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Preclinical Evaluation of an Integrin αvβ6-Targeted Photodynamic Therapy.

Photodynamic therapy (PDT) is a minimally invasive treatment in which an external light source activates an injected photosensitizer (PS) to generate reactive oxygen species, causing localized cell death. Although the first PDT received FDA approval in 1995, clinical adoption has been limited, in part due to the limited tumor selectivity of PSs. The goal of this study was to develop a PS with improved tumor selectivity by incorporating a targeting peptide that selectively binds to the integrin αvβ6. The integrin αvβ6 is an epithelial-specific cell-surface receptor that is overexpressed in seve

The Diverse Functions of the Calcium- and Integrin-Binding Protein Family.

The calcium- and integrin-binding protein (CIB) family, comprising four evolutionarily conserved members (CIB1, CIB2, CIB3, and CIB4), is characterized by canonical EF-hand motifs. The functions of CIBs in the inner ear have been investigated, although further research is still necessary to gain a comprehensive understanding of them. Among the CIB family members, CIB2 is essential for auditory function. CIB3 and CIB2 jointly participate in the regulation of balance. Beyond their sensory roles, CIBs exhibit multifunctionality through calcium-dependent interactions with diverse molecular partner

Потенциальный и терапевтический прогресс семьи интегрин в неврологических расстройствах.

Неврологические расстройства охватывают разнообразную и разнородную группу медицинских заболеваний, включая цереброваскулярные заболевания (например, инсульт), нейродегенеративные заболевания (например, болезнь Альцгеймера и болезнь Паркинсона) и аутоиммунные расстройства демиелионации (например, множественный склероз). По мере старения населения мира масштабы этих расстройств продолжают расти, что создает серьезные проблемы для систем здравоохранения и социально-экономических структур. Недавно проведенные исследования выявили интегрины - семейство трансмембранных рецепторов гликпротеина - в к

Совпадение в аннотации оригинала
Neurological disorders encompass a diverse and heterogeneous group of medical conditions, including cerebrovascular diseases (e.g., stroke), … ant challenges to healthcare systems and socio-economic structures. Recent studies have highlighted integrins-a family of transmembrane glycoprotein receptors-as critical regulators of central nervous system function, making them a focal point in neurological disease research. By interacting with the extracellular matrix, integrins modulate cell adhesion, s …

PACSIN2 regulates platelet integrin β1 hemostatic function.

BACKGROUND: Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein (GP)Ib-IX-V complex and integrins β1 and β3. In platelets, the Fes/CIP4-homology Bin-Amphiphysin-Rvs protein PACSIN2 associates with the cytoskeletal and scaffolding protein filamin A (FlnA), linking GPIbα and integrins to the cytoskeleton. OBJECTIVES: Here we investigated the role of PACSIN2 in platelet function. METHODS: Platelet parameters were evaluated in mice lacking PACSIN2 and platelet integrin β1. RESULTS: Pacsin2…

Toward the mechanism of jarastatin (rJast) inhibition of the integrin αVβ3.

Disintegrins are a family of cysteine-rich small proteins that were first identified in snake venom. The high divergence of disintegrins gave rise to a plethora of functions, all related to the interaction with integrins. Disintegrins evolved to interact selectively with different integrins, eliciting many physiological outcomes and being promising candidates for the therapy of many pathologies. We used NMR to determine the structure and dynamics of the recombinant disintegrin jarastatin (rJast) and its interaction with the cancer-related integrin αVβ3. rJast displayed the canonical fold of a …

Ihog proteins contribute to integrin-mediated focal adhesions.

Integrin expression forms focal adhesions, but how this process is physiologically regulated is unclear. Ihog proteins are evolutionarily conserved, playing roles in Hedgehog signaling and serving as trans-homophilic adhesion molecules to mediate cell-cell interactions. Whether these proteins are also engaged in other cell adhesion processes remains unknown. Here, we report that Drosophila Ihog proteins function in the integrin-mediated adhesions. Removal of Ihog proteins causes blister and spheroidal muscle in wings and embryos, respectively. We demonstrate that Ihog proteins interact with in

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability.

Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation.

Molecular Delivery of Cytotoxic Agents via Integrin Activation.

Integrins are cell adhesion receptors overexpressed in tumor cells. A direct inhibition of integrins was investigated, but the best inhibitors performed poorly in clinical trials. A gained attention towards these receptors arouse because they could be target for a selective transport of cytotoxic agents. Several active-targeting systems have been developed to use integrins as a selective cell entrance for some antitumor agents. The aim of this review paper is to report on the most recent results on covalent conjugates between integrin ligands and antitumor drugs. Cytotoxic drugs thus conjugate…

Guidelines To Predict Binding Poses of Antibody-Integrin Complexes.

Integrins are cell adhesion receptors that transmit bidirectional signals across the plasma membrane. They are noncovalently linked heterodimeric molecules consisting of two subunits and act as biomarkers in several pathologies. Thus, according to the increase of therapeutic antibody production, some efforts have been applied to produce anti-integrin antibodies. Here, we purposed to evaluate methods of generation and identification of the binding pose of integrin-antibody complexes, through protein-protein docking and molecular dynamics simulations, and propose a strategy to assure the confide…

Coronin 1 Is Required for Integrin β2 Translocation in Platelets.

Remodeling of the actin cytoskeleton is one of the critical events that allows platelets to undergo morphological and functional changes in response to receptor-mediated signaling cascades. Coronins are a family of evolutionarily conserved proteins implicated in the regulation of the actin cytoskeleton, represented by the abundant coronins 1, 2, and 3 and the less abundant coronin 7 in platelets, but their functions in these cells are poorly understood. A recent report revealed impaired agonist-induced actin polymerization and cofilin phosphoregulation and altered thrombus formation in vivo as

A Genetic Model of Constitutively Active Integrin CD11b/CD18.

Pharmacological activation of integrin CD11b/CD18 (αMβ2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promote

Integrin β1 Promotes Peripheral Entry by Rabies Virus.

Rabies virus (RABV) is a widespread pathogen that causes fatal disease in humans and animals. It has been suggested that multiple host factors are involved in RABV host entry. Here, we showed that RABV uses integrin β1 (ITGB1) for cellular entry. RABV infection was drastically decreased after ITGB1 short interfering RNA knockdown and moderately increased after ITGB1 overexpression in cells. ITGB1 directly interacts with RABV glycoprotein. Upon infection, ITGB1 is internalized into cells and transported to late endosomes together with RABV. The infectivity of cell-adapted RABV in cells and stre

α4β7 Integrin Antagonist Vedolizumab for the Treatment of Refractory Ileitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is a superficial diffuse inflammation restricted to the colon and rectum. Inflammation within the small bowel may occur several years after a pancolectomy. The pathogenesis is unknown and seems to be different from Crohn's disease or other causes of diseases of the small intestine, but an association with colectomy due to UC is very likely. METHODS AND RESULTS: We describe the case of a patient with a probable diagnosis of pan-UC accompanied by Sjögren's syndrome and partial IgA deficiency, who developed enteritis after a restorative pancolectomy.

Integrin αvβ6: Structure, function and role in health and disease.

Integrins are cell surface receptors that traditionally mediate cell-to-extracellular matrix and cell-to-cell adhesion. They can, however, also bind a large repertoire of other molecules. Integrin αvβ6 is exclusively expressed in epithelial cells where it can, for example, serve as a fibronectin receptor. However, its hallmark function is to activate transforming growth factor-β1 (TGF-β1) to modulate innate immune surveillance in lungs and skin and along the gastrointestinal tract, and to maintain epithelial stem cell quiescence. The loss of αvβ6 integrin function in mice and humans leads to a…

Integrin α8 Is Abundant in Human, Rat, and Mouse Trophoblasts.

OBJECTIVE: Integrins exert regulatory functions in placentogenesis. Null mutation of certain integrin α subunits leads to placental defects with subsequent fetal growth restriction or embryonic lethality in mice. So far, the placental role of α8 integrin remains to be determined. METHODS: Localization of α8 integrin and its ligands, fibronectin (FN) and osteopontin (OPN), was studied by immunohistochemistry in human, rat, and mouse placenta. The vascularization of the placental labyrinth layer of α8 integrin-deficient mice was determined by CD31 staining. In humans, α8 integrin expression was…

Integrin linked kinase regulates the transcription of AQP2 by NFATC3.

Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to-intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-me

Integrin αvβ3 Signaling in Tumor-Induced Bone Disease.

Tumor-induced bone disease is common among patients with advanced solid cancers, especially those with breast, prostate, and lung malignancies. The tendency of these cancers to metastasize to bone and induce bone destruction is, in part, due to alterations in integrin expression and signaling. Substantial evidence from preclinical studies shows that increased expression of integrin αvβ3 in tumor cells promotes the metastatic and bone-invasive phenotype. Integrin αvβ3 mediates cell adhesion to several extracellular matrix proteins in the bone microenvironment which is necessary for tumor cell c

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… Like other integrins, αvβ3 acts as a bidirectional signaling molecule. … Talin binding to integrin β tails: A final common step in integrin activation Science 2003 302 103 106 10.1126/science.1086652 14526080 16. Ma Y.Q. Qin J. Wu C. Plow E.F. Kindlin-2 (Mig-2): A co-activator of beta3 integrins J. Cell. …

The pathogenic relevance of αM-integrin in Guillain-Barré syndrome.

The molecular determinants and mechanisms involved in leukocyte trafficking across the blood-nerve barrier (BNB) in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) variant of Guillain-Barré syndrome are incompletely understood. Prior work using a flow-dependent in vitro human BNB model demonstrated a crucial role for αM-integrin (CD11b)-intercellular adhesion molecule-1 interactions in AIDP patient leukocyte trafficking. The aim of this study is to directly investigate the biological relevance of CD11b in AIDP pathogenesis. Immunohistochemistry was performed on three AIDP pa

Integrin αvβ3 promotes infection by Japanese encephalitis virus.

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that is one of the major causes of viral encephalitis diseases worldwide. The JEV envelope protein facilitates viral entry, and its domain III contains an Arg-Gly-Asp (RGD) motif, that may modulate JEV entry through the RGD-binding integrin. In this study, the roles of integrin αv and β3 on the infection of JEV were evaluated. Reduced expression of integrin αv/β3 by special shRNA confers 2 to 4-fold inhibition of JEV replication in BHK-21 cells. Meanwhile, antibodies specific for integrin αv/β3 displayed ~58% and ~33% inhibition