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 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic stellate cells (PSCs) are thought to be the primary source of the extensive fibrotic reaction characteristic of pancreatic cancer and chronic pancreatitis in humans. PSCs share many morphological and functional characteristics with hepatic stellate cells (HSCs), whose central role in liver fibrosis is well established. However, it has remained unclear if hepatic and pancreatic stellate cells are derived from a common cell lineage and if they are completely similar or if they possess organ-specific features. We have analysed the transcriptomes of HSCs, PSCs and skin fibroblasts to assess how the transcriptional phenotype of stellate cells differs from that of a typical fibroblast lineage cell and if there is evidence for a common stellate cell precursor. To this end, we have performed expression profiling of primary cultures of human HSCs, PSCs and skin fibroblasts using 23,000-feature 'whole genome' oligonucleotide micro-arrays. Expression data were verified using real-time PCR. The expression profiles of HSCs and PSCs displayed a great extent of similarity, clearly separating them from the fibroblasts. Predominantly extracellular and cell surface genes, but also signalling molecules, transcription factors and novel neural markers, were concordantly expressed in both stellate cell types. Despite this high degree of similarity, distinct differences in expression patterns were observed between HSCs and PSCs, reflecting organ-specific variations of the common stellate cell-specific phenotype.
J Mol Med (Berl) 2005 Oct
PMID:Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype. 1597 18

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis, transdifferentiating in chronic liver disease from "quiescent" HSC to fibrogenic myofibroblasts. Transforming growth factor-beta (TGF-beta), acting both directly and indirectly, is a critical mediator of this process. To characterize the function of the TGF-beta signaling intermediates Smad2 and Smad3 in HSC, we infected primary rat HSC in culture with adenoviruses expressing wild-type and dominant negative Smads 2 and 3. Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. Additionally, coinfection experiments suggested that Smad2 and Smad3 signal via independent pathways. Smad3-overexpressing cells as well as TGF-beta-treated cells demonstrated more focal adhesions and increased alpha-smooth muscle actin (alpha-SMA) organization in stress fibers, although all cells reached the same level of alpha-SMA expression, indicating that Smad3 also regulates cytoskeletal organization in HSC. We suggest that TGF-beta, signaling via Smad3, plays an important role in the morphological and functional maturation of hepatic myofibroblasts.
Mol Biol Cell 2005 Sep
PMID:Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization. 1598 42

The question addressed here is: does the bile duct reactive component of hepatitis C disease progress during the progression of the disease to cirrhosis? The question is important because if the answer to the question is yes, then an important correllated question is: does the bile duct reactive component contribute to the fibrotic change which leads to cirrhosis? The first question is addressed in the present study of a series of liver biopsies taken at the four stages of liver fibrosis in patients with hepatitis C. Sixty-four patients with hepatitis who had been biopsied for staging purposes were reviewed retrospectively. The liver biopsies were routinely stained with antibodies for liver cells, bile duct cells, activated stellate cells and cells in S phase of the cell cycle and histochemical stains for collagen and basement membrane. Selective biopsies were stained for stem cells and oval cells. There was a progressive increase in metaplastic bile ductules but the increase did not reach a significant level until stages III and IV of fibrosis. There was a positive correlation between the number of ductules formed and the stage of liver fibrosis. The incidence of proliferating metaplastic ductules was low and did not change significantly during the progression of the stage of the fibrosis. Stains for oval cells and stem cells were negative. It is concluded that the answer to the question posed is: bile ductule reaction does increase during the development of cirrhosis caused by hepatitis C but the increase is due to bile ductular metaplasia, not due to proliferation.
Exp Mol Pathol 2005 Oct
PMID:The role of bile duct reactive change in the pathogenesis of liver fibrosis due to hepatitis C. 1604 6

Increasing evidence suggests that non-sex-linked genetic factors play a role in determining both susceptibility to, and progression of, liver fibrosis. The elucidation of these factors will have many potential benefits in the management of patients with chronic liver disease. A variety of approaches can be used to look for genetic factors playing a role in liver fibrosis. In the future, genome-wide single nucleotide polymorphism (SNP) scanning of cases and controls may become feasible; however, to date, studies have relied on candidate-gene, case-control, allele-association methodology. This section will focus on the design and interpretation of case-control association studies in liver disease using non-alcoholic fatty liver disease (NAFLD) to illustrate the key issues and potential pitfalls of this approach.
Methods Mol Med 2005
PMID:Genetic studies to identify hepatic fibrosis genes and SNPs in human populations. 1611 60

The pathogenesis of liver fibrosis has evolved dramatically in recent years. Hepatic stellate cells (HSCs) have been recognized as the main fibrogenic cells in the injured liver, and key fibrogenic cytokines have been identified. We propose the use of DNA microarrays to study changes in gene expression in activated HSCs and in fibrotic livers in order to identify key genes involved in liver fibrosis. For this purpose, RNA can be extracted from both cultured cells and liver tissue. The target RNA is hybridized to probes, which are gene-specific sequences immobilized on chips. The hybridization signal is assessed using a confocal laser scanner. Comparison of hybridization signals and patterns allows the identification of mRNAs that are differentially expressed. Statistical analysis enables classification and clustering of genes according to their up- or downregulation. By using this powerful technique, we have identified genes that are differentially regulated in both HSCs and the fibrotic human liver.
Methods Mol Med 2005
PMID:DNA microarrays and data mining to study hepatic fibrosis. 1611 62

Stellate cells are principal producers of extracellular matrix proteins in the liver and play a major role in the development of liver fibrosis. Molecular basis of the cell activation has therefore been analyzed intensively during the past decade. Proteomics analysis is one of the most powerful tools with which to reveal the total protein synthesis in stellate cells, in particular the dynamic change in their expression level in response to activation. We have successfully analyzed over 300 stellate cell proteins by proteomics, several of which represented activation-associated change. Change in the level of some of these proteins was confirmed in liver tissue level. In addition, this approach led to the discovery of a novel globin in the vertebrate. Thus, proteomics is a research method for comprehensive understanding of the molecular basis of liver fibrosis.
Methods Mol Med 2005
PMID:Analysis of proteins dominantly expressed in hepatic stellate cells of activated phenotype. 1611 63

Catechins such as epigallocatechin-3-gallate (EGCG), epicatechin-3-gallate (ECG), and epigallocatechin (EGC) are polyphenol components of green tea. EGCG is the major component and has been reported to possess a wide range of biological properties including anti-fibrogenic activity. In hepatic fibrosis, activated hepatic stellate cells (HSCs) play a central role. In this study, we investigated the effect of catechins, including EGCG, on collagen production and collagenase activity in rat primary HSCs and activated human HSC-derived TWNT-4 cells. EGCG (50 microM) suppressed type I collagen production in rat HSCs more than ECG (50 microM) did; however, EGC (50 microM) did not show suppressive effects. EGCG also inhibited both collagen production and collagenase activity (active matrix metalloproteinase-1 [MMP-1]) in a dose-dependent manner, but did not affect the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) production in TWNT-4 cells. Real-time PCR unexpectedly revealed that EGCG enhanced the transcription of type I collagen and TIMP-1, but did not affect the transcription of alpha-smooth muscle actin (alpha-SMA), and reduced the transcription MMP-1 in TWNT-4 cells. These findings demonstrated that EGCG inhibited collagen production regardless of enhanced collagen transcription and suppressed collagenase activity, and suggested that EGCG might have therapeutic potential for liver fibrosis.
Int J Mol Med 2005 Oct
PMID:Epigallocatechin-3-gallate, a polyphenol component of green tea, suppresses both collagen production and collagenase activity in hepatic stellate cells. 1614 4

Cell cycle regulating proteins are known to have close relation with the proliferation of the mammalian cells. In injured liver, the number of HSCs is increased from proliferation. However, the expression of cell cycle proteins of HSCs during proliferation remains unevaluated. Therefore, cell cycle protein profiles of HSCs were studied in dimethyl-nitrosamine (DMN)-induced rat liver fibrosis model. Sprague-Dawley rats were intraperitoneally injected of DMN and the animals were sacrificed every week up to 4 weeks. HSCs were separated and the number of the cells in S phase was counted to evaluate the cell proliferation by flow cytometry. The expression of cyclin A, cyclin B, cyclin D1, cdk2, cdk4, cdc2, proliferating cell nuclear antigen (PCNA), p21(Cip/WAF1), and p27 was examined with immunoblotting analysis. Portion of S-phase cells peaked 7days after DMN injection. At that time, cyclin A, and PCNA showed significant increase in HSCs compared to untreated HSCs (114% and 116%, respectively, P<0.001). p21(Cip/WAF1) was decreased significantly in DMN-treated HSCs compared to control cells (88%, P<0.001). The increase of cyclin A, and PCNA and the decrease of p21(Cip/WAF1) seem to play important roles in the proliferation of HSCs during the early period of DMN treatment.
Exp Mol Med 2005 Aug 31
PMID:Cell cycle protein profile of the hepatic stellate cells(HSCs)in dimethylnitrosamine-induced rat hepatic fibrosis. 1615 10

The progression of rat liver fibrosis induced by intraperitoneal administration of thioacetamide (TAA) was evaluated by immunocytochemistry using anti-alpha-smooth muscle actin (alpha-SMA), antiendothelin-converting enzyme (ECE)-1, and anti-monocyte chemotactic protein (MCP)-1 antibodies. The fibrous septal spaces gradually increased after administration of TAA, and pseudolobules were established in the 7-week TAA-treated groups. Immunoreactivities against alpha-SMA were not detected in hepatic stellate cells (HSCs) of the control group without TAA treatment, although they were observed in the HSCs around the fibrous septal spaces in all TAA-treated groups, indicating that activation of HSCs occurs during the establishment of pseudolobules. Immunoreactivities against ECE-1 and MCP-1 were seen in such HSCs of the TAA-treated groups, but few or no immunoreactivities were detected in the HSCs of the control group. The most significant increase in the ECE-1 immunoreactivities was detected in the 1-week TAA-treated group, whereas that in MCP-1 was observed in the 7-week TAA-treated group. The present immunocytochemistry indicated a difference in the accelerated expression period between immunoreactivities against ECE-1 and MCP-1 in the HSCs during the progression of TAA-induced liver fibrosis, suggesting that ECE-1 is involved in the early phase of liver fibrosis and that MCP-1 plays a role during the later phase.
Med Mol Morphol 2005 Sep
PMID:Increased immunoreactivities against endothelin-converting enzyme-1 and monocyte chemotactic protein-1 in hepatic stellate cells of rat fibrous liver induced by thioacetamide. 1617 Apr 64

The plasticity of bone marrow has been confirmed by the autopsy of a female recipient of bone marrow cell transplantation from a male donor. To establish new clinical cell therapies using autologous bone marrow cells for patients with liver failure, we developed a new in vivo model named the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model. Using the GFP/CCl4 model, we found that transplanted Liv8-negative cells efficiently repopulated into cirrhotic liver tissue and differentiated into albumin-producing hepatocytes under persistent liver damage induced by carbon tetrachloride. Moreover, bone marrow cell transplantation into mice with liver cirrhosis improved liver function and liver fibrosis with the strong expression of matrix metalloproteinases (MMPs), especially MMP-9 activity, resulting in an improved survival rate. Results from the GFP/CCl4 model showed that cell therapy using autologous bone marrow cells has the potential to become an effective treatment for patients with liver failure. A summary of findings from the GFP/CCl4 model is described.
Med Mol Morphol 2005 Dec
PMID:Development of cell therapy using autologous bone marrow cells for liver cirrhosis. 1637 27


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