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Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IκB signaling pathways.
Eur J Pharmacol. 2011 Jan 10; 650(1):102-9.EJ

Abstract

Psoralidin has been reported to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, but the mechanisms of the action remain unclear. Thus, the impact of psoralidin on signaling pathways known to be implicated in NO synthesis was explored in LPS-activated RAW264.7 macrophages by using RT-PCR and Western blotting. Consistent with NO inhibition, psoralidin suppressed LPS-induced expression of inducible NO synthase (iNOS) by abolishing IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. Exposure to wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression, suggesting activation of such a signal pathway might also be phosphoinositide-3-kinase (PI3K) dependent. By using Src inhibitor PP2, Janus kinase 2 (JAK-2) inhibitor AG490, Bruton's tyrosine kinase (Btk) inhibitor LFM-A13 and spleen tyrosine kinase (Syk) inhibitor piceatannol, the results showed that piceatannol clearly repressed NO production more potently than the other inhibitors. Furthermore, piceatannol significantly repressed LPS-induced PI3K/Akt phosphorylation and the downstream IKK/IκB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/Akt-mediated signaling. In fact, transfection with siRNA targeting Syk obviously reduced iNOS expression. Interestingly, LPS-induced phosphorylations of Syk and PI3K-p85 were both significantly blunted by psoralidin treatment. The present results show that interfering with Syk-mediated PI3K phosphorylation might contribute to the NO inhibitory effect of psoralidin via blocking IKK/IκB signaling propagation in LPS-stimulated RAW 264.7 macrophages.

Authors+Show Affiliations

National Research Institute of Chinese Medicine, Taipei, Taiwan. wfchiou@nricm.edu.twNo 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

20951127

Citation

Chiou, Wen-Fei, et al. "Psoralidin Inhibits LPS-induced iNOS Expression Via Repressing Syk-mediated Activation of PI3K-IKK-IκB Signaling Pathways." European Journal of Pharmacology, vol. 650, no. 1, 2011, pp. 102-9.
Chiou WF, Don MJ, Liao JF, et al. Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IκB signaling pathways. Eur J Pharmacol. 2011;650(1):102-9.
Chiou, W. F., Don, M. J., Liao, J. F., & Wei, B. L. (2011). Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IκB signaling pathways. European Journal of Pharmacology, 650(1), 102-9. https://doi.org/10.1016/j.ejphar.2010.10.004
Chiou WF, et al. Psoralidin Inhibits LPS-induced iNOS Expression Via Repressing Syk-mediated Activation of PI3K-IKK-IκB Signaling Pathways. Eur J Pharmacol. 2011 Jan 10;650(1):102-9. PubMed PMID: 20951127.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IκB signaling pathways. AU - Chiou,Wen-Fei, AU - Don,Ming-Jaw, AU - Liao,Jyh-Fei, AU - Wei,Bai-Lu, Y1 - 2010/10/14/ PY - 2010/06/28/received PY - 2010/09/06/revised PY - 2010/10/03/accepted PY - 2010/10/19/entrez PY - 2010/10/19/pubmed PY - 2011/3/25/medline SP - 102 EP - 9 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 650 IS - 1 N2 - Psoralidin has been reported to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, but the mechanisms of the action remain unclear. Thus, the impact of psoralidin on signaling pathways known to be implicated in NO synthesis was explored in LPS-activated RAW264.7 macrophages by using RT-PCR and Western blotting. Consistent with NO inhibition, psoralidin suppressed LPS-induced expression of inducible NO synthase (iNOS) by abolishing IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. Exposure to wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression, suggesting activation of such a signal pathway might also be phosphoinositide-3-kinase (PI3K) dependent. By using Src inhibitor PP2, Janus kinase 2 (JAK-2) inhibitor AG490, Bruton's tyrosine kinase (Btk) inhibitor LFM-A13 and spleen tyrosine kinase (Syk) inhibitor piceatannol, the results showed that piceatannol clearly repressed NO production more potently than the other inhibitors. Furthermore, piceatannol significantly repressed LPS-induced PI3K/Akt phosphorylation and the downstream IKK/IκB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/Akt-mediated signaling. In fact, transfection with siRNA targeting Syk obviously reduced iNOS expression. Interestingly, LPS-induced phosphorylations of Syk and PI3K-p85 were both significantly blunted by psoralidin treatment. The present results show that interfering with Syk-mediated PI3K phosphorylation might contribute to the NO inhibitory effect of psoralidin via blocking IKK/IκB signaling propagation in LPS-stimulated RAW 264.7 macrophages. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/20951127/Psoralidin_inhibits_LPS_induced_iNOS_expression_via_repressing_Syk_mediated_activation_of_PI3K_IKK_IκB_signaling_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(10)01006-X DB - PRIME DP - Unbound Medicine ER -