title: Ganoderic acid C1 isolated from the anti-asthma formula, ASHMI™ suppresses TNF-α production by mouse macrophages and peripheral blood mononuclear cells from asthma patients.
abstract: Asthma is a heterogeneous airway inflammatory disease, which is associated with Th2 cytokine-driven inflammation and non-Th2, TNF-α mediated inflammation. Unlike Th2 mediated inflammation, TNF-α mediated asthma inflammation is generally insensitive to inhaled corticosteroids (ICS). ASHMITM, aqueous extract of three medicinal herbs-Ganoderma lucidum (G. lucidum), Sophora flavescens Ait (S. flavescens) and Glycyrrhiza uralensis Fischer (G. uralensis), showed a high safety profile and was clinically beneficial in asthma patients. It also suppresses both Th2 and TNF-α associated inflammation in murine asthma models. We previously determined that G. uralensis flavonoids are the key active compounds responsible for ASHMITM suppression of Th2 mediated inflammation. Until now, there are limited studies on anti-TNF-α compounds presented in ASHMITM. The objective of this study was to isolate and identify TNF-α inhibitory compounds in ASHMITM. Here we report that G. lucidum, but not the other two herbal extracts, S. flavescens or G. uralensis inhibited TNF-α production by murine macrophages; and that the methylene chloride (MC)-triterpenoid-enriched fraction, but not the polysaccharide-enriched fraction, contained the inhibitory compounds. Of the 15 triterpenoids isolated from the MC fraction, only ganoderic acid C1 (GAC1) significantly reduced TNF-α production by murine macrophages (RAW 264.7 cells) and peripheral blood mononuclear cells (PBMCs) from asthma patients. Inhibition was associated with down-regulation of NF-κB expression, and partial suppression of MAPK and AP-1 signaling pathways. Ganoderic acid C1 may have potential for treating TNF-α mediated inflammation in asthma and other inflammatory diseases.
authors.affiliation: Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, NY 10029, United States.
authors.forename: Changda
authors.initials: C
authors.lastname: Liu
authors.affiliation: Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, NY 10029, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, NY 10029, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, NY 10029, United States; Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated with Shanghai TCM University, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT 84322, United States.
authors.forename: Jiachen
authors.initials: J
authors.lastname: Zi
authors.affiliation: Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT 84322, United States.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pediatric Gastroenterology, Pediatric Department, Icahn School of Medicine at Mount Sinai, NY 10029, United States.
authors.forename: David
authors.initials: D
authors.lastname: Dunkin
authors.affiliation: Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Busse
authors.affiliation: Division of Pulmonary, Critical Care Medicine, and Sleep Medicine , Mount Sinai Medical Center, NY 10029, United States.
authors.forename: David
authors.initials: D
authors.lastname: Weir
authors.affiliation: Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, MD 21224, United States.
authors.forename: Jody
authors.initials: J
authors.lastname: Tversky
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University, New York, NY, 10032, United States; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Columbia University, New York, NY 10032, United States; Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, United States.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Miller
authors.affiliation: Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, NY, 10029, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Goldfarb
authors.affiliation: Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT 84322, United States. Electronic address: jixun.zhan@usu.edu.
authors.forename: Jixun
authors.initials: J
authors.lastname: Zhan
authors.affiliation: Pediatric Allergy & Immunology, Icahn School of Medicine at Mount Sinai, NY 10029, United States. Electronic address: xiu-min.li@mssm.edu.
authors.forename: Xiu-Min
authors.initials: XM
authors.lastname: Li
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D005260:Female; D029882:Glycyrrhiza uralensis / Q000737:chemistry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020940:Reishi / Q000737:chemistry*; D029909:Sophora / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C555782:ASHMI herbal formula; D018927:Anti-Asthmatic Agents; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C556862:ganoderic acid; D020928:Mitogen-Activated Protein Kinases
keywords: ASHMITM; Asthma; Ganoderic acid C1; Ganoderma lucidum; Inflammation; Macrophages; PBMCs; Peripheral blood mononuclear cells; RAW 264.7 cells; TNF-α; Traditional Chinese medicines