Результаты поиска

Surface relocation of alpha 6 beta 4 integrins and assembly of hemidesmosomes in an in vitro model of wound healing.

A transmembrane extracellular matrix receptor of the integrin family, alpha 6 beta 4, is a component of the hemidesmosome, an adhesion compl … en type VII-containing anchoring fibrils. We have monitored the incorporation of the alpha 6 beta 4 integrins into forming hemidesmosomes in an in vitro wound-healing explant model. In epithelial cells recently migrated from the edges of unwounded sites over bare connective tissue, alpha 6 beta 4 first appears along the entire cell surface. At this stage, t …

Beyond Integrin Activation: Kindlin-3 as an Organiser of Immune Receptor Signalling.

Kindlins are best known for their roles in integrin regulation, but studies across the family have revealed additional functions in receptor … shed role of kindlin-3 in immune cells and raises important questions about how kindlins coordinate integrins with other signalling receptors.

Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.

Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise-inducible myokine with neuroprotective potential, but its receptor mechanisms and its role in α-syn clearance in PD-CI are poorly defined. Here, we observed that aerobic exercise markedly increased circulating irisin levels, reduced serum α-syn levels, and improved cognitive performance in a cohort of 21 PD patients. In addition, irisin signals through integrin αV/β5 to enhanc

Integrin αv contributes to the regulation of vascular smooth muscle cell stiffness.

Arterial stiffening is influenced by the organization of focal adhesions in vascular smooth muscle cells (VSMCs). We investigated the contribution of αv integrins to both arterial wall stiffness (Young's modulus measured by echography) and VSMC stiffness (assessed by atomic force microscopy). Mice with VSMC-specific deletion of αv integrins (αvSMKO) were compared with controls at baseline and following angiotensin II infusion. Unstimulated cultured αv-deficient (αv-KD) VSMCs exhibited higher stiffness than controls, with a further increase after angiotensin II. To interpret AFM measurements pe…

MRC2 Links Collagen Turnover to Integrin/PI3K/AKT-Driven Fibrogenesis.

Liver fibrosis is characterized by excessive collagen accumulation, the principal component of the extracellular matrix (ECM), produced by a … KT axis, accompanied by increased AKT phosphorylation. Pharmacological inhibition of either PI3K or integrins reversed ECM gene expression and collagen phenotypes induced by MRC2 depletion, establishing these pathways as required mediators. Our findings identify a novel, non-canonical signaling function of MRC2 as a negative regulator of HSC activation.

The novel [68Ga]Ga-DOTA-C6-anti-integrin peptide in glioblastoma.

Glioblastoma (GB) is the most aggressive primary brain tumor. Patient survival remains poor, with current therapies bringing no improvements, and the assessment of therapy response and tumor progression using conventional imaging exams is challenging for clinicians during patient follow-up. Integrins, transmembrane proteins related to cell invasion and motility, are overexpressed in GB. This study evaluates the effects of [68Ga]Ga-DOTA-C6-anti-integrin peptide on GB binding, internalization, survival, migration, and biodistribution, as well as its mechanism of action against the tumor. Binding…

Platelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation.

Platelet integrin αIIbβ3 is essential for hemostasis, thrombosis, and inflammation. We found that ligation of αIIbβ3 by von Willebrand factor or fibrin under flow triggered its accumulation in plasma membrane extensions or "platelet-derived integrin- and tetraspanin-enriched tethers" (PITTs). PITTs remained anchored to leukocytes or endothelial cells, whereas the partially αIIbβ3-deficient platelet body detached. Although still responsive to stimuli, αIIbβ3-deficient platelets did not support thrombus formation. PITTs promoted leukocyte activation and vascular inflammation in mouse models of i

Electrostatic steering in integrin recognition revealed by a programmable heterotrimeric collagen platform.

Robust cell adhesion within complex, diffusion-limited microenvironments hinges on the rapid recognition of extracellular matrix (ECM) collagen macromolecules by integrins. However, the traditional "lock-and-key" model, which emphasizes static thermodynamic affinity, fails to adequately explain the dynamic kinetics of this rapid recognition. A major bottleneck in resolving this mechanism has been the lack of precise macromolecular models capable of decoupling local charge density from spatial arrangement. Here, leveraging a programmable heterotrimeric collagen engineering platform, we systemat…

Secondary Site Ligand for Integrin αVβ3 Enables Targeted mRNA Delivery.

Poor perfusion and abnormal vasculature constrain direct drug delivery to solid tumors. Hence, targeting neighboring tumor endothelial cells via the upregulated marker integrin αVβ3 is a promising strategy. Orthosteric arginine-glycine-aspartate (RGD) ligands of αVβ3 achieve high affinities but suffer from cross-reactivity. Alternatively, selective targeting of αVβ3 could potentially be achieved via low-affinity ligands, displayed multivalently on nanoparticles to leverage avidity. To avoid orthosteric site competition, we performed a fragment screening under RGD saturation. Structure-activity

Empagliflozin inhibits cardiac hypertrophy via a mechanism involving integrin signalling.

BACKGROUND AND PURPOSE: Pathological cardiac hypertrophy precipitates heart failure. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, confers cardiovascular protection beyond glycaemic control, but the molecular basis of its direct anti-hypertrophic action remains undefined. EXPERIMENTAL APPROACH: Angiotensin II (Ang II)-induced hypertrophy was modelled in AC16 and H9c2 cardiomyocytes, and pressure overload was modelled in mice undergoing transverse aortic constriction (TAC). Outcomes were assessed by cell surface area, marker expression, histology and echocardiograph

Интегрин α4β7:: патогенные роли в заболеваниях метаболики и воспаления и в терапии перевода.

Интегрин α4β7 является ключевым рецептором сцепления, который является посредником лимфоцита, движущегося к кишечной слизи через взаимодействие с MAdCAM-1, VCAM-1, и фибронектин, тем самым играя центральную роль в иммунной слежке и мукозаловом иммунитете. Появляющиеся данные расширили его функциональный охват за пределы кишечного гомеостаза, с тем чтобы охватить различные подстрекательские и метаболические заболевания. В настоящем обзоре систематически резюмируются структурные характеристики, взаимодействия лигандов и положения о соответствии α.4β7, с акцентом на патогенную роль в провокационн

Совпадение в полном тексте источника
… in humans that can combine to form 24 distinct integrin receptors. 3 Integrin signaling is involved in numerous physiological processes, and its functions are exquisitely regulated both biochemically and mechanically. 4 The regulatory functions of integrins in innate and adaptive immunity, together … The initial search strategy focused on the integrin receptor and its primary ligands using a combination of Medical Subject Headings (MeSH) and free-text keywords: “integrin alpha4beta7”, “α4β7 integrin”, “LPAM-1”, “MAdCAM-1”, “mucosal addressin cell adhesion molecule 1”, “VCAM-1”, “vascular cell adhesion …

Integrin-deficient T cell leukemia accumulates in the central nervous system.

T-cell acute lymphoblastic leukemia (T-ALL) spreads aggressively to the central nervous system (CNS), particularly the leptomeninges. Children with T-ALL are treated with high-dose, CNS-directed chemotherapy, which can cause lasting neurotoxicity and is not always effective. Little is known about how T-ALL enters and persists within the CNS. However, normal T cell migration into the CNS has been extensively studied. Two integrins-VLA-4 and LFA-1-mediate normal T cell entry to the CNS, and VLA-4 blockade effectively treats multiple sclerosis by excluding T cells from the brain. We hypothesized …

Elastic properties of leukemic cells linked to maturation stage and integrin activation.

Acute myeloid leukemia (AML) remains challenging to cure. In addition to mutations that alter cell functioning, biophysical properties are modulated by external cues. In particular, membrane proteins that interact with the bone marrow niche can induce cellular changes. Here, we develop an atomic force microscopy (AFM) approach to measure non-adherent AML cell mechanical properties. The Young's modulus of the AML cell line, THP-1, increased in response to retronectin, whereas knock-out of the adhesion protein ITGB1 resulted in no response to retronectin. Confocal microscopy revealed different a

Carnosic acid inhibits integrin expression and prevents pulmonary metastasis of melanoma.

Carnosic acid is a naturally occurring, plant-derived polyphenolic abietane diterpene with antitumor properties. However, its underlying mechanisms are still unclear. Therefore, we investigated the effects of carnosic acid on lung metastasis in a murine melanoma model. C57BL/6 mice were intravenously injected with B16-BL6 cells, followed by carnosic acid treatment. Lung weights were recorded, and tumor cell colonies were counted at the end of the experiment. Integrin expression was evaluated using flow cytometry and cell adhesion assays. Lung weights were significantly lower in the carnosic ac

MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis.

Cancer metastasis is governed by physical cues at the cell-matrix interface, with matrix stiffness, ligand density, and topography established as key determinants. Here, a fourth critical factor in cancer metastasis, the architecture of the cell-surface glycocalyx is identified. Using MUC15 as a representative small glycoprotein, mathematical modeling and domain truncation experiments are combined to show that glycoprotein size distribution governs integrin adhesion states and metastatic outcomes. MUC15 localizes to focal adhesions and interact with integrins, while larger glycoproteins such a…

Force-dependent development of the myodural bridge in rats: The impact of Integrin α7.

The myodural bridge (MDB) represents specialized fibrous structures establishing connectivity between suboccipital musculature and the spinal dura mater (SDM). The suboccipital muscles, ligaments, and myodural bridge fibers together form a functional unit known as the myodural bridge complex (MDBC). Mechanical stress from suboccipital muscles may contribute to MDB maturation. Integrin α7 (ITGA7) is critical for skeletal muscle attachment to connective tissues, and is involved in the transmission of lateral and longitudinal forces in skeletal muscle. Given the muscle force transmission characte

Nanoscopy reveals integrin clustering reliant on kindlin-3 but not talin-1.

BACKGROUND: Neutrophils are the most abundant leukocytes in human blood, and their recruitment is essential for innate immunity and inflammatory responses. The initial and critical step of neutrophil recruitment is their adhesion to vascular endothelium, which depends on G protein-coupled receptor (GPCR) triggered integrin inside-out signaling that induces β2 integrin activation and clustering on neutrophils. Kindlin-3 and talin-1 are essential regulators for the inside-out signaling induced β2 integrin activation. However, their contribution in the inside-out signaling induced β2 integrin clu

A Study on Regulating OSCC Cell Function by Blocking Integrin αvβ3 With Cilengitide.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most important histologic type of oral tumor. Integrin- and integrin-dependent processes are involved in almost every step of cancer progression. Integrin αvβ3 was initially considered an integrin associated with tumor angiogenesis. With the gradual deepening of research, it was found that αvβ3 also plays a role in tumor cells. This study aimed to explore the function of tumor cell integrin αvβ3 in the progression of OSCC. METHODS: Immunohistochemical methods in OSCC tissues explored the expression of integrin αvβ3. CCK-8, EdU, Cell cycle

Tunable Integrin-Ligand Coupling Strength Modulates Cellular Adaptive Mechanosensing.

Cells sense and respond to the matrix by exerting traction force through binding of integrins to an integrin-specific ligand. Here, Arg-Gly-Asp (RGD) peptide is covalently conjugated to the double-stranded DNA (dsDNA) and stem-loop DNA (slDNA) tethers with a tension tolerance of 43pN and immobilized on a PEG substrate. Unlike dsDNA, which is ruptured under high tension, leading to the removal of RGD, slDNA remains bound even when ruptured. Our results suggest that cells adapt their adhesion state by modulating actin filament polymerization and cofilin phosphorylation, effectively balancing the…