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Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway.
Biochem Pharmacol. 2007 Jun 01; 73(11):1796-806.BP

Abstract

In the present study, a novel synthetic compound 4-(2-(cyclohex-2-enylidene)hydrazinyl)quinolin-2(1H)-one (CYL-4d) was found to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production without affecting cell viability or enzyme activity of expressed inducible NO synthase (iNOS) in RAW 264.7 macrophages. CYL-4d exhibited parallel inhibition of LPS-induced expression of iNOS protein, iNOS mRNA and iNOS promoter activity in the same concentration range. LPS-induced activator protein-1 (AP-1) DNA binding, AP-1-dependent reporter gene activity and c-Jun nuclear translocation were all markedly inhibited by CYL-4d with similar efficacy, whereas CYL-4d produced a weak inhibition of nuclear factor-kappaB (NF-kappaB) DNA binding, NF-kappaB-dependent reporter gene activity and p65 nuclear translocation without affecting inhibitory factor-kappa B alpha (I kappa B alpha) degradation. CYL-4d had no effect on the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and its upstream activator MAPK kinase (MEK) 3, whereas it significantly attenuated the phosphorylation of c-Jun, c-Jun NH(2)-terminal kinase (JNK) and its upstream activator MEK4 in a parallel concentration-dependent manner. Other Toll-like receptors (TLRs) ligands (peptidoglycans, double-stranded RNA, and oligonucleotide containing unmethylated CpG motifs)-induced iNOS protein expression were also inhibited by CYL-4d. Furthermore, the NO production from BV-2 microglial cells as well as rat alveolar macrophages in response to LPS was diminished by CYL-4d. These results indicate that the blockade of NO production by CYL-4d in LPS-stimulated RAW 264.7 cells is attributed mainly to interference in the MEK4-JNK-AP-1 signaling pathway. CYL-4d inhibition of NO production is not restricted to TLR4 activation and immortalized macrophage-like cells.

Authors+Show Affiliations

Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan, ROC.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17379190

Citation

Lin, Meng-Wei, et al. "Inhibition of Lipopolysaccharide-stimulated NO Production By a Novel Synthetic Compound CYL-4d in RAW 264.7 Macrophages Involving the Blockade of MEK4/JNK/AP-1 Pathway." Biochemical Pharmacology, vol. 73, no. 11, 2007, pp. 1796-806.
Lin MW, Tsao LT, Chang LC, et al. Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. Biochem Pharmacol. 2007;73(11):1796-806.
Lin, M. W., Tsao, L. T., Chang, L. C., Chen, Y. L., Huang, L. J., Kuo, S. C., Tzeng, C. C., Lee, M. R., & Wang, J. P. (2007). Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. Biochemical Pharmacology, 73(11), 1796-806.
Lin MW, et al. Inhibition of Lipopolysaccharide-stimulated NO Production By a Novel Synthetic Compound CYL-4d in RAW 264.7 Macrophages Involving the Blockade of MEK4/JNK/AP-1 Pathway. Biochem Pharmacol. 2007 Jun 1;73(11):1796-806. PubMed PMID: 17379190.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. AU - Lin,Meng-Wei, AU - Tsao,Lo-Ti, AU - Chang,Ling-Chu, AU - Chen,Ye-Long, AU - Huang,Li-Jiau, AU - Kuo,Sheng-Chu, AU - Tzeng,Cherng-Chyi, AU - Lee,Miau-Rong, AU - Wang,Jih-Pyang, Y1 - 2007/02/20/ PY - 2007/01/17/received PY - 2007/02/15/revised PY - 2007/02/15/accepted PY - 2007/3/24/pubmed PY - 2007/6/19/medline PY - 2007/3/24/entrez SP - 1796 EP - 806 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 73 IS - 11 N2 - In the present study, a novel synthetic compound 4-(2-(cyclohex-2-enylidene)hydrazinyl)quinolin-2(1H)-one (CYL-4d) was found to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production without affecting cell viability or enzyme activity of expressed inducible NO synthase (iNOS) in RAW 264.7 macrophages. CYL-4d exhibited parallel inhibition of LPS-induced expression of iNOS protein, iNOS mRNA and iNOS promoter activity in the same concentration range. LPS-induced activator protein-1 (AP-1) DNA binding, AP-1-dependent reporter gene activity and c-Jun nuclear translocation were all markedly inhibited by CYL-4d with similar efficacy, whereas CYL-4d produced a weak inhibition of nuclear factor-kappaB (NF-kappaB) DNA binding, NF-kappaB-dependent reporter gene activity and p65 nuclear translocation without affecting inhibitory factor-kappa B alpha (I kappa B alpha) degradation. CYL-4d had no effect on the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and its upstream activator MAPK kinase (MEK) 3, whereas it significantly attenuated the phosphorylation of c-Jun, c-Jun NH(2)-terminal kinase (JNK) and its upstream activator MEK4 in a parallel concentration-dependent manner. Other Toll-like receptors (TLRs) ligands (peptidoglycans, double-stranded RNA, and oligonucleotide containing unmethylated CpG motifs)-induced iNOS protein expression were also inhibited by CYL-4d. Furthermore, the NO production from BV-2 microglial cells as well as rat alveolar macrophages in response to LPS was diminished by CYL-4d. These results indicate that the blockade of NO production by CYL-4d in LPS-stimulated RAW 264.7 cells is attributed mainly to interference in the MEK4-JNK-AP-1 signaling pathway. CYL-4d inhibition of NO production is not restricted to TLR4 activation and immortalized macrophage-like cells. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/17379190/Inhibition_of_lipopolysaccharide_stimulated_NO_production_by_a_novel_synthetic_compound_CYL_4d_in_RAW_264_7_macrophages_involving_the_blockade_of_MEK4/JNK/AP_1_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(07)00126-8 DB - PRIME DP - Unbound Medicine ER -