Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported proliferative and anti-mineralogenic effects of vanadate on fish chondrocytes and here we investigate the signalling pathways associated with these effects. Our data show that vanadate stimulates chondrocyte proliferation through the MAPK pathway, using signalling mechanisms similar to those used by IGF-1, while it inhibits chondrocyte differentiation/mineralization through a putative PI-3K/Ras/Erk signalling, a pathway shared with insulin. Our data also suggest that vanadate impairs ECM mineralization not only by interfering with regulatory pathways but also by inhibiting enzymatic activity of ALP. Finally, this work provides additional evidence for the conservation, throughout evolution, of mechanisms regulating chondrocyte proliferation and differentiation.
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PMID:Vanadate proliferative and anti-mineralogenic effects are mediated by MAPK and PI-3K/Ras/Erk pathways in a fish chondrocyte cell line. 1837 8

Osteosarcoma is the most common primary malignant bone tumor, accounting for approximately 20% of all primary sarcomas in bone. Although treatment modalities have been improved over the past decades, it is still a tumor with a high mortality rate in children and young adults. Based on histological considerations, osteosarcoma arises from impaired differentiation of these immature cells into more mature types and that correction of this impairment may reduce malignancy and increase the efficiency of chemotherapy. The purpose of this study was to determine the effect of specific inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK) and p38 on the differentiation of human osteosarcoma cell line SaOS-2 cells. We found that PD98059, a specific inhibitor of MEK, inhibited the serum-stimulated proliferation of SaOS-2 cells; whereas SB203580, a specific inhibitor of p38 MAPK, had little effect on it. SB203580 suppressed ALPase activity, gene expression of type I collagen, and expression of ALP and BMP-2 mRNAs; whereas PD98059 upregulated them dose dependently. In addition, immunoblot and immunostaining analysis revealed that phosphorylation of ERK was increased by treatment with SB203580; whereas PD98059 increased the phosphorylation of p38, which implies a seesaw-like balance between ERK and p38 phosphorylation. We suggest that osteosarcoma cell differentiation is regulated by the balance between the activities of the ERK and p38 pathways and that the MEK/ERK pathway negatively regulates osteosarcoma cell differentiation, whereas the p38 pathway does so positively. MEK inhibitor may thus be a good candidate for altering the expression of the osteosarcoma malignant phenotype.
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PMID:Specific inhibitor of MEK-mediated cross-talk between ERK and p38 MAPK during differentiation of human osteosarcoma cells. 1848 Dec 1

Lanthanum chloride (LaCl(3)) has been shown to retard the progression of established atherosclerotic lesions in animal models, and used as a calcium channel blocker in various cellular experiments. In this study, we assessed the role of lanthanum chloride (LaCl(3)) in H(2)O(2)-enhanced calcification in rat calcifying vascular cells (CVCs) and examined the involvement of MAPK signaling pathways. H(2)O(2) induced growth inhibition of CVCs, as well as increases in intracellular levels of calcium and reactive oxygen species, ALP activity, apoptosis and calcium deposition. These effects of H(2)O(2) were suppressed by pretreatment of the cells with 1 muM of LaCl(3) for 2 h. In addition, H(2)O(2) activated the phosphorylation of ERK1/2, JNK and p38 MAPK, but only the last two were associated with the ALP activity. Our findings demonstrate that H(2)O(2)-enhanced osteoblastic differentiation and apoptosis are responsible for the increased calcification in rat CVCs, and LaCl(3) can counteract these effects by suppressing the activation of JNK (JNK2, but not JNK1) and p38 MAPK signaling pathway.
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PMID:Lanthanum chloride suppresses hydrogen peroxide-enhanced calcification in rat calcifying vascular cells. 1894 4

Arterial calcification is common, but the mechanisms remain unclear. This study was undertaken to investigate the arterial calcification in adiponectin-deficient mice in vivo and the effects of adiponectin on cultured vascular smooth muscle cells in vitro. Alizarin red S staining was used to detect arterial calcification of adiponectin(-/-) mice. Alkaline phosphatase activity, osteocalcin secretion, and Runx2 protein expression were examined in cultured calcifying vascular smooth muscle cells (CVSMCs). The involved signal pathway was studied using a mitogen-activated protein kinase (MAPK) inhibitor and adiponectin receptor 1 (AdipoR1) siRNA. Adiponectin(-/-) mice developed slight arterial calcification after being fed with normal chow diet for 30 wk. Adenovirus-mediated supplement of adiponectin attenuated arterial calcification in these mice. On cultured CVSMCs, adiponectin inhibited ALP activity, osteocalcin secretion, Runx2 protein expression, and the formation of mineralized nodules. Adiponectin receptor 1 (AdipoR1) protein was detected in CVSMCs, and adiponectin activated p38 mitogen-activated protein kinase. Furthermore, inhibition of AdipoR1 expression or p38 activation reversed the effects of adiponectin on ALP activity. These results showed that adiponectin inhibited osteoblastic differentiation of CVSMCs through the AdipoR1/p38 signaling pathway. Our findings showed that adiponectin(-/-) mice developed arterial calcification, and this could be attributed to the loss of inhibitory action of adiponectin on osteoblastic differentiation of CVSMCs. It suggested that adiponectin plays a protective role against arterial calcification.
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PMID:Development of arterial calcification in adiponectin-deficient mice: adiponectin regulates arterial calcification. 1925 34

Mechanical factors are related to periprosthetic osseointegration following total hip arthroplasty. However, osteoblast response to strain in implanted femurs is unclear because of the absence of accurate stress-measuring methods. In our study, finite element analysis was performed to calculate strain distribution in implanted femurs. 0.8-3.2% tensile strain was then applied to human osteoblasts. Higher magnitudes of strain enhanced the expression of osteocalcin, type I collagen, and Cbfa1/Runx2. Lower magnitudes significantly increased ALP activity. Among these, type I collagen expression increased with the activation of ERK1/2 phosphorylation in a strain-magnitude-dependent manner. Our study marks the first investigation of osteoblast response at different magnitudes of periprosthetic strain. The results indicate that the functional status of human osteoblasts is determined by strain magnitude. The strain distribution in the proximal region of implanted femur should be improved for osseointegration.
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PMID:Different magnitudes of tensile strain induce human osteoblasts differentiation associated with the activation of ERK1/2 phosphorylation. 1933 78

Natural compounds with bone-forming (or anabolic) activity have been recently focused on in bone research. The present study investigated the effect of undecylenic acid (UA) on osteoblast differentiation in mouse osteoblastic MC3T3-E1 subclone 4 cells and primary mouse calvarial cells. Low concentrations of UA (up to 5 microM) exhibited no cytotoxicity and significantly increased the expression and activity of alkaline phosphatase (early differentiation marker of osteoblast) and calcium deposition with the induction of expression of the osteocalcin gene in both cells. Interestingly, at low concentration of UA, the induction of NF-kappaB p65 translocation into nucleus and the up-regulation of AP-1 and NFATc1 transcript levels were also observed, suggesting that the stimulatory effect of UA on osteoblast differentiation could be mediated through the activation of transcription factors. Additionally, although the patterns of UA-induced activation of MAP kinases (JNK and p38) were not completely consistent with the increase of both ALP activity and calcium deposition by UA, MAP kinases might be partially involved in the biological function of UA during the early and late stages of osteoblast differentiation.
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PMID:Stimulatory effect of undecylenic acid on mouse osteoblast differentiation. 1977 59

Development of bone morphogenetic protein (BMP) signaling modulators may provide useful therapeutic options for the treatment of large bony defects in clinical settings. Controversy remains over whether hepatocyte growth factor (HGF) is a positive or negative modulator of BMP-induced osteogenesis. This study analyzed osteogenic properties of HGF, particularly during BMP-2-induced bone formation. Using a mouse model of ectopic bone formation, HGF-impregnated gelatin sponges displayed significantly reduced bone formation induced by BMP-2, both radiologically and histologically. Abrogation of endogenous HGF production by knockdown of HGF mRNA resulted in upregulation of BMP-2-induced ALP activity for C2C12 myoblasts in vitro. In contrast, addition of exogenous HGF inhibited BMP-2-induced ALP activity and osteocalcin production by mouse embryonic fibroblasts (MEFs) through HGF-c-Met interactions. Inhibition of ALP activity by HGF was rescued by U0126, a MEK1/2 inhibitor, indicating that HGF suppresses the BMP-2-Smad axis via activation of ERK1/2. Importantly, treatment with HGF prior to administration of BMP-2 induced cellular proliferation of MEFs and did not influence subsequent osteoblast differentiation induced by BMP-2. The effects of HGF may differ according to the differentiation stage of mesenchymal stem cells, which would explain the inconsistencies seen in osteogenic properties of HGF in previous reports. The timing of HGF treatment is critical and should be carefully determined for successful induction of bone formation by BMPs.
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PMID:The effect of timing in the administration of hepatocyte growth factor to modulate BMP-2-induced osteoblast differentiation. 1991 94

The present study was carried out to investigate whether taurine plays any beneficial role in acetaminophen (APAP)-induced acute hepatotoxicity. APAP exposure increased the plasma levels of ALT, ALP, LDH, TNF-alpha and NO production. Moreover, APAP treatment reduced the glutathione level and antioxidant enzyme activities, increased lipid peroxidation and caused hepatic DNA fragmentation which ultimately leads to cellular necrosis. Also, incubation of hepatocytes with APAP reduced cell viability, enhanced ROS generation and increased CYP2E1 activity. APAP overdose caused injury in the hepatic tissue and hepatocytes via the upregulation of CYP2E1 and JNK. Taurine treatment was effective in counteracting APAP-induced hepatic damages, oxidative stress and cellular necrosis. Results indicate that APAP overdose caused hepatic injury due to its metabolism to hepatotoxic NAPQI (N-acetyl-p-benzoquinone imine), usually catalysed by CYP2E1, and via the direct activation of JNK-dependent cell death pathway. Taurine possesses prophylactic as well as therapeutic potentials against APAP-induced hepatic injury.
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PMID:Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. 2016 95

Diabetic mellitus, a chronic metabolic disorder, is one of the most important health problems in the world, especially in developing countries. Our earlier investigations reported the beneficial action of arjunolic acid (AA) against streptozotocin-mediated type 1 hyperglycemia. We have demonstrated that AA possesses protective roles against drug- and chemical- (environmental toxins) induced hepatotoxicity. Liver is the main organ of detoxification. The purpose of this study was to explore whether AA plays any protective role against hyperglycemic hepatic dysfunctions and, if so, what molecular pathways it utilizes for the mechanism of its protective action. In experimental rats, type 1 hyperglycemia was induced by streptozotocin. AA was administered orally at a dose of 20mg/kg body wt both before and after diabetic induction. An insulin-treated group was included in the study as a positive control for type 1 diabetes. Hyperglycemia caused a loss in body weight, reduction in serum insulin level, and increased formation of HbA(1C) as well as advanced glycation end products (AGEs). Elevated levels of serum ALT and ALP, increased production of ROS and RNS, increased lipid peroxidation, increased 8-OHdG/2-dG ratio, and decreased GSH content and cellular antioxidant defense established the hyperglycemic liver dysfunction. Activation of iNOS, IkappaBalpha/NF-kappaB, and MAPK pathways as well as signals from mitochondria were found to be involved in initiating apoptotic cell death. Hyperglycemia caused overexpression of PARP, reduction in intracellular NAD as well as ATP level, and increased DNA fragmentation in the liver tissue of the diabetic animals. Results of immunofluorescence (using anti-caspase-3 and anti-Apaf-1 antibodies), DAPI/PI staining, and DNA ladder formation and information obtained from FACS analysis confirmed the apoptotic cell death in diabetic liver tissue. Histological studies also support the experimental findings. AA treatment prevented or ameliorated the diabetic liver complications and apoptotic cell death. The effectiveness of AA in preventing the formation of ROS, RNS, HbA(1C), AGEs, and oxidative stress signaling cascades and protecting against PARP-mediated DNA fragmentation can speak about its potential uses for diabetic patients.
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PMID:Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Prophylactic role of arjunolic acid. 2018 23

In order for human embryonic stem cells (hESCs) to be cultured on mouse embryonic fibroblast (MEFs) feeder cells, continuous basic fibroblast growth factor (bFGF) supplementation is required. However, the role of bFGF in a culture system using human-derived feeder cells has not been evaluated until now. In this study, we propagated the widely used hESC lines, H1 and HSF6, on human placenta-derived feeder cells (HPCs) without exogenous bFGF supplementation, and were able to propagate hESCs on HPC feeders up to 50 passages. The absence of bFGF in culture media did not interrupt the undifferentiated propagation and the expression of pluripotent stem cell markers ALP, SSEA-4, TRA-60, Oct-4, Nanog, and Rex-1, as well as the formation of embryoid bodies (EBs) and their differentiation potential. In contrast, hESCs cocultured with MEF feeders could not propagate and form EBs without exogenous bFGF supplementation. Expression of bFGF and the activation of the ERK1/2-c-Fos/c-Jun pathway, which is known as the signaling pathway of bFGF, were identifiable not only in hESCs cultured in bFGF-containing media regardless of feeder cell type, but also in hESCs cocultured with HPC feeder cells in media without bFGF. These findings may support the hypothesis that HPC feeder cells enhance endogenous bFGF production and activation of the ERK1/2-c-Fos/c-Jun pathway, which suggests that HPCs have an additional advantage in their hESC propagation compared with MEF.
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PMID:Undifferentiated propagation of the human embryonic stem cell lines, H1 and HSF6, on human placenta-derived feeder cells without basic fibroblast growth factor supplementation. 2020 81


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