Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis and inflammation. Inhibition of activation and cell functions of PSCs is a potential target for the treatment of pancreatic fibrosis and inflammation. The polyphenol compound curcumin is the yellow pigment in curry, and has anti-inflammatory and anti-fibrotic properties. We here evaluated the effects of curcumin on the activation and cell functions of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. The effects of curcumin on proliferation, alpha-smooth muscle actin gene expression, monocyte chemoattractant protein (MCP)-1 production, and collagen expression were examined. The effect of curcumin on the activation of freshly isolated cells in culture was also assessed. Curcumin inhibited platelet-derived growth factor (PDGF)-induced proliferation, alpha-smooth muscle actin gene expression, interleukin-1beta- and tumor necrosis factor (TNF)-alpha-induced MCP-1 production, type I collagen production, and expression of type I and type III collagen genes. Curcumin inhibited PDGF-BB-induced cyclin D1 expression and activation of extracellular signal-regulated kinase (ERK). Curcumin inhibited interleukin-1beta- and TNF-alpha-induced activation of activator protein-1 (AP-1) and mitogen-activated protein (MAP) kinases (ERK, c-Jun N-terminal kinase (JNK), and p38 MAP kinase), but not of nuclear factor-kappaB (NF-kappaB). In addition, curcumin inhibited transformation of freshly isolated cells to myofibroblast-like phenotype. In conclusion, curcumin inhibited key cell functions and activation of PSCs.
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PMID:Curcumin blocks activation of pancreatic stellate cells. 1629 27

We investigated the effects of oscillatory flow in regulating the gene expressions of type I collagen (COL1, the main component of human bone tissues) and osteopontin (OPN, the key gene for calcium deposition) in human osteoblast-like (MG-63) cells, and the roles of mitogen-activated protein kinases (MAPKs) in this regulation. The cells were subjected to oscillatory flow (0.5 +/- 4 dyn/cm(2)) or kept under static condition for various time periods (15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 16 h). Oscillatory flow caused significant up-regulations of both COL1 and OPN gene expressions over the 16 h of study, and a transient activation of MAPKs was starting at 15 min and declining to basal level in 2 h. The flow-induction of COL1 was blocked by an ERK inhibitor (PD98059) and reduced by a JNK inhibitor (SP600125), whereas that of OPN was abolished by PD98059. Analysis of the cis-elements in the COL1 and OPN promoters suggests the involvement of transacting factors Elk-1 and AP-1 in the transcription regulation. The ERK inhibitor (PD98059) blocked Elk-1 phosphorylation, as well as COL1 and OPN gene expression. The JNK inhibitor (SP600125) abolished c-jun phosphorylation and COL1 expression. These results suggest that the flow-induction of OPN was mediated through the ERK-Elk1-OPN pathway, and that COL1 was regulated by both the ERK-Elk1-COL1 and JNK-c-JUN-COL1 pathway.
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PMID:Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow. 1644 Mar 9

p38 MAPKs (mitogen-activated protein kinases) play important roles in the regulation of cellular responses to environmental stress. Recently, this signalling pathway has also been implicated in the regulation of processes unrelated to stress, for example, in T lymphocytes and cardiomyocytes. In order to identify molecular targets responsible for the housekeeping functions of p38 MAPKs, we have analysed the differences in the transcriptomes of normally proliferating wild-type and p38alpha knockout immortalized embryonic cardiomyocytes. Interestingly, many potential components of the myocardium extracellular matrix were found to be upregulated in the absence of p38alpha. Further analysis of the microarray data identified TEF-1 (transcriptional enhancer factor-1), a known regulator of heart-specific gene expression, and C/EBPbeta (CCAAT/enhancer-binding protein beta), as the two transcription factors the binding sites of which were most enriched in the promoters of p38alpha-regulated genes. We have focused on the study of the extracellular matrix component COL1A1 (alpha1 chain of type I collagen) and found evidence for the involvement of both TEF-1 and C/EBPbeta in the p38alpha-dependent inhibition of COL1A1 transcription. Our data therefore show that p38 MAPKs regulate TEF-1 and C/EBPbeta transcriptional activity in the absence of environmental stress and suggests a role for p38alpha in the expression of extracellular matrix components that maintain organ architecture.
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PMID:TEF-1 and C/EBPbeta are major p38alpha MAPK-regulated transcription factors in proliferating cardiomyocytes. 1649 36

Cells in various anatomical locations are constantly exposed to mechanical forces from shear, tensile and compressional forces. These forces are significantly exaggerated in a number of pathological conditions arising from various etiologies e.g., hypertension, obstruction and hemodynamic overload. Increasingly persuasive evidence suggests that altered mechanical signals induce local production of soluble factors that interfere with the physiologic properties of tissues and compromise normal functioning of organ systems. Two immediate early gene-encoded members of the family of the Cyr61/CTGF/Nov proteins referred to as cysteine-rich protein 61 (Cyr61/CCN1) and connective tissue growth factor (CTGF/CCN2), are highly expressed in several mechanical stress-related pathologies, which result from either increased externally applied or internally generated forces by the actin cytoskeleton. Both Cyr61 and CTGF are structurally related but functionally distinct multimodular proteins that are expressed in many organs and tissues only during specific developmental or pathological events. In vitro assessment of their biological activities revealed that Cyr61 expression induces a genetic reprogramming of angiogenic, adhesive and structural proteins while CTGF promotes distinctively extracellular matrix accumulation (i.e., type I collagen) which is the principal hallmark of fibrotic diseases. At the molecular level, expression of the Cyr61 and CTGF genes is regulated by alteration of cytoskeletal actin dynamics orchestrated by various components of the signaling machinery, i.e., small Rho GTPases, mitogen-activated protein kinases, and actin binding proteins. This review discusses the mechanical regulation of the Cyr61 and CTGF in various tissues and cell culture models with a special attention to the cytoskeletally based mechanisms involved in such regulation.
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PMID:Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. 1685 34

Myricetin (3,3',4',5,5',7-hexahydroxyflavone), a flavonoid compound, is present in vegetables and fruits. By means of alkaline phosphatase (ALP) activity, osteocalcin, and type I collagen enzyme-linked immunosorbent assay (ELISA), we have shown that myricetin exhibits a significant induction of differentiation in MG-63 and hFOB human osteoblasts. Alkaline phosphatase and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively. Our results indicate that myricetin stimulates osteoblast differentiation at various stages, from maturation to terminally differentiated osteoblasts. Induction of differentiation by myricetin is associated with increased bone morphogenetic protein-2 (BMP-2) production. The BMP-2 antagonist noggin blocked myricetin-mediated ALP activity and osteocalcin secretion enhancement, indicating that BMP-2 production is required in myricetin-mediated osteoblast maturation and differentiation. Induction of differentiation by myricetin is associated with increased activation of SMAD1/5/8 and p38 mitogen-activated protein kinases. Cotreatment of p38 inhibitor SB203580 inhibited myricetin-mediated ALP upregulation and osteocalcin production. In conclusion, myricetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and p38 MAPK, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass.
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PMID:Myricetin induces human osteoblast differentiation through bone morphogenetic protein-2/p38 mitogen-activated protein kinase pathway. 1711 42

In this manuscript, we showed that following a fibrogenic stimulus of leptin, hepatic stellate cells (HSCs) underwent a complex activation process characterized by increased proliferation and excessive deposition of type I collagen. Studies with special chemical inhibitors demonstrated that this process involved Janus protein tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-linase (PI3K)/Protein kinase B (AKT) signal pathways. Leflunomide pretreatment significantly inhibited the deposition of type I collagen in HSCs and the proliferation of primary HSC by interrupting the three proliferative signal transduction pathways in vitro, which was indicated by [(3)H]thymidine incorporation and cell cycle analysis. Furthermore, leptin-induced cyclin D1 protein expression, which correlates well with HSC proliferation, was also significantly inhibited by leflunomide. On the other hand, leflunomide also prevented leptin-induced Kupffer cell (KC) activation and HSC collagen synthesis induced by KC-conditioned medium (KCCM). Collectively, these results provided a novel insight into the mechanisms by which leflunomide may exert in liver fibrosis.
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PMID:Suppressive effects of leflunomide on leptin-induced collagen I production involved in hepatic stellate cell proliferation. 1732 77

Recently, natural products have gained more interest as alternative treatments for metabolic bone disorders and for the maintenance of bone health. In this study, the anabolic activities of 89 natural compounds were evaluated by measuring the amount of newly synthesized calcium in the differentiation process of mouse osteoblastic MC3T3-E1 subclone 4 cells. Of these compounds, a low concentration (up to 5 microm) of 3-carene, which is a bicyclic monoterpene in essential oils extracted from pine trees, was shown to stimulate significantly the activity and expression of alkaline phosphatase, an early phase marker of osteoblastic differentiation, on differentiation day 9. On day 15, it dramatically promoted the induction of calcium in a dose-dependent manner. The stimulatory effect of 3-carene on mineralization might be associated with its potential to induce the protein expression/activation of the mitogen-activated protein kinases and the transcript levels of osteoblast mineralization-related genes such as osteopontin and type I collagen. Further studies are needed to determine the precise mechanism, but the anabolic activity of 3-carene in bone metabolism suggested that the use of natural additives to the diet including essential oils could have a beneficial effect on bone health.
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PMID:Low concentration of 3-carene stimulates the differentiation of mouse osteoblastic MC3T3-E1 subclone 4 cells. 1768 87

Integrins play significant roles in mechanical responses of cells on extracellular matrix (ECM). We studied the roles of integrins and ECM proteins (fibronectin [FN], type I collagen [COL1], and laminin [LM]) in shear-mediated signaling and the expression of bone formation-related genes (early growth response-1 [Egr-1], c-fos, cyclooxygenase-2 [Cox-2], and osteopontin [OPN]) in human osteosarcoma MG63 cells. MG63 cells on FN, COL1, and LM were kept as controls or subjected to shear stress (12 dynes/cm(2)), and the association of alpha(v)beta(3) and beta(1) integrins with Shc, phosphorylation of mitogen-activated protein kinases (MAPKs, i.e., extracellular signal-regulated kinase [ERK], c-jun-NH(2)-terminal kinase [JNK], and p38), and expressions of Egr-1, c-fos, Cox-2, and OPN were determined. In MG63 cells, shear stress induces sustained associations of alpha(v)beta(3) and beta(1) with Shc when seeded on FN, but sustained associations of only beta(1) with Shc when seeded on COL1/LM. Shear inductions of MAPKs and bone formation-related genes were sustained (24 h) in cells on FN, but some of these responses were transient in cells on COL1/LM. The shear activations of ERK, JNK, and p38 were mediated by integrins and Shc, and these pathways differentially modulated the downstream bone formation-related gene expression. Our findings showed that beta(1) integrin plays predominant roles for shear-induced signaling and gene expression in osteoblast-like MG63 cells on FN, COL1, and LM and that alpha(v)beta(3) also plays significant roles for such responses in cells on FN. The beta(1)/Shc association leads to the activation of ERK, which is critical for shear induction of bone formation-related genes in osteoblast-like cells.
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PMID:Integrin-mediated expression of bone formation-related genes in osteoblast-like cells in response to fluid shear stress: roles of extracellular matrix, Shc, and mitogen-activated protein kinase. 1833 55

Insulin-like growth factor I (IGF-I) is expressed in many tissues, including bone, and acts on the proliferation and differentiation of osteoblasts as an autocrine/paracrine regulator. Tight-junction proteins have been detected in osteoblasts, and direct cell-to-cell interactions may modulate osteoblast function with respect, for example, to gap junctions. In order to investigate the regulation of expression of tight-junction molecules and of function during bone differentiation, osteoblast-like MC3T3-E1 cells and osteocyte-like MLO-Y4 cells were treated with IGF-I. In both MC3T3-E1 cells and MLO-Y4 cells, the tight-junction molecules occludin, claudin-1, -2, and -6, and the gap-junction molecule connexin 43 (Cx43) were detected by reverse transcription with polymerase chain reaction. In MC3T3-E1 cells but not MLO-Y4 cells, mRNAs of claudin-1, -2, and -6, Cx43, and type I collagen, and proteins of claudin-1 and Cx43 were increased after treatment with IGF-I. Such treatment significantly decreased paracellular permeability in MC3T3-E1 cells. The expression of claudin-1 in MC3T3-E1 cells after IGF-I treatment was mainly upregulated via a mitogen-activated protein (MAP)-kinase pathway and, in part, modulated by a PI3-kinase pathway, whereas Cx43 expression and the mediated gap-junctional intercellular communication protein did not contribute to the upregulation. Furthermore, in MC3T3-E1 cells during wound healing, upregulation of claudin-1 was observed together with an increase of IGF-I and type I collagen. These findings suggest that the induction of tight-junction protein claudin-1 and paracellular permeability during the differentiation of osteoblast-like MC3T3-E1 cells after treatment with IGF-I is regulated via a MAP-kinase pathway, but not with respect to gap junctions.
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PMID:IGF-I regulates tight-junction protein claudin-1 during differentiation of osteoblast-like MC3T3-E1 cells via a MAP-kinase pathway. 1885 15

Pancreatic fibrosis is a characteristic feature of chronic pancreatitis and of desmoplastic reaction associated with pancreatic cancer. For over a decade, there has been accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis in these pathological settings. In response to pancreatic injury or inflammation, quiescent PSCs undergo morphological and functional changes to become myofibroblast-like cells, which express alpha-smooth muscle actin (alpha-SMA). Activated PSCs actively proliferate, migrate, produce extracellular matrix (ECM) components, such as type I collagen, and express cytokines and chemokines. In addition, PSCs might play roles in local immune functions and angiogenesis in the pancreas. Following the initiation of activation, if the inflammation and injury are sustained or repeated, PSCs activation is perpetuated, leading to the development of pancreatic fibrosis. From this point of view, pancreatic fibrosis can be defined as pathological changes of ECM composition in the pancreas both in quantity and quality, resulting from perpetuated activation of PSCs. Because the activation and cell functions in PSCs are regulated by the dynamic but coordinated activation of intracellular signaling pathways, identification of signaling molecules that play a crucial role in PSCs activation is important for the development of anti-fibrosis therapy. Recent studies have identified key mediators of stimulatory and inhibitory signals. Signaling molecules, such as peroxisome proliferator-activated receptor-gamma (PPAR-gamma), Rho/Rho kinase, nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases, phosphatidylinositol 3 kinase (PI3K), Sma- and Mad-related proteins, and reactive oxygen species (ROS) might be candidates for the development of anti-fibrosis therapy targeting PSCs.
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PMID:Signal transduction in pancreatic stellate cells. 1927 Nov 15


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