title: A natural product from Cannabis sativa subsp. sativa inhibits homeodomain-interacting protein kinase 2 (HIPK2), attenuating MPP+-induced apoptosis in human neuroblastoma SH-SY5Y cells.
abstract: Homeodomain-interacting protein kinase 2 (HIPK2) is a conserved serine/threonine kinase, which regulate transcription, cell differentiation, proliferation and apoptosis. Previous evidences indicated that HIPK2 could be involved in the pathogenesis of neurodegenerative diseases, suggesting as a novel target for Parkinson's disease (PD) therapeutic development. Herein, gene microarray analysis was performed to verify the key regulatory function of HIPK2 in PD. (Z)-methylp-hydroxycinnamate (ZMHC, 7) with other eighteen compounds were isolated from Cannabis sativa subsp. sativa, growing in Bama Yao Autonomous County, one of the five largest longevity regions of the world. Intriguingly, ZMHC was identified to bind HIPK2 with high affinity through molecular modeling and molecular dynamics (MD) simulations. Moreover, cell morphology, flow cytometry and western blot assay suggested that ZMHC inhibited HIPK2, which attenuated MPP+-induced apoptosis in SH-SY5Y cells. In conclusion, these findings discovered a natural product that inhibited HIPK2, and highlighted that ZMHC could be a potential precursor agent for future PD therapy.
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Suyu
authors.initials: S
authors.lastname: Gao
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Sun
authors.affiliation: Guangxi Botanical Garden of Medicinal Plants, Nanning 530023, PR China.
authors.forename: Jingquan
authors.initials: J
authors.lastname: Yuan
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: syzxalice@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: tyaoxs@jnu.edu.cn.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Yao
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002188:Cannabis / Q000737:chemistry*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D001688:Biological Products; D002352:Carrier Proteins; D002934:Cinnamates; D047428:Protein Kinase Inhibitors; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: (Z)-methylp-hydroxycinnamate; Apoptosis; Cannabis sativa subsp. sativa; Homeodomain-interacting protein kinase 2; Parkinson’s disease; SH-SY5Y cells