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

We previously reported that in vitro hypoxic condition enhanced VEGF level and its receptor expression in hepatic cancer cell line, HepG2. Transcatheter hepatic arterial embolization (TAE) therapy is one of the vasculo-occlusive and hypoxic challenges to hepatocellular carcinoma (HCC). Therefore, we examined the level of VEGF in sera of patients with HCC who underwent TAE during the course of the treatment. Thirty-eight patients with HCC and hepatitis C virus-positive cirrhosis were studied. Peripheral blood samples were taken before and 1, 3 and 7 days after TAE with informed consent. The serum levels of VEGF as well as hepatocyte growth factor (HGF), another hepatic remodeling factor, were measured. The molar ratio (BTR) of serum branched chain amino acid (BCAA) to tyrosine (Tyr), the serum levels of AST, ALT and LDH were also examined. Although the level of AST, ALT and LDH reached the peak value within 1 day after TAE, VEGF level increased significantly 7 days later. On the other hand, there were no significant alterations in the levels of HGF and BTR during the course of TAE. Although the level of HGF was significantly correlated with the level of VEGF before TAE, this correlation was no more observed after TAE. These data collectively suggest that VEGF may be secreted in response to clinical hypoxic intervention, TAE, independent of HGF or altered amino acid metabolism. VEGF may play a role as a sensitive marker for tumor ischemia.
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PMID:Serum vascular endothelial growth factor in the course of transcatheter arterial embolization of hepatocellular carcinoma. 1033 62

Ninety individuals (76 males and 14 females) were classified into four groups. G1 (Control) included 20 healthy individuals. G2 (Chronic hepatitis) included 20 patients, G3 (Liver cirrhosis group) included 30 patients, and G4 (HCC) included 20 patients with HCC. All groups were subjected to clinical examination, abdominal ultrasonography, complete blood picture, HCV antibodies, HBs Ag, and function tests (total and direct bilirubin, total plasma proteins and albumin, prothrombin time and concentration, and liver enzymes AST, ALT and ALP). Patients of G3 & 4 were classified according to Child-Pugh classification into A. B and C. Upper endoscopic examination was done for 36/50 patients with chronic hepatitis or HCC. Circulating VEGF levels were determined by ELISA. There was a statistically high significant levels of circulating VEGF in G1, 2 & 3 than in the controls. A statistically significant higher level of circulating VEGF in G4 than in G3 & G4, and a statistically negative significant between VEGF levels and platelet count in G2. No significant correlation between VEGF and the grade of esophageal varices in G3 & G4. and no significant correlation between VEGF and upper GIT bleeding or spider naevi (vascular skin changes) in G2. A statistically significant was in correlation between VEGF and degree of hepatic dysfunction.
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PMID:Vascular endothelial growth factor level in chronic liver diseases. 1251 23

This study evaluated the significance of circulating bone marrow-derived endothelial progenitor cells (EPCs) in patients with hepatocellular carcinoma (HCC), a solid tumor with rich neovasculature. Eighty patients with HCC were recruited for the study, and 16 patients with liver cirrhosis and 14 healthy subjects were also included for comparison. Blood samples were taken before treatment. Total mononuclear cells were isolated from peripheral blood, preplated to eliminate mature circulating endothelial cells, and colony-forming units (CFUs) formed by circulating EPCs were counted. To validate the CFU scores, FACS quantification of EPCs using CD133, VEGFR2, and CD34 as markers was performed in 30 cases. Our study showed significantly higher mean CFU scores in patients with HCC compared to patients with cirrhosis and healthy controls (P = .001 and .009, respectively). Furthermore, the CFU scores of patients with HCC positively correlated with levels of serum alpha-fetoprotein (r = .303, P = .017), plasma VEGF (r = .242, P = .035), and plasma interleukin-8 (IL-8) (r = .258, P = .025). Patients with unresectable HCC had higher CFU scores than patients with resectable tumors (P = .027). Furthermore, for those who underwent curative surgery, higher preoperative CFU scores were observed in patients with recurrence within 1 year compared with those who were disease-free after 1 year (P = .013). In conclusion, higher circulating levels of EPCs are seen in patients with advanced unresectable HCC as compared to patients with resectable HCC or those with liver cirrhosis. Our evidence supports the potential use of circulating level of EPCs as a prognostic marker in patients with HCC.
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PMID:Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. 1700 19

The enlarged spleen in liver cirrhosis is considered to play a role in the pathogenesis of portal hypertension, but the splenic hemodynamics and molecular mechanisms behind the phenomenon have not been elucidated. The present study aimed to examine the splenic hemodynamics associated with splenic microcirculation and congestion, and to determine the status of the endothelial nitric oxide synthase (eNOS) signaling pathway in the spleen of rats with liver cirrhosis. Liver cirrhosis was induced by bile duct ligation. In rats with bile duct ligation (BDL rats) and control rats, splenic blood flow was measured using a laser Doppler flowmeter, and splenic blood volume was measured using a near-infrared spectrophotometer. The expressions of eNOS and its upstream effectors, Akt, TNF-alpha and VEGF, in the spleen were also determined. Specific splenic blood flow was significantly decreased in BDL rats compared with control rats. Specific splenic blood volume was also decreased in BDL rats, while their total splenic blood volume, especially the deoxygenated volume, was significantly increased. The expressions of phosphorylated and total eNOS, and the eNOS phosphorylation ratio, were all significantly decreased in the spleen of BDL rats. The Akt phosphorylation ratio and TNF-alpha concentration were also decreased in the spleen of BDL rats although the expression of VEGF was increased. These findings suggest that the eNOS signaling pathway is suppressed in the spleen of cirrhotic rats, and may contribute to the measured decreases in specific blood flow and volume in the spleen of liver cirrhosis. Determination of the factors influencing the suppression of eNOS in the spleen may shed light on how liver cirrhosis results in hypodynamic intrasplenic circulation.
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PMID:Splenic hemodynamics and decreased endothelial nitric oxide synthase in the spleen of rats with liver cirrhosis. 1748 68

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
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PMID:Cellular and molecular mechanisms of fibrosis. 1816 45

Angiogenesis, the development of new blood vessels from the existing vasculature, is essential in normal developmental processes. Uncontrolled angiogenesis is a major contributor to a number of disease states such as inflammatory disorders, obesity, asthma, diabetes, cirrhosis, multiple sclerosis, endometriosis, AIDS, bacterial infections and autoimmune disease. It is also considered a key step in tumour growth, invasion, and metastasis. Angiogenesis is required for proper nourishment and removal of metabolic wastes from tumour sites. Therefore, modulation of angiogenesis is considered as therapeutic strategies of great importance for human health. Numerous bioactive plant compounds are recently tested for their antiangiogenic potential. Among the most frequently studied are polyphenols present in fruits and vegetables. Plant polyphenols inhibit angiogenesis and metastasis through regulation of multiple signalling pathways. Specifically, flavonoids and chalcones regulate expression of VEGF, matrix metalloproteinases (MMPs), EGFR and inhibit NFkappaB, PI3-K/Akt, ERK1/2 signalling pathways, thereby causing strong antiangiogenic effects. This review focuses on the antiangiogenic properties of flavonoids and chalcones and examines underlying mechanisms.
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PMID:Antiangiogenic effects of flavonoids and chalcones. 1838 17

Local therapies such as radiofrequency ablation (RFA) represent a valuable choice in limited hepatocellular carcinoma (HCC) and are increasingly used also in advanced tumors. Medical treatments generally gave frustrating results in advanced HCC especially if comorbidities exist. Several biologic non-chemotherapeutic drugs are currently tested in HCC and, among them, octreotide was evaluated in single series of HCC patients reporting conflicting results. We have treated a series of 35 patients affected by advanced HCC (26 M and 9 F; age range: 55-85 years, median: 73 years) with RFA followed by octreotide to primarily evaluate the safety of combined treatment and to give preliminary evaluation on its activity. We have also evaluated serum VEGF changes during the study. Child A and Child B represented 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included in this study. All patients have multiple liver HCC nodules and one had bone metastases. Two complete responses, 3 partial responses and 23 disease stabilization for at least three months were obtained (overall response rate, 14,2%; clinical benefit, 80%). Mean overall survival was 31.4 months. The combined treatment was well tolerated. Statistically significant correlation was found between serum VEGF and tumor progression. In conclusion, the combination of RFA and octreotide was active in advanced HCC, however, confirmation in a larger series is required.
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PMID:Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience. 1863 2

Ang-(1-7) (angiotensin-1-7), a peptide product of the recently described ACE (angiotensin-converting enzyme) homologue ACE2, opposes the harmful actions of AngII (angiotensin II) in cardiovascular tissues, but its role in liver disease is unknown. The aim of the present study was to assess plasma levels of Ang-(1-7) in human liver disease and determine its effects in experimental liver fibrosis. Angiotensin peptide levels were measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects of Ang-(1-7) on experimental fibrosis were determined using the rat BDL (bile-duct ligation) model. Liver histology, hydroxyproline quantification and expression of fibrosis-related genes were assessed. Expression of RAS (renin-angiotensin system) components and the effects of Ang-(1-7) were examined in rat HSCs (hepatic stellate cells). In human patients with cirrhosis, both plasma Ang-(1-7) and AngII concentrations were markedly elevated (P<0.001). Non-cirrhotic patients with hepatitis C had elevated Ang-(1-7) levels compared with controls (P<0.05), but AngII concentrations were not increased. In BDL rats, Ang-(1-7) improved fibrosis stage and collagen Picrosirius Red staining, and reduced hydroxyproline content, together with decreased gene expression of collagen 1A1, alpha-SMA (smooth muscle actin), VEGF (vascular endothelial growth factor), CTGF (connective tissue growth factor), ACE and mas [the Ang-(1-7) receptor]. Cultured HSCs expressed AT1Rs (AngII type 1 receptors) and mas receptors and, when treated with Ang-(1-7) or the mas receptor agonist AVE 0991, produced less alpha-SMA and hydroxyproline, an effect reversed by the mas receptor antagonist A779. In conclusion, Ang-(1-7) is up-regulated in human liver disease and has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1-7)/mas receptor axis represents a potential target for antifibrotic therapy in humans.
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PMID:Angiotensin-(1-7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat. 1937 Dec 32

Sorafenib, a multitargeted anti-VEGF receptor and raf kinase inhibitor, was recently approved by the FDA for treating unresectable hepatocellular carcinoma (HCC) based on 2 randomized phase III studies. In addition, a phase II study evaluating sorafenib in patients with HCC and Child-Pugh A and B and a phase I study evaluating sorafenib in patients with organ dysfunction have provided insight about the safety and efficacy of sorafenib in patients with HCC and more advanced cirrhosis, and any difference in outcome based on etiology of HCC. The lack of objective responses observed in the sorafenib arm in the SHARP study also raises practical issues about how to assess response or efficacy of the therapy and thus how long a patient should receive sorafenib. This article addresses these questions on the use of sorafenib in HCC, both in the locally advanced and metastatic settings, in addition to the potential future applications and uses of sorafenib.
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PMID:Selection of patients with hepatocellular carcinoma for sorafenib. 1940 40

PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, the mechanisms that regulate PDGF signaling remain incompletely defined. Here, we found that in two rat models of liver fibrosis, the axonal guidance molecule neuropilin-1 (NRP-1) was upregulated in activated HSCs, which exhibit the highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor beta (PDGFRbeta) in HSCs both in the injury models and in human and rat HSC cell lines. In human HSCs, siRNA-mediated knockdown of NRP-1 attenuated PDGF-induced chemotaxis, while NRP-1 overexpression increased cell motility and TGF-beta-dependent collagen production. Similarly, mouse HSCs genetically modified to lack NRP-1 displayed reduced motility in response to PDGF treatment. Immunoprecipitation and biochemical binding studies revealed that NRP-1 increased PDGF binding affinity for PDGFRbeta-expressing cells and promoted downstream signaling. An NRP-1 neutralizing Ab ameliorated recruitment of HSCs, blocked liver fibrosis in a rat model of liver injury, and also attenuated VEGF responses in cultured liver endothelial cells. In addition, NRP-1 overexpression was observed in human specimens of liver cirrhosis caused by both hepatitis C and steatohepatitis. These studies reveal a role for NRP-1 as a modulator of multiple growth factor targets that regulate liver fibrosis and the vascular changes that accompany it and may have broad implications for liver cirrhosis and myofibroblast biology in a variety of other organ systems and disease conditions.
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PMID:Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells. 2217 87


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