title: AP-1-Targeted Inhibition of Macrophage Function and Lipopolysaccharide/D-Galactosamine-Induced Hepatitis by Phyllanthus acidus Methanolic Extract.
abstract: Traditionally, Phyllanthus acidus (Phyllanthaceae) has been used for the treatment of rheumatism, bronchitis, asthma, respiratory disorders, and hepatitis. Recently, we showed that a methanol extract of Phyllanthaceae (Pa-ME) has a potent anti-inflammatory activity in RAW264.7 cells and strongly ameliorates HCl / EtOH -induced gastric ulcers in mice by targeting the Src/Syk of NF-κB. In the present study, we explored the molecular mechanism of Pa-ME on the AP-1 activation pathway and evaluated its potential hepatoprotective effects. To do this, we employed lipopolysaccharide (LPS)-stimulated RAW264.7 cells and U937 cells and an LPS/D-galactosamine (D- GaIN )-induced acute hepatitis mouse model. We utilized a multitude of assays, including immunoblotting analysis, reporter gene assays, and mRNA expression analysis, to determine the effect of Pa-ME on the AP-1 pathway. Pa-ME strikingly suppressed the production of LPS-induced pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Furthermore, Pa-ME also strongly inhibited activator protein-1 (AP-1) activation and mitogen-activated protein kinase (MAPK) phosphorylation in LPS-stimulated RAW264.7 macrophages cells and the U937 monocyte like human cell line. Moreover, pre-treatment with Pa-ME exhibited strong hepatoprotective and curative effects in an LPS/D-Gal-induced mouse hepatitis model as evidenced by a decrease in elevated serum AST and ALT levels and the amelioration of histological damage. Taken together, our data suggest that Pa-ME might play a crucial ethnopharmacological role as a hepatoprotective herbal remedy by suppressing MAPK signaling and the activity of the downstream transcription factor AP-1.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.|Department of Animal Science, Patuakhali Science and Technology University, Patuakhali 8602, Bangladesh.
authors.forename: Muhammad Jahangir
authors.initials: MJ
authors.lastname: Hossen
authors.affiliation: School of Systems Biological Science, Soongsil University, Seoul 156-743, Republic of Korea.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D005688:Galactosamine / Q000009:adverse effects; D006505:Hepatitis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D029803:Phyllanthus / Q000737:chemistry*; D010936:Plant Extracts / Q000008:administration & dosage*; D000067996:RAW 264.7 Cells; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D020298:U937 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D018808:Transcription Factor AP-1; D005688:Galactosamine
keywords: AP-1; Hepatitis; IL-1β; IL-6; MAPK; Phyllanthus acidus (Phyllanthaceae); TNF-α