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)

The mycotoxin citrinin (CTN), a natural contaminant in foodstuffs and animal feeds, exerts cytotoxic and genotoxic effects on various mammalian cells. CTN causes cell injury, including apoptosis, but its precise regulatory mechanisms of action are currently unclear. Resveratrol, a member of the phytoalexin family found in grapes and other dietary plants, possesses antioxidant and anti-tumor properties. In the present study, we examined the effects of resveratrol on apoptotic biochemical events in Hep G2 cells induced by CTN. Resveratrol inhibited CTN-induced ROS generation, activation of JNK, loss of mitochondrial membrane potential (MMP), as well as activation of caspase-9, caspase-3 and PAK2. Moreover, resveratrol and the ROS scavengers, NAC and alpha-tocopherol, abolished CTN-stimulated intracellular oxidative stress and apoptosis. Active JNK was required for CTN-induced mitochondria-dependent apoptotic biochemical changes, including loss of MMP, and activation of caspases and PAK2. Activation of PAK2 was essential for apoptosis triggered by CTN. These results collectively demonstrate that CTN stimulates ROS generation and JNK activation for mitochondria-dependent apoptotic signaling in Hep G2 cells, and these apoptotic biochemical events are blocked by pretreatment with resveratrol, which exerts antioxidant effects.
 ...
PMID:Inhibition of citrinin-induced apoptotic biochemical signaling in human hepatoma G2 cells by resveratrol. 2011 78

Nickel compounds are carcinogenic to humans, possibly through induction of reactive oxygen species (ROS) that damage macromolecules including DNA and proteins. The aim of the present study is to elucidate the role of the ROS-mediated Akt/apoptosis-regulating signal kinase (ASK) 1/p38 pathway in nickel-induced apoptosis. Exposure of human bronchial epithelial cells (BEAS-2B) to nickel compounds induced the generation of ROS and activation of Akt that is associated with the activation of ASK1 and p38 mitogen-activated protein kinase. Immunoblotting suggested a down-regulation of several antiapoptotic proteins, including Bcl-2 and Bcl-xL in the nickel compound-treated cells. Indeed, a notable cell apoptosis following nickel compound treatment is evident as revealed by flow cytometry analysis. N-Acetyl-L-cysteine (NAC, a general antioxidant) and vitamin E or catalase (a specific H(2)O(2) inhibitor) all decreased nickel-induced ROS generation. Scavenging of nickel-induced ROS by NAC or catalase attenuated Akt, ASK1, and p38 MAPK activation and apoptosis, which implies involvement of ROS in the Akt/ASK1/p38 pathway. In addition, nickel-induced activation of p38 MAPK was attenuated by a small interference of RNA specific to ASK1 (siRNA ASK1), implying that p38 MAPK was downstream of ASK1, while ASK1 activation was not reversely regulated by the inhibition of p38 MAPK by SB203580, a widely used p38 MAPK inhibitor. Silencing Akt by siRNA reduced the activation of ASK1 and p38 MAPK and cell apoptosis, whereas without nickel stimulation, siRNA Akt had no effect on the activation of ASK1 and p38 MAPK. Thus, these results suggest that the ROS-dependent Akt-ASK1-p38 axis is important for nickel-induced apoptosis.
 ...
PMID:Reactive oxygen species-activated Akt/ASK1/p38 signaling pathway in nickel compound-induced apoptosis in BEAS 2B cells. 2011 89

CKD (chronic kidney disease) is a public health problem, mediated by haemodynamic and non-haemodynamic events including oxidative stress. We investigated the effect of two GSH (glutathione) precursors, NAC (N-acetylcysteine) and cystine as the physiological carrier of cysteine in GSH with added selenomethionine (F1) in preventing spermine (uraemic toxin)-induced apoptosis in cultured human aortic VSMC (vascular smooth muscle cells). VSMCs exposed to spermine (15 microM) with or without antioxidants (doses 50, 100, 200 and 500 microg/ml) were assessed for apoptosis, JNK (c-Jun-NH2-terminal kinase) activation and iNOS (inducible nitric oxide synthase) induction and activation of intrinsic pathway signalling. Spermine exposure resulted in activation of JNK and iNOS induction and apoptosis. NAC and F1 (dose range 50-500 microg/ml) attenuated spermine-induced acceleration of VSMC apoptosis but only F1 (at 200 and 500 microg/ml) maintained spermine-induced apoptosis at control levels. Spermine-induced JNK activation was prevented by 200 microg/ml of both NAC and F1, while iNOS induction was blocked only by F1. Notably, the adverse effects of spermine on BAX/BCL-2 ratio, cytochrome c release and caspase activation was fully attenuated by F1. In conclusion, F1 was more effective than NAC in preventing spermine-induced apoptosis and downstream changes in related signal transduction pathways in VSMCs. Further studies are needed to examine the effect of these compounds in preventing CKD-associated vascular disease.
 ...
PMID:Inhibition of apoptotic signalling in spermine-treated vascular smooth muscle cells by a novel glutathione precursor. 2012 5

CMS-9, a phospholipase A(2) (PLA(2)) isolated from Naja nigricollis venom, induced apoptosis of human leukemia K562 cells, characterized by mitochondrial depolarization, modulation of Bcl-2 family members, cytochrome c release and activation of caspases 9 and 3. Moreover, an increase in intracellular Ca2+ concentration and the production of reactive oxygen species (ROS) was noted. Pretreatment with BAPTA-AM (Ca2+ chelator) and N-acetylcysteine (NAC, ROS scavenger) proved that Ca2+ was an upstream event in inducing ROS generation. Upon exposure to CMS-9, activation of p38 MAPK and JNK was observed in K562 cells. BAPTA-AM or NAC abrogated CMS-9-elicited p38 MAPK and JNK activation, and rescued viability of CMS-9-treated K562 cells. SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor) suppressed CMS-9-induced dissipation of mitochondrial membrane potential, Bcl-2 down-regulation, Bax up-regulation and increased mitochondrial translocation of Bax. Inactivation of PLA(2) activity reduced drastically the cytotoxicity of CMS-9, and a combination of lysophosphatidylcholine and stearic acid mimicked the cytotoxic effects of CMS-9. Taken together, our data suggest that CMS-9-induced apoptosis of K562 cells is catalytic activity-dependent and is mediated through mitochondria-mediated death pathway triggered by Ca2+/ROS-evoked p38 MAPK and JNK activation.
 ...
PMID:Involvement of p38 MAPK- and JNK-modulated expression of Bcl-2 and Bax in Naja nigricollis CMS-9-induced apoptosis of human leukemia K562 cells. 2014 38

Vpr, a HIV-1 accessory protein, was believed to be present in the plasma of HIV-1-positive patients, and our previous work demonstrated the presence of plasma Vpr in 20 out of 52 patients. Interestingly, our data revealed that patients' viral titer was correlated with the level of Vpr detected in their plasma. Here, we first show that rVpr, when incubated with human monocytes or MDMs, caused viral production from latently infected cells, and IL-6 was identified as a responsible factor. The induction of IL-6 by rVpr was dependent on signaling through TLR4 and its adaptor molecule, MyD88. We next provide evidence that rVpr induced the formation of OxPC and that a mAb against OxPC blocked rVpr-induced IL-6 production with the concomitant attenuation of MAPK activation. Moreover, the addition of NAC, a scavenger of ROS, abrogated the rVpr-induced formation of OxPC, the phosphorylation of C/EBP-beta, a substrate of MAPK, and IL-6 production. As rIL-6 reactivated viral replication in latently infected cells, our data indicate that rVpr-induced oxidative stress triggers cell-based innate immune responses and reactivates viral production in latently infected cells via IL-6 production. Our results suggest that Vpr should be monitored based on the viral titer, and they provide the rationale for the development of novel, anti-AIDS therapeutics targeting Vpr.
 ...
PMID:HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. 2014 98

Plumbagin, derived from the plant Plumbago zeylanica, has been shown to chronically activate ERK1/2 and inhibit Akt activity in cancer cells. However, the acute effects of plumbagin on ERK1/2 and Akt activities remain unknown. In this study, we examined the effects of plumbagin on ERK1/2 and Akt activities in 3T3-L1 cells. Exposure of 3T3-L1 cells to plumbagin generated superoxide and activated both ERK1/2 and Akt. The plumbagin-stimulated ERK1/2 and Akt activities were sensitive to an antioxidant NAC, superoxide dismutase mimetic MnTBAP, superoxide scavenger Tiron and NAD(P)H oxidase inhibitor DPI. Plumbagin-stimulated ERK1/2 activity was attenuated by the MEK1/2 inhibitor PD98059 and Ras inhibitor manumycin A, whereas plumbagin-stimulated Akt activity was blocked by the PI3K inhibitor LY294002. Both plumbagin-stimulated ERK1/2 and Akt activities were attenuated by PP2, a Src inhibitor. Interestingly, inhibition of phosphatidylinositol 3-kinase (PI3-kinase), but not Akt, activity leaded to attenuation of plumbagin-stimulated ERK1/2 activity. These results suggest that plumbagin activates NAD(P)H oxidase, Src, and PI3K, and that the activated PI3K or PDK1 subsequently stimulate Akt and Ras-Raf-MEK1/2-ERK1/2 in 3T3-L1 cells.
 ...
PMID:Plumbagin activates ERK1/2 and Akt via superoxide, Src and PI3-kinase in 3T3-L1 cells. 2042 Aug 21

Previously, we demonstrated that LYG-202, a newly synthesized flavonoid with a piperazine substitution, exhibited obvious antitumor activity in vivo and in vitro. The exact mechanism of this new compound remains unclear. In the present study, we examined the effects of LYG-202 on reactive oxygen species (ROS) production and the downstream signaling pathway in the apoptosis of human hepatocellular carcinoma HepG(2) cells. Pretreatment with NAC (N-acetylcysteine), a ROS production inhibitor, partly inhibited the apoptosis induced by LYG-202 via blocking the ROS generation. Further data revealed that LYG-202 induced ROS accumulation followed by a decrease in mitochondrial membrane potential (MMP), release of cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) to cytosol, which induced apoptosis of the cells. Moreover, the mitogen-activated protein kinases (MAPK), the downstream effect of ROS accumulation including c-Jun N-terminal kinase (JNK) and p38 MAPK, could be activated by LYG-202. Taken together, the generation of ROS might play an important role in LYG-202-induced mitochondrial apoptosis pathway, which provided further support for LYG-202 as a novel anticancer therapeutic candidate.
 ...
PMID:Reactive oxygen species-mitochondria pathway involved in LYG-202-induced apoptosis in human hepatocellular carcinoma HepG(2) cells. 2058 Sep 89

In an extension of our earlier studies, we examined the inhibitory effects of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine (PEITC-NAC), myo-inositol (MI) and indole-3-carbinol (I3C) or 3,3'-diindolylmethane (DIM), alone and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (BaP)-induced A/J mouse lung tumorigenesis and proliferation of A549 cells and human bronchial epithelial cells (HBECs) and relevant potential mechanisms. Mice treated with NNK plus BaP and fed non-supplemented diet had 13.0 + or - 4.1 lung tumors per mouse. Dietary feeding of mice with PEITC-NAC (5 mumol/g diet), I3C (5 mumol/g diet) or MI (56 mumol/g diet), beginning at 50% in the carcinogen treatment phase, significantly reduced tumor multiplicity to 8.2 + or - 2.0, 8.4 + or - 1.5 and 6.8 + or - 1.7 tumors per mouse, respectively. In mice given combinations of the chemopreventive agents, lung tumor multiplicity was significantly reduced to 6.3 + or - 2.2, 4.9 + or - 1.8, 4.8 + or - 1.9 and 3.6 + or - 1.4 by PEITC-NAC plus I3C, PEITC-NAC plus MI, I3C plus MI or PEITC-NAC plus I3C plus MI, respectively. Post-carcinogen administration of combinations of the agents also caused significant but weaker effects. Assessment of the anti-proliferative effects of the individual agents or their combinations showed significant reductions in the proliferation of cigarette smoke condensate (CSC)-pretreated HBEC (reduction by 30-41% at 48 h and 41-58% at 72 h) and A549 cells (30-43% at 48 h and 40-59% at 72 h), but not in dimethyl sulfoxide-pretreated HBEC. Combinatorial treatment with the agents also caused marked reductions in the activation of Akt, extracellular signal-regulated kinase and nuclear factor-kappaB in lung tumor tissues, CSC-pretreated HBEC and A549 cells. In conclusion, our studies demonstrated the promise of combinations of PEITC-NAC, I3C/DIM and MI for the chemoprevention of lung carcinogenesis in current and former smokers.
 ...
PMID:Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myo-inositol, alone and in combination. 2060 42

We showed previously that vascular smooth muscle cells (VMSC) from spontaneously hypertensive rats (SHR) exhibit increased proliferation. The present study was undertaken to examine whether the enhanced levels of endogenous angiotensin (ANG) II and endothelin (ET)-1 contribute to the enhanced proliferation of VSMC from SHR and to further investigate the underlying mechanisms responsible for this response. The enhanced proliferation of VSMC from SHR compared with Wistar-Kyoto (WKY) rats was attenuated by losartan, BQ-123, BQ-788, and AG-1478, inhibitors of AT(1), ET(A), ET(B) and epidermal growth factor (EGF-R) receptors, respectively. In addition, BQ-123 and BQ-788 also attenuated the enhanced production of superoxide anion (O(2)(-)) and NADPH oxidase activity. Furthermore, diphenyleneiodonium (DPI, inhibitor of NADPH oxidase), N-acetyl-L-cysteine (NAC, O(2)(-) scavenger), and PP2 (inhibitor of c-Src) also inhibited the augmented proliferation of VSMC from SHR to WKY levels. In addition, the enhanced phosphorylation of EGF-R in VSMC from SHR compared with WKY was also attenuated by inhibitors of AT(1), ET(A), ET(B), and EGF-R but not by inhibitors of platelet-derived growth factor receptor or insulin-like growth factor receptor. Furthermore, the enhanced phosphorylation of ERK1/2 in VSMC from SHR was also attenuated by AT(1), ET(A), ET(B), c-Src, and EGF-R inhibitors. The phosphorylation of c-Src was significantly augmented in VSMC from SHR compared with VSMC from WKY and was attenuated by DPI and NAC. These data suggest that endogenous vasoactive peptides, through increased oxidative stress and resultant activation of c-Src, transactivate EGF-R, which through mitogen-activated protein (MAP) kinase signaling may contribute to the hyperproliferation of VSMC from SHR.
 ...
PMID:Epidermal growth factor receptor transactivation by endogenous vasoactive peptides contributes to hyperproliferation of vascular smooth muscle cells of SHR. 2085 45

The alkylating agent N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG) can cause excess DNA strand breaks that lead to poly(ADP-ribose)polymerase-1 (PARP-1) overactivation and cell death (parthanatos). However, the detail mechanism of MNNG-induced parthanatos was not well-investigated. In this study, we used MNNG-treated mouse embryonic fibroblasts (MEFs) to elucidate the signaling pathways of MNNG-induced parthanatos. We found that MNNG-induced cell death accompanied by rapid PARP-1 activation, c-Jun N-terminal kinase (JNK) activation, biphasic reactive oxygen species (ROS) production and intracellular calcium increase. The early ROS production occurring at 1 min and peaking at 5-15 min after MNNG treatment partially resulted from NADPH oxidase. In contrast, the late phase of ROS production occurring at 30 min and time-dependently increasing up to 6h after MNNG treatment was generated by mitochondria. The antioxidant, NAC can abrogate all phenomena caused by MNNG. Results indicate that the calcium rise was downstream of early ROS production, and was involved in PARP-1 and JNK activation. Moreover, the PARP inhibitor was able to reduce MNNG-induced late-phase ROS production, calcium elevation, and cell death. Results further indicated the involvement of RIP1 in sustained ROS production and calcium increase. We characterized the interactive roles of ROS, calcium, JNK, and RIP1 in MNNG-induced cell death. We found that in addition to the alkylating property previously demonstrated, ROS production triggered by MNNG results in enhanced DNA damage and PARP-1 activation. Moreover, intracellular calcium elevation and ROS production have mutual amplification effects and thus contribute to PARP-1-mediated parthanatos.
 ...
PMID:Oxidative stress initiates DNA damager MNNG-induced poly(ADP-ribose)polymerase-1-dependent parthanatos cell death. 2105 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>