Andrographolide Derivative AL-1 Ameliorates Dextran Sodium Sulfate-Induced Murine Colitis by Inhibiting NF-κB and MAPK Signaling Pathways.

Abstract

Trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulfate (DSS) are commonly used to induce experimental murine ulcerative colitis (UC). Our recent study has demonstrated that a novel andrographolide derivative, AL-1, ameliorated TNBS-induced colitis in mice. However, the effect of AL-1 on DSS-induced murine colitis and the underlying mechanisms are yet unknown. In the present study, we aimed to investigate the therapeutic potential of AL-1 against DSS-induced UC in mice and to define its mechanisms of action. Oral administration of AL-1 attenuated body weight loss, reduced colon length shortening, lowered the disease activity index score, and alleviated colon histological damage. AL-1 significantly inhibited myeloperoxidase activity and suppressed immune inflammatory responses in colonic tissues. Moreover, AL-1 reversed DSS-altered expression of inflammatory cytokines in DSS-induced colitis mice. Importantly, the efficacy of 45 mg/kg of AL-1 was higher than that of 100 mg/kg of the positive control drugs 5-aminosalicylic acid and mesalazine. AL-1 decreased lipopolysaccharide-induced generation of reactive oxygen species and nitric oxide in cultured macrophages in vitro; it also reversed the altered expression of inflammatory cytokines. In both in vivo and in vitro studies, Western blot analysis revealed that AL-1 reduced the expression of phosphorylated NF-κB p65 and IκBα, downregulated the expression of iNOS and COX-2, and attenuated the expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), ERK, and JNK. In conclusion, AL-1 alleviated DSS-induced murine colitis by inhibiting activation of the NF-κB and MAPK signaling pathways. Our data suggest that AL-1 could be a potential new treatment for UC.

• Authors: Mei Jing, Yuqiang Wang, Lipeng Xu
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2019 Pg. 6138723 ( 2019) ISSN: 1942-0994 [Electronic] United States
• PMID: 31687082 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Mei Jing et al.

Chemical References

• Cytokines
• Diterpenes
• Inflammation Mediators
• Lipopolysaccharides
• NF-kappa B
• Reactive Oxygen Species
• Nitric Oxide
• andrographolide
• Dextran Sulfate
• Peroxidase

Topics

• Animals
• Cell Nucleus (drug effects, metabolism)
• Colitis (blood, chemically induced, drug therapy, enzymology)
• Cytokines (blood)
• Dextran Sulfate
• Disease Models, Animal
• Diterpenes (pharmacology, therapeutic use)
• Female
• Inflammation (blood, complications, pathology)
• Inflammation Mediators (blood)
• Lipopolysaccharides
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Biological
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Peroxidase (metabolism)
• RAW 264.7 Cells
• Reactive Oxygen Species (metabolism)