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: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to ultraviolet radiation (UVR) and reactive oxygen species (ROS) can damage the human lens and contribute to cataract formation. Recent evidence suggests that apoptosis in lens epithelial cells (LEC) is an initiating event in noncongenital cataract formation in humans and animals. The present study examines the cellular and molecular mechanisms by which environmental (ultraviolet B [UVB]) and chemical (hydrogen peroxide [H(2)O(2)], t-butyl hydroperoxide [TBHP]) stress induces cell death in an SV-40 immortalized human lens epithelial (HLE) cell line. Treatment of HLE cells with UVB, H(2)O(2), and TBHP significantly decreased cell density with LD50 values of 350 J/m(2), 500 muM, and 200 muM, respectively. Cellular morphology, DNA fragmentation, and annexin/propidium iodide staining consistent with apoptosis was observed only in UVB-treated cells, whereas lactate dehydrogenase (LDH) release was significantly higher in H(2)0(2)- and TBHP-treated cells. In addition, activation of apoptotic stress-signaling proteins, including c-Jun NH2-terminal kinase (JNK), caspase-3, and DNA fragmentation factor 45 (DFF45) was observed only in UVB-treated cells. Inhibition of JNK activity increased UVB-induced cell death, suggesting that this pathway may serve a prosurvival role in HLE cells. These findings suggest UVB predominantly induces apoptosis in HLE cells, whereas H(2)O(2) and TBHP induce necrosis.
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PMID:Apoptotic and necrotic mechanisms of stress-induced human lens epithelial cell death. 1552 44

The objectives of the present study were to determine the effect of nicotine on MAPK signaling and on the proliferation of AR42J cells as well as to assess the relationship between MAPK activation and exocrine secretion in these cells. AR42J cells were incubated with nicotine and analyzed for the activation of MAPK by Western blot analysis using their respective antibodies and confirmed by immunohistochemistry. The effect of nicotine on cell proliferation was determined by the spectrophotometric method, and cell function was assessed by cholecystokinin (CCK)-stimulated amylase release into the culture medium. Nicotine at a dose of 100 microM induced phospho-ERK1/2 activation maximally in 3 min compared with untreated cells. Furthermore, immunofluorescence study confirmed the nicotine-induced increase in translocation of phospho-ERK1/2 to the nucleus. Activation of phospho-ERK1/2 was inhibited by an ERK1/2 pathway inhibitor but not by a nicotine receptor antagonist. At the same dose, there was significantly enhanced proliferation of AR42J cells until 72 h without toxic effect, as the percentage of lactate dehydrogenase release remained unchanged. Other MAPKs, c-Jun NH2-terminal kinase 1/2 and p38 MAPK, were not affected by nicotine treatment. At a nicotine dose of 100 microM, the CCK-stimulated release of amylase was maximal at 6 min, and, although a nicotinic receptor antagonist inhibited this response, it was not inhibited by the ERK1/2 pathway inhibitor. We conclude that nicotine treatment induced activation of ERK1/2 and increased the proliferation of AR42J cells. The data further indicate that MAPK signaling by nicotine is independent of the secretory response.
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PMID:Activation of p-ERK1/2 by nicotine in pancreatic tumor cell line AR42J: effects on proliferation and secretion. 1605 20

As aged population dramatically increases in these decades, efforts should be made on the intervention for curing age-associated neurodegenerative diseases such as Alzheimer's disease (AD). Natural plant extracts of Lycium barbarum are well-known to exhibit anti-aging effects. We therefore hypothesized that they exhibit neuroprotective effects against toxins in aging-related neurodegenerative diseases. In this study, we aimed to investigate whether extracts from L. barbarum have neuroprotective effects against toxicity of fibrillar Abeta(1-42) and Abeta(25-35) fragments. Primary rat cortical neurons exposed to Abeta peptides resulted in apoptosis and necrosis. Pre-treatment with extract isolated from L. barbarum significantly reduced the release of lactate dehydrogenase (LDH). In addition, it attenuated Abeta peptide-activated caspases-3-like activity. The extract elicited a typical dose-dependent neuroprotective effect. Effective dosage of this extract was wider than that of a well-known western neuroprotective medicine lithium chloride (LiCl). We have further examined the underlying mechanisms of the neuroprotective effects. In agreement with other laboratories, Abeta peptides induce a rapid activation of c-Jun N-terminal kinase (JNK) by phosphorylation. Pre-treatment of aqueous extract markedly reduced the phosphorylation of JNK-1 (Thr183/Tyr185) and its substrates c-Jun-I (Ser 73) and c-Jun-II (Ser 63). Taken together, we have proved our hypothesis by showing neuroprotective effects of the extract from L. barbarum. Study on anti-aging herbal medicine like L. barbarum may open a new therapeutic window for the prevention of AD.
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PMID:Neuroprotective effects of anti-aging oriental medicine Lycium barbarum against beta-amyloid peptide neurotoxicity. 1613 64

Using human neuroblastoma SH-SY5Y cells, effects of acrylamide on p53 protein and intracellular signal transducting pathways were examined. Acrylamide increased p53, phosphorylated p53, and p53-associated protein murine double minute 2 (MDM2). The phosphorylation of p53 was specific for the Ser15 site. Among mitogen-activated protein kinases (MAPKs), acrylamide caused phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38 but not c-Jun NH(2)-terminal kinase. Nevertheless, blocking p38 pathway by LL-Z1640-2 did not suppress the phosphorylation of p53 at Ser15. In contrast, a specific inhibitor of ERK kinase (U0126 or PD98059) could abolish the accumulation as well as the phosphorylation of p53 at Ser15. Elevation of MDM2 was also abolished by U0126. An inhibitor of phosphatidylinositol 3-kinase-related kinase (PIKK) pathway (wortmannin) suppressed the increase of p53 and its phosphorylation at Ser15. Hence, acrylamide increases p53 protein and its phosphorylation at Ser15 through ERK and/or PIKK pathways. On the other hand, U0126 and PD98059 suppressed to some extent the cytotoxicity of acrylamide evaluated by trypan blue exclusion and lactate dehydrogenase (LDH) leakage, whereas neither LL-Z1640-2 nor wortmannin was effective in suppressing the toxicity. Thus, ERK pathway seems to play a role both in causing the phosphorylation of p53 at Ser15 and in the cytotoxicity of acrylamide in SH-SY5Y cells.
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PMID:Involvement of the extracellular signal-regulated protein kinase pathway in phosphorylation of p53 protein and exerting cytotoxicity in human neuroblastoma cells (SH-SY5Y) exposed to acrylamide. 1618 10

Pramipexole, a novel non-ergot dopamine (DA) agonist, has been successfully applied to the treatment of Parkinson's disease (PD). Although the specific cause of PD remains unknown, recent studies have provided evidence that oxidative stress plays a role in the parthenogenesis of the disease. In the present study, we examined the effect of pramipexole on hydrogen peroxide (H2O2, 100 microM)-induced PC12 cell death, and the intracellular mechanism of this effect. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that pretreatment of PC12 cells with pramipexole (1-100 microM) resulted in significant protection against H2O2-induced cell death in a concentration-dependent manner. The protective effect of pramipexole was not affected by pretreatment with the DA receptor antagonists sulpiride, spiperone or domperidone, suggesting that the effect of pramipexole is not mediated by DA receptors. In PC12 cells, pramipexole inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, as well as H2O2-induced cytochrome c release and caspase-3 activation with the resultant apoptosis. It was also observed in PC12 cells that H2O2 stimulated phosphorylation of mitogen-activated protein (MAP) kinases, i.e., extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase. Pramipexole inhibited H2O2-induced JNK and p38 MAP kinase, but not ERK1/2 phosphorylation. Furthermore, in these cells experiments with a fluorescent probe, 2-[6-(4'-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid, revealed that pramipexole, the JNK inhibitor SP600125 and the p38 MAP kinase inhibitor SB203580 inhibited the generation of H2O2-induced reactive oxygen species. Caspase inhibitors Z-DEVD-FMK and Z-IETD-FMK, as well as SP600125 and SB203580, inhibited H2O2-induced PC12 cell death to a similar extent as pramipexole. These results suggest that pramipexole exerts a protective effect against oxidative stress-induced PC12 cell death in part through an inhibition of JNK and p38 MAP kinase.
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PMID:Pramipexole protects against H2O2-induced PC12 cell death. 1636 28

The ability of modified low-density lipoptoteins (LDLs) to induce both proliferation and death of endothelial cells is considered to be a mechanism of early atherosclerosis development. We previously showed that carbamylated LDL (cLDL) induces human coronary artery endothelial cell (HCAEC) death in vitro. This effect is similar to the atherogenic action of oxidized LDL (oxLDL) that induces the proliferation and death of endothelial cells. The present study was designed to analyze a potential proliferative effect of cLDL and whether proliferation caused by modified LDLs is related to cell death. Cultured HCAECs were exposed to different concentrations of modified LDL or native LDL for varying periods of time. Cell proliferation measured by bromodeoxyuridine incorporation and S-phase analysis was dose-dependently increased in the presence of cLDL (6.25-200 microg/ml). The proliferation induced by cLDL or oxLDL was associated with cell death and increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK). Inhibition of cLDL- or oxLDL-induced proliferation by aphidicolin (1 microg/ml) was protective against both short-term cell death measured by lactate dehydrogenase release into the medium and long-term cell viability visualized by cell multiplication. Inhibition of ERK phosphorylation led to a significant decrease of DNA synthesis and cell rescue from injury by modified LDLs, while inhibition of JNK phosphorylation had an only partial rescue effect without involvement in cell proliferation. These data are the first evidence that endothelial cell death induced by cLDL or oxLDL is mediated by cell proliferation through the mitogen-activated protein kinase pathway.
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PMID:Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway. 1715 46

Doxorubicin (DOX) is a potent anticancer drug, whose clinical use is limited on account of its toxicity. DOX cytotoxic effects have been associated with reactive oxygen species (ROS) generated during drug metabolism. ROS induce signaling cascades leading to changes in the phosphorylation status of target proteins, which are keys for cell survival or apoptosis. The mitogen-activated protein kinase (MAPK) cascades are routes activated in response to oxidative stress. In this work, the effects of DOX on cytotoxicity, indicators of oxidative stress (malondialdehyde -MDA- and GSH), and the phosphorylation status of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 kinases were analyzed in primary cultures of rat hepatocytes. DOX (1-50 microM) did not modify lactate dehydrogenase (LDH) release into the medium, the levels of MDA (determined by high-performance liquid chromatography [HPLC]) or the intracellular GSH during the incubation time up to 6 h. GSH levels from mitochondria extracted by Percoll gradient from cultured hepatocytes were not modified by DOX, thus excluding its depletion or any impaired mitochondrial uptake. Characterization of proteins by Western blot analysis revealed that DOX increased phosphorylation of p38 kinases and JNK1 and JNK2 in a dose- and time-dependent manner. DOX also increased ERK2 phosphorylation at latter time points. In conclusion, DOX triggers activation of ERK, JNK, and p38 kinases in primary cultures of rat hepatocytes independently of oxidant damage.
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PMID:Doxorubicin-induced MAPK activation in hepatocyte cultures is independent of oxidant damage. 1738 85

Glomerulosclerosis is a common disorder in many types of chronic kidney diseases. Previous studies have shown that glomerular mesangial cells (MCs) play an important role in the pathogenesis of glomerulosclerosis. The ability of saikosaponin-d (SSd) to reduce the damage of kidney in progressive glomerulosclerosis has been demonstrated. In this study, the effects of saikosaponin-d on MC proliferation and synthesis of extracellular matrix proteins were investigated. Rat MCs were isolated from Wistar rats and cultured in Dulbecco's modified Eagle's medium. MCs were challenged with lipopolysacchorides and incubated with different concentrations of SSd. Cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and lactate dehydrogenase assays. Type IV collagen, fibronectin, and TGF-beta1 in the conditioned medium were measured. The expression of cyclin-dependent kinase 4, c-Jun, and c-Fos was determined by immunohistochemistry. At a concentration of 4 microg/mL or lower, SSd inhibited MC proliferation but did not cause cell death. SSd also inhibited lipopolysaccharide-induced secretion of type IV collagen, fibronectin, and TGF-beta1 in MCs. Additionally, SSd reduced the expression of CDK4, c-Jun, and c-Fos in MCs. We conclude that SSd inhibited MC proliferation and synthesis of extracullular matrix proteins through the downregulation of the CDK4, c-Jun, and c-Fos genes.
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PMID:Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteins. 1753 96

This study was carried out to investigate the chemopreventive potentials of plant originated glycoprotein (UDN glycoprotein, 116 kDa) isolated from the stems of Ulmus davidiana Nakai (UDN) on aberrant crypt foci (ACF) formation in 1,2-dimethylhydrazine (DMH)-treated ICR mice. UDN glycoprotein was administered to mice at 0.01% and 0.02% levels for 5 weeks. The mice were treated with 20 mg/kg DMH twice a week for 2 weeks in presence of UDN glycoprotein and killed at week 6. We found that UDN glycoprotein has inhibitory effects on the frequency of colonic aberrant crypt foci (ACF), activation of colonic proliferating cell nuclear antigen (PCNA), and release of plasma lactate dehydrogenase (LDH) in DMH-treated mice. In addition, UDN glycoprotein has anti-oxidative effects on the formation of plasma thiobarbituric acid reactive substances (TBARS) and the production of plasma inducible nitric oxide (NO) in DMH-treated mouse. Also, 0.02% UDN glycoprotein suppressed the DNA binding activities of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1), accompanying the inhibitions of its subunits (p50, p65, c-Jun, and c-Fos), pro-inflammatory proteins [inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)], and pro-inflammatory cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL)-6] on DMH-stimulated ACF formation. On the basis of these results, we assume that UDN glycoprotein may be useful for colon cancer prevention at initiation stage.
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PMID:Inhibitory effect of phytoglycoprotein on tumor necrosis factor-alpha and interleukin-6 at initiation stage of colon cancer in 1,2-dimethylhydrazine-treated ICR mice. 1786 52

Protein kinase C-betaII (PKCbetaII) is an important modulator of cellular stress responses. To test the hypothesis that PKCbetaII modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKCbeta-null (PKCbeta(-/-)) and wild-type mice fed the PKCbeta inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKCbetaII in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKCbeta protected ischemic myocardium. Homozygous deletion of PKCbeta significantly diminished phosphorylation of c-Jun NH(2)-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKCbeta in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCbeta may represent a potent strategy to protect the vulnerable myocardium.
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PMID:PKCbeta modulates ischemia-reperfusion injury in the heart. 1824 60


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