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integrins and their potential roles in mammalian pregnancy

Journal of Animal Science and Biotechnology 2024年第1期15卷 1-19页

作者： Gregory A.Johnson Robert C.Burghardt Fuller W.Bazer Heewon Seo Joe W.Cain Department of Veterinary Integrative Biosciences School of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTX 77843‑4459USA Department of Animal Science College of Agriculture and Life SciencesTexas A&M UniversityCollege StationTX 77843‑2471USA

integrins are a highly complex family of receptors that, when expressed on the surface of cells, can mediate reciprocal cell-to-cell and cell-to-extracellular matrix(ECM) interactions leading to assembly of integrin adhesion complexes(IACs) that initiate many signaling functions both at the membrane and deeper within the cytoplasm to coordinate processes including cell adhesion, migration, proliferation, survival, differentiation, and metabolism. All metazoan organisms possess integrins, and it is generally agreed that integrins were associated with the evolution of multicellularity, being essential for the association of cells with their neighbors and surroundings, during embryonic development and many aspects of cellular and molecular biology. integrins have important roles in many aspects of embryonic development, normal physiology, and disease processes with a multitude of functions discovered and elucidated for integrins that directly influence many areas of biology and medicine, including mammalian pregnancy, in particular implantation of the blastocyst to the uterine wall, subsequent placentation and conceptus(embryo/fetus and associated placental membranes) development. This review provides a succinct overview of integrin structure, ligand binding, and signaling followed with a concise overview of embryonic development, implantation, and early placentation in pigs, sheep, humans, and mice as an example for rodents. A brief timeline of the initial localization of integrin subunits to the uterine luminal epithelium(LE) and conceptus trophoblast is then presented, followed by sequential summaries of integrin expression and function during gestation in pigs, sheep, humans, and rodents. As appropriate for this journal, summaries of integrin expression and function during gestation in pigs and sheep are in depth, whereas summaries for humans and rodents are brief. Because similar models to those illustrated in Fig. 1, 2, 3, 4, 5 and 6 are present throughout the scientific literature, the illustrations in this m

关键词： Humans Implantation integrins Pigs Pregnancy Rodents Sheep

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Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions

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Neural Regeneration Research 2025年第4期20卷 1031-1041页

作者： Ramón Pérez-Núñez María Fernanda González Ana María Avalos Lisette Leyton Cellular Communication Laboratory Programa de Biología Celular y MolecularCenter for Studies on ExerciseMetabolism and Cancer(CEMC)Instituto de Ciencias Biomédicas(ICBM)Facultad de MedicinaUniversidad de ChileSantiagoChile Advanced Center for Chronic Diseases(ACCDiS) Faculty of Chemical and Pharmaceutical Sciences&Faculty of MedicineUniversidad de ChileSantiagoChile Instituto de Ciencias Biomédicas Facultad de Ciencias de la SaludUniversidad Autónoma de ChileSantiagoChile

Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models

关键词： inflammation integrins neuroprotective neurotoxic phosphatidylinositol 3-kinase reactive astrocytes signal transduction Thy-1(CD90)

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integrins in human hepatocellular carcinoma tumorigenesis and therapy

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Chinese Medical Journal 2023年第3期136卷 253-268页

作者： Qiong Gao Zhaolin Sun Deyu Fang College of Basic Medical Sciences Dalian Medical UniversityDalianLiaoning 116044China Department of Pathology Northwestern University Feinberg School of MedicineChicagoIL 60611USA

integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

关键词： integrins Hepatocellular carcinoma Antitumor therapy

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integrins as attractive targets for cancer therapeutics

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2726-2737页

作者： Meng Li Ying Wang Mengwei Li Xuezhen Wu Sarra Setrerrahmane Hanmei Xu National Institutes for Food and Drug Control Beijing 102629China State Key Laboratory of Natural Medicines Ministry of Educationthe Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu ProvinceDepartment of Marine PharmacyChina Pharmaceutical University Nanjing 211198ChinaAffiliated Hospital of Chifeng CollegeInner Mongolia Autonomous Region 024005China

integrins are transmembrane receptors that have been implicated in the biology of various human physiological and pathological processes.These molecules facilitate cell-extracellular matrix and cell-cell interactions,and they have been implicated in fibrosis,inflammation,thrombosis,and tumor metastasis.The role of integrins in tumor progression makes them promising targets for cancer treatment,and certain integrin antagonists,such as antibodies and synthetic peptides,have been effectively utilized in the clinic for cancer therapy.Here,we discuss the evidence and knowledge on the contribution of integrins to cancer biology.Furthermore,we summarize the clinical attempts targeting this family in anti-cancer therapy development.

关键词： integrins Extracellular matrix Tumor progression Targeted drug Antagonists Clinical trial

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The importance of laminin at the blood-brain barrier

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Neural Regeneration Research 2023年第12期18卷 2557-2563页

作者： Sebok K.Halder Arjun Sapkota Richard Milner San Diego Biomedical Research Institute San DiegoCAUSA

The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier is found at multiple levels,including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes,microglia,and astrocyte endfeet.In addition,extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity,not only by providing an adhesive substrate for blood-brain barrier cells to adhere to,but also by providing guidance cues that strongly influence vascular cell behavior.The extracellular matrix protein laminin is one of the most abundant components of the basement membrane,and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior.In this review,we describe the basic structure of laminin and its receptors,the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states,and most importantly,how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity.Finally,we discuss some of the important unanswered questions in the field and provide a“to-do”list of some of the critical outstanding experiments.

关键词： astrocytes basement membrane blood vessels blood-brain barrier integrity dystroglycan endothelial cells inflammation integrins laminin pericytes

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Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells

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Precision Clinical Medicine 2022年第2期5卷 63-71页

作者： Linghui Deng Kun Jin Xianghong Zhou Zilong Zhang Liming Ge Xingyu Xiong Xingyang Su Di Jin Qiming Yuan Chichen Zhang Yifan Li Haochen Zhao Qiang Wei Lu Yang Shi Qiu National Clinical Research Center of Geriatrics the Center of Gerontology and GeriatricsWest China HospitalSichuan UniversityChengdu 610041China Department of Urology Institute of Urology and National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China West China School of Medicine Sichuan UniversityChengdu 610041China Department of Pharmaceutical and Bioengineering School of Chemical EngineeringSichuan UniversityChengdu 610065China Department of Molecular Oncology Institute of Oncology Research(IOR)Oncology Institute of Southern Switzerland(IOSI)Bellinzona 6500Switzerland

Background:Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer.However,the critical elements in control of chemotherapy resistance remain obscure.Methods:We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin(DOX)and mitomycin C(MMC)of bladder cancer cells in a 3D culture system.We then detected the expression of multidrug resistant gene ABCB1,dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1(COUPTF1),cell proliferation marker Ki-67,and cellular senescence marker senescence-associatedβ-galactosidase(SA-β-Gal)in these cells.We further tested the effects of integrin blockade or protein kinase B(AKT)inhibitor on the senescent state of bladder cancer.Also,we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrinα2β1 ligand peptide TFA(TFA).Results:Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC.In mechanism,collagen activated the integrinβ1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p21/p53 pathway,thus attenuating chemotherapy-induced apoptosis.In addition,TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice.Meanwhile,TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo.Conclusions:Based on our finding that integrinβ1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel,we suggest that integrinβ1 might be a feasible target for bladder cancer eradication.

关键词： premature senescence integrins bladder cancer chemotherapy collagen

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The progression of intracerebral hemorrhage (ICH) is related to the expression of integrin B1 (ITGB1)

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Chinese Neurosurgical Journal 2022年第1期8卷 10-15页

作者： Hai-Yang Ma Yan Xu Chun-You Qiao Yi Peng Qi Ding Li-Zhong Wang Jun-Fei Yan Yuan Hou Fei Di Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100160China Department of Endocrinology ZhangJiakou First HospitalZhangjiakou 075041China Department of Neurosurgery ZhangJiakou First HospitalZhangjiakou 075041China

Background:Intracerebral hemorrhage (ICH) is fatal and detrimental to quality of life.Clinically,options for monitoring are often limited,potentially missing subtle neurological changes.Integrin β 1 (ITGB1) and β 3 (ITGB3) are the main components of integrin family receptors,which regulate the formation and stability of blood vessels.This study explored the relationship between the expression of ITGB1 and ITGB3 in intracerebral hemorrhage (ICH) to analyze their functional and clinical relevance.Methods:The expression of ITGB1 and ITGB3 in ICH was accomplished by immunohistochemical (IHC) staining and western blotting (WB) analysis,respectively.Results:Furthermore,the results demonstrated that ITGB1 was expressed in ICH tissues,but ITGB3 was not expressed in ICH tissues.Conclusions:In summary,the clinical progression of ICH was related to the expression of ITGB1.ITGB1 may be a potential biomarker and contribute to the treatment of ICH.

关键词： Biomarker Immunohistochemical staining Inflammation integrins Intracerebral hemorrhage Western blotting

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Integrin binding peptides facilitate growth and interconnected vascular-like network formation of rat primary cortical vascular endothelial cells in vitro

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Neural Regeneration Research 2023年第5期18卷 1052-1056页

作者： Ram Kuwar Xuejun Wen Ning Zhang Dong Sun Department of Anatomy and Neurobiology Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondVAUSA Department of Chemical and Life Science Engineering College of EngineeringVirginia Commonwealth UniversityRichmondVAUSA Department of Biomedical Engineering College of EngineeringVirginia Commonwealth UniversityRichmondVAUSA

Neovascularization and angiogenesis in the brain are important physiological processes for normal brain development and repair/regeneration following insults. integrins are cell surface adhesion receptors mediating important function of cells such as survival, growth and development during tissue organization, differentiation and organogenesis. In this study, we used an integrin-binding array platform to identify the important types of integrins and their binding peptides that facilitate adhesion, growth, development, and vascular-like network formation of rat primary brain microvascular endothelial cells. Brain microvascular endothelial cells were isolated from rat brain on post-natal day 7. Cells were cultured in a custom-designed integrin array system containing short synthetic peptides binding to 16 types of integrins commonly expressed on cells in vertebrates. After 7 days of culture, the brain microvascular endothelial cells were processed for immunostaining with markers for endothelial cells including von Willibrand factor and platelet endothelial cell adhesion molecule. 5-Bromo-2′-dexoyuridine was added to the culture at 48 hours prior to fixation to assess cell proliferation. Among 16 integrins tested, we found that α5β1, αvβ5 and αvβ8 greatly promoted proliferation of endothelial cells in culture. To investigate the effect of integrin-binding peptides in promoting neovascularization and angiogenesis, the binding peptides to the above three types of integrins were immobilized to our custom-designed hydrogel in three-dimensional(3 D) culture of brain microvascular endothelial cells with the addition of vascular endothelial growth factor. Following a 7-day 3 D culture, the culture was fixed and processed for double labeling of phalloidin with von Willibrand factor or platelet endothelial cell adhesion molecule and assessed under confocal microscopy. In the 3 D culture in hydrogels conjugated with the integrin-binding peptide, brain microvascular endothelial cells formed interconnected vascular-like network

关键词： 3D culture angiogenesis brain microvascular endothelial cells hydrogel integrins platelet endothelial cell adhesion molecule(PECAM-1) vascular endothelial growth factor(VEGF) vascularization

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integrins and focal adhesion kinase in the malignant behavior of gliomas

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Neuroimmunology and Neuroinflammation 2015年第1期2卷 4-7页

作者： Efstathia Giannopoulou Andreas Tzakos Andreas A.Argyriou Clinical Oncology Laboratory Division of OncologyDepartment of MedicineUniversity of Patras26504 PatrasGreece Section of Organic Chemistry and Biochemistry Department of ChemistryUniversity of Ioannina45110 IoanninaGreece Department of Neurology “Saint Andrew’s”General Hospital26335 PatrasGreece

Glioblastoma multiforme(GBM)is the most common type of glioma and is associated with a very poor prognosis.The standard treatment includes radiotherapy concurrent with temozolomide,however recently the Food and Drug Administration approved bevacizumab for use in patients with progressive glioblastoma following prior therapy.The limited number of treatment options points to the need for novel effective therapeutic approaches.A promising approach is the use of tyrosine kinase inhibitors(TKIs)in GBM treatment.However,the results from the majority of clinical trials using TKIs are not very encouraging.One growing area is the development of tumor-homing peptides that resemble the integrin recognition sequence RGD.In this article,the role of integrins and focal adhesion kinase in malignant glioma is reviewed,and an experimental study is proposed that will apply a strategy for peptide-mediated delivery of compounds deep into tumor parenchyma using tumor-homing peptides.

关键词： Focal adhesion kinase glioblastoma multiforme integrins

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integrins在间充质干细胞向内皮细胞分化中的作用研究

Integrins在间充质干细胞向内皮细胞分化中的作用研究

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作者：张曼天津科技大学

学位级别：硕士

体内外的研究证实间充质干细胞(MSCs)可以向内皮细胞分化,为血管组织工程提供种子细胞。实验室前期工作已证实VEGF可以诱导骨髓间充质干细胞(BMSCs)向内皮细胞分化。integrins(整合素)在血管内皮细胞中有高表达,对血管生成起重要作用。... 详细信息

体内外的研究证实间充质干细胞(MSCs)可以向内皮细胞分化,为血管组织工程提供种子细胞。实验室前期工作已证实VEGF可以诱导骨髓间充质干细胞(BMSCs)向内皮细胞分化。integrins(整合素)在血管内皮细胞中有高表达,对血管生成起重要作用。本论文拟研究integrins在VEGF诱导的骨髓间充质干细胞向内皮细胞分化及其血管生成过程中的作用。首先用50 ng/mL VEGF诱导骨髓间充质干细胞向内皮细胞分化,利用LDL吸收实验证实骨髓间充质干细胞分化为内皮细胞,能吸收DiI-Ac-LDL;然后通过Matrigel基质胶成血管实验证实骨髓间充质干细胞的血管生成能力;利用RT-PCR和Western blot的方法检测integrins (Integrin α1、Integrin α5、Integrin αV、Integrin β1、Integrin β4、 Integrin β5)表达随着诱导时间的增长有上升趋势。前期实验已证实Rho信号通路参与VEGF的诱导过程,因此为了验证integrins是否受到Rho信号通路的调控,本实验分别利用两种Rho信号通路抑制剂2 μg/mL C3或10 μmol/L Y27632对细胞进行预处理,然后用VEGF诱导分化。结果发现,骨髓间充质干细胞不能分化为内皮细胞,且血管生成能力下降,integrins的表达下降。已有研究证实Rho信号通路的活化会引起MRTF-A入核并激活下游靶基因,为进一步确定integrins是否会受到MRTF-A的调控,通过在骨髓间充质干细胞中分别转染sh-MRTF-A干扰质粒和合成的siMRTF-A抑制内源性MRTF-A功能,然后用VEGF诱导分化。结果显示,干扰MRTF-A组的骨髓间充质干细胞不能分化为内皮细胞,且血管生成能力下降,integrins的表达也下降。利用划痕实验和Transwell迁移小室实验证实骨髓间充质干细胞的迁移能力下降。进一步通过荧光素酶报告基因分析实验,证实MRTF-A对于Integrin α1和Integrin α5启动子有转录激活作用。最后利用人脐静脉血内皮细胞系(HUVECs)进一步证实了MRTF-A对integrins的调控作用。在HUVEC细胞中转染siMRTF-A后再用VEGF处理。利用MTT检测到干扰MRTF-A对细胞的增殖没有显著影响。鬼笔环肽染色、划痕、transwell及matrigel实验证实低表达MRTF-A的细胞粘附、迁移和血管生成能力均下降,细胞迁移特异性标志物MYL9和CYR61以及integrins的表达降低。最后证实了MRTF-A对于Integrin α1和Integrin α5启动子有转录激活作用。

关键词：间充质干细胞内皮细胞 integrins 血管内皮生长因子 MRTF-A Rho

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