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World Journal of Diabetes 2022年第6期13卷 434-441页

作者： Arjun Jain Kristof Bozovicar Vidhi Mehrotra Tomaz Bratkovic Martin H Johnson Ira Jha ET-Traps Limited Cambridge CB30JEUnited Kingdom Department of Physiology Development and NeuroscienceUniversity of CambridgeCambridge CB23DYUnited Kingdom Accelerate Cambridge Judge Business SchoolUniversity of CambridgeCambridge CB21AGUnited Kingdom Department of Pharmaceutical Biology Faculty of PharmacyUniversity of LjubljanaSlovenia 1000Slovenia

BACKGROUND endothelin(ET)-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1.Previous work has shown that use of the selected ET-traps potently and significantly reduces different markers of diabetes pathology back to normal,non-disease levels.AIM To demonstrate the selected ET-traps potently and significantly bind to ET-1.METHODS We performed phage display experiments to test different constructs of ET-traps,and conducted bio-layer interferometry binding assays to verify that the selected ET-traps bind specifically to ET-1 and display binding affinity in the double-digit picomolar range(an average of 73.8 rM,n=6).RESULTS These experiments have confirmed our choice of the final ET-traps and provided proof-of-concept for the potential use of constructs as effective biologics for diseases associated with pathologically elevated ET-1.CONCLUSION There is increased need for such therapeutics as they could help save millions of lives around the world.

关键词： endothelin-1 endothelin-traps Diabetes Heart failure Chronic kidney disease Novel therapeutic

Serum and lung endothelin-1 increased in a canine model of ventilator-induced lung injury

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Chinese Medical Journal 2010年第8期123卷 1021-1027页

作者： LAI Tian-shun CAI Shao-xi GUO Zhen-hui Department of Respiratory Medicine Nanfang Hospital Affiliated to Nanfang Medical University Guangzhou Guangdong 510515 China Department of Medical Intensive Care Unit Guangzhou General Hospital of Guangzhou Military Command Guangzhou Guangdong 510010 China

Background Nitric oxide （NO） plays an important role in acute lung injury （ALl）, acute respiratory distress syndrome （ARDS）, and in ventilator-induced lung injury （VILI）. A change in the balance of endothelin-1 （ET-1） and NO in the ALI/ARDS can also add to these problems. However, the profile of ET-1 and the balance of ET-1 and NO are still unknown in a VILI model. Methods Models of oleic acid induced ALl were established in dogs; these models were then randomized into three groups undergone different tidal volume （VT） mechanical ventilation, which included a VT6 group （VT equaled to 6 ml/kg body weight, positive end expiratory pressure （PEEP） equaled to 10 cmH20, n=-6）, a VT10 group （VT equaled to 10 ml/kg body weight, PEEP equaled to 10 cmH20, n=-4） and a VT20 group （VT equaled to 20 ml/kg body weight, PEEP equaled to 10 cmH20, n=-6） for 6-hour ventilation. The levels of ET-1 and NO in serum and tissue homogenates of lung were observed throughout the trial. Results PaO2 was increased after mechanical ventilation, but hypercapnia occurred in the VT6 group. The magnitudes of lung injury in the VT20 group were more severe than those in the VT6 group and the VT10 group. Serum levels of ET-1 and NO increased after ALl models were established and slightly decreased after a 6-hour ventilation in both the VT6 group and the VT20 group. The serum ET-1 level in the VT20 group was higher than that in the VT6 group and the VT10 group after the 6-hour ventilation （P 〈0.05） while the serum NO levels were similar in the three groups （all P 〉0.05）. There was no significant difference in serum ratio of ET-1/NO between any two out of three groups （P 〉0.05）, although there was a significant positive relationship between serum ET-1 and serum NO （r=0.80, P 〈0.01）. The levels of ET-1 and NO in the lung were increased after ventilation. The lung ET-1 level in the VT20 group was significantly higher than that in the VT6 group and VT10 group （both P 〈0.05） while there was no significant difference in lung NO levels between two groups （P

关键词： acute lung injury tidal volume positive end expiratory pressure hypercapnia nitric oxide endothelin-1 ventilator-induced lung injury

Effects of endothelin-1 on differentiation of cardiac myocyte induced from rabbit bone marrow stromal cells

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Chinese Medical Journal 2006年第10期119卷 832-839页

作者： DONG Hong-yan ZHANG Zhong-ming ZHOU Zhong-xin Centre of Neurobiological Research Xuzhou Medical CollegeXuzhou 221002 China Department of Thoracic Cardiovascular Surgery AffiliatedHospital of Xuzhou Medical College Xuzhou 221002 China

Background Cardiomyocyte transplantation for the therapy of myocardial ischaemia is being paid close attention. However, how the microenvironment controls the differentiation of transplanted bone marrow stromal cells （BMSCs） is unknown. endothelin-1 （ET-1）, a cytokine, increases during myocardial infarction, but it is not known whether ET-1 is responsible for the fate of transplanted BMSCs. In the present study, we investigated the effects of ET-1 on differentiation and maturation of induced rabbit BMSCs, in vitro, to elucidate the cellular biological mechanisms.

关键词： bone marrow stromal cells endothelin-1 differentiation cell culture

Taurine protects against retinal and optic nerve damage induced by endothelin-1 in rats via antioxidant effects

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Neural Regeneration Research 2018年第11期13卷 2014-2021页

作者： Natasha Najwa Nor Arfuzir Renu Agarwal Igor Iezhitsa Puneet Agarwal Sabrilhakim Sidek Nafeeza Mohd Ismail Center for Neuroscience Research Faculty of MedicineUniversiti Teknologi MARA Sungai Buloh Campus Volgograd State Medical University Research Institute of Pharmacology Faculty of Medicine International Medical UniversityIMU Clinical School

endothelin-1（ET-1）, a potent vasoconstrictor, is involved in retinal vascular dysregulation and oxidative stress in glaucomatous eyes. Taurine（TAU）, a naturally occurring free amino acid, is known for its neuroprotective and antioxidant properties. Hence, we evaluated its neuroprotective properties against ET-1 induced retinal and optic nerve damage. ET-1 was administered intravitreally to Sprague-Dawley rats and TAU was injected as pre-, co-or post-treatment. Animals were euthanized seven days post TAU injection. Retinae and optic nerve were examined for morphology, and were also processed for caspase-3 immunostaining. Retinal redox status was estimated by measuring retinal superoxide dismutase, catalase, glutathione, and malondialdehyde levels using enzyme-linked immuosorbent assay. Histopathological examination showed significantly improved retinal and optic nerve morphology in TAU-treated groups. Morphometric examination showed that TAU pre-treatment provided marked protection against ET-1 induced damage to retina and optic nerve. In accordance with the morphological observations, immunostaining for caspase showed a significantly lesser number of apoptotic retinal cells in the TAU pre-treatment group. The retinal oxidative stress was reduced in all TAU-treated groups, and particularly in the pre-treatment group. The findings suggest that treatment with TAU, particularly pre-treatment, prevents apoptosis of retinal cells induced by ET-1 and hence prevents the changes in the morphology of retina and optic nerve. The protective effect of TAU against ET-1 induced retinal and optic nerve damage is associated with reduced retinal oxidative stress.

关键词： endothelin-1 retina optic nerve taurine oxidative stress

Differential modulation of bradykinin-induced relaxation of endothelin-1 and phenylephrine contractions of rat aorta by antioxidants

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Acta Pharmacologica Sinica 2007年第10期28卷 1566-1572页

作者： Ogechukwu ANOZIE Richonda ROSS Adebayo O OYEKAN Momoh A YAKUBU Vascular Biology UnitCenter for Cardiovascular Diseases College of Pharmacy and Health Sciences Texas Southern University Houston Texas 77004 USA

Aim:We tested the hypothesis that bradykinin （BK）-induced relaxation of phe-nylephrine （PE） and endothelin-1 （ET-1） contractions can be differentially modu-lated by reactive oxygen species （ROS）.Methods:Aortic rings isolated fromSprague-Dawley rats were used for the study.The contribution of ROS to PE(1×10-9-1×10-5mol/L)-and ET-1 (1×10-10-1×10-8mol/L)-induced contractions andthe influence of ROS in BK (1×10-9-1×10-5mol/L) relaxation of PE (1×10-7mol/L) orET-1 (1×10-9mol/L)-induced tension was evaluated in the aorta in the presence orabsence of the following antioxidants:catalase （CAT,300 U/mL）,superoxidedismutase （SOD,300 U/mL）,and vitamin C (1×10-4mol/L).Results:Tension gen-erated by ET-1 (1×10-9mol/L) or PE (1×10-7mol/L) was differentially relaxed by BK(1×10-5mol/L),producing a maximal relaxation of 75%±5% and 35±4%,respectively.The BK (1×10-5mol/L)-induced relaxation of PE (1×10-7mol/L) tension was signifi-cantly enhanced from 35%±4% （control） to 56%±9%,60%±5%,and 49%±6% bySOD,CAT,and vitamin C,respectively （P1 (1×10-9mol/L) tension was significantly attenuated from 75%±5% （control）to 37%±9%,63%±4%,and 39%±7% by SOD,CAT,and vitamin C,respectively（P10） and vitamin C attenuated（66%,P1.Conclusion:We have demonstrated that O2-and H2O2differentially modulate BKrelaxation in an agonist-specific manner.O2-attenuates BK-induced relaxation ofPE contraction,but contributes to the relaxation of ET-1 contraction.O2-seems toinhibit PE contraction,while H2O2contributes to ET-1-induced contraction.Thus,ROS differentially modulate vascular tone depending on the vasoactive agentthat is used to generate the tone.

关键词： bradykinin endothelin-1 phenylephrine reactive oxygen species superoxide hydrogen peroxide relaxation contraction antioxidants

Effect of Lycium barbarum Polysaccharides on the expression of endothelin-1 and its receptors in an ocular hypertension model of rat glaucoma

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Neural Regeneration Research 2012年第9期7卷 645-651页

作者： Xue-Song Mi Kin Chiu Geoffrey Van Justin Wai Chung Leung Amy Cheuk Yin Lo SookjaKim Chung Raymond Chuen-Chung Chang Kwok-Fai So Department of Anatomy and the State Key Laboratory of Brain and Cognitive Science Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina Eye Institute Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina Research Centre of Heart BrainHormone and Healthy AgingLi Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina The Joint Laboratory for Brain Function and Health （BFAH） Jinan University and The University of Hong Kong Guangzhou 510632Guangdong Province China

Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells （RGCs） in a rat chronic ocular hypertension （COH） model. Here, we investigated the expression of endothelin-1 （ET-1）, a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis. Elevated intraocular pressure （IOP） was induced in the right eye of SD rats using argon laser photocoagulation. （1） The expression of ET-1, ETA and ETB in normal and COH retinas was studied. （2） Some COH rats were fed daily with Lycium barbarum Polysaccharides （LBP） using 1 mg/kg or phosphate-buffered saline （PBS） for 3 weeks （started 1 week before photocoagulation）. The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated. A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET-1, ETA and ETB in retinal vasculature. We found that （1） Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity. （2） After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs. （3） By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB. In summary, ET-1 expression was up-regulated in the retina in COH model. LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH. The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature.

关键词： retinal ganglion cell Lycium barbarum Polysaccharides glaucoma endothelin-1

Tanshinone IIA inhibits endothelin-1 production in TNF-α-induced brain microvascular endothelial cells through suppression of endothelin-con-verting enzyme-1 synthesis

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Acta Pharmacologica Sinica 2007年第8期28卷 1116-1122页

作者： Chao TANG~1 An-hua WU~(1,3) Hong-li XUE~2 Yurl-jie WANG~1 ~1Department of Neurosurgery,the First Affiliated Hospital,China Medical University ~2Department of Neurosurgery,General Hospital of Shenyang Military Command,Shenyang 110001,China. Department of Neurosurgery the First Affiliated Hospital China Medical University Shenyang China Department of Neurosurgery General Hospital of Shenyang Military Command Shenyang China

Aim:To investigate the effects of tanshinone ⅡA（Tan ⅡA）on the regulation ofthe production of endothelin（ET）-1（including large ET-1）,mRNA levels of ET-1,endothelin-converting enzyme-1（ECE-1）,endothelin-A receptor（ETA）andendothelin-B receptor（ETB）induced by TNF-α in rat brain microvascular endo-thelial cells（BMVEC）.Methods:The ET-1 release（including large ET-1）into theculture medium was determined by enzyme immunoassay.The levels of ET-1,ECE- 1,ETA,and ETBmRNA were measured by RT-PCR.endothelin receptor bind-ing was also tested.Results:The induction of ET-1 release by TNF-α from cul-tured BMVEC was dose-dependently reduced by Tan IIA,but large ET-1 levelsprogressively increased in response to Tan ⅡA;the mRNA expression of ET-1 wasunaffected.Tan ⅡA also caused a decrease in ETAreceptor mRNA and ECE-1expression in a dose-dependent manner.endothelin receptor binding was unal-tered in BMVEC stimulated with TNF-α alone or a combination of TNF-α and TanⅡA.Conclusion:These findings suggest that Tan ⅡA may inhibit ET-1 produc-tion in TNF-α-induced BMVEC through the suppression of ECE-1 synthesis.

关键词： tanshinone IIA endothelin-1 TNF-α brain microvascular endothelial cells

Downregulation of endothelin-1 by somatostatin improves liver function of recipients undergoing adult-to-adult living donor liver transplantation

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Chinese Medical Journal 2010年第15期123卷 1961-1966页

作者： FENG Zhi-ying XU Xiao WU Ling-jiao WU Jian ZHU Sheng-mei ZHENG Shu-sen Department of Anesthesiology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310003China Division of Hepatobiliary and Pancreatic Surgery Department of Surgery the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310003China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases Institute of Infectious Diseases the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310003China

Background The aim of this study was to investigate the possible effect of somatostatin on the liver function of recipients undergoing living donor liver transplantation.Methods Forty recipients were randomized into group A （n=20） and group B （n=20）. Recipients in group A received no somatostatin whereas somatostatin was administrated for recipients in group B perioperatively. Liver function, the plasma concentration of endothelin-1 and nitric oxide, the intragraft expressions of endothelin-1 and inducible nitric oxide syntheses at 2 hours after declamping of the portal vein were compared between the two groups.Results Compared to group A, alanine transaminase values in group B were significantly reduced at 2 hours after portal vein declamping, at the end of the operation and postoperation day 1 （P 〈0.05）, whereas aspartate aminotransferase values in group B decreased at 30 minutes after portal vein clamping, at 2 hours after portal vein declamping and at the end of the operation （P 〈0.05）. Total bilirubin values in group B were reduced significantly at 2 hours after portal vein declamping and at the end of the operation when compared to group A （P 〈0.05）. Intragraft expression of endothelin-1 was significantly downregulated at 2 hours after declamping of the portal vein accompanied with a reduction of plasma concentration of endothelin-1 in the peripheral blood （P 〈0.05）.Conclusions Somatostatin had a protective effect on liver function during the early phase after declamping of portal vein for recipients undergoing living donor liver transplantation, and the possible mechanism might be partially attributed to the downregulation of endothelin-1.

关键词： somatostatin endothelin-1 liver function tests liver transplantation

Perihematomal endothelin-1 level is associated with an increase in blood-brain barrier permeability in a rabbit model of intracerebral hematoma

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Chinese Medical Journal 2013年第18期126卷 3433-3438页

作者： WANG Li-kun HONG Zhen WU Guo-feng LI Chang Department of Neurology Affiliated Huashan Hospital of Fudan University Shanghai 200036 China Department of Neurology Affiliated Hospital of Guiyang Medical University Guiyang Guizhou 550004 China

Background endothelin-1 （ET-1） has deleterious effects on water homeostasis, cerebral edema, and blood-brain barrier （BBB） integrity. Highly expressed ET-1 was observed after intracerebral hemorrhage （ICH）; however, ET-1 changes and their relationship with BBB disruption within 24 hours of ICH have not been thoroughly investigated. The aim of the present study was to observe the changes in perihematomal ET-1 levels in various phases of ICH and their correlation with the BBB integrity in a rabbit model of ICH. Methods Twenty-five rabbits （3.2-4.3 kg body weight） were randomly divided into a normal control group （five rabbits） and a model group （20 rabbits）. Animals in the model group were equally divided into four subgroups （five rabbits each to be sacrificed at 6, 12, 18, and 24 hours following ICH establishment）. An ICH model was prepared in the model group by infusing autologous arterial blood into the rabbit brain. ET-1 expression in perihematomal brain tissues was determined using immunohistochemistry and color image analysis, and the permeability of the BBB was assayed using the Evan＇s Blue （EB） method. A repeated measures analysis of variance was used to make comparisons of the ET-1 and EB content across the entire time series. Results The number of perihematomal endothelial cells with ET-1 positive expressions following 6, 12, 18, and 24 hours ICH model establishment was 9.32, 13.05, 15.90, and 20.44, respectively, but as low as 6.67 in the control group. The average transmittance of ET-1-positive cell bodies at 6, 12, 18, and 24 hours after ICH was 99.10, 97.40, 85.70, and 80.80, respectively, but 100.12 in the control group. These data reveal that the expression of ET-1 was significantly increased at 6, 12, 18, and 24 hours after ICH compared with the control group, and a marked decrease in the average transmittance of ET-l-positive cell bodies was noted （P 〈0.05）. Similarly, the perihematomal EB content at 6, 12, 18, and 24 hours after ICH was 29.39±1.16, 32.20±0.73, 33.63±1.08, and 35.26±1.12, respecti

关键词： intracerebral hemorrhage endothelin-1 blood-brain barrier Evan＇s blue brain edema

Effect of Electroacupuncture Stimulation on mRNA Expression of Angiotensinogen,Angiotensin Ⅱ Type 1 Receptor,endothelin-1,and endothelin A Receptor in Spontaneously Hypertensive Rat Aorta

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Chinese Journal of Integrative Medicine 2016年第10期22卷 778-782页

作者：霍则军李东郭佳李赛丁宁李志新 Department of Traditional Chinese Medicine the Third Hospital of Peking University Department of Integration of Chinese and Western Medicine Peking University Health Science Center

Objective： To observe the effect of electroacupuncture （EA） stimulation on the expressions of angiotensinogen （AGT）, angJotensin Ⅱ type 1 receptor （ATIR）, endothelin-1 （ET1）, and endothelin A receptor （ETAR） mRNA in spontaneously hypertensive rat （SHR） aorta. Methods： Eighteen male SHRs were randomly divided into three groups, an SHR group, an SHR Baihui （DU 20） and Zusanli （ST 36） acupoint （SHR-AP） group, and an SHR non-acupoJnt （SHR-NAP） group, with 6 rats in each group. Six Wistar rats were used as a control. Rats in the SHR-AP group were stimulated by DU 20 and ST 36 acupoints, both of which were connected with EA. EA was handled one time every Monday, Wednesday and Friday, for total 24 times （8 weeks）. SHR- NAP rats were acupointed at a 15° angle flat into 0.5 cm to two points, which were 1 and 2 cm from rail tip separately. EA parameters were the same as the SHR-AP rats. SHR control rats and Wistar rats were fixed without EA. Real-time quantitative polymerase chain reaction （PCR） was used to measure AGT, AT1 R, ET1, and E-TAR mRNA expression in rat aorta. Results： EA stimulation significantly reduced rat aorta vascular AGT, ET1, ETAR and AT1R mRNA expressions in the SHR-AP and SHR-NAP groups （P〈0.01）. Among these four genes, ATIR mRNA expression was significantly lower in the SHR-AP than in the SHR-NAP group （P〈0.01）. Conclusion： EA could reduce the ATIR mRNA expression in SHR-AP rat aorta, indicating a potential mechanism for the hypotensive effects of EA.

关键词： electricacupunture angiotensinogen angiotensin Ⅱ type 1 receptor endothelin-1 endothelin-1A receptor