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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia induces an inflammatory activation of microglia during cerebral ischemia. The transcription factor of hypoxia-inducible genes hypoxia-inducible factor-1 (HIF-1) is known to be involved in inflammation and immune response. Although baicalein (BE), a flavonoid, is shown to have anti-inflammatory effects and attenuate ischemic injury, its action mechanism is not understood well. Thus, we examined effect of BE on hypoxia-induced HIF-1 activation and its signaling mechanism in BV2 microglial cells. BE inhibited hypoxia-induced HIF-1alpha protein accumulation and HIF-1 transcriptional activation. Consistently, BE suppressed hypoxia-induced expression of hypoxia responsive genes, iNOS, COX-2, and VEGF. We then showed that BE inhibited hypoxia-induced phosphorylation of Akt but not that of ERK and p38. Moreover, BE inhibited hypoxia-induced PI 3-kinase activation. Finally, we showed that BE inhibited hypoxia-induced ROS generation, and an antioxidant N-acetylcysteine reduced hypoxia-induced HIF-1alpha and iNOS protein expression and PI 3-kinase/Akt activation in BV2 microglia. Taken together, these results suggest that BE suppresses hypoxia-induced HIF-1alpha protein and activation as well as expression of hypoxia responsive genes by inhibiting ROS and PI 3-kinase/Akt pathway in BV2 microglia.
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PMID:Baicalein suppresses hypoxia-induced HIF-1alpha protein accumulation and activation through inhibition of reactive oxygen species and PI 3-kinase/Akt pathway in BV2 murine microglial cells. 1877 9

Lupus nephritis is one manifestation of systemic lupus erythematosus (SLE). Interleukin (IL)-10 is involved in the pathogenesis of SLE. To determine whether IL-20, a member of the IL-10 family, is associated with lupus nephritis, we analyzed the expression of IL-20 and its receptors in mesangial cells derived from SLE-prone, NZB/W, and DBA/W mice. IL-20 and its receptors were upregulated in mesangial cells from NZB/W mice. Incubating IL-20 with mesangial cells upregulated the transcripts of CCL2 (MCP-1), CCL5 (RANTES), CXCL10 (IP-10), IL-6, iNOS, and ROS, all of which are involved in the pathogenesis of lupus nephritis. IL-20 specifically activated the downstream signal ERK 1/2. We also detected human IL-20 protein in both mesangial cells and inflammatory cells in kidney biopsies of patients with lupus nephritis. Our results reveal the novel effects of IL-20 on mesangial cells and its association with lupus nephritis.
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PMID:Interleukin-20 targets renal mesangial cells and is associated with lupus nephritis. 1877 58

Former vascular endothelial growth factor (VEGF)-head and neck squamous cell carcinoma (HNSCC) studies have focused on VEGF's contributions toward tumor-associated angiogenesis. Previously, we have shown that HNSCC cells produce high levels of VEGF. We therefore hypothesized that VEGF serves a biphasic role, that is, pro-angiogenic and pro-tumorigenic in HNSCC pathogenesis. Western blots confirmed the presence of VEGF's primary mitogenic receptors, VEGFR-2/KDR and VEGFR-1/Flt-1 in cultured HNSCC cells. Subsequent studies evaluated VEGF's effects on HNSCC intracellular signaling, mitogenesis, invasive capacities, and matrix metalloproteinases (MMPs) activities. Introduction of hrVEGF(165) initiated ROS-mediated intracellular signaling, resulting in kinase activation and phosphorylation of KDR and Erk1/2. As high endogenous VEGF production rendered HNSCC cells refractory to exogenous VEGF's mitogenic effects, siRNA was employed, inhibiting endogenous VEGF production for up to 96 h. Relative to transfection vector matched controls, siRNA treated HNSCC cells showed a significant decrease in proliferation at both 30 and 50 nM siRNA doses. Addition of exogenous hrVEGF(165) (30 and 50 ng/ml) to siRNA-silenced HNSCC cells resulted in dose-dependent increases in cell proliferation. Cell invasion assays showed VEGF is a potent HNSCC chemoattractant and demonstrated that VEGF pre-treatment enhanced invasiveness of HNSCC cells. Conditioned media from VEGF challenged HNSCC cells showed a moderate increase in gelatinase activity. Our results demonstrate, for the first time, that HNSCC cells are both targets and effectors for VEGF. These data introduce the prospect that VEGF targeted therapy has the potential to fulfill both anti-angiogenic and anti-tumorigenic functions.
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PMID:Human head and neck squamous cell carcinoma cells are both targets and effectors for the angiogenic cytokine, VEGF. 1880 21

Increased nitric oxide (NO) has been correlated with diabetic retinopathy. In this study we investigated the cell injury, production of NO in retinal pigment epithelial (RPE) cells exposed to increased glucose concentration, and its molecular mechanism involved. Cultured human RPE cells (ARPE-19) were exposed for 4 days with normal blood glucose concentration (5.5mM D-glucose), followed by exposure to either normal (5.5mM) or high (33 mM) concentrations of D-glucose for 48 h. To determine the cytotoxicity of high glucose, cell viability, ROS production and SOD activity were measured, respectively. The end product of NO (nitrite and nitrate) was determined by a colorimetric assay and nitrotyrosine levels were quantified by a competitive ELISA. The expression of iNOS and the activation of p38MAPK, ERK and JNK were analyzed by Western blot. Treatment of RPE cells with high glucose-induced a significant increased of iNOS, accompanied by an increase in cell damage, NO and nitrotyrosine levels. High glucose caused activation of p38MAPK and ERK, inhibition for p38MAPK and ERK abrogated the high glucose-induced increase in iNOS, cell injury and levels of NO and nitrotyrosine. High glucose causes increased cell damage and NO generation in RPE cells by a process of iNOS expression that requires the activation of p38MAPK and ERK.
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PMID:p38MAPK and ERK promote nitric oxide production in cultured human retinal pigmented epithelial cells induced by high concentration glucose. 1885 22

The aim of the present study is to elucidate the signaling pathway involved in death of human neuroblastoma SK-N-SH cells induced by Naja naja atra phospholipase A(2) (PLA(2)). Upon exposure to PLA(2), p38 MAPK activation, ERK inactivation, ROS generation, increase in intracellular Ca(2+) concentration, and upregulation of Fas and FasL were found in SK-N-SH cells. SB202190 (p38MAPK inhibitor) suppressed upregulation of Fas and FasL. N-Acetylcysteine (ROS scavenger) and BAPTA-AM (Ca(2+) chelator) abrogated p38 MAPK activation and upregulation of Fas and FasL expression, but restored phosphorylation of ERK. Activated ERK was found to attenuate p38 MAPK-mediated upregulation of Fas and FasL. Deprivation of catalytic activity could not diminish PLA(2)-induced cell death and Fas/FasL upregulation. Moreover, the cytotoxicity of arachidonic acid and lysophosphatidylcholine was not related to the expression of Fas and FasL. Taken together, our results indicate that PLA(2)-induced cell death is, in part, elicited by upregulation of Fas and FasL, which is regulated by Ca(2+)- and ROS-evoked p38 MAPK activation, and suggest that non-catalytic PLA(2) plays a role for the signaling pathway.
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PMID:Upregulation of Fas and FasL in Taiwan cobra phospholipase A2-treated human neuroblastoma SK-N-SH cells through ROS- and Ca2+-mediated p38 MAPK activation. 1900 58

Hyperactivated extracellular signal-regulated kinase (ERK) signaling is common in human cancer and is often the result of activating mutations in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of lung cancers harboring BRAF kinase domain mutations, we screened a large panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for BRAF mutations. We found that non-small cell lung cancers (NSCLC) cells with both V600E and non-V600E BRAF mutations were selectively sensitive to MEK inhibition compared with those harboring mutations in epidermal growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions. Supporting its classification as a "driver" mutation in the cells in which it is expressed, MEK inhibition in (V600E)BRAF NSCLC cells led to substantial induction of apoptosis, comparable with that seen with EGFR kinase inhibition in EGFR mutant NSCLC models. Despite high basal ERK phosphorylation, EGFR mutant cells were uniformly resistant to MEK inhibition. Conversely, BRAF mutant cell lines were resistant to EGFR inhibition. These data, together with the nonoverlapping pattern of EGFR and BRAF mutations in human lung cancer, suggest that these lesions define distinct clinical entities whose treatment should be guided by prospective real-time genotyping. To facilitate such an effort, we developed a mass spectrometry-based genotyping method for the detection of hotspot mutations in BRAF, KRAS, and EGFR. Using this assay, we confirmed that BRAF mutations can be identified in a minority of NSCLC tumors and that patients whose tumors harbor BRAF mutations have a distinct clinical profile compared with those whose tumors harbor kinase domain mutations in EGFR.
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PMID:Genetic predictors of MEK dependence in non-small cell lung cancer. 1901 Sep 12

In the human acute myeloid leukemia cell line M07e, the growth factor interleukin-3 (IL-3) induces ROS formation, positively affecting Glut1-mediated glucose uptake and cell survival. The effect of IL-3 and exogenous hydrogen peroxide on cell viability seems to be mediated through inhibition of the cell death commitment, as shown by apoptotic markers such as caspase activities, apoptotic nuclei, and changes in the amount of proteins belonging to the Bcl-2 family. The pivotal role of ROS is confirmed using various antioxidants, such as EUK-134, ebselen, TEMPO, and hydroxylamine probe. In fact, these antioxidants, acting through different mechanisms, decrease glucose transport activity and cell proliferation activated by IL-3 or by low concentrations of hydrogen peroxide. Moreover, antioxidants foster programmed cell death commitment, as shown by the cited apoptotic parameters. EUK-134, a combined superoxide dismutase/catalase mimetic, opposes the effects of IL-3 and H(2)O(2), decreasing phosphorylation levels of signaling enzymes such as Akt, Src tyrosine kinase, and ERK. Results show that ROS production induced by IL-3 can protect leukemic cells from apoptosis, the effect being counteracted by antioxidants. This mechanism may play an important role in supporting acute myeloid leukemia treatment, thus representing a novel therapeutic strategy.
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PMID:Induction of apoptosis in a human leukemic cell line via reactive oxygen species modulation by antioxidants. 1901 34

Vanadium compounds display important pharmacological actions in vivo and in vitro systems. Semicarbazones are versatile ligands with therapeutic effects. Herein, we report the effects of V(V)O(2)(salicylaldehydesemicarbazone) (V(V)-Salsem) on two osteoblast cell lines in culture (MC3T3-E1 and UMR106). V(V)-Salsem inhibited cell proliferation in a dose response manner. At 100muM, the complex caused an inhibition of ca. 48% and 38% for the normal and the tumoral osteoblasts, respectively (p<0.001). This inhibition could be partially reversed to 35% and 28% by NAC (N-acetylcysteine) and a mixture of vitamins E and C. Changes in cell proliferation correlated with morphological alterations and the disruption of actin cytoskeleton fibers. The complex also enhanced the level of ROS (reactive oxygen species) up to ca. 100% over basal in both cell lines. Activation of ERK signalling cascade was also observed. These events led to apoptosis (up to 44% in MC3T3-E1 and 33% in UMR106 cells). Scavengers of ROS and inhibitors of ERK cascade allowed to elucidate the mechanisms involved in the cytotoxicity. In conclusion, V(V)-Salsem displayed cytotoxic effects on osteoblasts in culture through the production of free radicals and the activation of ERK cascade. These mechanisms triggered the apoptotic events that conveyed to cell death.
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PMID:Biological effects of a complex of vanadium(V) with salicylaldehyde semicarbazone in osteoblasts in culture: mechanism of action. 1911 8

Sustained hypoxia appears to be an early and pivotal condition in the pathogenesis of chronic kidney disease, and may induce a number of adaptive/protective or harmful cellular responses. Kojima and colleagues found an upregulation of metallothioneins (MTs) among dozens of altered expression patterns. They demonstrated the astonishing properties of MTs within major intracellular signaling pathways beyond their notorious functions in heavy metal metabolism, detoxification, and ROS scavenging-HRE stimulation during normoxia and hypoxia together with ERK phosphorylation and mTOR activation.
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PMID:Metallothionein: a new soldier in the fight against chronic renal hypoxia? 1914 52

Epidemiological evidence suggests that flavonoids may play an important role in the decreased risk of chronic diseases associated with a diet rich in plant-derived foods. Flavonoids are also common constituents of plants used in traditional medicine to treat a wide range of diseases. The purpose of this article is to summarize the distribution and biological activities of one of the most common flavonoids: luteolin. This flavonoid and its glycosides are widely distributed in the plant kingdom; they are present in many plant families and have been identified in Bryophyta, Pteridophyta, Pinophyta and Magnoliophyta. Dietary sources of luteolin include, for instance, carrots, peppers, celery, olive oil, peppermint, thyme, rosemary and oregano. Preclinical studies have shown that this flavone possesses a variety of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial and anticancer activities. The ability of luteolin to inhibit angiogenesis, to induce apoptosis, to prevent carcinogenesis in animal models, to reduce tumor growth in vivo and to sensitize tumor cells to the cytotoxic effects of some anticancer drugs suggests that this flavonoid has cancer chemopreventive and chemotherapeutic potential. Modulation of ROS levels, inhibition of topoisomerases I and II, reduction of NF-kappaB and AP-1 activity, stabilization of p53, and inhibition of PI3K, STAT3, IGF1R and HER2 are possible mechanisms involved in the biological activities of luteolin.
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PMID:Distribution and biological activities of the flavonoid luteolin. 1914 59


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