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Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice

文献类型：期刊论文

作者Li, Chao1,2,3,4; Luo, Jiao1,2,3,4; Guo, Shuju1,2,3; Jia, Xiaoling1,2,3; Guo, Chuanlong1,2,3,4; Li, Xiangqian1,2,3; Xu, Qi1,2,3,4; Shi, Dayong1,2,3,4,5
刊名MOLECULAR PHARMACEUTICS
出版日期2019-05-01
卷号16期号:5页码:1839-1850
ISSN号1543-8384
关键词type 2 diabetes mellitus protein tyrosine phosphatase 1B insulin resistance hypoglycemic activity dyslipidemia
DOI10.1021/acs.molpharmaceut.8b01106
通讯作者Shi, Dayong(shidayong@qdio.ac.cn)
英文摘要Protein tyrosine phosphatase 1B (PTP1B) is a widely confirmed target of the type 2 diabetes mellitus (T2DM) treatment. Herein, we reported a highly specific PTP1B inhibitor 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxy-diphenylmethane (compound 1), which showed promising hypoglycemic activity in diabetic BKS db mice. With the IC50 value of 2.4 mu M, compound 1 could directly bind to the catalytic pocket of PTP1B through a series of hydrogen bonds. Surface plasmon resonance analysis revealed that the target PTP1B affinity [KD (equilibrium dissociation constant) value] of compound 1 binding to PTP1B was 2.90 mu M. Moreover, compound 1 could activate the insulin signaling pathway in C2C12 skeletal muscle cells. We further evaluated the long-term effects of compound 1 in diabetic BKS db mice. Notably, oral administration of compound 1 significantly reduced the blood glucose levels of diabetic mice with increasing insulin sensitivity. In addition, the dyslipidemia of diabetic mice was also significantly improved by compound 1 gavage. The histological experiments showed that compound 1 treatment significantly ameliorated the disordered hepatic and pancreatic architecture and increased the glycogen content in the liver tissues as well as improved the insulin secretion function of pancreas. Taken together, our results manifested that the natural product compound 1 was a highly specific PTP1B inhibitor, which could activate insulin signaling pathway and ameliorate hyperglycemia and dyslipidemia in diabetic BKS db mice.
资助项目National Natural Science Foundation of China[81773586] ; National Natural Science Foundation of China[81703354] ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-DQC014] ; 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] ; Shandong Provincial Natural Science Foundation for Distinguished Young Scholars[JQ201722] ; National Program for Support of Top-notch Young Professionals ; Taishan scholar Youth Project of Shandong province
WOS研究方向Research & Experimental Medicine ; Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000467351300005
源URL[http://ir.qdio.ac.cn/handle/337002/161337]  
专题海洋研究所_实验海洋生物学重点实验室
通讯作者Shi, Dayong
作者单位1.Chinese Acad Sci, Inst Oceanol, CAS Key Lab Expt Marine Biol, Qingdao 266071, Shandong, Peoples R China
2.Qngdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266237, Shandong, Peoples R China
3.Chinese Acad Sci, Ctr Ocean Mega Sci, 7 Nanhai Rd, Qingdao 266071, Shandong, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Shandong Univ, State Key Lab Microbial Technol, Qingdao, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Li, Chao,Luo, Jiao,Guo, Shuju,et al. Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice[J]. MOLECULAR PHARMACEUTICS,2019,16(5):1839-1850.
APA Li, Chao.,Luo, Jiao.,Guo, Shuju.,Jia, Xiaoling.,Guo, Chuanlong.,...&Shi, Dayong.(2019).Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice.MOLECULAR PHARMACEUTICS,16(5),1839-1850.
MLA Li, Chao,et al."Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice".MOLECULAR PHARMACEUTICS 16.5(2019):1839-1850.

入库方式： OAI收割

来源：海洋研究所

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