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)

It has been shown that lipid peroxidation is associated with hepatic fibrosis and stellate cell activation. Sho-saiko-to (TJ-9) is an herbal medicine, which is commonly used to treat chronic hepatitis in Japan, although the mechanism by which TJ-9 protects against hepatic fibrosis is not known. As a result, we assayed the preventive and therapeutic effects of TJ-9 on experimental hepatic fibrosis, induced in rats by dimethylnitrosamine (DMN) or pig serum (PS), and on rat stellate cells and hepatocytes in primary culture, and assessed the antioxidative activities and the active components of TJ-9. Male Wistar rats were given a single intraperitoneal injection of 40 mg/kg DMN or 0.5 mL PS twice weekly for 10 weeks. In each model, rats were fed a basal diet throughout, or the same diet, which also contained 1.5% TJ-9, for 2 weeks before treatment or for the last 2 weeks of treatment. TJ-9 suppressed the induction of hepatic fibrosis, increased hepatic retinoids, and reduced the hepatic levels of collagen and malondialdehyde (MDA), a production of lipid peroxidation. Immunohistochemical examination showed that TJ-9 reduced the deposition of type I collagen and the number of alpha-smooth muscle actin (alpha-SMA) positive-stellate cells in the liver and inhibited, not only lipid peroxidation in cultured rat hepatocytes that were undergoing oxidative stress, but also the production of type I collagen, alpha-SMA expression, cell proliferation, and oxidative burst in cultured rat stellate cells. In addition, TJ-9 inhibited Fe2+/adenosine 5'-diphosphate-induced lipid peroxidation in rat liver mitochondria in a dose-dependent manner and showed radical scavenging activity. Among the active components of TJ-9, baicalin and baicalein were found to be mainly responsible for the antioxidative activity. These findings suggest that Sho-saiko-to (TJ-9) functions as a potent antifibrosuppressant by inhibition of lipid peroxidation in hepatocytes and stellate cells in vivo.
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PMID:Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats. 986 80

As a model for the analysis of the fibrosuppressive role of estradiol, hepatic fibrosis was induced in male and female rats by the administration of a single dose of dimethylnitrosamine (DMN). The fibrotic response of the male liver after DMN treatment was significantly stronger than that of the female liver. In the male DMN model, estradiol reduced hepatic mRNA for type I and III procollagens and the tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as deposition of type I and III collagen protein total hepatic collagen and malondialdehyde (MDA), a product of lipid peroxidation. Concomitant administration of a neutralizing antibody against rat estradiol enhanced fibrogenesis, as judged by the same parameters. Ovariectomy in the female model had a fibrogenic effect, inducing the hepatic expression of both types of procollagen and TIMP-1; in addition, the number of alpha-smooth muscle actin (alpha-SMA)-positive cells in the liver increased; estradiol replacement was fibrosuppressive in the castrated-female model. In rat hepatic stellate cells incubated in primary culture with estradiol, cell number, type I collagen production, and alpha-SMA expression were all reduced. These findings suggest that estradiol suppressed the induction of hepatic fibrosis, and may in part underlie the more rapid progression in males of hepatic fibrosis and its complications.
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PMID:Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. 1005 8

Wound contraction is mediated by myofibroblasts, specialized fibroblasts that appear in large numbers as the wound matures and when resistance to contractile forces increases. We considered that the regulation of myofibroblast differentiation by wound-healing cytokines may be dependent on the resistance of the connective tissue matrix to deformation. We examined transforming growth factor-beta1 (TGF-beta1) induction of the putative fibroblast contractile marker, alpha-smooth muscle actin (alpha-SMA), and the regulation of this process by the compliance of collagen substrates. Cells were cultured in three different types of collagen gels with wide variations of mechanical compliance as assessed by deformation testing. The resistance to collagen gel deformation determined the levels of intracellular tension as shown by staining for actin stress fibers. For cells plated on thin films of collagen-coated plastic (ie, minimal compliance and maximal intracellular tension), TGF-beta1 (10 ng/ml; 6 days) increased alpha-SMA protein content by ninefold as detected by Western blots but did not affect beta-actin content. Western blots of cells in anchored collagen gels (moderate compliance and tension) also showed a TGF-beta1-induced increase of alpha-SMA content, but the effect was greatly reduced compared with collagen-coated plastic (<3-fold increase). In floating collagen gels (high compliance and low tension), there were only minimal differences of alpha-SMA protein. Northern analyses for alpha-SMA and beta-actin indicated that TGF-beta1 selectively increased mRNA for alpha-SMA similar to the reported protein levels. In pulse-chase experiments, [35S]methionine-labeled intracellular alpha-SMA decayed most rapidly in floating gels, less rapidly in anchored gels, and not at all in collagen plates after TGF-beta1 treatment. TGF-beta1 increased alpha2 and beta1 integrin content by 50% in cells on collagen plates, but the increase was less marked on anchored gels and was undetectable in floating gels. When intracellular tension on collagen substrates was reduced by preincubating cells with blocking antibodies to the alpha2 and beta1 integrin subunits, TGF-beta1 failed to increase alpha-SMA protein content in all three types of collagen matrices. These data indicate that TGF-beta1-induced increases of alpha-SMA content are dependent on the resistance of the substrate to deformation and that the generation of intracellular tension is a central determinant of contractile cytoskeletal gene expression.
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PMID:The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. 1007 65

Fibrosis, a consequence of tissue repair, can become a final common pathway to organ failure, if progressive. Prevention and regression of organ fibrosis represent targets of considerable interest. The natural fate of fibrosis differs among various tissues being either persistent, progressive or regressive. Cellular and molecular responses involving myofibroblasts (myoFb), a phenotypically transformed fibroblast-like cell of considerable functional diversity, is involved in collagen turnover at sites of repair, where they govern the fate of fibrosis. Insights gained from the natural regression of established fibrous tissue may offer strategies to remove unwanted fibrosis in failing organs. In the present study, we addressed the temporal sequence to various components of collagen synthesis and degradation involved in the appearance and subsequent regression of pouch tissue induced in the rat by subcutaneous injection of air followed by instillation of the phorbol ester croton oil. Pouch tissue was collected on day 2, 4, 10, 14, 21, 28 and 35 (n=6 at each time point). Activities of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP-1 (TIMP-1) were determined by zymography and reverse zymography, respectively; collagen accumulation by hydroxyproline concentration; gene expression of TIMP-1 or tissue inhibitor of MMP-1, type I collagen and transforming growth factor-beta1 (TGF-beta1) by in situ hybridization; TGF-beta1 concentration by sandwich enzyme-linked immunosorbant assay (ELISA); and myoFb and its phenotypes by immunohistochemistry using antibodies to alpha-smooth muscle actin (alpha-SMA), vimentin or desmin. During pouch tissue formation, we found: (1) pouch weight increased progressively from day 2 to day 14 and then declined progressively thereafter; (2) type I collagen mRNA expression, barely detectable at day 2, increased at day 4, together with tissue hydroxyproline concentration (P<0.05) reaching a peak on day 10, and gradually decreased thereafter in association with declining tissue hydroxyproline concentration; (3) mRNA expression and concentration of TGF-beta1, detectable at day 2, significantly (P<0.05) increased at day 4, reached a peak at day 10, and gradually declined thereafter; (4) MMP-1 activity, low at day 2, increased continually over the course of 35 days; (5) TIMP-1 mRNA, detectable at day 2 and significantly (P<0.05) increased at day 4, gradually decreased thereafter; (6) activity of TIMP-1 increased continuously from day 2 to day 14 and then was markedly reduced thereafter; and (7) myoFb were first observed in pouch tissue at day 4 and became more extensive thereafter with their phenotype changing over time. Early appearing myoFb (day 4, 10, 14, and 21) expressed alpha -SMA and vimentin (VA phenotype), while later appearing cells (day 28 and 35) additionally expressed desmin (VAD phenotype). Thus, in croton oil-induced rat pouch model, the subcutaneous accumulation of pouch tissue hydroxyproline over the course of 10 days is initially associated with a VA-positive myoFb phenotype and its transcription of TGF-beta1, type I collagen and TIMP-1. Beyond day 10, a regression of pouch tissue collagen begins in association with the appearance of a VAD-positive myoFb phenotype and progressive increase in MMP-1 activity as the expression of TIMP-1 and TGF-beta1 are withdrawn. Regression of established fibrosis in failing organs may, therefore, be attainable through manipulation of myoFb phenotype and/or enhanced collagen degradation relative to collagen synthesis.
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PMID:Appearance and regression of rat pouch tissue. 1033 40

The recognition of hepatic stellate cells (HSC) around and within hepatocellular carcinoma (HCC) in human livers has generated interest in the interactions between HSC and HCC. We explored the possibility of creating an animal model to allow in vivo investigations of this interaction. Eighteen adult Buffalo rats were inoculated with 1 x 10(6) cells obtained from cultures of Morris 7777 hepatoma cell line (ATCC). The rats were sacrificed at 2-, 3-, and 4-week intervals. Identification of activated HSC was with immunohistochemistry for alpha-smooth muscle actin (alpha-SMA). There was 100% survival of all animals until sacrifice. Tumour formation occurred in 94.4% of rats, and was of a good size by two weeks. Expression of alpha-SMA was observed around and within all HCC, but absent from normal tissue, and this showed colocalisation with collagen deposition. These findings are consistent with those previously reported in resected HCC in humans. The high survival, good tumour yield, consistent generation of activated HSC around the tumours, and similarities in histological appearance to the human HSC-HCC distribution pattern, make this a reliable animal model for in vivo studies on HSC-HCC interaction.
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PMID:An animal model for the study of hepatic stellate cell and hepatocellular carcinoma interaction. 1037 33

We hypothesized that invasive ductal carcinomas (IDCs) with large central acellular zones comprising necrosis, tissue infarction, collagen, and hyaline material on their cut surfaces are formed in association with myoepithelial differentiation of the carcinoma cells. To verify this, the expression of S100 protein, alpha-smooth muscle actin (alpha-SMA), and glial fibrillary acidic protein (GFAP) and keratin 14, which has been shown to represent the myoepithelial immunophenotype, was examined immunohistochemically in 18 IDCs with such central zones covering more than 30% of each tumor area, 18 IDCs without such areas as negative controls, and 10 metaplastic carcinomas as positive controls for myoepithelial differentiation. Expression of S100, detected with a polyclonal antibody, S100-alpha, S100-beta, alpha-SMA, GFAP, and keratin 14, was observed in 61%, 83%, 39%, 33%, 28%, and 39% of the IDCs with large central acellular zones, 17%, 44%, 6%, 6%, 0%, and 6% of the IDCs without such zones, and 80%, 70%, 50%, 100%, 80%, and 50% of the metaplastic carcinomas, respectively. We concluded that IDCs with large central acellular zones frequently contain carcinomas showing myoepithelial differentiation. Such histological and immunohistochemical features in IDCs would be expected to be clinicopathologically significant.
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PMID:Myoepithelial differentiation in high-grade invasive ductal carcinomas with large central acellular zones. 1053 58

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

Although a substantial amount of molecular and cellular data have been generated in an effort to understand the process of wound contraction and scar contracture formation, questions remain. What seems apparent is that the myofibroblast is not the only cell that generates contractile forces within wounds, but it does appear to be intrinsically linked to the development of hypertrophic scars. The supposition that the formation of scar contractures is solely the result of a continuation of wound contraction is an oversimplification. Figure 4 provides a model of the possible evolution of contractile forces during the wound healing process and their role in the development of scar contractures. Migration of fibroblasts into and through the extracellular matrix during the initial phase of wound healing, prior to the expression of alpha-SMA, appears to be a fundamental component of wound contraction. During this migration, the pulling of collagen fibrils into a streamlined pattern in their wake, and the associated production of collagenase, may facilitate a more normal arrangement of collagen. Once the wound has been repopulated and the chemotactic gradient that was established by inflammatory cells is decreased, fibroblast migration will cease. It is at this point that myofibroblasts appear and play a key role in the production of hypertrophic scars, given that their prolonged presence and over-representation are hallmarks of this pathology. One of the pivotal differences between wounds that proceed to normal scar compared with those that develop hypertrophic scars and scar contractures may be a lack (or late induction) of myofibroblast apoptotic cell death. The combined contribution of fibroblasts and myofibroblasts to abnormal extracellular matrix protein production results in an excessive and rigid scar. The isometric application of contractile forces by myofibroblasts probably contributes to the formation of the whorls, nodules, and scar contractures characteristic of hypertrophic scars. Because the prolonged presence of myofibroblasts, producing an imbalance in extracellular matrix proteins and proteases, probably exacerbates hypertrophic scars and wound contraction, accelerating the rate of apoptotic cell death to reduce the cell number to that seen in normal scar may be a useful strategy for providing effective and efficient treatment of scar contracture.
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PMID:Control of wound contraction. Basic and clinical features. 1079 Nov 74

The alteration in sinusoidal collagen type IV occurrence, and myofibroblastic (alpha-SMA-positive) Ito cellular transformation are described in the liver of patients with malignant gastric and colorectal tumors, using electron microscopy as well as light microscopical and ultrastructural immunohistochemistry. The ultrastructural finding revealed transformation of Ito cells mostly into transitional cells in highly differentiated primary tumors and into transitional and myofibroblast-like cells with expressed changes in the other sinusoidal cells in poorly differentiated tumors. Ito cell numbers increased significantly in the livers of cancer patients. A highly significant statistical association was obtained between Ito cell numbers on the one hand and collagen type IV and alpha-SMA immunoreactivity on the other hand in the pericentral zone of the liver lobule. Ultrastructural immunohistochemistry showed increased collagen IV immune deposits in the space of Disse, assembled for the most part around and inside transitional cells. Alpha-SMA immunoreactivity was detected in activated Ito cells diffuse in the lobule, with stronger expression in the intermediate and pericentral zones. It is suggested that stimuli which can influence Ito cell transformation are produced by tumor cells from the primary tumor (TGF-beta1, TNF-alpha, PDGF-beta etc.) and from the metastasizing gastric or colorectal tumor cells--matrix metalloproteinase-2 (MMP-2). It is suggested that sinusoidal extracellular matrix deterioration creates a barrier for cancer invasion on the one hand, or possibly facilitates metastasizing by ensurance of matrix for adhesion on the other hand.
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PMID:Ito cell morphology, alpha-smooth muscle actin and collagen type IV expression in the liver of patients with gastric and colorectal tumors. 1084 10

To identify apoptosis of nonparenchymal cells in fibrotic livers, we established a triple staining method which combined immunohistochemistry for cell markers and Masson staining for collagen as well as terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL). Five microm formalin fixed, paraffin-embedded liver sections were prepared for staining. Firstly, TUNEL staining was carried out to detect apoptosis of liver cells. Then, the sections were subjected to immunohistochemistry for alpha-smooth muscle actin (alpha -SMA) or KP-1 to identify hepatic stellate cells or Kupffer cells. Finally, Masson staining was performed to show the relationship between apoptosis and collagens. In addition, we optimized different conditions of fixation, digestion and color development which may affect the results.
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PMID:Triple-staining to identify apoptosis of hepatic cells in situ. 1093 98


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