Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q16637 (SMA)
 8,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pericytes are cells localized at the abluminal side of the microvascular endothelium and completely enveloped by a basement membrane. Pericytes have close contact with endothelial cells and are probably involved in the regulation of endothelial cell functions. Previous studies suggested a role for pericytes in microvascular proliferation in tumors. To study this cell type, we isolated human brain pericytes from microvessel segments derived from autopsy brain tissue. These cells were characterized in vitro using a panel of monoclonal antibodies. Human brain pericytes were reactive with monoclonal antibodies directed against the high molecular weight-melanoma associated antigen and intercellular adhesion molecule-1, but only a minority of the cells expressed alpha-smooth muscle actin (alpha-SMA, 0 to 10%) or vascular cell adhesion molecule-1 (10 to 50%). In histologically normal human brain microvessels in situ, pericytes consistently lacked staining for these four markers. Tissue with microvascular proliferation, however, showed a marked pericyte staining for both alpha-SMA and high molecular weight-melanoma associated antigen. The expression of alpha-SMA in vitro could be slightly up-regulated by incubation with serum-containing medium. An increase in alpha-SMA expression up to 40% of the total cell population was seen when pericytes were treated with transforming growth factor-beta 1, whereas basic fibroblast growth factor slightly inhibited alpha-SMA expression. Incubation with other factors (platelet-derived growth factor-AA, heparin, interferon-gamma, tumor necrosis factor-alpha) had no effect on the alpha-SMA expression at all. Transforming growth factor-beta 1 thus induces smooth muscle-like differentiation in pericytes in vitro and might play a role in the activation of pericytes during angiogenesis in vivo.
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PMID:Induction of alpha-smooth muscle actin expression in cultured human brain pericytes by transforming growth factor-beta 1. 831 Nov 20

We investigated the effect of transforming growth factor-beta1 (TGF-beta1) on the expression of calponin-h1, alpha-smooth muscle actin (alpha-SMA), and extracellular matrix (ECM) components in a cultured human Ito cell line, LI90. The TGF-beta1 treatment stimulated productions of hyaluronic acid and laminin, and significantly decreased the secretion of hepatocyte growth factor in LI90 cells. The functional characteristics of LI90 cells were compatible with those of human-activated Ito cells that are known as pericyte-like mesenchymal liver cells. TGF-beta1 induced a slight growth-inhibition of LI90 cells. TGF-beta1 enhanced the expressions of both alpha-SMA and calponin-h1 at the protein level, while tumor necrosis factor-alpha and interleukin-1alpha did not affect the expressions of these cytoskeletal proteins on LI90 cells. The addition of TGF-beta1 to LI90 cells resulted in a significant increase of calponin-h1 mRNA levels, but not calponin-h2. These data suggest that the expression of calponin-h1 is controlled at the level of mRNA under the coordinate regulation together with alpha-SMA as the process of perpetuation of activated Ito cells promoted by TGF-beta1. The identification of smooth muscle features promoted by TGF-beta1 support the hypothesis that the activation of Ito cells coincides with their contractile behavior, indicating that these cells may be important in vasoregulation during liver injury and fibrosis.
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PMID:Induction of calponin-h1 by transforming growth factor-beta1 in cultured human ito cells, LI90. 962 88

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney. In this study, we report the contribution of tumor necrosis factor-alpha (TNF-alpha) to the fibrosis that develops after ureteral obstruction. Mice in which individual TNF-alpha receptors TNFR1 or TNFR2 had been genetically knocked out were used, and results were compared with mice of C57Bl/6 background after 5 days UUO. Both kidneys were removed and examined histologically for changes in interstitial volume (Vv(int)), collagen IV deposition, alpha-smooth muscle actin (alpha-SMA) matrix score, nuclear factor-kappaB (NF-kappaB) activity, and TNF-alpha mRNA levels. We found that the Vv(int) of contralateral unobstructed kidneys averaged approximately 7% and was indistinguishable among the three genotypes of mice. Vv(int) of ureteral obstructed kidney of C57Bl/6 mice averaged 33 +/- 3.9% after 5 days of UUO. Vv(int) of obstructed kidneys of TNFR1 mice was significantly reduced to 19.4 +/- 3.1%, whereas that of TNFR2 mice was significantly decreased to 25.4% +/- 4.8%. There was a modest but significant difference between Vv(int) of TNFR1 and TNFR2 (P < 0. 047). Both collagen IV and alpha-SMA matrix scores were decreased significantly in obstructed kidney of TNFR1 mouse compared with that of C57Bl/6 and TNFR2 mice. Nuclear extracts prepared from kidney cortex were found to have a significant increase in NF-kappaB binding activity in obstructed kidney compared with contralateral kidney. Individual knockout of the TNFR1 or TNFR2 genes resulted in significantly less NF-kappaB activation compared with the wild type, with TNFR1 being less than TNFR2 knockout. There was a significant increase in TNF-alpha mRNA in the kidney with ureteral obstruction in all three genotypes. TNFR1 knockout displayed a significant reduction in amount of TNF-alpha mRNA induced compared with wild-type or TNFR2 knockout mice. Treatment of TNFR1 knockout mice with an angiotensin converting enzyme inhibitor further decreased Vv(int) and TNF-alpha mRNA induction, suggesting an interaction of ANG II and TNF-alpha systems. These results suggest that TNF-alpha contributes, in part, to changes in interstitial volume, myofibroblast differentiation, and NF-kappaB activation in the kidney during ureteral obstruction. These changes appear to be mediated through both TNFR1 and TNFR2 gene products with effects through the TNFR1 receptor predominating. Furthermore, ANG II appears to stimulate TNF-alpha pathophysiological events leading to renal fibrosis.
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PMID:Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy. 1056 41

The suppressive effects of Platycodi Radix (Changkil: CK), the root of Platycodon grandiflorum A. DC (Campanulaceae), on the progress of acute carbon tetrachloride (CCl4)-induced hepatic fibrosis were investigated in the rat. CK significantly suppressed CCl4-induced hepatic necrosis and inflammation, as determined by the serum enzymatic activities of alanine and aspartate aminotransferase and serum tumor necrosis factor-alpha levels, in dose-dependent manners. In addition, the increased hepatic fibrosis after acute CCl4 treatment was suppressed by the administration of CK. CK also significantly prevented the elevation of hepatic alpha1 (I) procollagen (type I collagen) mRNA and alpha-smooth muscle actin (alpha-SMA) expressions in the liver of CCl4-intoxicated rats and also suppressed the induction of alpha-SMA and type I collagen in cultured hepatic stellate cells, in dose-dependent manners. These results suggest that the suppressive effects of CK against the progress of acute CCl4-induced hepatic fibrosis possibly involve mechanisms related to its ability to block both hepatic inflammation and the activation of hepatic stellate cells.
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PMID:Suppressive effects of Platycodon grandiflorum on the progress of carbon tetrachloride-induced hepatic fibrosis. 1564 98

Studies have shown that lipoxin A(4) (LXA(4)) inhibited proliferation of mesangial cells in vitro induced by platelet-derived growth factor, epidermal growth factor, leukotriene D(4) or tumor necrosis factor-alpha. In this study, we investigated the protective effects of 15(R/S)-methyl-LXA(4) on mesangioproliferative nephritis in rats and the signal transduction involved in actions of 15(R/S)-methyl-LXA(4). Mesangioproliferative nephritis was induced by a single intravenous injection of the mouse monoclonal anti-Thy1.1 antibodies. The nephritic rats were treated by intravenous injection of 15(R/S)-methyl-LXA(4) every 8h until the rats were sacrificed. There were increments in glomerular infiltration of leukocytes, expressions of protein and mRNA of interleukin (IL)-1beta and IL-6, activities of nuclear factor-kappaB (NF-kappaB) in nephritic rats from day 1 to 4 after induction of nephritis. The enhanced proteinuria, proliferation score of mesangial cells, glomerular proliferating cell nuclear antigen (PCNA) positive cells, activities of phosphorylated phosphoinositide 3-kinase (PI3-K), Akt(1), alpha-smooth muscle actin (alpha-SMA) and signal transducer and activator of transcription 3(STAT(3)), and reduced expression of p27(kip1) were found on day 4 after induction of nephritis. Treatment of nephritic rats with 15(R/S)-methyl-LXA(4) significantly reduced the protenuria, glomerular infiltration of leukocyte, expressions of protein and mRNA of IL-1beta and IL-6, proliferation score of mesangial cells, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt(1), alpha-SMA, NF-kappaB and STAT(3), and ameliorated the decrement in p27(kip1) induced by anti-Thy1.1 antibodies. Protective effects of 15(R/S)-methyl-LXA(4) on nephritis induced by anti-Thy1.1 antibodies were related to PI3-K/Akt(1)/p27(kip1)/cyclin pathway, STAT(3) and NF-kappaB pathway-dependent signal transduction.
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PMID:Signal transduction involved in protective effects of 15(R/S)-methyl- lipoxin A(4) on mesangioproliferative nephritis in rats. 1732 90

Abnormal wound healing encompasses a wide spectrum, from chronic wounds to hypertrophic scars. Both conditions are associated with an abnormal cytokine profile in the wound bed. In this study, we sought to understand the dynamic relationships between myofibroblast differentiation and mechanical performance of the collagen matrix under tissue growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) stimulation. We found TGF-beta increased alpha-smooth muscle actin (alpha-SMA) and TNF-alpha alone decreased the basal alpha-SMA expression. When TGF-beta1 and TNF-alpha were both added, the alpha-SMA expression was suppressed below the baseline. Real-time PCR showed that TNF-alpha suppresses TGF-beta1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, alpha-SMA, collagen type 1A, and fibronectin at the mRNA level. TNF-alpha suppresses TGF-beta1-induced gene expression by affecting its mRNA stability. Our results further showed that TNF-alpha inhibits TGF-beta1-induced Smad-3 phosphorylation via Jun N-terminal kinase signaling. Mechanical testing showed that TNF-alpha decreases the stiffness and contraction of the lattices after 5 days in culture. We proposed that changes in alpha-SMA, collagen, and fibronectin expression result in decreased contraction and stiffness of collagen matrices. Therefore, the balance of cytokines in a wound defines the mechanical properties of the extracellular matrix and optimal wound healing.
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PMID:TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing. 1755 69

Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An in vivo therapeutic study was conducted in bile duct-ligated (BDL) rats. BDL rats were given Arm (3 or 10 mg/kg) by gavage twice daily for 3 weeks starting from the onset of BDL. Liver sections were taken for fibrosis scoring, immuno-fluorescence staining and quantitative real-time mRNA measurements. In vitro, Arm (1-10 microM) concentration-dependently attenuated TNF-alpha- and LPS-stimulated alpha-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-alpha-induced collagen collagen deposition, NFkappaB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. In vivo, Arm treatment significantly reduced plasma AST and ALT levels, hepatic alpha-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of col 1alpha2, TGF-beta1, TIMP-1, ICAM-1, iNOS, and IL-6 genes, but up-regulated metallothionein genes. Our study results showed that Arm exerted both in vitro and in vivo antifibrotic effects in rats, possibly through anti-NF-kappaB activation pathways.
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PMID:Inhibitory effects of armepavine against hepatic fibrosis in rats. 1972 40

The aim of this study was twofold; first, we evaluated the influence of hepatitis C virus (HCV) and iron deposition on hepatic stellate cells (HSCs), and second, we determined the influence of HSCs on the development of interstitial fibrosis (IF) in renal allografts. Thirty chronic HCV positive patients bearing renal allografts underwent liver biopsies, which were scored for iron deposition and the number of HSCs. We evaluated the density of tumor necrosis factor-alpha (TNF-alpha) in liver biopsies and the expression of transforming growth factor-beta (TGF-beta) on tubules of renal allografts from the same patients. We examined the development of IF in renal allografts at 12 and 24 months after the reference biopsy. The density of HSCs was significantly greater among patients with compared with those without iron deposits (P < .01). TNF-alpha expression was localized mainly to liver sinusoidal cells; in some cases, it was also expressed in hepatocytes. Patients with higher-grade TNF-alpha expression in the liver showed higher-grade alpha-smooth muscle antibody (alpha-SMA)-positive HSCs (P < .001). In parallel, an increasing amount of HSCs in the liver increased the incidence of IF in the renal allograft at 12 (P < .01) and 24 (P < .01) months after the reference biopsy. In addition, the expression of TGF-beta on renal allograft tubules were increased with greater grades of alpha-SMA-positive HSCs in liver (P < .01). In conclusion, HCV infection seemed to trigger the development of IF in renal allografts by augmenting TGF-beta secretion through activation of HSC.
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PMID:Hepatic stellate cells in hepatitis C patients: relationship with the development of interstitial fibrosis in renal allografts. 1976 51

This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 micromol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (alpha-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1 alpha, alpha-SMA, tumor necrosis factor-alpha, tumor growth factor-beta, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 mumol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis.
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PMID:S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats. 2006 61

The detrimental role of superoxide anion (O(2)(-)) has been well documented in the pathogenesis of ischemia-reperfusion (I/R) injury. Our and other studies suggested that one critical source of O(2)(-) generation may be xanthine oxidase (XO). We thus hypothesized that I/R injury could be protected by inhibiting XO activity, which would reduce the amount of O(2)(-) and hence reduce pathogenic consequences. Among various XO inhibitors, we previously found 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) exhibited potent XO inhibitory activity. Here, we report that the covalent conjugate of AHPP with amphipathic styrene-maleic acid copolymer (SMA-AHPP) showed protective effect against I/R-induced injury in a rat hepatic I/R model. Liver ischemia was induced by occluding both the portal vein and the hepatic artery for 30 min, and followed by reperfusion. SMA-AHPP was administered via the tail vein two hours before ischemia was initiated. A remarkable increase of liver enzymes in plasma (aspartate aminotransferase, AST; alanine aminotransferase, ALT and lactate dehydrogenase, LDH) was detected three hours after reperfusion, whereas prior injection of SMA-AHPP greatly suppressed this increase of AST, ALT and LDH. Moreover, induction of inflammatory cytokines, i.e. tumor necrosis factor-alpha (TNF-alpha), interleukin-12 (IL-12) and monocyte chemotactic protein-1 (MCP-1) by I/R were significantly inhibited by SMA-AHPP treatment. Accordingly, cytotoxic effect or apoptosis in the liver caused by I/R was clearly reduced by SMA-AHPP pretreatment. Furthermore, thiobarbituric acid-reactive substance assay showed a significant decrease of lipid peroxidation in rat liver after the administration of SMA-AHPP, which is parallel with the decreased XO activity after SMA-AHPP treatment, indicating the involvement of reactive oxygen species generated by XO. In addition, SMA-AHPP was found to bind to albumin, thus to exhibit prolonged in vivo (plasma) half-life. These results suggest that SMA-AHPP exerted a potent cytoprotective effect against I/R injury in rat liver, by inhibiting XO activity and the subsequent generation of O(2)(-).
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PMID:Tissue protective effect of xanthine oxidase inhibitor, polymer conjugate of (styrene-maleic acid copolymer) and (4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine), on hepatic ischemia-reperfusion injury. 2040 81


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