Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cell cultures of human lung fibroblasts, we found that oxidized LDL (oxLDL), after 24-h treatment, stimulated arachidonic acid release. A putative role for phospholipases A(2) and MAPK activities in this process was postulated. Consequently, we studied the contribution of either Ca(2+)-dependent, cytosolic phospholipase A(2) (cPLA(2)) or Ca(2+)-independent phospholipase A(2) (iPLA(2)), and the role of the MAP kinase family in oxLDL toxicity to fibroblastic cells in vitro. Activation of extracellular signal-regulated kinases ERK1/2, p38 and c-Jun NH(2)-terminal kinase (JNK) was also assessed with Western blotting. Compared with cellular samples untreated or treated with native LDL, treatment with oxLDL (50-100 microM hydroperoxides) for 24 h significantly increased the levels of either cPLA(2) protein expression or constitutively phosphorylated cPLA(2) protein; in addition we observed enzyme translocation to membranes. iPLA(2) activity was not stimulated by oxLDL. Arachidonic acid release appeared to be associated with phosphorylation of ERK1/2 which was significantly enhanced in a dose-dependent manner whereas no activation of p38 and JNKs was found, indicating that these MAPKs are not involved in mediating the maximal oxLDL response. Western blotting on subcellular fractions and confocal microscopy analyses confirmed an increase in 15-lipoxygenase (15-LO) protein expression and translocation upon activation. A significant increase of cyclooxygenase-2 expression into membrane fraction was also found. Collectively, the data presented link the stimulation of ERK-cPLA(2)-15-LO pathway by oxLDL to the prooxidant mechanism of the lipoprotein complex. It may initially stimulate the fibroblast reaction against the oxidation challenge as well as metabolic repair, such as during lung inflammation and pulmonary fibrosis.
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PMID:Activation of cytosolic phospholipase A2 and 15-lipoxygenase by oxidized low-density lipoproteins in cultured human lung fibroblasts. 1734 94

We have shown previously that dietary grape seed proanthocyanidins (GSP) inhibit UVB-induced photocarcinogenesis in mice. As UVB-induced oxidative stress and oxidative stress-mediated signaling has been implicated in photocarcinogenesis, this study was designed to investigate the effect of dietary GSPs on UVB-induced oxidative stress in in vivo SKH-1 hairless mice. Here, we report that provision of dietary GSPs (0.2 and 0.5%, w/w) to mice exposed to either acute UVB irradiation (120 mJ/cm(2)) or chronic irradiation of UVB inhibited depletion of glutathione peroxidase, catalase, and glutathione, and inhibited UVB-induced H(2)O(2), lipid peroxidation, protein oxidation, and nitric oxide in mouse skin. As UV-induced oxidative stress mediates activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways, we determined the effect of dietary GSPs on these pathways. We observed that dietary GSPs inhibited UVB-induced phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun-NH(2)-kinase, and p38 proteins of MAPK family, which seems to be mediated through reactivation of MAPK phosphatases. GSPs inhibited UVB-induced activation of NF-kappaB/p65 through inhibition of degradation of IkappaBalpha and activation of IkappaB kinase alpha (IKKalpha). As NF-kappaB-targeted genes play critical roles in inflammation and cellular proliferation, we assessed the effect of GSPs on proteins encoded by these genes. Dietary GSPs resulted in inhibition of the expression of proliferating cell nuclear antigen, cyclin D1, inducible nitric oxide synthase, and cyclooxygenase-2 in the skin. Collectively, our data show that GSPs have the ability to protect the skin from the adverse effects of UVB radiation via modulation of the MAPK and NF-kappaB signaling pathways and provide a molecular basis for the photoprotective effects of GSPs in an in vivo animal model.
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PMID:Dietary grape seed proanthocyanidins inhibit UVB-induced oxidative stress and activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling in in vivo SKH-1 hairless mice. 1736 93

Activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFkappaB activation by interacting with NFkappaB p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67-expressing mice results in dramatic inhibition of tumor promoter-induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1- and/or NFkappaB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA-induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFkappaB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter.
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PMID:Dominant-negative activator protein 1 (TAM67) targets cyclooxygenase-2 and osteopontin under conditions in which it specifically inhibits tumorigenesis. 1736 60

Humulone, a bitter acid derived from hop (Humulus lupulus L.), possesses antioxidative, anti-inflammatory and other biologically active activities. Although humulone has been reported to inhibit chemically induced mouse skin tumor promotion, the underlying mechanisms are yet to be elucidated. Since an inappropriate over-expression of cyclooxygenase-2 (COX-2) is implicated in carcinogenesis, we investigated effects of humulone on COX-2 expression in mouse skin stimulated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of humulone (10 mumol) significantly inhibited TPA-induced epidermal COX-2 expression. Humulone also diminished TPA-induced DNA binding of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Pre-treatment with humulone attenuated TPA-induced phosphorylation of p65 and nuclear translocation of NF-kappaB subunit proteins. Humulone blunted TPA-induced activation of inhibitory kappaB (IkappaB) kinase (IKK) in mouse skin, which accounts for its suppression of phosphorylation and subsequent degradation of IkappaBalpha. An in vitro kinase assay revealed that humulone could directly inhibit the catalytic activity of IKKbeta. Humulone suppressed the activation of mitogen-activated protein kinases (MAPKs) in TPA-treated mouse skin. The roles of extracellular signal-regulated protein kinase-1/2 and p38 MAPK in TPA-induced activation of NF-kappaB in mouse skin had been defined in our previous studies. The present study revealed that topical application of SP600125, a pharmacological inhibitor of c-Jun-N-terminal kinase (JNK), abrogated the activation of AP-1 and the expression of COX-2 in TPA-treated mouse skin. Taken together, humulone suppressed TPA-induced activation of NF-kappaB and AP-1 and subsequent expression of COX-2 by blocking upstream kinases IKK and JNK, respectively, which may account for its antitumor-promoting effects on mouse skin carcinogenesis.
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PMID:Humulone inhibits phorbol ester-induced COX-2 expression in mouse skin by blocking activation of NF-kappaB and AP-1: IkappaB kinase and c-Jun-N-terminal kinase as respective potential upstream targets. 1737 74

Ginsenosides, ingredients of ginseng, have a wide array of pharmacologic effects. Especially, ginsenosides Rk1, Rg3, and Rg5 derived from heat-processed ginseng have been shown to possess substantial anti-tumor-promoting effects. KG-135 is a formulated complex that contains several antitumorigenic ginsenosides, such as Rk1, Rg3, Rg5, Rk2, Rk3, Rs3, Rs4, Rs5, Rs6, Rs7, etc. The present article was aimed at evaluating the chemopreventive as well as anti-inflammatory effects of KG-135 in the human breast epithelial cell line (MCF-10A). One of the well-recognized molecular targets for chemoprevention is cyclooxygenase-2 (COX-2) that is abnormally upregulated in many premalignant and malignant tissues and cells. In this study, we found that KG-135 inhibited COX-2 expression in MCF-10A cells stimulated with a prototype tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA). Since the transcription factor activator protein-1 (AP-1) plays a role in tumor promotion and is also known to regulate COX-2 induction, we attempted to determine the effect of KG-135 on TPA-induced activation of AP-1. Cotreatment with KG-135 resulted in a decrease in TPA-induced DNA binding of AP-1. In addition, KG-135 inhibited TPA-induced phosphorylation of c-Jun N-terminal kinases (JNK) that regulates COX-2 expression in MCF-10A cells. The JNK inhibitor SP600125 attenuated COX-2 expression in TPA-treated MCF-10A cells. Taken together, the above findings suggest that KG-135 inhibits TPA-induced COX-2 expression in MCF-10A cells by blocking the JNK/AP-1 signaling pathway.
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PMID:KG-135 inhibits COX-2 expression by blocking the activation of JNK and AP-1 in phorbol ester-stimulated human breast epithelial cells. 1740 68

The present study was performed to investigate the anti-inflammatory potential of a 116-kDa glycoprotein isolated from Ulmus davidiana Nakai (UDN glycoprotein) in lipopolysaccaride (LPS)-treated cancerous human colon epithelial cells (HT-29 cells). UDN glycoprotein inhibited the production of intracellular superoxide anion (O (2) (.-) ), hydrogen peroxides (H(2)O(2)), and nitric oxide (NO), whereas normalized the activity of anti-oxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX)], accompanying the inhibition of manganese-superoxide dismutases (Mn-SOD) activity in LPS-treated HT-29 cells. In addition, UDN glycoprotein blocked the DNA binding activity of activator protein-1 (AP-1) through suppression of c-Jun and c-Fos activities, respectively. We also evaluated the anti-inflammatory potential of UDN glycoprotein based on the activity of the pro-inflammatory signal mediators [inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9)]. The results showed that UDN glycoprotein (200 mug/ml) has an inhibitory effect on the activation of iNOS, COX-2, and MMP-9 proteins in the LPS-treated HT-29 cells. From these results, we suggest that UDN glycoprotein is one of the potential anti-inflammatory agents that blocks LPS-mediated inflammatory signal pathway in HT-29 cells. Here, we speculate that UDN glycoprotein could be used as an antioxidative agent for inflammatory gastrointestinal cancers.
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PMID:UDN glycoprotein inhibits activator protein-1 and matrix metalloproteinase-9 via blocking of oxygen radicals in HT-29 cells. 1745 55

This study was carried out to investigate the anti-inflammatory effects of glycoprotein (UDN glycoprotein, 116-kDa) isolated from Ulmus davidiana Nakai, which has been used to heal inflammatory diseases in Korean herbal medicine. We found that UDN glycoprotein has strong scavenging effect on the production of intracellular superoxide anion (O(2)(-)), hydrogen peroxides (H(2)O(2)), and nitric oxide (NO) without any cytotoxicity, and that the glycoprotein also selectively normalizes the aberrant activation of manganese-superoxide dismutases (Mn-SOD) activity in lipopolysaccaride (LPS)-treated cancerous human colon epithelial cells (HCT-116 cells). The results obtained from electrophoretic mobility shift assay (EMSA) and Western blot analysis showed that UDN glycoprotein blocks the DNA binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), and attenuates the activities of NF-kappaB subunits (p50 and p65), and AP-1 subunits (c-Jun and c-Fos), respectively. To further verify the anti-inflammatory effect of UDN glycoprotein, we investigated the activity of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9) in LPS-treated HCT-116 cells, using Western blot analysis and gelatin zymographic assay. Results in this study indicated that 200mug/ml of UDN glycoprotein has inhibitory effects on the activations of iNOS, COX-2, and MMP-9. Therefore, UDN glycoprotein, a natural antioxidant, is a potential modulator of inflammatory signal pathways in LPS-treated HCT-116 cells.
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PMID:UDN glycoprotein regulates activities of manganese-superoxide dismutase, activator protein-1, and nuclear factor-kappaB stimulated by reactive oxygen radicals in lipopolysaccharide-stimulated HCT-116 cells. 1745 74

Inonotus obliquus (Pers.:Fr.) Pil. is a white rot fungus that belongs to the family Hymenochaetaceae of Basidiomycetes. Extracts and fractions of this fungus have been known to have biological activities, including antimutagenic, anticancer, antioxidative, and immunostimulating effects. Recently, there have been reports that the anti-inflammatory and antinociceptive properties of the methanol extract of I. obliquus may be due to the inhibition of inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) expression via the down-regulation of nuclear factor kappaB (NF-kappaB) binding activity. However, the effects of I. obliquus on Akt and mitogen-activated protein kinase (MAPK) activation of inflammatory mediator production have not yet been elucidated. In the present study, a 70% ethanol extract of I. obliquus (IOE70) showed antioxidative effects. We also tested the ability of the I. obliquus extract to inhibit the inflammatory cascades in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells. The NO inhibition of IOE70 was better than that of other ethanol extracts from I. obliquus. To investigate the mechanism by which IOE 70 inhibits NO production and iNOS and COX-2 expression, we examined the activations of IkappaBalpha, Akt, and c-Jun NH(2) -terminal kinase (JNK) in LPS-activated macrophages. IOE70 markedly inhibited the phosphorylation of IkappaBalpha, Akt, and MAPKs in dose-dependent manners in LPS-activated macrophages. Taken together, these experiments demonstrated that IOE70 inhibition of LPS-induced expression of iNOS and COX-2 protein is mediated by Akt and JNK. Based on our findings, the most likely mechanism that can account for this biological effect of IOE70 involves the inhibition of NF-kappaB through the phosphatidylinositol 3-kinase/Akt/IkappaB pathway and the inhibition of JNK activation. Thus, IOE70 might have useful clinical applications in the management of inflammatory diseases and may also be useful as a medicinal food.
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PMID:Ethanol extract of Inonotus obliquus inhibits lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells. 1747 71

Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.
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PMID:Chemoprevention of esophageal squamous cell carcinoma. 1747

Taiwanofungus camphoratus (syn. Antrodia camphorata), a medicinal mushroom in Taiwan, is reputed to provide several therapeutic benefits, but the wild fruiting body is very rare. In this study, we used Taiwanofungus camphoratus extracts from wild fruiting bodies and two types of artificial cultivation (solid-state culture and liquid-state fermentation) to examine their anti-inflammatory effects in microglia cells and their possible roles in protection against neurodegenerative diseases. First, EOC13.31 microglia was treated with various kinds of Taiwanofungus camphoratus extracts and lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) to evaluate the iNOS expression. Western blot and RT-PCR analysis showed that among the various kinds of extracts from wild fruiting bodies, methanol extracts were the most potent inhibitors of iNOS expression. Secondly, the potency of methanol extracts could be ranked as follows: extracts of wild fruiting body>solid-state culture>liquid-state fermentation. To clarify the mechanisms involved, methanol extracts from fruiting body were found to inhibit the phosphorylation of extracellular signal-regulated protein kinases (ERK), c-Jun NH2-terminal protein kinases (JNK) and signal transducer and activator of transcription-1 (STAT-1) induced by LPS/IFN-gamma. Methanol extracts from fruiting body also inhibited NF-kappaB activation through the prevention of inhibitor kappaB (IkappaB) degradation. Moreover, methanol extracts from wild fruiting body inhibited both the iNOS and cyclooxygenase-2 (COX-2) expression induced by beta-amyloid in microglia in a dose-dependent manner. In an animal model, we confirmed that methanol extracts from fruiting bodies were able to suppress ear edema, indicating that they have anti-inflammatory activity in vivo. These results suggest that Taiwanofungus camphoratus exhibits an anti-inflammatory activity that might contribute to the prevention of neurodegenerative diseases.
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PMID:Comparative anti-inflammatory characterization of wild fruiting body, liquid-state fermentation, and solid-state culture of Taiwanofungus camphoratus in microglia and the mechanism of its action. 1759 Feb 97


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