title: A novel Pseudolaric acid B derivative, Hexahydropseudolaric acid B, exterts an immunomodulatory effect in vitro/in vivo evaluation.
abstract: Identification of immunosuppressants from natural sources has a proven track record in immune mediated disorders. Pseudolaric acid B is a diterpenoid isolated from the roots of Pseudolarix amabilis, possessing potent immunomodulatory effect. However, the cytotoxicity limits its future clinical application. The purpose of this study was to investigate the immunosuppressive activity of Hexahydropseudolaric acid B, a Pseudolaric acid B derivative, on T cell-mediated immune response both in vitro and in vivo, and investigated its immunomodulatory effect to develop a more ascendant immunosuppressive agent. The results showed that Hexahydropseudolaric acid B could exert more preferable immunosuppressive activity and lower cytotoxicity than Pseudolaric acid B. Hexahydropseudolaric acid B significantly inhibited T cell proliferation activated by mitogen and alloantigen without obvious cytotoxicity in vitro. Furthermore, Hexahydropseudolaric acid B could ameliorate ear swelling in a mouse model of 2,4-dinitrofluorobenzene-induced delayed-type hypersensitivity in vivo. Mechanistic study revealed that Hexahydropseudolaric acid B could enhance regulatory T cells via promoting Foxp3 expression and TGF-β level, accompanied by attenuating Akt activation, blocking p38MAPK/MK2-HSP27 signal cascades, and up-regulating PPAR-γ expression. Taken together, these results suggest that Hexahydropseudolaric acid B exerts more preferable immunosuppressive activity than its precursor Pseudolaric acid B by affecting multiple targets, which support the need for continued efforts to characterize the efficacy of HPAB as a promising and safe candidate to treat immune-related diseases.
authors.affiliation: Department of Pathogen Biology and Immunology, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300309, China; Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Institute of Cardiovascular Disease and Heart Center, The Affiliated Hospital of Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China. Electronic address: tanli20042001@163.com.
authors.forename: Tan
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmacognosy and Pharmaceutics, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300309, China; Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental Hazard, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300309, China. Electronic address: chenhongtian06@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Pingjin Hospital, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Pingjin Hospital, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacognosy and Pharmaceutics, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300309, China.
authors.forename: Yi-teng
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Department of Pharmacognosy and Pharmaceutics, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300309, China.
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Institute of Cardiovascular Disease and Heart Center, The Affiliated Hospital of Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China; Pingjin Hospital, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China.
authors.forename: Ji-hong
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Institute of Cardiovascular Disease and Heart Center, The Affiliated Hospital of Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China; Pingjin Hospital, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Institute of Cardiovascular Disease and Heart Center, The Affiliated Hospital of Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China; Pingjin Hospital, Logistics University of the Chinese People׳s Armed Police Force, Tianjin 300162, China.
authors.forename: Yu-ming
authors.initials: YM
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D028201:Pinaceae / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D007166:Immunosuppressive Agents; D047495:PPAR gamma; D016212:Transforming Growth Factor beta; C000600436:hexahydropseudolaric acid B; C058391:pseudolaric acid B; D051057:Proto-Oncogene Proteins c-akt
keywords: Delayed-type hypersensitivity; Hexahydropseudolaric acid B; Immunosuppression; MAPK; Regulatory T cells