title: Improved Biological Activities of Isoepoxypteryxin by Biotransformation.
abstract: Isoepoxypteryxin is the major coumarin of a Japanese medicinal plant Angelica shikokiana. This research was designed to study the effect of structural changes through fungal biotransformation on the reported biological activities of isoepoxypteryxin. Among the tested microorganisms, only Cordyceps sinensis had enzymes that could catalyze the ester hydrolysis and the reductive cleavage of the epoxide ring of isoepoxypteryxin, separately, to give two more polar metabolites (+)-cis-khellactone (P1) and a new coumarin derivative (+)-cis-3'-[(2-methyl-3-hydroxybutanoyl)oxy]-4'-acetoxy-3',4'-dihydroseselin (P2), respectively. The polar metabolite P2 showed stronger cytotoxicity and higher selectivity than isoepoxypteryxin. On the molecular level, P2 showed more in vitro inhibition of both tubulin polymerization and histone deacetylase 8 (HDAC8). Similarly, P2 showed more neuroprotection against amyloid beta fragment 1 - 42 (Aβ1 - 42)-induced neurotoxicity in human neuroblastoma cells (SH-SY5Y) and exhibited more inhibition of the in vitro aggregation of Aβ1 - 42. Both metabolites showed stronger antiplatelet aggregation by increased inhibition of thromboxane-A2 synthase (TXS) activity and thromboxane-A2 (TXA2) production. This study is the first to describe the improved cytotoxic, neuroprotective, and antiplatelet aggregation activities of isoepoxypteryxin through its biotransformation by C. sinensis.
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
authors.forename: Amira
authors.initials: A
authors.lastname: Mira
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
authors.forename: Wael
authors.initials: W
authors.lastname: Alkhiary
authors.affiliation: Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, 812-8581, Japan.
authors.forename: Qinchang
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, 812-8581, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, 812-8581, Japan.
authors.forename: Hai-Bang
authors.initials: HB
authors.lastname: Tran
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.|Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, 812-8581, Japan.
authors.forename: Yhiya M
authors.initials: YM
authors.lastname: Amen
authors.affiliation: Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, 812-8581, Japan. shimizu@agr.kyushu-u.ac.jp.
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Shimizu
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D029969:Angelica / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D032661:Cordyceps / Q000201:enzymology* / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003374:Coumarins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D066329:Protein Aggregates; D012097:Repressor Proteins; D014404:Tubulin; C075222:amyloid beta-protein (1-42); C000613488:isoepoxypteryxin; D013928:Thromboxane A2; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D013930:Thromboxane-A Synthase
keywords: 
  Cordyceps sinensis
  ; Antiplatelet; Cytotoxic activities; Isoepoxypteryxin; Neuroprotection