions of hepatocytes, as well as their proliferation. The use of HGF for the treatment of liver disease, especially hepatic failure, has been suggested. Because patients with decompensated liver cirrhosis have decreased plasma concentrations of branched-chain amino acids (BCAAs), many investigations in laboratory animals and patients have been designed to demonstrate the benefits of supplementation of BCAAs on the hepatic metabolism of proteins. However, the mechanisms involved in the specific actions of BCAAs remain to be elucidated. Amino acids are molecules that modulate numerous cellular functions. BCAAs are known to influence gene expression, cellular metabolism, amino acid transport, and protein turnover. In this paper, we show the potential of BCAAs for stimulating HGF synthesis in the liver and discuss the possibility that BCAAs stimulate protein production by hepatocytes through the induction of HGF.
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PMID:Branched-chain amino acids, hepatocyte growth factor and protein production in the liver. 1560 33

Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.
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PMID:Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis. 1579 83

Because of their peculiar role in whole-body nitrogen metabolism and the competitive action on amino acid transport across the blood-brain barrier, branched-chain amino acids (BCAAs) have been extensively used in subjects with liver disease to preserve or to restore muscle mass and to improve hepatic encephalopathy. There are no data regarding safe limits of BCAA administration; the results appear to be better when BCAA-enriched formulas or BCAA-supplemented diets are preferred to pure BCAA formulas. Improved nitrogen retention might ameliorate the nutritional status, a prognostic index of long-term survival in cirrhosis and of short-term survival in patients undergoing surgical procedures. The effects on nutrition and ultimately on prognosis of patients with advanced cirrhosis were confirmed in a large multicenter, long-term trial where oral BCAA supplements were compared with equicaloric or equinitrogenous-equicaloric supplements (maltodextrin or lactoalbumin). Similarly, BCAA treatment improved the prognosis of patients with hepatocellular carcinoma, treated by surgical resection or chemoembolization, and of liver transplant patients. The mechanism(s) for the beneficial effects of BCAAs might be mediated by their stimulating activity on hepatocyte growth factor, favoring liver regeneration. The debate regarding the potential effectiveness of BCAAs dates back to the early 1980s. The number of patients who cannot tolerate dietary proteins in amounts sufficient to meet the higher catabolism of advanced liver disease is probably low, but BCAAs remain the sole treatment of proved efficacy in this specific setting.
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PMID:Branched-chain amino acid supplementation in patients with liver diseases. 1593 Apr 76

Hepatocyte growth factor (HGF) gene therapy may have potential for treating chronic hepatitis (CH) and liver cirrhosis (LC). However, the lack of an HGF gene therapy study on hepatomas that are often associated with CH or LC, together with the stimulatory effects of HGF on many types of cancer, may hamper its application. This study explored the effects of adenoviral HGF gene transduction and their mechanisms on two types of hepatoma cells (hepatoblastoma and hepatocellular carcinoma) in in vitro experiments. Both types of hepatomas were revealed to have higher adenoviral gene transduction efficiencies and more efficient expressions of the HGF transgene, which successfully activated the HGF receptor/c-Met in an autocrine fashion, than those of other types of cancer. Notably, not only HGF, but also adenoviral infection, inhibited DNA synthesis, whereas only HGF but not adenoviral infection exerted a potent apoptotic effect. Moreover, adenoviral HGF gene transduction additively exerted inhibitory effects on cisplatin-treated hepatomas. In conclusion, inhibitory and apoptotic effects of adenoviral HGF gene transduction in hepatomas in contrast to potent mitogenic and antiapoptotic effects of HGF for hepatocytes are not only of biological interest, but also pose clinical benefits for adenoviral HGF gene therapy for CH and LC.
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PMID:Adenoviral gene transduction of hepatocyte growth factor elicits inhibitory effects for hepatoma. 1594 46

Permanent alcohol abuse may lead to chronic liver injury with deleterious sequelae such as liver cirrhosis and hepatocellular carcinoma. Mechanisms of fibrogenesis encompass recruitment of inflammatory cells at the site of injury and cytokine mediated activation of hepatic stellate cells (HSC) with accumulation of interstitial collagens. HSC transdifferentiation and accompanying apoptosis result in destruction of liver architecture and are therefore key steps of disease progression. TGF-beta represents the main profibrogenic cytokine in liver fibrosis and other fibroproliferative disorders by inducing extracellular matrix deposition as part of the wound healing response. In parallel, TGF-beta triggers hepatocytes that are strongly responsive for this cytokine, to undergo apoptosis, thereby providing space for HSC proliferation and generation of a collagenous matrix. Anti TGF-beta approaches were established and successfully utilized for the treatment of experimental fibrogenesis. Dominant negative TGF-beta receptors (TbetaR), generated by fusing the Fc domain of human IgG and the N-terminal (extracellular) fragment of TbetaRII (Fc:TbetaRII) were applied to suppress fibrosis. Similarly TGF-beta binding proteins like decorin, antagonistic cytokines such as bone morphogenetic protein-7, hepatocyte growth factor, IL-10, or IFN-gamma were as efficient as camostat mesilate, a protease inhibitor that possibly abrogated proteolytic activation of TGF-beta. Further, our group recently overexpressed Smad7 in bile duct ligation induced liver fibrosis and achieved efficient inhibition of intracellular TGF-beta signaling, thereby counteracting profibrogenic effects in cultured HSC and in vivo. A direct link between the effect of alcohol and TGF-beta exists through reactive oxygen species that are generated in liver cells by alcohol metabolism and represent activators of TGF-beta signaling. Thus, soluble TbetaRII expression reduced experimental fibrogenesis in vitro and in vivo partially by decreasing intracellular ROS and inhibiting NADH oxidase. Approaches that specifically target profibrogenic TGF-beta signaling are promising to treat alcoholic liver disease in the future. However, to ensure safety for the patients to be treated, approaches with strong specificity need to be established. Therefore, it is essential to delineate the profibrogenic actions of TGF-beta and the influence of alcohol abuse in molecular detail.
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PMID:Anti-TGF-beta strategies for the treatment of chronic liver disease. 1634 96


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