Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophil elastase is a neutral serine proteinase produced by polymorphonuclear leukocytes and monocytes/macrophages, especially under surgical stress. In the present study, we investigated whether NE promotes cell growth by activation of EGFR to elucidate whether surgical stress induces tumor proliferation and progression. Furthermore, we examined the antitumor effect of a specific NE inhibitor, sivelestat. Cell growth assays were carried out in vitro and in vivo using TMK-1 gastric cancer cells. TMK-1 cell growth was stimulated to 118% of that of the control cells after 48 h stimulation with 1 microg/mL NE according to an MTT assay. Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1,000 microg/mL, respectively. NE rapidly phosphorylated EGFR in only 5 min and triggered the ERK1/2-mitogenic signaling pathway in TMK-1. It was further demonstrated that NE-induced EGFR phosphorylation was transactivated through TGF-alpha, using ELISA. NE increased the cleavage of TGF-alpha from the cell surface 30-fold compared with the cells without treatment. Interestingly, sivelestat significantly reduced NE-induced EGFR phosphorylation and ERK1/2 activation and completely blocked the release of TGF-alpha from the TMK-1 cell surface. In a xenograft study, the addition of ventrotomy as a surgical stress promoted tumor growth. Sivelestat significantly suppressed the tumor growth induced by surgical stress. These results indicate that sivelestat suppresses the growth of gastric cancer cells by inhibiting the release of TGF-alpha stimulated by NE, which often occurs after surgical stresses.
 ...
PMID:Sivelestat, a specific neutrophil elastase inhibitor, suppresses the growth of gastric carcinoma cells by preventing the release of transforming growth factor-alpha. 1691 98

Alteration of the epidermal growth factor (EGF) signaling pathway occurs frequently in human cancer cells and may subsequently affect the cell survival towards anti-cancer agents. To elucidate the effect of long-term EGF treatment on the chemo-sensitivity of human cancer cells, human squamous carcinoma A431 cells (AP) were incubated continuously with 50 ng/ml EGF for 30 weeks and these cells were designated as the AC cells. The long-term EGF treatment did not alter the EGFR level and the EGF-induced protein tyrosine phosphorylation pattern in the AC cells. By MTT assay, the AC cells were shown to be more resistant than the AP cells to doxorubicin, etoposide and amsacrine but not to cisplatin. Among the drug-resistant proteins, topoisomerase IIalpha (topoII) was downregulated in the AC cells while there was no apparent change in the levels of P-glycoprotein, MRP-1 or glutathione- S-transferase-pi as compared to the AP cells. Furthermore, knockdown of topoII by antisense topoII oligonucleotide transfection decreased the sensitivity to doxorubicin, etoposide and amsacrine in the A431 cells. Results from the present study support an idea that long-term treatment with EGF may induce drug resistance in cells through the downregulation of topoII.
 ...
PMID:Epidermal growth factor induction of resistance to topoisomerase II toxins in human squamous carcinoma A431 cells. 1696 95

The present study investigated the effects of raloxifene, a second generation selective estrogen receptor modulator (SERM), plus 17-betaE2 on aortic atherosclerosis and mammary gland hyperplasia in ovariectomized, cholesterol-fed rabbits. Following 10 weeks of raloxifene, 17-betaE2, or raloxifene plus 17-betaE2 administration, serum total cholesterol, triglyceride, low density lipoprotein were significantly decreased in the drug groups compared to the placebo group. Consistent with serum lipid results, the total lesion area for each aorta of the drug groups decreased significantly as compared to the placebo group. HE staining of aorta paraffin section showed that in the drug groups the endothelial monolayer was almost continuous. While in mammary gland, HE staining of paraffin sections indicated the hyperplasia of epithelial cells (in 17-betaE2 group) was obviously inhibited in raloxifene plus 17-betaE2 group. In cultured vascular smooth muscle cell (VSMC), the results of MTT and [3H]TdR incorporation showed that the drug groups could inhibit AngII-induced proliferation of VSMC. Western blotting proved that raloxifene plus 17-betaE2 inhibited the expression of phosphorylated ERK protein, similar to 17-betaE2 but different from raloxifene. This effect was inhibited by PD98059 (inhibitor of MAPK) or ICI182780 (ER antagonist). In conclusion, this study suggests that SERM raloxifene plus 17-betaE2 improves the lipid metabolism and relieves the aorta changes of female experimental atherosclerosis rabbits, which are partly implemented by the inhibition of VSMC growth through ERK cascade. The hyperplasia of mammary gland epithelial cells could be significantly inhibited by raloxifene plus 17-betaE2.
 ...
PMID:Effects of selective estrogen receptor modulator raloxifene plus 17-beta estradiol in aorta and mammary gland of female experimental atherosclerosis rabbits and possible involvement of ERK signal transduction pathway. 1697 Feb 44

Although skin and respiratory sensitizing properties of platinum compounds have been proved in humans and mice, little is known about signal transduction pathways leading to cytokine production in the induction phase. It is generally assumed that induction of skin sensitization, but not skin irritation, is associated with a rapid increase in the IL-1beta mRNA expression. In this study, IL-1beta expression and a role of mitogen-activated protein kinases (MAPKs) in this process were investigated in murine macrophages J774A.1 exposed to four platinum compounds. Potassium tetrachloroplatinate (K(2)PtCl(4); TCPP), ammonium tetrachloroplatinate ((NH(4))(2)PtCl(4); TCPA), ammonium hexachloroplatinate ((NH(4))(2)PtCl(6); HCPA) showed a very similar range of cytotoxic concentrations (IC(50) values: 238 microM+/-30; 269 microM+/-39 and 245 microM+/-31, respectively) as assessed in the 24-h MTT reduction test. Cytotoxicity of cis-diammineplatinum dichloride (cisplatin) was considerably higher (IC(50) of 23 microM+/-4). While increased expression of IL-1beta mRNA was observed in the macrophages exposed to each test compound, IL-1beta protein production was detected in cell lysates after treatment with TCPP, TCPA and HCPA for 24h (concentration range of 150-350 microM) as well as for 2h (450-650 microM). The treatment with each compound resulted in the phosphorylation of both p38 MAPK and ERK 1/2 (p44/42). Blocking the activation of p38 MAPK as well as ERK 1/2 with specific inhibitors (SB203580 and U0126, respectively) down-regulated the IL-1beta expression. Interestingly, the skin irritant sodium dodecyl sulfate did not trigger phosphorylation of these kinases, nor induced IL-1beta production. These data suggest that p38 MAPK and ERK 1/2 play an important role in induction of IL-1beta expression in J774A.1 macrophages exposed to test platinum compounds.
 ...
PMID:Interleukin-1beta expression in murine J774A.1 macrophages exposed to platinum compounds: the role of p38 and ERK 1/2 mitogen-activated protein kinases. 1708 86

Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely distributed neuropeptide that has various different functions in the nervous system and in non-neural tissues. Little is known about the effects of PACAP in endothelial cells. The aim of the present study was to investigate the effects of PACAP on endothelial cell survival and apoptotic signaling pathways under oxidative stress. Mouse hemangioendothelioma (EOMA) cells were exposed to 0.5mM H(2)O(2) which resulted in a marked reduction of cell viability and a parallel increase of apoptotic cells assessed by MTT test and flow cytometry. Co-incubation with 20nM PACAP1-38 increased cell viability and reduced the percentage of apoptotic cells. Flow cytometry analysis showed that oxidative stress reduced the phosphorylation of the anti-apoptotic ERK and increased the phosphorylation of the pro-apoptotic JNK and p38 MAP kinases. PACAP1-38 treatment ameliorated these changes: levels of phospho-ERK were elevated and those of phospho-JNK and p38 were decreased. All these effects were abolished by simultaneous treatment with the PACAP antagonist PACAP6-38. In summary, our results show that PACAP effectively protects endothelial cells against the apoptosis-inducing effects of oxidative stress.
 ...
PMID:Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis. 1727 Jan 84

Titanium dioxide (TiO(2)) and TiO(2) glasses containing poly(epsilon-caprolactone) (PCL) up to 24% by weight were obtained by the sol-gel process. Powder compaction was achieved providing heat and pressure. Properties were evaluated through compression and bending tests assisted by X-ray micro-computed tomography imaging. The effects of compaction conditions (i.e. temperature, pressure and duration) on mechanical properties of inorganic/organic composites were investigated. Biocompatibility tests on organic/inorganic composites were carried out using human cells and the MTT assay to determine viability. Results indicated that the mechanical properties (i.e. Young's modulus and maximum strength), in both compression and bending, were a function of the compression moulding conditions. Highest mechanical properties were measured using a compaction pressure of 1500 MPa acting for 90 min at a die temperature of 100 degrees C. The results, however, also suggest that mechanical properties can be tailored by varying the amount of PCL to TiO(2). Strength and stiffness spanned between the properties of spongy and cortical bone. Young's modulus in both compression and bending were higher for PCL amounts of 6%. Instead, higher bending strength values were measured for PCL amounts of 12%. These weight amounts of PCL also provide higher average density values, thus suggesting that the polymeric phase is effective in toughening TiO(2)-based materials. The investigated materials also showed a very good cytocompatibility as indicated by the MTT assay results.
 ...
PMID:Effects of polymer amount and processing conditions on the in vitro behaviour of hybrid titanium dioxide/polycaprolactone composites. 1736 35

We previously found that endothelin-1(1-31) (ET-1(1-31)) exhibited a pro-arrhythmogenic effect in isolated rat hearts. In this study, we further investigated the effects of ET-1(1-31) on a cell viability and observed [Ca(2+)](i) in cultured cardiomyocytes. Cultured neonatal rat cardiomyocytes were treated with 0.1, 1, and 10 nM ET-1(1-31) for 24h in the presence or absence of ET(A) receptor antagonist (BQ(123)) or phosphoramidon, a NEP/ECE inhibitor. Cell injury was evaluated by supernatant lactate dehydrogenase (LDH) assay, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content. Cell viability was assessed by MTT assay. [Ca(2+)](i) was measured with Fluo-3/AM under a laser confocal microscope. 1) ET-1(1-31) dose-dependently increased LDH release and decreased cell viability. 2) LDH and MDA levels were significantly elevated and SOD activity decreased after administration of 1 nM ET-1(1-31) for 24h, and these changes were markedly attenuated by 1 uM BQ(123). 3) Exposure to 10 nM ET 1(1-31) caused a continuous increase in [Ca(2+)](i) to cultured beating cardiomyocytes and termination of [Ca(2+)](i) transient within 6 min, and this change was reversed by 1 uM BQ(123) and attenuated by 0.5 mM phosphoramidon. These results suggest that ET-1(1-31) could cause cell injury, and that the effect of ET-1(1-31) on [Ca(2+)](i) transients is mainly mediated by ET(A) receptor and partially attributed to the conversion of ET-1(1-31) to ET-1(1-21).
 ...
PMID:Effects of endothelin-1 1-31 on cell viabililty and [Ca2+]i in cultured neonatal rat cardiomyocytes. 1746 91

The study was aimed to investigate the molecular mechanisms of histone deacetylase inhibitor SAHA-induced apoptosis of acute myeloid leukemia cell line HL-60. The effect of SAHA on HL-60 cell proliferation was detected by MTT assay and the cell morphological changes were observed with Wright-Giemsa and Hoechst33342 staining. The cell cycle distribution was determined by flow cytometry and the expression of cell signaling proteins were detected by Western-blot analysis. The results showed that SAHA inhibited the proliferation of HL-60 cells in dose- and time-dependent manners, after 2 micromol/L SAHA exposure for 12 - 48 hours, the cell cycle was arrested at G(0)/G(1) phase and apoptotic cell death was confirmed by either defined apoptotic bodies stained by Hoechst33342, Western blot showed cleaved-PARP, which represents the activation of caspase 3. The Western blot analysis indicated the activation of two important survival signal pathways after SAHA treatment, the phosphorylation of Raf and its downstream ERK kinases were remarkable downregulated, whereas the phosphorylation of AKT and its downstream molecular mTOR were not changed. It is concluded that SAHA-induced apoptosis of HL-60 cells is mediated by inactivation of p44/42 MAPK signaling pathway.
 ...
PMID:[Histone deacetylase inhibitor SAHA induces inactivation of MAPK signaling and apoptosis in HL-60 cells]. 1749 29

Retinoic acid (RA) is an active metabolite of vitamin A and plays an important role in biological processes including cell proliferation. MAPKs play a pivotal role in regulating many critical cellular processes in the heart. The aim of the study was to determine whether all-trans RA (atRA) affects the proliferation of H9c2 rat ventricular cells and whether ERK family is involved in this process. H9c2 myocardial cells were cultured and subjected to MTT and (3)H-thymidine incorporation assays for proliferation detection. Luciferase reporter gene and Western blot assays were used to detect the transcription and protein expression of c-jun. In addition, the activities of ERK5 and ERK1 were determined by Western blot assay. The subcellular distribution of ERK5 and ERK1 was analyzed by confocal microscopy. It was shown that atRA (0.05 microM) facilitated the proliferation of H9c2 myocardial cells and increased the transcription and protein expression of c-jun. Inhibition of ERK5 significantly decreased atRA-induced pJluc expression (P<.01). The activity of ERK5 but not ERK1 was induced by atRA. Furthermore, atRA promoted the nuclear translocation of ERK5 but not ERK1. These results suggest that ERK5 pathway may be involved in the process that atRA regulates proliferation in the developing heart.
 ...
PMID:All-trans retinoic acid regulates c-jun expression via ERK5 in cardiac myoblasts. 1750 54

12-Lipoxygenase (12-LOX) is over-expressed in a variety of human tumors, but its exact effect on the tumorogenesis of gastric cancer remains largely obscure. To investigate the effect of 12-LOX and its inhibitor baicalein on proliferation and apoptosis of human gastric cancer, AGS cells were separately treated with 12-hydroxyeicosatetraenoic acid (12-HETE, a metabolite of 12-LOX) and baicalein. MTT assay revealed that the absorbance of the 12-HETE-treated group was significantly (P < 0.01) higher than that of control group and that the absorbance of baicalein-treated group was significantly (P < 0.01) less than that of the control group, and that 48 h after treatment the apoptosis index of the baicalein-treated group was significantly (P < 0.01) higher than that of the untreated group and was significantly (P < 0.01) lower in the 12-HETE-treated group. Western blotting analysis was used to investigate the mechanism of these effects. The results revealed that the concentration of phosphorylated ERK in cells treated with 100 nmol L(-1) 12-HETE was significantly (P < 0.05) higher than in the untreated group and that the concentration of phosphorylated ERK1/2 in cells treated with 40 micromol L(-1) baicalein was significantly (P < 0.05) lower than in the untreated group. The expression level of bcl-2 was up-regulated and down-regulated after separate treatment with 12-HETE and baicalein, respectively, and both of these effects could be blocked by PD98059. Protein kinase C (PKC) activity was increased by treatment with 12-HETE and reduced by treatment with baicalein (P < 0.05). The PKC inhibitor BIM (bisindolymaleimide-I) blocked the phosphorylation of ERK1/2 and activation of PKC induced by 12-LOX. When pretreated with BIM, the concentration of phospho-ERK1/2 or bcl-2 in the BIM + 12-HETE-treated group was significantly (P < 0.05) lower than in that treated with 12-HETE only, and the concentration in the BIM + baicalein-treated group was significantly (P < 0.05) higher than in that treated with baicalein only. On the basis of these data we conclude that, via its metabolite 12-HETE, 12-LOX abolishes proliferation of AGS cells and protect cells from apoptosis by activating the ERK1/2 pathway and, eventually, enhances expression of bcl-2. Because PKC is also involved in the activation of ERK1/2 induced by 12-LOX, 12-LOX inhibitors would be potentially powerful anticancer agents for prevention and cure of human gastric cancer.
 ...
PMID:12-lipoxygenase induces apoptosis of human gastric cancer AGS cells via the ERK1/2 signal pathway. 1752 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>