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 a...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 manuscript are drafted as Viking imagery for entertainment purposes.展开更多
Integrins are a large family of adhesion molecules broadly expressed on the surface of a wide variety of cells as heterodimers.Binding of integrins to ligands provides anchorage and signals for the cell,making them pr...Integrins are a large family of adhesion molecules broadly expressed on the surface of a wide variety of cells as heterodimers.Binding of integrins to ligands provides anchorage and signals for the cell,making them prime candidates for mechanosensing molecules.To elucidate how force regulates integrin/ligand dissociation,we used molecular mechanics experiments展开更多
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 ca...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.展开更多
Introduction Hematogenous metastasis is the mainly leading cause of death in breast carcinoma patients.A better understanding of the underlying molecular and cellular mechanisms is crucial for the development of effec...Introduction Hematogenous metastasis is the mainly leading cause of death in breast carcinoma patients.A better understanding of the underlying molecular and cellular mechanisms is crucial for the development of effective treatment for metastatic breast cancer<sup>[</sup>1].It has been well established that cell adhesion and invasion is mediated by a variety of transmembrane proteins,including integrins,cadherins,selectins,and intercellular adhesion molecules.Among these adhesion molecules,the integrins and their downstream signaling pathways have been extensively studied<sup>[2]</sup>.On the other hand,the specific events determining tumor cell interactions with endo-展开更多
Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the prin...Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the principles,main preforming procedures,and advances of MDS,as well as its applications on the studies of conformational and allosteric dynamics of proteins especially on that of the mechanosensitive integrins.Future perspectives were also proposed.This review could provide clues in understanding the potentiality of MD simulations in structure–function relationship investigation of biological proteins.展开更多
The purpose of this study was to investigate changes of β 3 integrins and extra cellular matrix proteins including fibronectin (FN), laminin (LN) and collagen type Ⅳ (CL typeⅣ) on the endometrium of secret...The purpose of this study was to investigate changes of β 3 integrins and extra cellular matrix proteins including fibronectin (FN), laminin (LN) and collagen type Ⅳ (CL typeⅣ) on the endometrium of secretory phase from 31 fertile women (fertility group)and 34 women with unexplained infertility (infertility group) by a histochemical method.The results were as follows:In glandular epithelium, β 3 integrin appeared in the mid secretory phase and continued to late secretory phase in the fertility group, but was not expressed during the secretory phase in the infertility group. Extracellular matrix proteins from the fertility group were expressed more strongly in mid secretory phase than that in the early secretory phase, and were weakest in the late secretory phase. Compared with the fertility group, the levels of extracellular matrix proteins in the infertility group were elevated in the secretory phase. In conclusion: our current study demonstrate that β 3 integrin and extracellular matrix proteins are expressed at different levels in the endometrium during the menstrual cycle. They are involved in endometrial changes during the menstrual cycle and during the implantation of the blastocyst. Their unusual expression result in the failure of implantation.展开更多
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 sign...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.展开更多
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 ...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 are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.展开更多
BACKGROUND Liver injury is common in severe acute pancreatitis(SAP).Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes,which induces lipid peroxidation and mitochondrial iron deposition and ...BACKGROUND Liver injury is common in severe acute pancreatitis(SAP).Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes,which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis.Our previous study found that milk fat globule epidermal growth factor 8(MFG-E8)alleviates acinar cell damage during SAP via binding toαvβ3/5 integrins.MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy.AIM To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.METHODS SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50μg/kg cerulein plus lipopolysaccharide.mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAPinduced liver injury.Cilengitide,a specificαvβ3/5 integrin inhibitor,was used to investigate the possible mechanism of MFG-E8.RESULTS The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice,enhanced autophagy flux in hepatocyte,and worsened the degree of ferroptosis.Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner.Mechanistically,MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells.Cilengitide abolished MFG-E8’s beneficial effects in SAP-induced liver injury.CONCLUSION MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury.MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrinαVβ3/5.展开更多
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,...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.展开更多
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 A...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.展开更多
To study whether integrins on cell membrane ligate with intracellular cytoskeletal proteins and mediate their reorganization in egg activation, female mice were used for su- perovulation. The zona-free oocytes were in...To study whether integrins on cell membrane ligate with intracellular cytoskeletal proteins and mediate their reorganization in egg activation, female mice were used for su- perovulation. The zona-free oocytes were incubated separately with specific ligand of integrins, an active RGD peptide, in vitro for certain period of time. RGE peptide and mouse capacitated sperm were used as controls. Freshly ovulated oocytes and those treated with different factors were immunostained with FITC-labeled anti-actin antibody, then detected with confocal micro- scope. The results demonstrated that freshly ovulated mouse oocytes, oocytes incubated for 2 h in vitro and those treated with control RGE peptide for 15 min showed hardly visible fluorescene or only thin fluorescence in plasma membrane region. Oocytes coincubated with sperms for 15 min and those treated with active RGD peptide for 10 min, 30 min and 2 hours respectively had strong and thick fluorescence in the plasma membrane and cortical region of oocytes, and some of them showed asymmetrically fluorescent distribution. It is proved that integrins on membrane are ligated directly with cytoskeletal protein. Integrins binding with their ligands regulate reor- ganization of cytoskelal protein, which may be involved in transmembrane signaling in egg acti- vation.展开更多
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...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.展开更多
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 im...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 with clearly discernable lumens, which is reminiscent of brain microvascular network in vivo. With the novel integrin-binding array system, we identified the specific types of integrins on brain microvascular endothelial cells that mediate cell adhesion and growth followed by functionalizing a 3 D hydrogel culture system using the binding peptides that specifically bind to the identified integrins, leading to robust growth and lumenized microvascular-like network formation of brain microvascular endothelial cells in 3 D culture. This technology can be used for in vitro and in vivo vascularization of transplants or brain lesions to promote brain tissue regeneration following neurological insults.展开更多
Background:To investigate the detailed mechanism underlying the pro-metastatic effect of spleen deficiency(SD)syndrome on hepatocellular carcinoma(HCC).Methods:In the present study,our model was established based on a...Background:To investigate the detailed mechanism underlying the pro-metastatic effect of spleen deficiency(SD)syndrome on hepatocellular carcinoma(HCC).Methods:In the present study,our model was established based on an HCC mouse model induced by diethylnitrosamine using reserpine to induce SD.Exosomes were isolated and purified from mouse plasma samples using an exosome isolation kit.Subsequently,we verified the pro-metastatic effects of exosomes from the HCC mice with SD on HCC cells by transwell assays,wound healing assays,phalloidin staining in vitro,and lung metastasis assay of mice in vivo.Finally,we further explored the detailed mechanism underlying the pro-metastatic effect of exosomes from the HCC mice with SD on HCC cells.Results:We found that SD promoted the malignant progression of HCC in mice.Exosomes from HCC mice with SD enhanced the invasion and metastasis of HCC cells in vitro and in vivo.Mechanistically,upregulation of integrinα1,integrinβ1,and integrinβ5 seemed to play a key role in mediating the pro-metastatic effect of exosomes isolated from the HCC mice with SD,which was largely abrogated upon co-treatment with a broad-spectrum integrin inhibitor.Conclusion:Our findings demonstrated that exosomes promote the invasion and metastasis of HCC cells via an integrin-dependent manner in the spleen-deficient state that would contribute to our better understanding of the role of SD in HCC progression in traditional Chinese medicine,and thus management of the disease.展开更多
基金supported by USDA-NRICGP 98-35203-6337 to FWB.and RCB,NRSA DHHS/NIH 1-F32-HDO 8501 O1A1 to GAJ,USDA-NRI 2006-35203-17199 to GAJ and Kayla J.BaylessUSDA National Institute of Food and Agriculture Research Initiative Competitive Fellowship Grant no.2012-67011-19892 to James W.Frank and GAJ+1 种基金Agriculture and Food Research Initiative Competitive Grant no.2016-67015-24955 from the USDA National Institute of Food and Agriculture to GAJ and FWBNational Institutes of Health Grant 1R21HD071468-01 to GAJ and KJB。
文摘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 manuscript are drafted as Viking imagery for entertainment purposes.
基金supported by US National Institutes of Health grant R01 AI44902by a Scientist Development Grant 0735224Na Pre-doctoral Fellowship from the American Heart Association
文摘Integrins are a large family of adhesion molecules broadly expressed on the surface of a wide variety of cells as heterodimers.Binding of integrins to ligands provides anchorage and signals for the cell,making them prime candidates for mechanosensing molecules.To elucidate how force regulates integrin/ligand dissociation,we used molecular mechanics experiments
文摘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.
基金The financial supports provided,in whole or in part,by the National Natural Science Foundation of China(11272083)the New Century Excellent Talents Program in Chinese Universities(NCET09-0263)
文摘Introduction Hematogenous metastasis is the mainly leading cause of death in breast carcinoma patients.A better understanding of the underlying molecular and cellular mechanisms is crucial for the development of effective treatment for metastatic breast cancer<sup>[</sup>1].It has been well established that cell adhesion and invasion is mediated by a variety of transmembrane proteins,including integrins,cadherins,selectins,and intercellular adhesion molecules.Among these adhesion molecules,the integrins and their downstream signaling pathways have been extensively studied<sup>[2]</sup>.On the other hand,the specific events determining tumor cell interactions with endo-
基金Project supported by the National Key Research and Development Program of China(Grant No.2016YFA0501601)the National Natural Science Foundation of China(Grant Nos.91642203,31627804,and 11972042)+2 种基金the Frontier Science Key Project of the Chinese Academy of Sciences(Grant No.QYZDJ-SSWJSC018)the Scientific Instrument Developing Project of the Chinese Academy of Sciences(Grant No.GJJSTU20190005)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB22040101)。
文摘Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the principles,main preforming procedures,and advances of MDS,as well as its applications on the studies of conformational and allosteric dynamics of proteins especially on that of the mechanosensitive integrins.Future perspectives were also proposed.This review could provide clues in understanding the potentiality of MD simulations in structure–function relationship investigation of biological proteins.
文摘The purpose of this study was to investigate changes of β 3 integrins and extra cellular matrix proteins including fibronectin (FN), laminin (LN) and collagen type Ⅳ (CL typeⅣ) on the endometrium of secretory phase from 31 fertile women (fertility group)and 34 women with unexplained infertility (infertility group) by a histochemical method.The results were as follows:In glandular epithelium, β 3 integrin appeared in the mid secretory phase and continued to late secretory phase in the fertility group, but was not expressed during the secretory phase in the infertility group. Extracellular matrix proteins from the fertility group were expressed more strongly in mid secretory phase than that in the early secretory phase, and were weakest in the late secretory phase. Compared with the fertility group, the levels of extracellular matrix proteins in the infertility group were elevated in the secretory phase. In conclusion: our current study demonstrate that β 3 integrin and extracellular matrix proteins are expressed at different levels in the endometrium during the menstrual cycle. They are involved in endometrial changes during the menstrual cycle and during the implantation of the blastocyst. Their unusual expression result in the failure of implantation.
文摘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.
基金supported by Fondo Nacional de Desarrollo Científico y Tecnológico(FONDECYT)#1200836,#1210644,and#1240888,and Agencia Nacional de Investigación y Desarrollo(ANID)-FONDAP#15130011(to LL)FONDECYT#3230227(to MFG).
文摘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 are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.
基金Supported by the National Natural Science Foundation of China,No.82100685the Scientific Research Fund of Xi’an Health Commission,No.2021yb08+1 种基金Scientific Research Fund of Xi’an Central Hospital,No.2022QN07Innovation Capability Support Plan of Xi’an Science and Technology Bureau,No.23YXYJ0097.
文摘BACKGROUND Liver injury is common in severe acute pancreatitis(SAP).Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes,which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis.Our previous study found that milk fat globule epidermal growth factor 8(MFG-E8)alleviates acinar cell damage during SAP via binding toαvβ3/5 integrins.MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy.AIM To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.METHODS SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50μg/kg cerulein plus lipopolysaccharide.mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAPinduced liver injury.Cilengitide,a specificαvβ3/5 integrin inhibitor,was used to investigate the possible mechanism of MFG-E8.RESULTS The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice,enhanced autophagy flux in hepatocyte,and worsened the degree of ferroptosis.Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner.Mechanistically,MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells.Cilengitide abolished MFG-E8’s beneficial effects in SAP-induced liver injury.CONCLUSION MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury.MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrinαVβ3/5.
基金supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(2018ZX09101001-003)in China
文摘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.
文摘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.
文摘To study whether integrins on cell membrane ligate with intracellular cytoskeletal proteins and mediate their reorganization in egg activation, female mice were used for su- perovulation. The zona-free oocytes were incubated separately with specific ligand of integrins, an active RGD peptide, in vitro for certain period of time. RGE peptide and mouse capacitated sperm were used as controls. Freshly ovulated oocytes and those treated with different factors were immunostained with FITC-labeled anti-actin antibody, then detected with confocal micro- scope. The results demonstrated that freshly ovulated mouse oocytes, oocytes incubated for 2 h in vitro and those treated with control RGE peptide for 15 min showed hardly visible fluorescene or only thin fluorescence in plasma membrane region. Oocytes coincubated with sperms for 15 min and those treated with active RGD peptide for 10 min, 30 min and 2 hours respectively had strong and thick fluorescence in the plasma membrane and cortical region of oocytes, and some of them showed asymmetrically fluorescent distribution. It is proved that integrins on membrane are ligated directly with cytoskeletal protein. Integrins binding with their ligands regulate reor- ganization of cytoskelal protein, which may be involved in transmembrane signaling in egg acti- vation.
文摘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.
基金supported by NIH grant RO1 NS093985 (to DS, NZ, XW) and RO1 NS101955 (to DS)the VCU Microscopy Facility,supported,in part,by funding from NIH-NCI Cancer Center Support Grant P30 CA016059。
文摘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 with clearly discernable lumens, which is reminiscent of brain microvascular network in vivo. With the novel integrin-binding array system, we identified the specific types of integrins on brain microvascular endothelial cells that mediate cell adhesion and growth followed by functionalizing a 3 D hydrogel culture system using the binding peptides that specifically bind to the identified integrins, leading to robust growth and lumenized microvascular-like network formation of brain microvascular endothelial cells in 3 D culture. This technology can be used for in vitro and in vivo vascularization of transplants or brain lesions to promote brain tissue regeneration following neurological insults.
基金This study was funded by the National Science Foundation of China(No.82174173,No.82104962,No.81903967 and No.81873248).
文摘Background:To investigate the detailed mechanism underlying the pro-metastatic effect of spleen deficiency(SD)syndrome on hepatocellular carcinoma(HCC).Methods:In the present study,our model was established based on an HCC mouse model induced by diethylnitrosamine using reserpine to induce SD.Exosomes were isolated and purified from mouse plasma samples using an exosome isolation kit.Subsequently,we verified the pro-metastatic effects of exosomes from the HCC mice with SD on HCC cells by transwell assays,wound healing assays,phalloidin staining in vitro,and lung metastasis assay of mice in vivo.Finally,we further explored the detailed mechanism underlying the pro-metastatic effect of exosomes from the HCC mice with SD on HCC cells.Results:We found that SD promoted the malignant progression of HCC in mice.Exosomes from HCC mice with SD enhanced the invasion and metastasis of HCC cells in vitro and in vivo.Mechanistically,upregulation of integrinα1,integrinβ1,and integrinβ5 seemed to play a key role in mediating the pro-metastatic effect of exosomes isolated from the HCC mice with SD,which was largely abrogated upon co-treatment with a broad-spectrum integrin inhibitor.Conclusion:Our findings demonstrated that exosomes promote the invasion and metastasis of HCC cells via an integrin-dependent manner in the spleen-deficient state that would contribute to our better understanding of the role of SD in HCC progression in traditional Chinese medicine,and thus management of the disease.