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Molecular mechanism of endocrine-disruptive effects induced by Bisphenol A:The role of transmembrane G-protein estrogen receptor 1 and integrin αvβ3

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Journal of Environmental Sciences 2019年第1期31卷 1-13页

作者： Zhiguo Sheng Cong Wang Furong Ren Yuxiang Liu Benzhan Zhu Research Center for Eco-Environmental Sciences Chinese Academy of Sciences University of Chinese Academy of Sciences College of Chemistry and Chemical Engineering Xinjiang Normal University

Bisphenol A(BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy ***, general population has been widely exposed to BPA due to extensive use of BPAcontaining products. BPA has similar chemical structure with the natural estrogen and has been shown to induce a variety of estrogen-like endocrine effects on organism in vivo or in vitro. High doses of BPA tend to act as antagonist of estrogen receptors(ERs) by directly regulating the genomic transcription. However, BPA at environmentally relevant low-dose always disrupt the biological function via a non-genomic manner mediated by membrane receptors, rather than ERs. Although some studies had investigated the non-genomic effects of low-dose BPA, the exact molecular mechanism still remains unclear. Recently, we found that membrane G protein-coupled estrogen receptor 1 and integrin αvβ3 and its relative signal pathways participate in the induction of male germ cell proliferation and thyroid transcription disruption by the low-dose BPA. A profound understanding for the mechanism of action of the environmentally relevant BPA exposure not only contributes to objectively evaluate and predict the potential influence to human health, but also provides theoretical basis and methodological support for assessing health effects trigged by other estrogen-like environmental endocrine disruptors. Based mainly on our recent findings, this review outlines the research progress of molecular mechanism on endocrine disrupting effects of environmental low-dose BPA, existing problems and some consideration for future studies.

关键词： Bisphenol A Low-dose effects G protein-coupled estrogen receptor 1 integrin αvβ3 Reproductive toxicity Thyroxine interference effect

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Ischemic preconditioning partially suppresses and postpones integrin α_vβ_3 mRNA expression following transient global cerebral ischemia in C57BL/6 mice

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Neural Regeneration Research 2010年第23期5卷 1782-1786页

作者： Mei Liu Xiaomeng Ma Xiaohong Chen Ying Jiang Aimin Wu Fuhua Peng Yingying Liu Rongbiao Pi Department of Neurology the Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510630 Guangdong Province China Department of Pharmacology and Toxicology School of Pharmaceutical Sciences Sun Yat-sen University Guangzhou 510020 Guangdong Province China

Previous studies of integrin αvβ3 have focused on ischemic brain damage, although the role of integrin αvβ3 in ischemic preconditioning （IP） has rarely been reported. The present study analyzed the effects of IP on integrin αvβ3 mRNA expression following cerebral ischemia through the use of hematoxylin-eosin staining and real-time quantitative polymerase chain reaction techniques. integrin avid3 mRNA expression in the ischemia group peaked at 24 hours after ischemia-reperfusion. In the IP ＋ ischemia group, integrin αvβ3 mRNA expression increased after 24 hours, but remained significantly less than the ischemia group, and expression continued to increase until 7 days after ischemiaJreperfusion. These results demonstrate that IP effectively attenuated upregulation of integrin αvβ3 mRNA expression at 24 hours after ischemia.

关键词： integrin αvβ3 ischemic preconditioning ischemic tolerance global cerebral ischemia blood-brain barrier: mice

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Lack of association between integrin αvβ3 gene polymorphisms and hemorrhagic fever with renal syndrome in Han Chinese from Hubei, China

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virologica Sinica 2017年第1期32卷 73-79页

作者： Xiao-Ping Chen Hai-Rong Xiong Ni Zhu Qing-Zhou Chen Hui Wang Chao-Jie Zhong Mei-Rong Wang Shuang Lu Fan Luo Wei Hou State Key Laboratory of virology Institute of Medical Virology School of Basic Medical Sciences Wuhan University

Hantaviruses belong to the family Bunyaviridae and cause hemorrhagic fever with renal syndrome （HFRS） in humans. 133 integrins, including αvβ3 and αⅡbβ3 integrins, act as receptors on endothelial cells and play key roles in cellular entry during the pathogenesis of hantaviruses. Previous study demonstrated that the polymorphisms of integrin αⅡbβ3 are associated with susceptibility to hantavirus infection and the disease severity of HFRS in Shaanxi Province of China, rather than in Finland. However, the polymorphisms of integrin av133 in patients with HFRS was incompletely understood. Here, we aimed to investigate the associations between polymorphisms in human integrin αvβ3 and HFRS in Han Chinese individuals. Ninety patients with HFRS and 101 healthy controls were enrolled in this study. Analysis of five single nucleotide polymorphism （SNP） sites （rs3768777 and rs3738919 on ITGAv; rs13306487, rs5921, and rs5918 on ITGB3） was performed by TaqMan SNP genotyping assays and bi-directional PCR allele-specific amplification method. No significant differences were observed between the HFRS group and controls regarding the genotype and allele frequency distributions of any of the five SNP sites, and no associations were found between ITGAv polymorphisms/genotypes and disease severity. In conclusion, our results implied that these five SNPs in the integrin αvβ3 gene were not associated with HFRS susceptibility or severity in Han Chinese individuals in Hubei Province.

关键词： hemorrhagic fever with renal syndrome (HFRS) polymorphisms hantavirus integrin αvβ3

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Effects of integrins and integrin αvβ3 Inhibitor on Angiogenesis in Cerebral Ischemic Stroke

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第3期34卷 299-305页

作者：毕佳佳易黎 Department of Neurology Peking University Shenzhen Hospital

Summary： integrins such as αvβ3, α5β31 play a key role in angiogenesis regulation, invasion and metastasis, inflammation, wound healing, etc. The up-regulation of integrin αvβ3 after cerebral ischemic stroke can promote angiogenesis, which in turn improves functional recovery. In addition, the integrin αvβ3 inhibitor can block the blood-brain barrier （BBB） leakage induced by vascular endothelial growth factor （vEGF） and also can reduce inflammatory reaction, decrease the deposition of fibrinogen. Other studies showed that integrin αvβ3 is not essential in revascularization. Therefore, the effect of integrin αvβ3 in the whole process of brain function recovery merits further study.

关键词： integrin αvβ3 cerebral ischemic stroke vascular endothelial growth factor cyclo[Arg-Gly-Asp-D-Phe-val]

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Implication of Expression of Osteopontin and Its Receptor integrin αvβ3 in the Placenta in the Development of Preeclampsia

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2009年第6期29卷 755-760页

作者：夏俊霞乔福元苏放明刘海意 Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Department of Obstetrics Shenzhen People’s Hospital the Second Clinical Medical College of Jinan University

To investigate the expression of osteopontin （OPN） and its receptor integrin αvβ3 in the placental tissue from pregnant women complicated with preeclampsia, the expression of OPN and αvβ3 in the placenta of the pregnant women with preeclampsia and healthy pregnant women was detected by immunohistochemistry, Western blotting and RT-PCR. Our results showed that OPN and αvβ3 protein were expressed in the placenta from normal pregnant woman and those with preeclampsia. OPN was located in the placental syncytiotrophoblasts and the cytoplasm of capillary endothelial cells and integrin αvβ3 was mainly expressed on the surface of trophoblast cells. Expression of OPN and integrin αvβ3 in the placental tissue from preeclampsia subjects was significantly lower than that from the control group （P〈0.05）. Compared with the control group, expression of OPN in the placental tissue from preeclampsia group was significantly lower （P〈0.05） but there was no significant difference in the expression of αv and β3 between the preeclampsia group and the controls. It is concluded that OPN and its receptor integrin αvβ3 may be involved in the pathogenesis of preeclampsia.

关键词： osteopontin integrin αvβ3 placenta preeclampsia

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Design and Preliminary Activity Determination of anti-tumor peptides targeting integrin αvβ3

Design and Preliminary Activity Determination of anti-tumor ...

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中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年

作者： ZHAO Qi YANG Tao LU Pei-fen YANG Li-jun Department of Pharmacology Shanxi Medical University

Objective Design a couple of RGD loop-containing peptides on the basis of the structure of echistatin and evaluate the preliminary activity. Methods The peptides were designed based on the spatial structure of echistatin with combination of other reports. The preliminary activity of the peptides was analyzed using MTT. The expression of integrin αvβ3 in five colorectal cancer cells was analyzed by Western blot. Results Six peptides(cEchi-L-1, cEchi-L-2, Ω-Echi, Echi-L, cEchi-M and cEchi) were designed and synthesized. Among them, cEchi-L-1 and cEchi-L-2 exhibited antitumor activity, and their IC50 were 59.92 μmol/L and 18.33 μmol/L, respectively. Conclusion Two peptides with a certain anti-tumor activity were found, the results indicate that the quantity of amino acids between the RGD loops and the C-terminal of echistatin may play a role on the anti-tumor activity of the peptidemimetics.

关键词： integrin αvβ3 RGD loop Echistatin Colorectal cancer

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BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK

BKCa promotes growth and metastasis of prostate cancer throu...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青年科学家论坛

作者： Cheng Du Zhendong Zheng Na Li Li Chen Yang Yang Fang Guo Wenchao Liu Xiaodong Xie Manjiang Xie Department of Oncology General Hospital of Shenyang Military Area Command Department of Oncology Xijing HospitalFourth Military Medical University Key Laboratory of Aerospace Medicine Ministry of EducationFourth Military Medical University Department of Gynaecology and Obstetrics First Affiliated HospitalJilin University

BKCa is a large conductance calcium activated potassium channel involved in prostate cancer cell proliferation. The coding gene of BKCa is amplified in nearly 16% of advanced prostate cancer, although its clinical relevance is not fully elucidated. In addition, whether BKCa participates in the metastatic processes of prostate cancer and how it promotes prostate cancer progression remains to be explored. Here, we report that BKCa is overexpressed in prostate cancer and its expression is positively correlated with Ki67 index and clinical stage of prostate cancer. Upregulation of BKCa promoted proliferation, migration and invasion of prostate cancer cells, whereas downregulation of BKCa inhibited the proliferative and metastastic potential of prostate cancer cells both in vitro and in vivo. Moreover, the ion-conducting function of BKCa contributed partially to prostate cancer proliferation and migration, however, it was not the main driving force. BKCa action seemed to be mainly mediated through forming a functional complex with integrin αvβ3. The BKCa/αvβ3 complex regulates the phosphorylation of focal adhesion kinase(FAK) independent of the channel activity. Overexpression of BKCa enhanced its association with αvβ3 and FAK, and subsequently increased the phosphorylation of FAK. Conversely, disrupting the complex by downregulation of BKCa resulted in a reduction of phosphorylated FAK. Finally, BKCa-enhanced cell proliferation and migration were markedly abrogated upon the treatment of either integrin αvβ3 blocking antibody LM609 or FAK specific inhibitor Y15. Taken together, these results suggest that targeting BKCa/αvβ3/FAK may inaugurate innovative approaches to inhibit prostate cancer growth and metastasis.

关键词： BKCa prostate cancer proliferation metastasis integrin αvβ3 FAK

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Ischemic preconditioning protects against ischemic brain injury

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Neural Regeneration Research 2016年第5期11卷 765-770页

作者： Xiao-meng Ma Mei Liu Ying-ying Liu Li-li Ma Ying Jiang Xiao-hong Chen Department of Neurology the Third Affiliated Hospital of Sun Yat-sen University

In this study, we hypothesized that an increase in integrin αβand its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αβ, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αβand vascular endothelial growth factor levels in the brain following ischemia.

关键词： nerve regeneration brain injury integrin αvβ3 vascular endothelial growth factor vascular endothelial growth factor receptor vascular endothelial growth factor receptor-2 fetal liver kinase 1 ischemic preconditioning ischemic tolerance global cerebral ischemia cerebral ischemia cerebral infarction NSFC grant neural regeneration

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Radiolabeled cyclic RGD peptides as radiotracers for tumor imaging

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Biophysics Reports 2016年第1期2卷 1-20页

作者： Jiyun Shi Fan Wang Shuang Liu Interdisciplinary Laboratory Institute of BiophysicsChinese Academy of Sciences Medical Isotopes Research Center Peking University School of Health Sciences Purdue University

The integrin family comprises 24 transmembrane receptors, each a heterodimeric combination of one of 18 α and one of 8 β subunits. Their main function is to integrate the cell adhesion and interaction with the extracellular microenvironment with the intracellular signaling and cytoskeletal rearrangement through transmitting signals across the cell membrane upon ligand binding. integrin αβis a receptor for the extracellular matrix proteins containing arginine–glycine–aspartic(RGD) tripeptide *** αβis generally expressed in low levels on the epithelial cells and mature endothelial cells, but it is highly expressed in many solid tumors. The αβlevels correlate well with the potential for tumor metastasis and aggressiveness, which make it an important biological target for development of antiangiogenic drugs, and molecular imaging probes for early tumor diagnosis. Over the last decade,many radiolabeled cyclic RGD peptides have been evaluated as radiotracers for imaging tumors by SPECT or PET. Even though they are called ’αβ-targeted’ radiotracers, the radiolabeled cyclic RGD peptides are also able to bind αβ, αβ, αβ, αβ, and αβintegrins, which may help enhance their tumor uptake due to the "increased receptor population." This article will use the multimeric cyclic RGD peptides as examples to illustrate basic principles for development of integrin-targeted radiotracers and focus on different approaches to maximize their tumor uptake and T/B ratios. It will also discuss important assays for pre-clinical evaluations of the integrin-targeted radiotracers, and their potential applications as molecular imaging tools for noninvasive monitoring of tumor metastasis and early detection of the tumor response to antiangiogenic therapy.

关键词： integrin αvβ3 PET and SPECT radiotracers Tumor imaging

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IvF促排卵周期取卵日前血清高孕酮浓度对着床期子宫内膜腔上皮黏附分子表达的影响

IVF促排卵周期取卵日前血清高孕酮浓度对着床期子宫内膜腔上皮黏...

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作者：王央央浙江大学

学位级别：硕士

背景我们在前期工作中统计分析了2011年1月至2013年5月间所有于本生殖中心行IvF/ICSI的全部5828例促排卵周期资料。注射hCG日和/或注射hCG次日高孕酮均使鲜胚移植未妊娠周期数增加,这提示妊娠丢失发生在胚胎着床的最初期阶段,从而表现... 详细信息

背景我们在前期工作中统计分析了2011年1月至2013年5月间所有于本生殖中心行IvF/ICSI的全部5828例促排卵周期资料。注射hCG日和/或注射hCG次日高孕酮均使鲜胚移植未妊娠周期数增加,这提示妊娠丢失发生在胚胎着床的最初期阶段,从而表现为未妊娠周期数的增加。我们推测,注射hCG日及注射hCG次日高孕酮可能诱导了LE功能的改变,高孕酮可能导致了LE与囊胚间的粘附力下降,从而降低了内膜容受性。子宫内膜不同类型细胞的特殊功能及在内膜容受性建立过程中可能有不同的角色,从hCG日和/或hCG次日孕酮升高与种植窗期子宫内膜腔上皮黏附分子表达水平的关系这一点切入的研究未见报道。目的探讨取卵日前孕酮浓度、与常见粘附分子,Intergrin avP3, Osteopoton, Mucin16间在着床期子宫内膜腔上皮表达量间的相关性。探讨IvF促排卵周期取卵日前过早的孕酮升高,是否与着床期子宫内膜腔上皮常见粘附分子表达的异常有相关性。方法本研究所使用的内膜样本,来自于2013年7月-2014年12月间于浙江大学医学院附属邵逸夫医院生殖中心开展的一项为单中心,前瞻性队列研究中所收集的内膜样本。研究期间,医学院附属邵逸夫医院生殖中心的鲜胚移植策略：仅患者获卵数≦15枚,注射hCG日孕酮≦2.0 ng/ml,且无卵巢过度刺激(ovarian hyperstimulation syndrome, OHSS)倾向等条件均同时满足的前提下,方可进行新鲜胚胎移植。否则,建议患者考虑全部新鲜胚胎冷冻,择期行冻融胚胎移植。40名患者均从按照本中心已建立的新鲜胚胎移植策略选择进行全部胚胎冷冻的患者中选取。为模拟新鲜胚胎在体内的环境,在获取所有患者知情同意之后,取卵术后仍按照本中心常规黄体支持方案给予肌注黄体酮(40 mg im bid,仙居制药厂),于注射hCG+7天使用一次性宫腔组织吸取管(Prodimed, France)自宫腔内轻柔吸取内膜组织。获取内膜组织后,立即将其置入10%中性福尔马林中室温固定24-48小时后,按照标准方法进行石蜡包埋。所有患者均签署知情同意书。所有研究对象均于注射hCG日及注射hCG次日的清晨采取血样检测血清雌二醇浓度和孕酮浓度。根据2011年-2013年间本中心的5828个IvF刺激周期注射hCG日及注射hCG次日血清孕酮浓度数据,将孕酮浓度“升高”定义为孕酮值高于整体孕酮值分布的90%百分位数,未能达到此标准则定义为孕酮浓度“正常”。由此,注射hCG日孕酮正常或升高的cut-off值为1.7 ng/ml;注射hCG次日孕酮正常或升高的cut-off值为9.5 ng/ml。本研究共包括了40位患者,其中20例为从既往获得的取卵日前孕酮均正常的内膜样本中随机挑选,另20例为从既往获得的取卵日前孕酮升高的内膜样本中随机挑选。所有40例样本,均依据Noyes et al(1950)进行组织形态学评分,并依据h—score评分方法进行粘附分子integrin αvβ3, OPN, Mucin 16在内膜腔上皮表达的半定量分析。所有评分均由2位经验丰富的观察者按照盲法独立完成。H-score评分方法：H-score=ΣPi (i+1),i代表染色密度(1=弱,2=中和3=强),Pi代表细胞每种染色密度的百分比(0-100%).计算腔上皮的H-scores评分。每张切片由两位观察者分别独立评分。若两位观察者所得的评分结果有差异,则由两位观察者再次重新读片并讨论以获得最终结果。结果1.孕酮升高组OPN在腔上皮的表达(3.44±0.58)较孕酮正常组(3.42±0.6)升高,但无统计学差异(P>0.05)。2.孕酮升高组αvβ3在腔上皮的的表达(2.73±1.35)较孕酮正常组(2.47±1.33)升高,但无统计学差异(P>0.05)。3.孕酮升高组MUC16在腔上皮的的表达(3.54±0.77)较孕酮正常组(2.51±1.19)升高,有统计学差异(PvF刺激周期中注射hCG日及注射hCG次日血清孕酮升高与着床期内膜腔上皮抗粘附因子Mucin16的表达升高有相关性,高孕酮可能导致着床期内膜腔上皮粘附功能下降。

关键词：孕酮粘附分子/osteopontin mucin16 integrin αvβ3 IvF

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