Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation.

Abstract

Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47(phox) and p67(phox) to the cell membrane. Yuwen02f1 also reverses IκBα degradation and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes.

• Authors: Chun-Chieh Hsu, Jin-Cherng Lien, Chia-Wen Chang, Chien-Hsin Chang, Sheng-Chu Kuo, Tur-Fu Huang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 85 Issue 3 Pg. 385-95 (Feb 01 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23142712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Furans
• Lipoproteins
• NF-kappa B
• Pyrazoles
• Reactive Oxygen Species
• Yuwen02f1
• Nitric Oxide
• L-Lactate Dehydrogenase
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Arthritis, Experimental (chemically induced, drug therapy)
• Cell Line
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Endotoxemia (chemically induced, drug therapy)
• Furans (chemistry, pharmacology)
• Gene Expression Regulation (drug effects)
• Humans
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lipoproteins (toxicity)
• Macrophages
• Male
• Mice
• Mice, Inbred ICR
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Molecular Structure
• Monocytes
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Pyrazoles (chemistry, pharmacology)
• Reactive Oxygen Species