Diabetic retinopathy(DR),a leading cause of visual loss,is the result of microvascular damage induced by prolonged hyperglycemia.Numerous studies have revealed the pivotal role of integrins in the pathogenesis of DR,p...Diabetic retinopathy(DR),a leading cause of visual loss,is the result of microvascular damage induced by prolonged hyperglycemia.Numerous studies have revealed the pivotal role of integrins in the pathogenesis of DR,particularly in key processes such as inflammation,vascular leakage,microthrombus formation,and angiogenesis.Consequently,targeting integrins is considered a promising strategy for the treatment of DR.This review focuses on the function of integrins in DR and their potential as therapeutic targets.It describes the molecular mechanisms through which integrins influence DR progression and summarizes the latest outcomes of integrin antagonist-based therapeutic strategies in clinical studies,evaluating their efficacy and potential challenges,which offer promise as novel treatment options for DR.展开更多
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
Insect hemocytes eliminate foreign substances from the hemocoel through various immune reactions.Integrins,receptor proteins present on the cell membrane,are formed as a heterodimer from α and β subunits and are kno...Insect hemocytes eliminate foreign substances from the hemocoel through various immune reactions.Integrins,receptor proteins present on the cell membrane,are formed as a heterodimer from α and β subunits and are known to be involved in various immune reactions.To elucidate the role of integrins in the immunity of the lepidoptera Mythimna separata,genes encoding integrins were screened from the genome,resulting in the identification of eightαand fourβintegrin genes.The expression levels of the integrin genes did not change in response to the injection of small abiotic beads undergoing phagocytosis in M.separata larvae.However,significant inductions of some integrin gene expressions were observed in hemocytes that formed capsules around large abiotic beads during encapsulation,especially in MysIntα2.Under biotic stimulation,induction of the MysIntα2 was evident after exposures to Gram-negative bacteria(Escherichia coli)and entomopathogenic nematodes(Steinernema carpocapsae),but not to Gram-positive bacteria(Micrococcus luteus).Immunostaining analysis revealed that MysIntα2 was specifically localized to hemocytes surrounding the beads during the encapsulation reaction.Furthermore,the spreading and encapsulation abilities of hemocytes were significantly inhibited by incubation with MysIntα2 antibodies.Suppression of MysIntα2 expression in M.separata larvae by injecting double-stranded RNA also resulted in a decrease in encapsulation activity.Collectively,these results indicate that MysIntα2 plays pivotal roles in the cellular immune response of M.separata,particularly during encapsulation.This likely occurs through the regulation of hemocyte spreading activity,thereby facilitating the formation of multilayered capsules around large invaders.展开更多
Integrins are heterodimers composed ofαandβsubunits that are bonded through non-covalent interactions.Integrins mediate the dynamic connection between extracellular adhesion molecules and the intracellular actin cyt...Integrins are heterodimers composed ofαandβsubunits that are bonded through non-covalent interactions.Integrins mediate the dynamic connection between extracellular adhesion molecules and the intracellular actin cytoskeleton.Integrins are present in various tissues and organs where these heterodimers participate in diverse physiological and pathological responses at the molecular level in living organisms.Wound healing is a crucial process in the recovery from traumatic diseases and comprises three overlapping phases:inflammation,proliferation and remodeling.Integrins are regulated during the entire wound healing process to enhance processes such as inflammation,angiogenesis and re-epithelialization.Prolonged inflammation may result in failure of wound healing,leading to conditions such as chronic wounds.Bacterial colonization of a wound is one of the primary causes of chronic wounds.Integrins facilitate the infectious effects of bacteria on the host organism,leading to chronic inflammation,bacterial colonization,and ultimately,the failure of wound healing.The present study investigated the role of integrins as bridges for bacteria-cell interactions during wound healing,evaluated the role of integrins as nodes for bacterial inhibition during chronic wound formation,and discussed the challenges and prospects of using integrins as therapeutic targets in wound healing.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
Connective tissue is a dynamic structure that reacts to environmental cues to maintain homeostasis,including mechanical properties.Mechanical load influences extracellular matrix(ECM)—cell interactions and modulates ...Connective tissue is a dynamic structure that reacts to environmental cues to maintain homeostasis,including mechanical properties.Mechanical load influences extracellular matrix(ECM)—cell interactions and modulates cellular behavior.Mechano-regulation processes involve matrix modification and cell activation to preserve tissue function.The ECM remodeling is crucial for force transmission.Cytoskeleton components are involved in force sensing and transmission,affecting cellular adhesion,motility,and gene expression.Proper mechanical loading helps to maintain tissue health,while imbalances may lead to pathological processes.Active and passive movement,including manual mobilization,improves connective tissue elasticity,promotes ECM-cell homeostasis,and reduces fibrosis.In rehabilitation,understanding mechanical-regulation processes is necessary for ameliorating and developing treatments aimed at preserving tissue elasticity and preventing fibrosis.In this commentary,we aim to globally describe the biological processes involved in mechanical force transmission in connective tissue as support for translational studies and clinical applications in the rehabilitation field.展开更多
Vedolizumab is a humanized monoclonal antibody and one of the safest biologics for the treatment ofboth forms of inflammatory bowel disease(IBD)-Crohn’s disease and ulcerative colitis.It targets theα4β7 integrinand...Vedolizumab is a humanized monoclonal antibody and one of the safest biologics for the treatment ofboth forms of inflammatory bowel disease(IBD)-Crohn’s disease and ulcerative colitis.It targets theα4β7 integrinand blocks leukocyte trafficking to the gut.Regardless of its efficacy in many patients,non-response to vedolizumabtreatment poses a significant clinical challenge.In this review,we synthesize recent findings on genomic,transcriptomic,proteomic,and cellular biomarkers of vedolizumab response,emphasizing their roles in predicting therapeutic outcomesand understanding non-responsiveness.Key insights include the identification of epigenetic and transcriptomicsignatures,the involvement of Th17 and IL-6 signaling,and the role of baseline inflammatory markers like albumin.Discrepancies in findings highlight the complexity of biomarker discovery and underscore the need for standardized,multiparametric approaches to refine personalized treatment strategies.By bridging knowledge gaps in vedolizumabresponsiveness,this review aims to advance biomarker-driven decision-making and improve outcomes for patientswith IBD.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
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
Secondary injury following spinal cord injury is primarily characterized by a complex inflammatory response,with resident microglia and infiltrating macrophages playing pivotal roles.While previous studies have groupe...Secondary injury following spinal cord injury is primarily characterized by a complex inflammatory response,with resident microglia and infiltrating macrophages playing pivotal roles.While previous studies have grouped these two cell types together based on similarities in structure and function,an increasing number of studies have demonstrated that microglia and macrophages exhibit differences in structure and function and have different effects on disease processes.In this study,we used single-cell RNA sequencing and spatial transcriptomics to identify the distinct evolutionary paths of microglia and macrophages following spinal cord injury.Our results showed that microglia were activated to a pro-inflammatory phenotype immediately after spinal cord injury,gradually transforming to an anti-inflammatory steady state phenotype as the disease progressed.Regarding macrophages,our findings highlighted abundant communication with other cells,including fibroblasts and neurons.Both pro-inflammatory and neuroprotective effects of macrophages were also identified;the pro-inflammatory effect may be related to integrin β2(Itgb2) and the neuroprotective effect may be related to the oncostatin M pathway.These findings were validated by in vivo experiments.This research underscores differences in the cellular dynamics of microglia and macrophages following spinal cord injury,and may offer new perspectives on inflammatory mechanisms and potential therapeutic targets.展开更多
Salmonella enterica serovar Typhimurium,the causative agent of gastroenteritis,is one of the most successful intracellular pathogens.Although certain host factors for Salmonella infection have been unveiled,the factor...Salmonella enterica serovar Typhimurium,the causative agent of gastroenteritis,is one of the most successful intracellular pathogens.Although certain host factors for Salmonella infection have been unveiled,the factors mediating Salmonella entry,particularly the invasion process,remain obscure.Here,we have unearthed β2 integrin,a crucial member of the integrin family,as an important host factor facilitating Salmonella invasion.It is demonstrated that overexpression of β2 integrin promotes Salmonella invasion,while the knockdown of β2 integrin significantly diminishes the extent of invasion.Moreover,Salmonella exhibits specific binding affinity towards β2 integrin,and the block of β2 integrin on cell surface substantially reduces the infection of cells in vitro.The ectodomain soluble protein of β2 integrin neutralized Salmonella infection both in cells(in vitro)and in mice(in vivo).Additionally,Salmonella protein YrbD directly interacts with β2 integrin to facilitate its invasion.To our knowledge,this study showed for the first time that the protein YrbD mediates Salmonella adhesion and internalization into host cells by interacting with β2 integrin.These findings not only broaden our understanding of the mechanisms underlying Salmonella entry,but also identify a prospective target for therapeutic control.展开更多
基金Supported by the Natural Science Foundation of Inner Mongolia,No.2022MS080572022 Autonomous Region Medical and Health Science and Technology Plan Projects,No.202202190.
文摘Diabetic retinopathy(DR),a leading cause of visual loss,is the result of microvascular damage induced by prolonged hyperglycemia.Numerous studies have revealed the pivotal role of integrins in the pathogenesis of DR,particularly in key processes such as inflammation,vascular leakage,microthrombus formation,and angiogenesis.Consequently,targeting integrins is considered a promising strategy for the treatment of DR.This review focuses on the function of integrins in DR and their potential as therapeutic targets.It describes the molecular mechanisms through which integrins influence DR progression and summarizes the latest outcomes of integrin antagonist-based therapeutic strategies in clinical studies,evaluating their efficacy and potential challenges,which offer promise as novel treatment options for DR.
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.
基金supported by the Japan Society for the Promotion of Science KAKENHI[Grant Number JP17K08157].
文摘Insect hemocytes eliminate foreign substances from the hemocoel through various immune reactions.Integrins,receptor proteins present on the cell membrane,are formed as a heterodimer from α and β subunits and are known to be involved in various immune reactions.To elucidate the role of integrins in the immunity of the lepidoptera Mythimna separata,genes encoding integrins were screened from the genome,resulting in the identification of eightαand fourβintegrin genes.The expression levels of the integrin genes did not change in response to the injection of small abiotic beads undergoing phagocytosis in M.separata larvae.However,significant inductions of some integrin gene expressions were observed in hemocytes that formed capsules around large abiotic beads during encapsulation,especially in MysIntα2.Under biotic stimulation,induction of the MysIntα2 was evident after exposures to Gram-negative bacteria(Escherichia coli)and entomopathogenic nematodes(Steinernema carpocapsae),but not to Gram-positive bacteria(Micrococcus luteus).Immunostaining analysis revealed that MysIntα2 was specifically localized to hemocytes surrounding the beads during the encapsulation reaction.Furthermore,the spreading and encapsulation abilities of hemocytes were significantly inhibited by incubation with MysIntα2 antibodies.Suppression of MysIntα2 expression in M.separata larvae by injecting double-stranded RNA also resulted in a decrease in encapsulation activity.Collectively,these results indicate that MysIntα2 plays pivotal roles in the cellular immune response of M.separata,particularly during encapsulation.This likely occurs through the regulation of hemocyte spreading activity,thereby facilitating the formation of multilayered capsules around large invaders.
基金supported by the National Natural Science Foundation of China[grant number 81802792]Project of Yangzhou University Medical Innovation and Transformation Special Fund New Medical Cross Innovation Team[grant number AHYZUCXTD 202108]+2 种基金Postgraduate Research&Practice Innovation Program of Jiangsu Province[grant number SJCX22_1822]Postdoctoral Science Foundation of Jiangsu Province[grant number 2020Z409]Science and technology projects for social development of Yangzhou City[grant number YZ2022106].
文摘Integrins are heterodimers composed ofαandβsubunits that are bonded through non-covalent interactions.Integrins mediate the dynamic connection between extracellular adhesion molecules and the intracellular actin cytoskeleton.Integrins are present in various tissues and organs where these heterodimers participate in diverse physiological and pathological responses at the molecular level in living organisms.Wound healing is a crucial process in the recovery from traumatic diseases and comprises three overlapping phases:inflammation,proliferation and remodeling.Integrins are regulated during the entire wound healing process to enhance processes such as inflammation,angiogenesis and re-epithelialization.Prolonged inflammation may result in failure of wound healing,leading to conditions such as chronic wounds.Bacterial colonization of a wound is one of the primary causes of chronic wounds.Integrins facilitate the infectious effects of bacteria on the host organism,leading to chronic inflammation,bacterial colonization,and ultimately,the failure of wound healing.The present study investigated the role of integrins as bridges for bacteria-cell interactions during wound healing,evaluated the role of integrins as nodes for bacterial inhibition during chronic wound formation,and discussed the challenges and prospects of using integrins as therapeutic targets in wound healing.
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Connective tissue is a dynamic structure that reacts to environmental cues to maintain homeostasis,including mechanical properties.Mechanical load influences extracellular matrix(ECM)—cell interactions and modulates cellular behavior.Mechano-regulation processes involve matrix modification and cell activation to preserve tissue function.The ECM remodeling is crucial for force transmission.Cytoskeleton components are involved in force sensing and transmission,affecting cellular adhesion,motility,and gene expression.Proper mechanical loading helps to maintain tissue health,while imbalances may lead to pathological processes.Active and passive movement,including manual mobilization,improves connective tissue elasticity,promotes ECM-cell homeostasis,and reduces fibrosis.In rehabilitation,understanding mechanical-regulation processes is necessary for ameliorating and developing treatments aimed at preserving tissue elasticity and preventing fibrosis.In this commentary,we aim to globally describe the biological processes involved in mechanical force transmission in connective tissue as support for translational studies and clinical applications in the rehabilitation field.
基金supported by the Slovenian Research and Innovation Agency(ARIS)—Young Researcher Program(contract no.104-04/TK–6811)Research Core Funding P3-0427.
文摘Vedolizumab is a humanized monoclonal antibody and one of the safest biologics for the treatment ofboth forms of inflammatory bowel disease(IBD)-Crohn’s disease and ulcerative colitis.It targets theα4β7 integrinand blocks leukocyte trafficking to the gut.Regardless of its efficacy in many patients,non-response to vedolizumabtreatment poses a significant clinical challenge.In this review,we synthesize recent findings on genomic,transcriptomic,proteomic,and cellular biomarkers of vedolizumab response,emphasizing their roles in predicting therapeutic outcomesand understanding non-responsiveness.Key insights include the identification of epigenetic and transcriptomicsignatures,the involvement of Th17 and IL-6 signaling,and the role of baseline inflammatory markers like albumin.Discrepancies in findings highlight the complexity of biomarker discovery and underscore the need for standardized,multiparametric approaches to refine personalized treatment strategies.By bridging knowledge gaps in vedolizumabresponsiveness,this review aims to advance biomarker-driven decision-making and improve outcomes for patientswith IBD.
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.
文摘Secondary injury following spinal cord injury is primarily characterized by a complex inflammatory response,with resident microglia and infiltrating macrophages playing pivotal roles.While previous studies have grouped these two cell types together based on similarities in structure and function,an increasing number of studies have demonstrated that microglia and macrophages exhibit differences in structure and function and have different effects on disease processes.In this study,we used single-cell RNA sequencing and spatial transcriptomics to identify the distinct evolutionary paths of microglia and macrophages following spinal cord injury.Our results showed that microglia were activated to a pro-inflammatory phenotype immediately after spinal cord injury,gradually transforming to an anti-inflammatory steady state phenotype as the disease progressed.Regarding macrophages,our findings highlighted abundant communication with other cells,including fibroblasts and neurons.Both pro-inflammatory and neuroprotective effects of macrophages were also identified;the pro-inflammatory effect may be related to integrin β2(Itgb2) and the neuroprotective effect may be related to the oncostatin M pathway.These findings were validated by in vivo experiments.This research underscores differences in the cellular dynamics of microglia and macrophages following spinal cord injury,and may offer new perspectives on inflammatory mechanisms and potential therapeutic targets.
基金supported by the National Key R&D Program of China(2022YFF0710500)the the National Natural Science Foundation,China(31802192,32172853 and 32373013)+2 种基金the Natural Science Foundation of Heilongjiang Province of China(C2018070)China Postdoctoral Science Foundation(2017M620076)the Central Public-interest Scientific Institution Basal Research Fund,China(1610302022001)。
文摘Salmonella enterica serovar Typhimurium,the causative agent of gastroenteritis,is one of the most successful intracellular pathogens.Although certain host factors for Salmonella infection have been unveiled,the factors mediating Salmonella entry,particularly the invasion process,remain obscure.Here,we have unearthed β2 integrin,a crucial member of the integrin family,as an important host factor facilitating Salmonella invasion.It is demonstrated that overexpression of β2 integrin promotes Salmonella invasion,while the knockdown of β2 integrin significantly diminishes the extent of invasion.Moreover,Salmonella exhibits specific binding affinity towards β2 integrin,and the block of β2 integrin on cell surface substantially reduces the infection of cells in vitro.The ectodomain soluble protein of β2 integrin neutralized Salmonella infection both in cells(in vitro)and in mice(in vivo).Additionally,Salmonella protein YrbD directly interacts with β2 integrin to facilitate its invasion.To our knowledge,this study showed for the first time that the protein YrbD mediates Salmonella adhesion and internalization into host cells by interacting with β2 integrin.These findings not only broaden our understanding of the mechanisms underlying Salmonella entry,but also identify a prospective target for therapeutic control.
