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
Objective: To gain the knowledge of expression levels of integrins in hypertrophic scar--derived andnormal skin-derived fibroblasts. Methods: Using anti--β1 α1. α2. α3 and a4 integrin McAbs, the expressions ofinte...Objective: To gain the knowledge of expression levels of integrins in hypertrophic scar--derived andnormal skin-derived fibroblasts. Methods: Using anti--β1 α1. α2. α3 and a4 integrin McAbs, the expressions ofintegrins were detected in hypertrophic scar--derived and normal skin-- derived fibroblasts of passage 5 and 15 byenzyme--linked immunosorbent assay (ELISA ) technique. ResultS: The hypertrophic scar-- derived fibroblastspossessed higher expression levels of integrin subunits than normal skin--derived fibroblasts. After the cells werecultured from passage 5 to passage 15, the decrease range of integrin expression in hypertrophic scar-derived was5. 94%~18. 26%, and 26. 19% ~ 46. 84% in normal skin- derived fibroblasts, showing a statistical difference(P<0. 01). Conclusion: Overexpression of integrins in hypertrophic scar fibroblasts may play an important rolein the hypertrophic scar formation and contemporaneous tissue contracture.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
Integrin-mediated adhesions play critical roles in diverse cell functions. Integrins offers a platform on which mechanical stimuli, cytoskeletal organization, biochemical signals can concentrate. Mechanical stimuli tr...Integrin-mediated adhesions play critical roles in diverse cell functions. Integrins offers a platform on which mechanical stimuli, cytoskeletal organization, biochemical signals can concentrate. Mechanical stimuli transmitted by integrins influence the cytoskeleton, in turn, the cytoskeleton influences cell adhesion via integrins, then cell adhesion results in a series of signal transduction cascades. In skeleton, integrins also have a key role for bone resoption by osteoclasts and reformation by osteoblasts. In present review, the proteins involved in integrin signal transduction and integrin signal transduction pathways were discussed, mainly on the basic mechanisms of integrin signaling and the roles of integrins in bone signal transduction, which may give insight into new therapeutic agents to all kinds of skeletal diseases and new strategies for bone tissue engineering.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
This article navigates the relationship between biomaterials and osteogenic cell adhesion,highlighting the importance of mimicking the physiological response for bone tissue regeneration.Within this spirit is an initi...This article navigates the relationship between biomaterials and osteogenic cell adhesion,highlighting the importance of mimicking the physiological response for bone tissue regeneration.Within this spirit is an initial description of the interaction between osteoblasts and osteoprogenitor cells with the extracellular matrix,explaining the leading role of integrins and cadherins in cell adhesion,and the intracellular signaling pathways elicited.Additionally,there is a focus on the strategies of advanced biomaterials that foster osteogenesis by replicating the native environment,taking advantage of these known specific signaling pathways.Thefinal remarks lay on the need for careful consideration of in-vitro and in-vivo complexities in biomaterial development.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
目的探究Plectin响应基质刚度变化调控肝癌细胞迁移的分子机理。方法制备刚度可调的聚丙烯酰胺水凝胶,划痕实验测定不同基质刚度对MHCC-97H和MHCC-97L迁移的影响。RT-q PCR和Western blotting检测Plectin和Integrinβ1在不同基质刚度上...目的探究Plectin响应基质刚度变化调控肝癌细胞迁移的分子机理。方法制备刚度可调的聚丙烯酰胺水凝胶,划痕实验测定不同基质刚度对MHCC-97H和MHCC-97L迁移的影响。RT-q PCR和Western blotting检测Plectin和Integrinβ1在不同基质刚度上的表达水平,免疫荧光检测F-actin的聚合程度。通过敲减Plectin和Integrinβ1及F-actin的解聚,探究Plectin和Integrinβ1在基质刚度调控肝癌细胞F-actin聚合和迁移中的作用。结果与低基质刚度组(7 k Pa)比较,高基质刚度(53 k Pa)明显增强肝癌细胞迁移能力,同时上调细胞Plectin和Integrinβ1的表达,促进F-actin聚合。敲减Plectin抑制了高基质刚度诱导的F-actin聚合和细胞迁移能力。敲减Integrinβ1抑制了高刚度对Plectin表达、F-actin聚合和细胞迁移能力的促进作用。此外,使用F-actin抑制剂Latrunculin A处理后,同样抑制了高刚度条件下细胞迁移能力的增强。结论高基质刚度通过Integrinβ1上调Plectin的表达,促进F-actin的聚合,从而增强肝癌细胞的迁移能力。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
There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and th...There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.展开更多
BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrinαvβ3-targeted m...BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrinαvβ3-targeted molecular imaging modality to differentiate NASH.METHODS Integrinαvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids(FFA).Hepatic integrinαvβ3 expression was analyzed in rabbits fed a high-fat diet(HFD)and in rats fed a high-fat,high-carbohydrate diet(HFCD).After synthesis,cyclic arginine-glycine-aspartic acid peptide(cRGD)was labeled with gadolinium(Gd)and used as a contrast agent in magnetic resonance imaging(MRI)performed on mice fed with HFCD.RESULTS Integrinαvβ3 was markedly expressed on FFA-cultured hepatocytes,unlike the control hepatocytes.Hepatic integrinαvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver(FL)progressed to steatohepatitis.The distribution of integrinαvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas.In comparison to mice with simple FL,the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis(P<0.05),showing a positive correlation with the NAFLD activity score(r=0.945;P<0.01).Hepatic integrinαvβ3 expression was significantly upregulated during NASH development,with hepatocytes being the primary cells expressing integrinαvβ3.CONCLUSION After using Gd-labeled cRGD as a tracer,NASH was successfully distinguished by visualizing hepatic integrinαvβ3 expression with MRI.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
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Objective: To gain the knowledge of expression levels of integrins in hypertrophic scar--derived andnormal skin-derived fibroblasts. Methods: Using anti--β1 α1. α2. α3 and a4 integrin McAbs, the expressions ofintegrins were detected in hypertrophic scar--derived and normal skin-- derived fibroblasts of passage 5 and 15 byenzyme--linked immunosorbent assay (ELISA ) technique. ResultS: The hypertrophic scar-- derived fibroblastspossessed higher expression levels of integrin subunits than normal skin--derived fibroblasts. After the cells werecultured from passage 5 to passage 15, the decrease range of integrin expression in hypertrophic scar-derived was5. 94%~18. 26%, and 26. 19% ~ 46. 84% in normal skin- derived fibroblasts, showing a statistical difference(P<0. 01). Conclusion: Overexpression of integrins in hypertrophic scar fibroblasts may play an important rolein the hypertrophic scar formation and contemporaneous tissue contracture.
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Integrin-mediated adhesions play critical roles in diverse cell functions. Integrins offers a platform on which mechanical stimuli, cytoskeletal organization, biochemical signals can concentrate. Mechanical stimuli transmitted by integrins influence the cytoskeleton, in turn, the cytoskeleton influences cell adhesion via integrins, then cell adhesion results in a series of signal transduction cascades. In skeleton, integrins also have a key role for bone resoption by osteoclasts and reformation by osteoblasts. In present review, the proteins involved in integrin signal transduction and integrin signal transduction pathways were discussed, mainly on the basic mechanisms of integrin signaling and the roles of integrins in bone signal transduction, which may give insight into new therapeutic agents to all kinds of skeletal diseases and new strategies for bone tissue engineering.
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.
文摘This article navigates the relationship between biomaterials and osteogenic cell adhesion,highlighting the importance of mimicking the physiological response for bone tissue regeneration.Within this spirit is an initial description of the interaction between osteoblasts and osteoprogenitor cells with the extracellular matrix,explaining the leading role of integrins and cadherins in cell adhesion,and the intracellular signaling pathways elicited.Additionally,there is a focus on the strategies of advanced biomaterials that foster osteogenesis by replicating the native environment,taking advantage of these known specific signaling pathways.Thefinal remarks lay on the need for careful consideration of in-vitro and in-vivo complexities in biomaterial development.
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.
文摘目的探究Plectin响应基质刚度变化调控肝癌细胞迁移的分子机理。方法制备刚度可调的聚丙烯酰胺水凝胶,划痕实验测定不同基质刚度对MHCC-97H和MHCC-97L迁移的影响。RT-q PCR和Western blotting检测Plectin和Integrinβ1在不同基质刚度上的表达水平,免疫荧光检测F-actin的聚合程度。通过敲减Plectin和Integrinβ1及F-actin的解聚,探究Plectin和Integrinβ1在基质刚度调控肝癌细胞F-actin聚合和迁移中的作用。结果与低基质刚度组(7 k Pa)比较,高基质刚度(53 k Pa)明显增强肝癌细胞迁移能力,同时上调细胞Plectin和Integrinβ1的表达,促进F-actin聚合。敲减Plectin抑制了高基质刚度诱导的F-actin聚合和细胞迁移能力。敲减Integrinβ1抑制了高刚度对Plectin表达、F-actin聚合和细胞迁移能力的促进作用。此外,使用F-actin抑制剂Latrunculin A处理后,同样抑制了高刚度条件下细胞迁移能力的增强。结论高基质刚度通过Integrinβ1上调Plectin的表达,促进F-actin的聚合,从而增强肝癌细胞的迁移能力。
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.
基金supported by grants from the National Natural Science Foundation of China (81972531, 82373175, 82102775, and 82002466)the Major Scientific and Technological Projects of Guangdong Province (2019B020202002)the Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0067)
文摘There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.
基金Supported by the National Natural Science Foundation of China,No.81670513and Young Scientists Fund of the National Natural Science Foundation of China,No.81900511。
文摘BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrinαvβ3-targeted molecular imaging modality to differentiate NASH.METHODS Integrinαvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids(FFA).Hepatic integrinαvβ3 expression was analyzed in rabbits fed a high-fat diet(HFD)and in rats fed a high-fat,high-carbohydrate diet(HFCD).After synthesis,cyclic arginine-glycine-aspartic acid peptide(cRGD)was labeled with gadolinium(Gd)and used as a contrast agent in magnetic resonance imaging(MRI)performed on mice fed with HFCD.RESULTS Integrinαvβ3 was markedly expressed on FFA-cultured hepatocytes,unlike the control hepatocytes.Hepatic integrinαvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver(FL)progressed to steatohepatitis.The distribution of integrinαvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas.In comparison to mice with simple FL,the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis(P<0.05),showing a positive correlation with the NAFLD activity score(r=0.945;P<0.01).Hepatic integrinαvβ3 expression was significantly upregulated during NASH development,with hepatocytes being the primary cells expressing integrinαvβ3.CONCLUSION After using Gd-labeled cRGD as a tracer,NASH was successfully distinguished by visualizing hepatic integrinαvβ3 expression with MRI.
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.
