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Antidiabetic activity in vitro and in vivo of BDB, a selective inhibitor of protein tyrosine phosphatase 1B, fromRhodomela confervoides
Luo, Jiao2,3; Zheng, Meiling6; Jiang, Bo3,5; Li, Chao3,5; Guo, Shuju3,5; Wang, Lijun3,5; Li, Xiangqian1,4; Yu, Rilei6; Shi, Dayong1,4
2020-10-01
Source PublicationBRITISH JOURNAL OF PHARMACOLOGY
ISSN0007-1188
Volume177Issue:19Pages:4464-4480
AbstractBackground and Purpose Protein tyrosine phosphatase (PTP) 1B (PTP1B) plays a critical role in the regulation of obesity, Type 2 diabetes mellitus and other metabolic diseases. However, drug candidates exhibiting PTP1B selectivity and oral bioavailability are currently lacking. Here, the enzyme inhibitory characteristics and pharmacological benefits of 3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol (BDB) were investigated in vitro and in vivo. Experimental Approach Surface plasmon resonance (SPR) assay was performed to validate the direct binding of BDB to PTP1B, and Lineweaver-Burk analysis of the enzyme kinetics was used to characterise the inhibition by BDB. Both in vitro enzyme-inhibition assays and SPR experiments were also conducted to study the selectivity exhibited by BDB towards four other PTP-family proteins: TC-PTP, SHP-1, SHP-2, and LAR. C2C12 myotubes were used to evaluate cellular permeability to BDB. Effects of BDB on insulin signalling, hypoglycaemia and hypolipidaemia were investigated in diabetic BKS db mice, after oral gavage. The beneficial effects of BDB on pancreatic islets were examined based on insulin and/or glucagon staining. Key Results BDB acted as a competitive inhibitor of PTP1B and demonstrated high selectivity for PTP1B among the tested PTP-family proteins. Moreover, BDB was cell-permeable and enhanced insulin signalling in C2C12 myotubes. Lastly, oral administration of BDB produced effective antidiabetic effects in spontaneously diabetic mice and markedly improved islet architecture, which was coupled with an increase in the ratio of beta-cells to alpha-cells. Conclusion and Implications BDB application offers a potentially practical pharmacological approach for treating Type 2 diabetes mellitus by selectively inhibiting PTP1B.
Keywordbromophenol PTP1B inhibitor selectivity cell permeability oral bioavailability
DOI10.1111/bph.15195
Indexed BySCI
Language英语
Funding ProjectNational Natural Science Foundation of China[81703354] ; Key research and development project of Shandong province[2018GSF118200] ; NSFC-Shandong Joint Fund[U1706213] ; Shandong Provincial Natural Science Foundation for Distinguished Young Scholars[JQ201722] ; National Program for Support of Top-notch Young Professionals ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-DQC014] ; Fund of Taishan Scholar Project ; Qingdao Marine Biomedical Science and Technology Innovation Center Project[2017-CXZX01-1-1] ; Qingdao Marine Biomedical Science and Technology Innovation Center Project[2017-CXZX01-3-9] ; Key Research and Development Project of Shandong province[2018GSF118208]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000563751300001
PublisherWILEY
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Version出版稿
Identifierhttp://ir.qdio.ac.cn/handle/337002/168280
Collection实验海洋生物学重点实验室
Corresponding AuthorLuo, Jiao; Shi, Dayong
Affiliation1.Shandong Univ, State Key Lab Microbial Technol, Jinan 250100, Peoples R China
2.Qingdao Univ, Sch Publ Hlth, Qingdao 266071, Peoples R China
3.Chinese Acad Sci, Inst Oceanol, CAS Key Lab Expt Marine Biol, Qingdao, Peoples R China
4.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao, Peoples R China
5.Chinese Acad Sci, Ctr Ocean Megasci, Qingdao, Peoples R China
6.Ocean Univ China, Sch Med & Pharm, Key Lab Marine Drugs, Chinese Minist Educ, Qingdao, 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,Zheng, Meiling,Jiang, Bo,et al. Antidiabetic activity in vitro and in vivo of BDB, a selective inhibitor of protein tyrosine phosphatase 1B, fromRhodomela confervoides[J]. BRITISH JOURNAL OF PHARMACOLOGY,2020,177(19):4464-4480.
APA Luo, Jiao.,Zheng, Meiling.,Jiang, Bo.,Li, Chao.,Guo, Shuju.,...&Shi, Dayong.(2020).Antidiabetic activity in vitro and in vivo of BDB, a selective inhibitor of protein tyrosine phosphatase 1B, fromRhodomela confervoides.BRITISH JOURNAL OF PHARMACOLOGY,177(19),4464-4480.
MLA Luo, Jiao,et al."Antidiabetic activity in vitro and in vivo of BDB, a selective inhibitor of protein tyrosine phosphatase 1B, fromRhodomela confervoides".BRITISH JOURNAL OF PHARMACOLOGY 177.19(2020):4464-4480.
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