Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of macrophages with Leishmania parasites does not result in the production of IL-12. In addition, infection with Leishmania suppresses IL-12 production elicited by otherwise potent activators of IL-12. We provide evidence that engagement of phosphatidyl inositol-3 kinase (PI3K) signaling during Leishmania amazonensis infection leads to the prevention of IL-12 p70 production at the level of transcription of its p40 subunit in bone marrow derived macrophages (BMDMPhi). Inhibition of PI3K signaling with specific inhibitors of PI3K or the downstream kinase Akt, reverses the IL-12 blockade. Although the MAP kinase ERK (p44 and p42) was transiently activated by infection with L. amazonensis, inhibition of MEK, the kinase upstream of ERK, with PD98059, did not reverse the blockade of IL-12. Furthermore, inhibition of the other MAP kinases JNK and p38 as well as treatment of cells with pertussis toxin that blocks G protein mediated signaling, did not reverse the prevention of IL-12 production by Leishmania infection. Interestingly, activation of PI3K/Akt signaling had differential effects on ERK and p38 activation. Taken together we propose that infection of BMDMPhi with Leishmania promastigotes activates both positive and negative signaling pathways that control IL-12 production. PI3K signaling activated by the infection is the negative signaling pathway that prevents IL-12 production.
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PMID:Activation of PI3K/Akt signaling has a dominant negative effect on IL-12 production by macrophages infected with Leishmania amazonensis promastigotes. 1918 78

3'-Methoxy-3,4',5,7-tetrahydroxyflavone (isorhamnetin) is a plant flavonoid that occurs in fruits and medicinal herbs. Isorhamnetin exerts anticancer effects, but the underlying molecular mechanism for the chemopreventive potential of isorhamnetin remains unknown. Here, we report anti-skin cancer effects of isorhamnetin, which inhibited epidermal growth factor (EGF)-induced neoplastic cell transformation. It also suppressed anchorage-dependent and -independent growth of A431 human epithelial carcinoma cells. Isorhamnetin attenuated EGF-induced COX-2 expression in JB6 and A431 cells. In an in vivo mouse xenograft using A431 cells, isorhamnetin reduced tumor growth and COX-2 expression. The EGF-induced phosphorylation of extracellular signal-regulated kinases, p90 and p70 ribosomal S6 kinases, and Akt was suppressed by isorhamnetin. In vitro and ex vivo kinase assay data showed that isorhamnetin inhibited the kinase activity of MAP (mitogen-activated protein)/ERK (extracellular signal regulated kinase) kinase (MEK) 1 and PI3-K (phosphoinositide 3-kinase) and the inhibition was due to direct binding with isorhamnetin. Notably, isorhamnetin bound directly to MEK1 in an ATP-noncompetitive manner and to PI3-K in an ATP-competitive manner. This report is the first mechanistic study identifying a clear molecular target for the anticancer activity of isorhamnetin. Overall, these results indicate that isorhamnetin has potent anticancer activity and it primarily targets MEK and PI3-K, which might contribute to the chemopreventive potential of certain foods.
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PMID:Isorhamnetin suppresses skin cancer through direct inhibition of MEK1 and PI3-K. 2133 Mar 79

Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38(MAPK)), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells. Daily i.p. injection of CB3 to ZDF rats inhibited the phosphorylation of JNK and p38(MAPK), and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70(S6K) kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38(MAPK) activity in the absence of a change in plasma glucose implies a decrease in oxidative or neuroinflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK-AMPK-mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that by attenuating neuro-inflammatory processes in the brain Trx1 mimetic peptides could become beneficial for preventing neurological disorders associated with diabetes.
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PMID:Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain. 2462 34


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