Author: Wu, Hao ; Fu, Shengmiao ; Pei, Yechun ; Pei, Jinli ; Luo, Chenghui ; Xiao, Zhengpan ; Luo, Ying ; Wang, Dayong ; Yuan, Nan ; Wang, Jiaxuan ; Sun, Yan ; Wang, Baochun ; Wei, Shuangshuang

Background and PurposeHirudin variants are the most powerful thrombin inhibitors discovered to date, with a lower risk of bleeding than heparin. For anticoagulation, the C‐termini of hirudin variants bind to the exocite I of thrombin. Anticoagulant effects of gene‐recombinant hirudin are weaker than natural hirudin for the reason of lacking tyrosine O‐sulfation at C‐terminus.Experimental ApproachAn integrative pharmacological study was carried out using molecular dynamic, molecular biological and in vivo and in vitro experiments to elucidate the anticoagulant effects of protein‐engineered hirudins.Key ResultsMolecular dynamic analysis showed that modifications of the C‐termini of hirudin variant 1 of Hirudo medicinalis (HV1) and hirudin variant 2 of Hirudinaria manillensis (HM2) changed the binding energy of the C‐termini to human thrombin. The study indicated that Asp61 of HM2 that corresponds to sulfated Tyr63 of HV1 is critical for inhibiting thrombin activities. Further, the anticoagulant effects of HV1 and HM2 were improved when the amino acid residues adjacent to Asp61 were mutated to Asp. These improvements were prolongation of the activated partial thromboplastin time, prothrombin time and thrombin time of human blood, and decreased Ki and IC50 values. In the in vivo experiments, mutations at C‐termini of HV1 and HM2 significantly changed partial thromboplastin time, prothrombin and thrombin timeConclusion and ImplicationsThe study indicated that the anticoagulant effects of gene‐engineered HM2 are stronger than gene‐engineered HV1 and HM2‐E60D‐I62D has the strongest effects and could be an antithrombotic with better therapeutic effects.

01 May 2019·Biochemical and Biophysical Research Communications

Hv1-deficiency protects β cells from glucotoxicity through regulation of NOX4 level

Article

Author: Gao, Ying-Tang ; Wang, Xudong ; Jiang, Dan ; Du, Hongyan ; Wang, Yuzhou ; Li, Shu Jie ; Lv, Jili

High glucose (HG)-induced oxidative stress contributes to the dysfunction of pancreatic β cells in diabetes. The voltage-gated proton channel Hv1 has been proposed to support reactive oxygen species (ROS) production during respiratory bursts. However, the effect of Hv1 on glucotoxicity in pancreatic β cells is not clear yet. In this study, we examined the protective effects of Hv1-deficiency in HG cultured β cells. Following 48 h of treatment with 30 mM high glucose, Hv1 KO β cells showed higher cell viability, lower cell apoptosis and a more stable insulin gene expression level compared to WT β cells. In both control and HG cultured β cells, deficiency of Hv1 decreased the glucose- and PMA-induced ROS production. Finally, HG incubation led to NOX4 upregulation in WT β cells, which could be inhibited by HV1 deficiency. In conclusion, Hv1-deficiency prevents the HG treatment-induced NOX4 upregulation and protects β cells from glucotoxicity.

01 Apr 2018·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Deficiency of voltage-gated proton channel Hv1 attenuates streptozotocin-induced β-cell damage

Q3 · BIOLOGY

Article

Author: Zhang, Tianhao ; Wang, Xudong ; Li, Shu Jie ; Wang, Yuzhou ; Qin, Jiwei ; Lv, Jili ; Xi, Wang

Reactive oxygen species (ROS) impairs pancreatic β-cells and plays an important role in development of diabetes. Streptozotocin (STZ) can lead to β-cell dysfunction via inducing ROS production. The voltage-gated proton channel Hv1 contributes a majority of the charge compensation required for ROS production. Here, we investigated the effects of Hv1 on STZ-induced β-cell damage. We found that deficiency of Hv1 obviously inhibits STZ-induced glucose intolerance in mice, and prevents the decrease in β-cell mass and pancreatic insulin content from STZ-treatment. Further studies showed that loss of Hv1 significantly attenuates STZ-induced β-cell damage and ROS production in pancreatic β-cells. Our results suggest that Hv1 might contribute to development of diabetes through producing ROS.

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Indication	Highest Phase	Country/Location	Organization	Date
Blood Coagulation Disorders	Discovery	JP	Japan Energy, Inc.	-

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