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)

Bioflavonoid quercetin is known as an anti-cancer agent that induces apoptosis of tumor cells. Currently, however, little is understood about the effect of this drug on the function of normal cells. In this report, we address an unexpected, novel action of quercetin against apoptosis. Pretreatment with quercetin protected mesangial cells from hydrogen peroxide (H2O2)-induced apoptosis. A similar effect was observed in other cell types including LLC-PK1 epithelial cells and NRK49F fibroblasts. To explore the molecular mechanisms involved, we tested the effect of quercetin on c-Jun/activator protein-1 AP-1), the crucial mediator for H2O2-initiated apoptosis. Northern blot analysis revealed that quercetin suppressed the c-jun expression by H2O2. This was correlated with blunted activation of 12-O-tetradecanoylphorbol 13-acetate response element (TRE) in response to H2O2. These results suggested that quercetin inhibited apoptosis via intervention in the c-Jun/AP-1 pathway. To further investigate the action of quercetin, its effect on tyrosine kinases was studied. Immunoblot analysis revealed that H2O2 induced tyrosine phosphorylation. Quercetin inhibited this process in a dose-dependent manner. Inactivation of tyrosine kinases was an event upstream of c-Jun/AP-1, because tyrosine kinase inhibitors suppressed both activation of c-Jun/AP-1 and induction of apoptosis by H2O2. These findings elucidated the novel action of quercetin as an apoptosis inhibitor. This cytoprotective effect was found to be via suppression of the tyrosine kinase-c-Jun/AP-1 pathway triggered by oxidant stress.
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PMID:Unexpected protection of glomerular mesangial cells from oxidant-triggered apoptosis by bioflavonoid quercetin. 927 81

The cell adhesion molecule intercellular adhesion molecule-1 (ICAM-1) plays a pivotal role in inflammatory responses. Quercetin (3,3',4',5,7-pentahydroxyflavone), a naturally occurring dietary flavonol, has potent anti-inflammatory properties. The effect of quercetin on ICAM-1 expression induced by agonists phorbol 12-myristate 13-acetate (PMA) and tumor necrosis factor-alpha (TNF-alpha) in human endothelial cell line ECV304 (ECV) was investigated. Quercetin treatment downregulated both PMA- and TNF-alpha-induced surface expression, as well as the ICAM-1 mRNA levels, in ECV cells in a dose-dependent (10-50 microM) manner. Quercetin had no effect on PMA- or TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation. However, under similar conditions a remarkable dose-dependent downregulation of activator protein-1 (AP-1) activation was observed. This decrease in AP-1 activation was observed to be associated with the inhibitory effects of quercetin on the c-Jun NH2-terminal kinase (JNK) pathway. These results suggest that quercetin downregulates both PMA- and TNF-alpha-induced ICAM-1 expression via inhibiting both AP-1 activation and the JNK pathway.
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PMID:Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. 1048 27

Flavonoids are semiessential food components that possess anti-inflammatory properties. This report describes a novel potential of bioflavonoid quercetin as an inhibitor of monocyte chemoattractant protein-1 (MCP-1) in glomerular cells. Cultured mesangial cells as well as isolated glomeruli expressed MCP-1 mRNA in response to interleukin-1beta (IL-1beta). Quercetin dramatically inhibited the cytokine-triggered MCP-1 expression. To explore the mechanisms involved, effects of quercetin on the putative transcriptional activators of MCP-1, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), were examined. Exposure of the cells to IL-1beta caused activation of NF-kappaB without significant upregulation of AP-1 activity. NF-kappaB inhibitor MG132 diminished the IL-1-induced expression of MCP-1 in mesangial cells and isolated glomeruli, whereas c-Jun/AP-1 inhibitor curcumin did not affect this process. Consistently, NF-kappaB-inactive mesangial cells expressing a super-repressor mutant of IkappaBalpha showed blunted expression of MCP-1 by IL-1beta. In contrast, AP-1-inactive mesangial cells expressing a dominant-negative mutant of c-Jun exhibited the same level of MCP-1 mRNA as that in control cells. These results suggest that: (1) quercetin has the ability to attenuate activation of NF-kappaB; and (2) it inhibits IL-1-triggered MCP-1 expression via suppression of NF-kappaB, but not AP-1, in glomerular cells.
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PMID:Bioflavonoid quercetin inhibits interleukin-1-induced transcriptional expression of monocyte chemoattractant protein-1 in glomerular cells via suppression of nuclear factor-kappaB. 1054 Dec 87

The effect of quercetin on lipopolysaccharide (LPS)-induced nitric oxide (NO) production was studied. Quercetin pretreatment significantly inhibited NO production in an LPS-stimulated RAW 264.7 murine macrophage cell line. Post-treatment with quercetin partially inhibited NO production. The inhibitory action of quercetin was due to neither the cytotoxic action nor altered LPS binding. The expression of inducible-type NO synthase (iNOS) was markedly down-regulated by quercetin. Quercetin suppressed the release of free nuclear factor (NF)-kappaB by preventing degradation of IkappaB-alpha and IkappaB-beta. Moreover, quercetin blocked the phosphorylation of extracellular signal regulated kinase 1/2 (Erk 1/2), p38, and c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and, further, the activity of tyrosine kinases in LPS-stimulated RAW cells. Quercetin also inhibited interferon (IFN)-gamma-induced NO production. Taken together, these results indicate that the inhibitory action of quercetin on NO production in LPS- and/or IFN-gamma-stimulated macrophages might be due to abrogation of iNOS protein induction by impairment of a series of intracellular signal pathways.
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PMID:The inhibitory action of quercetin on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells. 1175 12

The bioflavonoid quercetin is a dietary anticancer chemical that is capable of inducing apoptosis in tumor cells. Although the activity of quercetin is believed to be due to its antioxidative properties, it has recently been suggested that quercetin also has prooxidant activities, which might effect cytotoxicity directly. In this study, we used mouse thymocytes to investigate whether quercetin behaved as a protector against oxidative stress or as a cytotoxic agent. Quercetin treatment did not induce oxidative damage, but protected mouse thymocytes from glucose oxidase (GO)-mediated apoptosis in a dose-dependent manner. Furthermore, electrophoretic mobility shift assays revealed that quercetin (50 microM) treatment suppressed the GO-mediated DNA binding activity of redox state-sensitive transcription factors, such as NF-kappaB, AP-1, and p53. This result suggests that quercetin has antioxidative effects on thymocytes. More interestingly, quercetin treatment alone (50 microM) increased the DNA-binding activity of AP-1, which consisted of heterodimer of c-Jun and Fra-2. Finally, the antioxidant activity of quercetin was confirmed using a cell-free system of radical generation. Our findings suggest that quercetin protects mouse thymocytes from oxidative stress-mediated apoptosis and modulates the intracellular redox state through its antioxidant activity.
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PMID:The antioxidant, rather than prooxidant, activities of quercetin on normal cells: quercetin protects mouse thymocytes from glucose oxidase-mediated apoptosis. 1464 60

Dietary phytochemicals have been shown to be protective against various types of cancers. However, the precise underlying protective mechanisms are poorly understood. In the present study, we report that treatment of A549 cells with quercetin resulted in a dose-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 1.2 +/- 0.8, 6.3 +/- 0.9, 16.5 +/- 1.5, 36.4 +/- 2.6 and 42.5 +/- 5.8% on treatment with 0.1% dimethylsulfoxide, 14.5, 29.0, 43.5 and 58.0 micro M quercetin, respectively. Concomitantly, quercetin treatments led to a 1.1-, 1.1-, 2.5- and 3.5-fold increase in Bax. Similar elevations were also observed in Bad, which increased 1.1-, 2.1-, 2.2- and 2.3-fold, respectively, as compared with control. While Bcl-2 was decreased by 30%, Bcl-x(L) was elevated in a dose-dependent fashion. Quercetin also induced the cleavage of caspase-3, caspase-7 and PARP (poly ADP-ribose polymerase). While Akt-1 and phosphorylated Akt-1 were inhibited, the extracellular signal-regulated kinase (ERK) was phosphorylated following quercetin treatment in a dose-dependent fashion. Phosphorylation of ERK and c-Jun occurred at 3 h and was sustained over 14 h. Phosphorylation of MEK1/2 was increased in concordance with ERK activation. Quercetin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and cleavage of caspase-3 occurred 6 h after quercetin exposure and before cleavage of caspase-7 and PARP was detected. Inhibition of MEK1/2 but not PI-3 kinase, p38 kinase or JNK abolished quercetin-induced phosphorylation of c-Jun, cleavage of caspase-3 and -7, cleavage of PARP and apoptosis. Inhibition of caspase activation completely blocked quercetin-induced apoptosis. Expression of constitutively activated MEK1 in A549 cells led to activation of caspase-3 and apoptosis. The results suggest that in addition to inactivation of Akt-1 and alteration in the expression of the Bcl-2 family of proteins, activation of MEK-ERK is required for quercetin-induced apoptosis in A549 lung carcinoma cells.
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PMID:The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. 1468 22

The bioflavonoid, quercetin, is believed to inhibit bone loss by regulating many systemic and local factors including hormones and cytokines. However, our previous findings revealed that quercetin did not inhibit but facilitate the tumor necrosis factor (TNF)-alpha-mediated apoptosis of MC3T3-E1 osteoblastic cells. Therefore, this study was carried out to examine the cellular mechanisms for how quercetin accelerates TNF-alpha-mediated apoptosis, and to determine whether the accelerating effect of quercetin is a general effect in osteoblastic cells. Quercetin promoted the TNF-alpha-induced apoptosis of MC3T3-E1 cells through both the mitochondrial-mediated and caspase-dependent mechanisms. Quercetin also augmented the TNF-alpha-mediated apoptosis by activating c-Jun N-terminal kinase (JNK) with the attendant activation of activator protein-1, where the nuclear translocation of c-Jun protein appeared to be a critical event responsible for the accelerating action of quercetin. However, TNF-alpha-mediated apoptosis and its acceleration by quercetin were not observed in primary osteoblasts. These results strongly suggest that quercetin accelerates TNF-alpha-mediated apoptosis of osteoblasts through caspase-dependent and JNK-mediated pathways, and that the cellular responses of osteoblasts to TNF-alpha and/or quercetin might differ according to their origins.
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PMID:Quercetin accelerates TNF-alpha-induced apoptosis of MC3T3-E1 osteoblastic cells through caspase-dependent and JNK-mediated pathways. 1798 64

Ultraviolet (UV) radiation is related to cataract formation. The dynamics of matrix proteins play crucial roles in cell proliferation, cell migration, and the remodeling of lens capsule and, possibly, cataract formation. However, the change of dynamics of matrix proteins, such as collagens, in lens cells in response to UV radiation has not been investigated. Using cultured human lens epithelial cells, we, for the first time, demonstrate that UV radiation induces a decrease of collagen type I in a time- and dose-dependent manner. Hydrogen peroxide (H(2)O(2)) also induces a collagen type I decrease in a similar pattern. We observed that UV and H(2)O(2) induce JNK and its downstream component, c-Jun, activation in both a time- and dose-dependent manner. The pharmacologic inhibitor of JNK or JNKi inhibits UV-induced JNK and c-Jun activation and attenuates a UV-induced decrease of collagen type I. Quercetin, a well known antioxidant, also protects against a UV- and H(2)O(2)-induced decrease of collagen type I in a dose-dependent manner. Quercetin inhibits UV- and H(2)O(2)-induced JNK and c-Jun activation. Collectively, we conclude that quercetin attenuates both a UV- and H(2)O(2)-induced decrease of collagen type I via the inhibiting of JNK/c-Jun activity. Understanding the cellular-signaling pathways involved in the UV- and H(2)O(2)-induced decrease of collagen type I may reveal potential therapeutic targets for the UV-induced cataract.
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PMID:Quercetin attenuates UV- and H(2)O(2)-induced decrease of collagen type I in cultured human lens epithelial cells. 1834 30

Quercetin (QUE; 3,5,7,3',4'-tetrahydroxyflavone) has been shown to possess several beneficial biological activities including antitumor, anti-inflammation and antioxidant properties; however, the effects of QUE in preventing invasion by breast carcinoma cells are still undefined. Increases in the protein, messenger RNA and enzyme activity levels of matrix metalloproteinase (MMP)-9 were observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells, and these were blocked by QUE, but not by quercitrin or rutin. A translocation of protein kinase C (PKC)delta from the cytosol to the membrane followed by activation of extracellular signal-regulated kinase (ERK) and c-Jun/activator protein-1 (AP-1) by TPA was demonstrated, and TPA-induced MMP-9 activation and migration were inhibited by the pan PKC inhibitor, GF109203X, the specific PKCdelta inhibitor, rottlerin, an ERK inhibitor (PD98059) and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKCdelta/ERK/AP-1-signaling cascade. To elucidate the importance of hydroxyl (OH) substitutions to QUE's inhibition of tumor migration, several structurally related flavones of QUE including 3',4'-diOH, 3',4'-diOCH(3), 3,5,7-triOH, 3,4',4'-triOH, 3,3',4'-triOCH(3), luteolin and fisetin were used. Results suggested that OH groups at both C3' and C4' play central roles in QUE's inhibition of TPA-induced MMP-9 activation and migration, and an additional OH at C3, C5 or C7 may increase the inhibitory potency of the 3',4'-diOH flavone against TPA-induced MMP-9 activity and migration. The antitumor invasion and migration effects of breast carcinoma cells induced by QUE with the structure-activity relationship analysis were identified.
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PMID:Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. 1862 48

Quercetin is a herbal flavonoid derived from various foods of plant origin and widely used as a major constituent of nutritional supplements. Quercetin has been shown to have anti-inflammatory properties and can play a role in anti-inflammatory procedure. Intercellular adhesion molecule-1 (ICAM-1) is one of the important pro-inflammatory factors, especially in early phage of inflammation. However, the mechanisms regulating ICAM-1 expression by quercetin in human A549 cells were still unclear. In this study, the inhibitory effect of quercetin on ICAM-1 expression by interleukin-1 beta (IL-1 beta)-stimulated A549 cells was investigated, and the roles of mitogen-activated protein kinases (MAPK) pathways were explored. Quercetin attenuated IL-1 beta-induced expression of ICAM-1 mRNA and protein in a dose-dependent manner. The experiment suggested that quercetin actively inhibited inhibitory protein of nuclear factor-kappa B (I kappa B) degradation, and nuclear factor-kappa B (NF-kappa B) activity. The c-fos and c-jun, components of activator protein-1 (AP-1), were mediated by MAPK pathways. ERK and p38 were involved in the c-fos mRNA expression, and JNK was involved in the c-jun mRNA expression. The inhibitory effect of quercetin on ICAM-1 expression was mediated by the sequential attenuation of the c-fos and c-jun mRNA expressions. These inhibitory effects were partially inhibited by SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a specific inhibitors of extracellular signal-regulated kinase (ERK), and SP600125, a specific inhibitor of c-Jun-N-terminal kinase (JNK). Taken together, these results suggest that quercetin negatively modulating ICAM-1 partly dependent on MAPK pathways.
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PMID:Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. 1898 26


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