Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence suggests that leukocyte type 12-lipoxygenase (12-LO) plays an important role in cell growth. However, the role of 12-LO in cardiac cell growth has not been tested. We have now stably overexpressed 12-LO cDNA in rat fetal cardiac fibroblasts to evaluate the role of the 12-LO pathway in cardiac cell growth. Overexpression of 12-LO increased cell [(3)H]leucine incorporation by 2.1+/-0.1-fold (P<0.01) and cell protein content by 2.2+/-0. 3-fold (P<0.01) over mock-transfected cells. These findings were confirmed in additional clones. Baicalein, a 12-LO enzyme inhibitor, dose-dependently inhibited serum-induced leucine incorporation in cardiac fibroblast cells as well as partially inhibited leucine incorporation in cells overexpressing 12-LO. 12-LO overexpression also caused cell [(3)H]thymidine incorporation to increase by 3.4+/-0.3-fold (P<0.01). Cell flow cytometry analysis showed that the size of 12-LO-overexpressing cells was markedly enlarged compared with that of mock-transfected cells. The fibronectin content of the 12-LO-overexpressing cardiac fibroblasts was also significantly increased. We next evaluated the effects of 12-LO RNA overexpression on kinase pathways linked to cellular growth. The overexpression of 12-LO enhanced extracellular signal-regulated kinase activity (4. 1+/-0.5-fold), c-Jun NH(2)-terminal kinase activity (2.9+/-0.5-fold), and p38 mitogen-activated protein kinase activity (2.2+/-0.3-fold). Pretreatment with SB202190 (100 nmol/L), a specific inhibitor of p38, prevented the increases in protein content of 12-LO-overexpressing cardiac fibroblast cells. These data clearly demonstrate that the overexpression of 12-LO causes cell growth of cardiac fibroblasts, thus supporting the role of 12-LO as a novel growth-promoting pathway in the heart.
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PMID:Overexpression of 12-lipoxygenase causes cardiac fibroblast cell growth. 1113 76

Baicalein is a flavonoid derived from the Scutellaria root. In investigations of the inhibitors of prostaglandin synthesis in C6 rat glioma cells, we found that baicalein had a potent inhibitory activity on prostaglandin synthesis induced by either histamine or A23187, a Ca(2+) ionophore. Baicalein inhibited histamine- or A23187-induced phosphorylation of p42/p44 extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), which causes the phosphorylation of cytosolic phospholipase A(2) (PLA(2)). Baicalein also inhibited the phosphorylation of MAPK kinase-1 (MEK-1) induced by histamine or A23187 in the cells. To examine the site of action of baicalein, MEK-1 and Raf-1 were prepared by immunoprecipitation with anti-MEK-1 and anti-Raf-1 antibodies, respectively. Baicalein inhibited the phosphorylation of exogenous MEK-1 by Raf-1 under cell-free conditions, while it did not change the phosphorylation of exogenous p42 MAPK by MEK-1. These results imply that baicalein inhibits the ERK/MAPK cascade, acting on the phosphorylation of MEK-1 by Raf-1.
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PMID:Baicalein inhibits Raf-1-mediated phosphorylation of MEK-1 in C6 rat glioma cells. 1256 9

Excessive production of nitric oxide (NO) in the central nervous system (CNS) mediated by activation of microglia has been implicated in neurotoxicity after stresses such as ischemia. Baicalein, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, anticarcinogenic, and neuroprotective effects. In the present study, we report the inhibitory effect of baicalein on endotoxin/cytokine-induced NO production and inducible nitric oxide synthase (iNOS) gene expression in microglia. Baicalein abolished the endotoxin/cytokine-induced expression of iNOS protein, iNOS mRNA, and iNOS promoter activity in a parallel concentration-dependent manner. The suppression of iNOS expression was not mediated through the down-regulation of tumor necrosis factor-alpha (TNF-alpha) by baicalein because TNF-alpha failed to enhance endotoxin/cytokine-induced NO production in microglia. From the electrophoretic mobility shift assay (EMSA), we found that baicalein exerted a distinct inhibitory effect on the DNA binding activity of transcription factors, and this was significantly greater in nuclear factor IL-6 (NF-IL6) than in nuclear factor kappa B (NF-kappaB) and activated protein 1 (AP-1). Although extracellular signal-regulated kinase (ERK) is critical to iNOS expression, endotoxin/cytokine-stimulated phosphorylation of ERK1/2 was not significantly inhibited by baicalein. These results indicate that NF-IL6 inactivation could be the major determinant for the suppression of NO production by baicalein in microglia. Furthermore, it suggests that the inhibitory effect of baicalein on microglia activation and neurotoxic factor production is responsible for its neuroprotective action.
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PMID:Inhibition of inducible nitric oxide synthase expression by baicalein in endotoxin/cytokine-stimulated microglia. 1510 49

Flavonoids are a family of polyphenolic compounds found ubiquitously in fruits and vegetables as well as in food products and beverages derived from plants. Baicalein is a flavonoid extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. Baicalein exerts either proapoptotic or anti-apoptotic effects in different cell types. The present study was, therefore, undertaken to examine the effect of baicalein on cisplatin-induced apoptosis of human glioma cells. Cisplatin resulted in cell death in a dose- and time-dependent manner and the cell death was attributed to apoptosis. Baicalein prevented loss of cell viability and apoptosis induced by cisplatin in a dose-dependent fashion over the concentrations of 2-10 microM. Exposure of cells to baicalein without cisplatin did not affect cell viability. Western blot analysis demonstrated that cisplatin induced activation of extracellular signal-regulated kinase (ERK), which was not affected by baicalein. Baicalein prevented Bax expression, mitochondrial depolarization, cytochrome c release from mitochondria, and caspase activation induced by cisplatin. Taken together, these findings suggest that baicalein prevents cisplatin-induced apoptosis through inhibition of the mitochondrial depolarization in human glioma cells.
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PMID:Beneficial effect of flavonoid baicalein in cisplatin-induced cell death of human glioma cells. 1591 Nov 24

It has been suggested that baicalein, a flavonoid obtained from the Scutellaria root, exerts a protective role on neurons against several neuronal insults. However, the protective mechanisms underlying this protective effect remain largely unknown. Our results indicate that baicalein protects SH-SY5Y cells, a dopaminergic neuronal cell line, from 6-hydroxydopamine (6-OHDA)-induced damage by the attenuation of reactive oxygen species (ROS). In order to determine the effects of baicalein on mitochondrial events, mitochondrial membrane potentials (deltapsim) and caspase cascades downstream of mitochondria were assessed. Baicalein inhibited the collapse of deltapsim, suggesting that baicalein reduces the mitochondrial dysfunction associated with 6-OHDA treatment. Baicalein also inhibited caspase-9 and caspase-3 activation, which can be triggered by mitochondrial malfunctions. Furthermore, baicalein induced a significant reduction in the level of phospho-JNK, which is known as an apoptotic mediator in 6-OHDA-induced neuronal cell death. Our results indicate that baicalein protects neurons from the deleterious effects of 6-OHDA via the attenuation of oxidative stress, mitochondrial dysfunction, caspase activity, and JNK activation.
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PMID:Baicalein attenuates 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. 1632 86

The bioactive flavonoid baicalein has been shown to have in vitro growth-inhibitory activity in human cancer cells, although the mechanism of action is poorly understood. Baicalein (40-80 mumol/L for 24 h) more effectively induced cytotoxicity compared with other flavonoids (baicalin, catechin, genistein, quercetin, and rutin) in bladder cancer cells. Baicalein induced cell proliferation inhibition and apoptosis. The levels of cyclin B1 and phospho-CDC2 (Thr(161)) were reduced, whereas the G(2)-M phases were elevated by baicalein. Treatment of CDC2 kinase or CDC25 phosphatase inhibitors augments the baicalein-induced cytotoxicity. A variety of human bladder cancer cell lines expressed survivin proteins, which were located on the mitotic phases and regulated mitotic progression. Baicalein markedly reduced survivin protein expression. Transfection of a survivin small interfering RNA diminished the level of survivin proteins and increased the baicalein-mediated cell death. Overexpression of survivin enhanced cell proliferation and resisted the baicalein-induced cytotoxicity. Interestingly, baicalein induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AKT. SB203580, a specific p38 MAPK inhibitor, attenuated proliferation inhibition and restored the protein levels of phospho-CDC2 (Thr(161)) and survivin in the baicalein-exposed cells; conversely, blockade of AKT activation enhanced cytotoxicity and the reduction of phospho-CDC2 (Thr(161)) and survivin proteins. As a whole, these findings provide that the opposite role of p38 MAPK and AKT regulates CDC2 kinase and survivin and the inhibition of CDC2-survivin pathway by baicalein contributes to apoptosis and proliferation retardation in cancer cells.
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PMID:Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT. 1802 87

The identification of anabolic agents that directly stimulate bone formation has recently attracted greater interest. Here, baicalein was identified as a natural compound that stimulates the differentiation of mouse osteoblastic MC3T3-E1 subclone 4 cells. Baicalein induced the activation of NF-kappaB in the initiation stage of osteoblast differentiation, and it activated the MAP kinase/NF-kappaB signaling pathway and induced the expression of osteoblast differentiation markers in the early stage. In the late stage, baicalein stimulated the calcium deposition with the activation of MAP kinases and AP-1 family members such as Fra-1 and Fra-2. Another transcription factor, NFATc1, was slightly induced by baicalein in the late stage. Thus, baicalein could stimulate the osteoblast differentiation via the activation of complexly coordinated signaling pathways that include MAP kinases and transcription factors such as NF-kappaB, AP-1, and NFATc1.
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PMID:Baicalein stimulates osteoblast differentiation via coordinating activation of MAP kinases and transcription factors. 1838 25

Baicalein (5,6,7-trioxyflavone-7-O-beta-D-glucuronide) derived from the Chinese herb Scutellaria baicalensis is well known as a lipoxygenase inhibitor. We investigated baicalein-mediated inhibitory effects on vascular smooth-muscle cell (VSMC) proliferation and intimal hyperplasia by balloon angioplasty in the rat. In vascular injury studies, baicalein significantly suppressed intimal hyperplasia by balloon angioplasty. Baicalein significantly inhibited cell proliferation via a lipoxygenase-independent pathway using [(3)H]thymidine incorporation, 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT), and flow cytometry assays. At the concentrations used, no cytotoxic effect on cell culture was found. Baicalein blocks cell-cycle progression in S/G2/M phase, consistent with the cell-cycle effects, baicalein significant inhibited cyclin D1, p42/44 mitogen-activated protein kinase (MAPK), and Akt phosphorylation without change in the other cell-cycle regulatory proteins. Furthermore, baicalein attenuated serum-induced deoxyribonucleic acid (DNA) binding activity of nuclear factor kappa B (NF-kappaB). These results show that baicalein blocks cell proliferation via blocking cell-cycle progression and proliferating events, including p42/44 MAPK and Akt activations as well as NF-kappaB activation. It also inhibits intimal hyperplasia after balloon vascular injury in the rat, indicating the therapeutic potential for treating restenosis after arterial injury.
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PMID:Baicalein attenuates intimal hyperplasia after rat carotid balloon injury through arresting cell-cycle progression and inhibiting ERK, Akt, and NF-kappaB activity in vascular smooth-muscle cells. 1866 31

Interleukin-6 (IL-6) is an important growth factor for myeloma cells. IL-6 promotes the survival and proliferation of multiple myeloma (MM) cells through the phosphorylated proteins, including STAT3, MAPK, and Akt. Chemical components that suppress the signaling proteins' phosphorylation have a potential role for MM therapy. We recently identified that baicalein, a component of Scutellaria radix, suppressed proliferation and induced apoptosis of myeloma cells by blocking IkappaB-alpha degradation followed by down-regulating IL-6 and XIAP gene expression. In the present study of four myeloma cell lines, namely U266, NOP2, AMO1, and ILKM2, we demonstrated that baicalein not only inhibited IL-6-mediated phosphorylation of signaling proteins, such as Jak, STAT3, MAPK, and Akt, but also inhibited the expression of their target genes, such as bcl-xl. Finally, baicalein facilitated myeloma cell proliferation inhibited by dexamethasone. In contrast, baicalin, another major flavonoid derived from Scutellaria radix, had no significant effect on IL-6-mediated protein phosphorylation. Baicalein had no effect on Akt phosphorylation induced by the insulin-like growth factor-1 (IGF-1) in NOP2 cells. Compared with PD98059, an MAPK inhibitor, baicalein exhibited a stronger inhibitory effect on Erk(1/2) phosphorylation. Our results demonstrate that baicalein is a potent inhibitor of protein phosphorylation induced by IL-6, and thus may be a useful agent for the treatment of MM.
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PMID:Inhibitory effect of baicalein on IL-6-mediated signaling cascades in human myeloma cells. 1987 71

Inflammatory damage and oxidative stress play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Baicalein, isolated from the traditional Chinese herbal medicine Huangqin, is an antioxidant and anti-inflammatory agent on one hand and a lipoxygenase inhibitor on the other hand. However, little is known regarding the mechanism of baicalein's neuroprotection in ischemic stroke. We therefore investigated the potential neuroprotective effects of baicalein and explored the underlying mechanisms. Male, Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) and baicalein was administered intravenously immediately after cerebral ischemia. At 24h after MCAO neurological deficit, brain water content and infarct sizes were measured. Immunohistochemistry, western blot and reverse transcription-polymerase chain reaction (RT-PCR) were used to analyse the expression of 12/15-lipoxygenase (12/15-LOX), p38 mitogen-activated protein kinase (p38 MAPK) and cytosolic phospholipase A2 (cPLA2) at gene and protein levels in ischemic brain cortex. The results showed that baicalein improved neurological deficit, reduced brain water content and infarct sizes, and downregulated the overexpression of 12/15-LOX, p38 MAPK and cPLA2 typically seen with MCAO. The results indicated that baicalein protected the brain from damage caused by MCAO, and this effect may be through downregulation of 12/15-LOX, p38 MAPK and cPLA2 expression.
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PMID:Baicalein is neuroprotective in rat MCAO model: role of 12/15-lipoxygenase, mitogen-activated protein kinase and cytosolic phospholipase A2. 2063 23


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