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

doi:10.1021/acs.molpharmaceut.8b01106

IOCAS-IR > 实验海洋生物学重点实验室

	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
	Li, Chao 1,2,3,4; Luo, Jiao 1,2,3,4; Guo, Shuju 1,2,3; Jia, Xiaoling 1,2,3; Guo, Chuanlong 1,2,3,4; Li, Xiangqian 1,2,3; Xu, Qi 1,2,3,4; Shi, Dayong 1,2,3,4,5
	2019-05-01
发表期刊	MOLECULAR PHARMACEUTICS
ISSN	1543-8384
卷号	16 期号:5 页码:1839-1850
通讯作者	Shi, Dayong([email protected])
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.
关键词	type 2 diabetes mellitus protein tyrosine phosphatase 1B insulin resistance hypoglycemic activity dyslipidemia
DOI	10.1021/acs.molpharmaceut.8b01106
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[81773586]###283; National Natural Science Foundation of China[81703354]###282; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-DQC014]###580; Qingdao Marine Biomedical Science and Technology Innovation Center Project[2017-CXZX01-1-1]###2458; Qingdao Marine Biomedical Science and Technology Innovation Center Project[2017-CXZX01-3-9]###2459; Shandong Provincial Natural Science Foundation for Distinguished Young Scholars[JQ201722]###556; National Program for Support of Top-notch Young Professionals###557; Taishan scholar Youth Project of Shandong province###558; 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
WOS类目	Medicine, Research & Experimental ; Pharmacology & Pharmacy
WOS记录号	WOS:000467351300005
出版者	AMER CHEMICAL SOC
引用统计	被引频次：8[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/161338
专题	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.