Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetaminophen (AAP), a widely used analgesic drug, can damage various organs when taken in large doses. In this study, we investigate whether AAP causes cell damage by altering the early signaling pathways associated with cell death and survival. AAP caused time- and concentration-dependent apoptosis and DNA fragmentation of C6 glioma cells used as a model. AAP activated c-Jun N-terminal protein kinase (JNK) by 5.3-fold within 15 min. The elevated JNK activity persisted for up to 4 h before it returned to the basal level at 8 h. In contrast, activities of other mitogen-activated protein (MAP) kinases and the level of Akt phosphorylation in the cell survival pathway remained unchanged throughout the treatment. Wortmannin, an inhibitor of phosphatidylinositol-3 kinase, or SB203580, an inhibitor of p38 MAP kinase, did not reduce AAP-induced toxicity, indicating that these enzymes do not play a major role in cell toxicity. AAP-induced apoptosis was preceded by the sequential elevation of the pro-apoptotic Bax protein, cytochrome c release, and caspase-3 activity. Treatment with caspase inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK) significantly reduced AAP-induced caspase-3 activation and cytotoxicity. Transfection of cDNA for the dominant-negative mutant JNK-KR or stress-activated protein kinase kinase-1 Lys-->Arg mutant (SEK1-KR), an immediate upstream kinase of JNK, significantly reduced AAP-induced JNK activation and cell death rate. The noncytotoxic analog of AAP, 3-hydroxyacetanilide, neither increased JNK activity nor caused apoptosis. Pretreatment with YH439, an inhibitor of CYP2E1 gene transcription, markedly reduced CYP2E1 mRNA, protein content, and activity, as well as the rate of AAP-induced JNK activation and cell death. These data indicate that AAP can cause cell damage by activating the JNK-related cell death pathway, providing a new mechanism for AAP-induced cytotoxicity.
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PMID:Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway. 1156 48

Leflunomide, a disease-modifying anti-rheumatic drug, protects against T-cell-mediated liver injury by poorly understood mechanisms. The active metabolite of leflunomide, A77 1726 (teriflunomide) has been shown to inhibit stress-activated protein kinases (JNK pathway), which are key regulators of mitochondria-mediated cell death. Therefore, we hypothesized that leflunomide may protect from drugs that induce the mitochondrial permeability transition (mPT) by blocking the JNK signaling pathway. To this end, we exposed cultured immortalized human hepatocytes (HC-04) to the standard protoxicant drug acetaminophen (APAP), which induces CsA-sensitive mPT-mediated cell death. We determined the effects of leflunomide on the extent of APAP-induced hepatocyte injury and the upstream JNK-mediated mitochondrial signaling pathways. We found that leflunomide or A77 1726 concentration-dependently protected hepatocytes from APAP (1 mM)-induced mitochondrial permeabilization and lethal cell injury. This was not due to proximal inhibition of CYP-catalyzed APAP bioactivation to its thiol-reactive metabolite. Instead, we demonstrate that leflunomide (20 microM) inhibited the APAP-induced early (3 h) activation (phosphorylation) of JNK1/2, thus inhibiting phosphorylation of the anti-apoptotic protein Bcl-2 and preventing P-Bcl-2-mediated induction of the mPT. This greatly attenuated mitochondrial cytochrome c release, which we used as a marker for mitochondrial permeabilization. The specific JNK2 inhibitor SP600125 similarly protected from APAP-induced cell death. In conclusion, these findings are consistent with our hypothesis that leflunomide protects from protoxicant-induced hepatocyte injury by inhibiting JNK signaling and preventing mPT induction.
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PMID:Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes. 1697 4

The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells.
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PMID:Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation. 1716 76

Estrogens play a crucial role in the development of ovarian tumors; however, the signal transduction pathways involved in hormone action are still poorly defined. The orphan G protein-coupled receptor 30 (GPR30) mediates the nongenomic signaling of 17beta-estradiol (E2) in a variety of estrogen-sensitive cancer cells through activation of the epidermal growth factor receptor (EGFR) pathway. Whether estrogen receptor alpha (ERalpha) also contributes to GPR30/EGFR signaling is less understood. Here, we show that, in ERalpha-positive BG-1 ovarian cancer cells, both E2 and the GPR30-selective ligand G-1 induced c-fos expression and estrogen-responsive element (ERE)-independent activity of a c-fos reporter gene, whereas only E2 stimulated an ERE-responsive reporter gene, indicating that GPR30 signaling does not activate ERalpha-mediated transcription. Similarly, both ligands up-regulated cyclin D1, cyclin E, and cyclin A, whereas only E2 enhanced progesterone receptor expression. Moreover, both GPR30 and ERalpha expression are required for c-fos stimulation and extracellular signal-regulated kinase (ERK) activation in response to either E2 or G-1. Inhibition of the EGFR transduction pathway inhibited c-fos stimulation and ERK activation by either ligand, suggesting that in ovarian cancer cells GPR30/EGFR signaling relays on ERalpha expression. Interestingly, we show that both GPR30 and ERalpha expression along with active EGFR signaling are required for E2-stimulated and G-1-stimulated proliferation of ovarian cancer cells. Because G-1 was able to induce both c-fos expression and proliferation in the ERalpha-negative/GPR30-positive SKBR3 breast cancer cells, the requirement for ERalpha expression in GPR30/EGFR signaling may depend on the specific cellular context of different tumor types.
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PMID:G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. 1730 28

Previously, we demonstrated JNK plays a central role in acetaminophen (APAP)-induced liver injury (Gunawan, B. K., Liu, Z. X., Han, D., Hanawa, N., Gaarde, W. A., and Kaplowitz, N. (2006) Gastroenterology 131, 165-178). In this study, we examine the mechanism involved in activating JNK and explore the downstream targets of JNK important in promoting APAP-induced liver injury in vivo. JNK inhibitor (SP600125) was observed to significantly protect against APAP-induced liver injury. Increased mitochondria-derived reactive oxygen species were implicated in APAP-induced JNK activation based on the following: 1) mitochondrial GSH depletion (maximal at 2 h) caused increased H2O2 release from mitochondria, which preceded JNK activation (maximal at 4 h); 2) treatment of isolated hepatocytes with H2O2 or inhibitors (e.g. antimycin) that cause increased H2O2 release from mitochondria-activated JNK. An important downstream target of JNK following activation was mitochondria based on the following: 1) JNK translocated to mitochondria following activation; 2) JNK inhibitor treatment partially protected against a decline in mitochondria respiration caused by APAP treatment; and 3) addition of purified active JNK to mitochondria isolated from mice treated with APAP plus JNK inhibitor (mitochondria with severe GSH depletion, covalent binding) directly inhibited respiration. Cyclosporin A blocked the inhibitory effect of JNK on mitochondria respiration, suggesting JNK was directly inducing mitochondrial permeability transition in isolated mitochondria from mice treated with APAP plus JNK inhibitor. Addition of JNK to mitochondria isolated from control mice did not affect respiration. Our results suggests that APAP-induced liver injury involves JNK activation, due to increased reactive oxygen species generated by GSH-depleted mitochondria, and translocation of activated JNK to mitochondria where JNK induces mitochondrial permeability transition and inhibits mitochondria bioenergetics.
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PMID:Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. 1833 50

Different cellular receptors mediate the biological effects induced by estrogens. In addition to the classical nuclear estrogen receptors (ERs)-alpha and -beta, estrogen also signals through the seven-transmembrane G-protein-coupled receptor (GPR)-30. Using as a model system SkBr3 and BT20 breast cancer cells lacking the classical ER, the regulation of GPR30 expression by 17beta-estradiol, the selective GPR30 ligand G-1, IGF-I, and epidermal growth factor (EGF) was evaluated. Transient transfections with an expression plasmid encoding a short 5'-flanking sequence of the GPR30 gene revealed that an activator protein-1 site located within this region is required for the activating potential exhibited only by EGF. Accordingly, EGF up-regulated GPR30 protein levels, which accumulated predominantly in the intracellular compartment. The stimulatory role elicited by EGF on GPR30 expression was triggered through rapid ERK phosphorylation and c-fos induction, which was strongly recruited to the activator protein-1 site found in the short 5'-flanking sequence of the GPR30 gene. Of note, EGF activating the EGF receptor-MAPK transduction pathway stimulated a regulatory loop that subsequently engaged estrogen through GPR30 to boost the proliferation of SkBr3 and BT20 breast tumor cells. The up-regulation of GPR30 by ligand-activated EGF receptor-MAPK signaling provides new insight into the well-known estrogen and EGF cross talk, which, as largely reported, contributes to breast cancer progression. On the basis of our results, the action of EGF may include the up-regulation of GPR30 in facilitating a stimulatory role of estrogen, even in ER-negative breast tumor cells.
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PMID:Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells. 1846 41

In this study, we isolated a glycoprotein from the brown alga Hizikia fusiformis (HFGP) and examined whether it could protect against Acetaminophen (AAP)-induced liver injury in vivo and in vitro. AAP, one of the most commonly abused drugs, may cause fatal liver injury. An analysis of the effects of HFGP on AAP toxicity in rats revealed that the serum glutamic pyruvic transaminase level was restored to the control level and glutathione level was also increased by co-treatment with HFGP and AAP. Furthermore, HFGP co-treatment decreased caspase-3/-9 activity. These results indicate that HFGP may inhibit AAP-induced liver injury in Sprague-Dawley rats. Several lines of evidence indicate that oxidative stress plays an important role in AAP-induced liver injury and mitogen-activated protein kinase (MAPK) signaling is involved in the regulation of oxidative stress. Therefore, Western blotting was used to determine which MAPK signaling pathway is involved in the protective effect of HFGP against AAP toxicity in HepG2 cells. We found that ERK activation was involved in the protective effect of HFGP against AAP-induced cell death. Therefore, we propose that MAPK signaling is involved in the protective effect of HFGP against AAP-induced liver injury.
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PMID:Effect of a glycoprotein from Hizikia fusiformis on acetaminophen-induced liver injury. 1880 56

Oestrogen increases facial allodynia through its actions on activation of the MAPK extracellular-signal regulated kinase (ERK) in trigeminal ganglion neurons. This goal of study was to determine which oestrogen receptor is required for behavioural sensitization. Immunohistochemical studies demonstrated the presence of oestrogen receptor alpha (ERalpha) in nuclei of larger neurons and cytoplasm of smaller neurons, and the novel oestrogen receptor G-protein coupled receptor 30 (GPR30) in small diameter neurons that also contained peripherin, a marker of unmyelinated C-fibres. Specific agonists for ERalpha (PPT) and GPR30 (G-1), but not ERbeta (DPN), activated ERK in trigeminal ganglion neurons in vitro. Both G-1 and PPT treatment increased allodynia after CFA injections into the masseter of ovariectomized Sprague-Dawley rats. Treatment with oestrogen increased expression of ERalpha but not GPR30, while masseter inflammation increased GRP30 but not ERalpha. Differential modulation of these ERK-coupled receptors by oestrogen and inflammation may play a role in painful episodes of temporomandibular disorder and migraine.
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PMID:Role of the oestrogen receptors GPR30 and ERalpha in peripheral sensitization: relevance to trigeminal pain disorders in women. 1922 Mar 8

There is extensive evidence that pro-inflammatory cytokines produced by macrophages are involved in toxicity induced by drugs such as acetaminophen (APAP). We investigated the effect of subtoxic concentrations of acetaminophen in conjunction with bacterial lipopolysaccharide (LPS) on the expression of the pro-inflammatory cytokines TNFalpha and IL-1beta using the mouse macrophage cell line RAW264.7 as a model. APAP alone induced in a dose-dependent manner the production of TNFalpha and IL-1beta in this cell line. When LPS was added to APAP-treated cells, the increase in TNFalpha and IL-1beta production observed was higher than the sum of cytokine amounts produced with each agent alone, suggesting a synergistic mechanism. Moreover, we found that p38MAPK, JNK, and ERK were activated by APAP or LPS alone or in association. In our model, the NFkappaB signaling pathway was not involved in cytokine production induced by APAP. When inhibiting MAPKs using pharmacological inhibitors, we showed that p38MAPK inhibition abrogated the synergistic effect of APAP and LPS found for TNFalpha production but not for IL-1beta production. JNK and ERK have comparable roles in the production of the cytokines. Furafylline, a CYP1A inhibitor, and indomethacin, a PGHS inhibitor, exhibited a significant inhibitory effect on TNFalpha and IL-1beta production induced by the APAP and LPS combination. This work suggests that in macrophages, APAP and LPS can synergistically provoke the induction of pro-inflammatory cytokines, an effect involving the MAPK pathway and APAP bioactivation by CYP and PGHS.
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PMID:Acetaminophen and lipopolysaccharide act in synergy for the production of pro-inflammatory cytokines in murine RAW264.7 macrophages. 1958 95

Premenopausal females have a lower incidence of cardiovascular disease than their male counterparts, but the mechanism is unclear. Estrogen has been thought to signal through two nuclear receptors: estrogen receptor-alpha or estrogen receptor-beta; however, a third, membrane-bound receptor G protein-coupled estrogen receptor (GPER), has been identified and shown to bind estrogen with high affinity. To date, there is little information on GPER in the heart and no study has looked at the effect of GPER activation during myocardial ischemia-reperfusion (I/R). Therefore, the goal of this study was to determine whether activation of GPER is cardioprotective in rats. A highly specific GPER agonist, G-1, was administered to Sprague-Dawley (200-350 g) rat hearts 10 min before 20 min of ischemic followed by 120 min of reperfusion using a Langendorff model. Similar levels of GPER were found in both male and female rat hearts. With administration of 110 nM of G-1, postischemic contractile dysfunction was significantly reduced compared with untreated controls (43.8 + or - 4.3% vs. 26.9 + or - 2.1% of preischemic rate pressure product; P < 0.05). Additionally, infarct size was reduced in the G-1-treated animals when compared with control (18.8 + or - 2.7% vs. 32.4 + or - 2.1%; P < 0.05). These observations were demonstrated in both male and intact female rat hearts. Through Western blot analysis, it was demonstrated that G-1 induces the activation of both Akt and ERK1/2. Furthermore, the protection afforded by G-1 was blocked by coadministration of a phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin, 100 nM). Taken together, the data show that G-1 activation of GPER improves functional recovery and reduces infarct size in isolated rat hearts following I/R through a PI3K-dependent, gender-independent mechanism.
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PMID:Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. 1971 35


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