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Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor
Luo, Jiao1,2,3; Xu, Qi1,2,3; Jiang, Bo1,2; Zhang, Renshuai1,2; Jia, Xiaoling1,2; Li, Xiangqian1,2; Wang, Lijun1,2; Guo, Chuanlong1,2,3; Wu, Ning1,2; Shi, Dayong1,2,3
2018
Source PublicationBRITISH JOURNAL OF PHARMACOLOGY
ISSN0007-1188
Volume175Issue:1Pages:140-153
Corresponding AuthorShi, Dayong(shidayong@qdio.ac.cn)
AbstractBACKGROUND AND PURPOSE Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling by tyrosine dephosphorylation of the insulin receptor. It is a highly validated target for type 2 diabetes therapeutics. Here, the anti-diabetic effects of HPN were evaluated in the diabetic BKS db mice. EXPERIMENTAL APPROACH The mode of inhibition of PTP1B by HPN was determined according to the Lineweaver-Burk plot. A surface plasmon resonance assay and molecular docking were used to study the interaction between HPN and PTP1B. C2C12 skeletal muscle cells were used to investigate the cell permeability of HPN and the effect of HPN on insulin signalling pathways. Long-term effects of HPN on glycaemic control were investigated in diabetic BKS db mice. Glycogen contents in liver and muscle were determined. Furthermore, changes in the number of beta cells were evaluated by Gomori staining. KEY RESULTS HPN was identified as a specific PTP1B inhibitor. HPN directly interacted with PTP1B by binding to the catalytic domain through hydrogen bonds in a competitive mode. Approximately 56.98% of HPN entered into the cultured C2C12 myotubes. HPN ameliorated the impaired insulin signalling in palmitate-treated C2C12 myocytes. Notably, oral administration of HPN significantly protected mice from hyperglycaemia, dyslipidemia and hyperinsulinaemia. HPN also enhanced the storage of glycogen in liver and muscle. Moreover, HPN obviously improved the beta cell numbers of the pancreatic islets. CONCLUSION AND IMPLICATIONS Our results indicate that HPN is a specific PTP1B inhibitor, with anti-diabetic properties and good cell permeability and oral availability.
DOI10.1111/bph.14080
Indexed BySCI
Language英语
Funding ProjectShandong Provincial Natural Science Foundation for Distinguished Young Scholars[JQ201722] ; National Natural Science Foundation of China[81773586] ; National Natural Science Foundation of China[81703354] ; Key Research and Development Project of Shandong Province[2016ZDJS07A13] ; Key Research and Development Project of Shandong Province[2016GSF115002] ; Key Research and Development Project of Shandong Province[2016GSF201193] ; Key Research and Development Project of Shandong Province[2016GSF115009] ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-DQC014] ; Project of Discovery, Evaluation and Transformation of Active Natural Compounds, Strategic Biological Resources Service Network Programme of Chinese Academy of Sciences[ZSTH-026] ; NSFC-Shandong Joint Fund for Marine Science Research Centres[U1606403] ; Scientific and Technological Innovation project - Qingdao National Laboratory for Marine Science and Technology[2015ASKJ02] ; Qingdao National Laboratory for Marine Science and Technology[2015ASTP] ; National Program for Support of Top-notch Young Professionals and Taishan scholar Youth Project of Shandong province
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000418678600011
PublisherWILEY
Citation statistics
Cited Times:14[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/157784
Collection实验海洋生物学重点实验室
Corresponding AuthorShi, Dayong
Affiliation1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, 7 Nanhai Rd, Qingdao 266071, Peoples R China
2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao, Peoples R China
3.Univ Chinese Acad Sci, Beijing, Peoples R China
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Corresponding Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Luo, Jiao,Xu, Qi,Jiang, Bo,et al. Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor[J]. BRITISH JOURNAL OF PHARMACOLOGY,2018,175(1):140-153.
APA Luo, Jiao.,Xu, Qi.,Jiang, Bo.,Zhang, Renshuai.,Jia, Xiaoling.,...&Shi, Dayong.(2018).Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor.BRITISH JOURNAL OF PHARMACOLOGY,175(1),140-153.
MLA Luo, Jiao,et al."Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor".BRITISH JOURNAL OF PHARMACOLOGY 175.1(2018):140-153.
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