228 results on '"Integrins drug effects"'
Search Results
2. Targeting of the COX-2/PGE2 axis enhances the antitumor activity of T7 peptide in vitro and in vivo .
- Author
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Yang J, Zhong J, Zhou M, Zhou Y, Xiu P, Liu F, Wang F, Li Z, Tang Y, Chen Y, Yao S, Huang T, Liu T, and Dong X
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation, Cyclooxygenase 2 metabolism, Drug Combinations, Endothelial Cells drug effects, Humans, Hypoxia pathology, Integrins drug effects, Mice, Neovascularization, Pathologic drug therapy, RNA, Small Interfering metabolism, Random Allocation, Xenograft Model Antitumor Assays, Carcinoma, Hepatocellular drug therapy, Collagen Type IV pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Dinoprostone antagonists & inhibitors, Liver Neoplasms drug therapy, Meloxicam pharmacology, Peptide Fragments pharmacology
- Abstract
T7 peptide is considered as an antiangiogenic polypeptide. The presents study aimed to further detect the antiangiogenic mechanisms of T7 peptide and determine whether combining T7 peptide and meloxicam (COX-2/PGE2 specific inhibitor) could offer a better therapy to combat hepatocellular carcinoma (HCC). T7 peptide suppressed the proliferation, migration, tube formation, and promoted the apoptosis of endothelial cells under both normoxic and hypoxic conditions via integrin α3β1 and αvβ3 pathways. Cell proliferation, migration, apoptosis, or tube formation ability were detected, and the expression of integrin-associated regulatory proteins was detected. The anti-tumor activity of T7 peptide, meloxicam, and their combination were evaluated in HCC tumor models established in mice. T7 peptide suppressed the proliferation, migration, tube formation, and promoted the apoptosis of endothelial cells under both normoxic and hypoxic conditions via integrin α3β1 and αvβ3 pathways. Meloxicam enhanced the activity of T7 peptide under hypoxic condition. T7 peptide partly inhibited COX-2 expression via integrin α3β1 not αvβ3-dependent pathways under hypoxic condition. T7 peptide regulated apoptosis associated protein through MAPK-dependent and -independent pathways under hypoxic condition. The MAPK pathway was activated by the COX-2/PGE2 axis under hypoxic condition. The combination of T7 and meloxicam showed a stronger anti-tumor effect against HCC tumors in mice. The data highlight that meloxicam enhanced the antiangiogenic activity of T7 peptide in vitro and in vivo . more...
- Published
- 2021
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3. The Antithrombotic Agent Pterostilbene Interferes with Integrin α IIb β 3 -Mediated Inside-Out and Outside-In Signals in Human Platelets.
- Author
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Huang WC, Lin KC, Hsia CW, Hsia CH, Chen TY, Bhavan PS, Sheu JR, and Hou SM
- Subjects
- Animals, Blood Coagulation drug effects, Blood Platelets drug effects, Clot Retraction drug effects, Collagen, Fibrinogen metabolism, Hemostasis drug effects, Humans, Integrin alpha2 drug effects, Integrin alpha2 metabolism, Integrin beta3 drug effects, Integrin beta3 metabolism, Integrins drug effects, Integrins metabolism, Mice, P-Selectin metabolism, Phosphorylation, Platelet Activation drug effects, Platelet Aggregation drug effects, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Signal Transduction drug effects, Stilbenes pharmacology, Thrombosis metabolism, Blood Platelets metabolism, Platelet Glycoprotein GPIIb-IIIa Complex drug effects, Stilbenes metabolism
- Abstract
Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies have reported the effects of pterostilbene on platelet activation. Thus, we examined the inhibitory mechanisms of pterostilbene in human platelets and its role in vascular thrombosis prevention in mice. At low concentrations (2-8 μM), pterostilbene strongly inhibited collagen-induced platelet aggregation. Furthermore, pterostilbene markedly diminished Lyn, Fyn, and Syk phosphorylation and hydroxyl radical formation stimulated by collagen. Moreover, PTE directly hindered integrin α
IIb β3 activation through interfering with PAC-1 binding stimulated by collagen. In addition, pterostilbene affected integrin αIIb β3 -mediated outside-in signaling, such as integrin β3 , Src, and FAK phosphorylation, and reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Furthermore, pterostilbene substantially prolonged the occlusion time of thrombotic platelet plug formation in mice. This study demonstrated that pterostilbene exhibits a strong activity against platelet activation through the inhibition of integrin αIIb β3 -mediated inside-out and outside-in signaling, suggesting that pterostilbene can serve as a therapeutic agent for thromboembolic disorders. more...- Published
- 2021
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4. An in Vitro Assay to Study the Role of Opioids in Modulating Immune Cell Adhesion.
- Author
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Baiula M
- Subjects
- Analgesics, Opioid metabolism, Analgesics, Opioid pharmacology, Animals, Cell Adhesion physiology, Cell Adhesion Molecules drug effects, Humans, Immunologic Factors pharmacology, Inflammation metabolism, Integrins drug effects, Integrins metabolism, Jurkat Cells, Leukocytes metabolism, U937 Cells, Cell Adhesion drug effects, Cell Adhesion Molecules metabolism, Immunohistochemistry methods
- Abstract
Opioids play a pivotal role in pain transmission but are also able to modulate immune cell functions. In the last decades a connection between opioids and integrins-adhesion molecules involved, among many other processes, in leukocyte recruitment at inflamed site-has been established. To study immune cell integrin-mediated adhesion, cell adhesion assay is a simple, reproducible, and valuable tool capable of unraveling concentration-dependent effects of a test candidate on integrin-mediated cell adhesion. more...
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- 2021
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5. c(RGDfK)- and ZnTriMPyP-Bound Polymeric Nanocarriers for Tumor-Targeted Photodynamic Therapy.
- Author
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de Las Heras E, Boix-Garriga E, Bryden F, Agut M, Mora M, Sagristá ML, Boyle RW, Lange N, and Nonell S
- Subjects
- Cell Line, Tumor, Humans, Integrins drug effects, Kinetics, Photosensitizing Agents therapeutic use, Singlet Oxygen chemistry, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet, Drug Carriers, Nanoparticles, Neoplasms drug therapy, Oligopeptides chemistry, Photochemotherapy, Photosensitizing Agents pharmacology, Polymers chemistry
- Abstract
Active targeting strategies are currently being extensively investigated in order to enhance the selectivity of photodynamic therapy. The aim of the present research was to evaluate whether the external decoration of nanopolymeric carriers with targeting peptides could add more value to a photosensitizer formulation and increase antitumor therapeutic efficacy and selectivity. To this end, we assessed PLGA-PLA-PEG nanoparticles (NPs) covalently attached to a hydrophilic photosensitizer 5-[4-azidophenyl]-10,15,20-tri-(N-methyl-4-pyridinium)porphyrinato zinc (II) trichloride (ZnTriMPyP) and also to c(RGDfK) peptides, in order to target α
v β3 integrin-expressing cells. In vitro phototoxicity investigations showed that the ZnTriMPyP-PLGA-PLA-PEG-c(RGDfK) nanosystem is effective at submicromolar concentrations, is devoid of dark toxicity, successfully targets αv β3 integrin-expressing cells and is 10-fold more potent than related nanosystems where the PS is occluded instead of covalently bound., (© 2020 American Society for Photobiology.) more...- Published
- 2020
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6. Integrin Antibody Decreases Deformability of Patient-Derived Pre-B Acute Lymphocytic Leukemia Cells as Measured by High-Frequency Acoustic Tweezers.
- Author
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Liu HC, Gang EJ, Kim HN, Abdel-Azim N, Chen R, Abdel-Azim H, Shung KK, and Kim YM
- Subjects
- Acoustics, Cells, Cultured, Humans, Immunoglobulin G administration & dosage, Ultrasonography methods, Cell Adhesion drug effects, Immunologic Factors therapeutic use, Integrins drug effects, Natalizumab therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnostic imaging, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Objectives: This article reports a study of cell mechanics in patient-derived (primary) B-cell acute lymphocytic leukemia (ALL) cells treated with antibodies against integrins. Leukemia cell adhesion to stromal cells mediates chemotherapeutic drug resistance, also known as cell adhesion-mediated chemotherapeutic drug resistance. We have previously shown that antibodies against integrin α
4 and α6 adhesion molecules can de-adhere ALL cells from stromal cells or counter-receptors. Because drug-resistant cells are more deformable, as evaluated by single-beam acoustic tweezers, we hypothesized that changes in cell mechanics might contribute to the de-adhesive effect of integrin-targeting antibodies., Methods: In this study, the deformability of primary pre-B ALL cells was evaluated by single-beam acoustic tweezers after treatments with the de-adhering antibody Tysabri or P5G10 against integrin α4 and α6 adhesion molecules., Results: We demonstrated that primary ALL cells treated with P5G10 expressed decreased deformability compared with immunoglobulin G1 -treated control cells (P < .05). Tysabri did not show an effect on deformability (P > .05)., Conclusions: These results suggest that decreased deformability is associated with an integrin α6 blockade. Further assessments of the functional roles of deformability and integrin blockades in B-ALL cell drug resistance and deformability, respectively, are necessary., (© 2019 by the American Institute of Ultrasound in Medicine.) more...- Published
- 2020
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7. Integrins as A New Target for Cancer Treatment.
- Author
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Łasiñska I and Mackiewicz J
- Subjects
- Antineoplastic Agents therapeutic use, Clinical Trials as Topic, Humans, Antineoplastic Agents pharmacology, Integrins drug effects, Neoplasms drug therapy
- Abstract
Despite the great progress in the development of targeted therapies for different types of cancer utilizing monoclonal antibodies (e.g., cetuximab for colorectal cancer and head and neck cancer therapy), kinase inhibitors (e.g., sorafenib for kidney cancer and gastrointestinal stromal tumours therapy), and immunomodulatory treatments (e.g., nivolumab and pembrolizumab for melanoma therapy and lung cancer therapy), there is still a need to search for new, more effective treatments. Integrins are responsible for intercellular adhesion and interaction with the cellular matrix. The function of integrins is related to the transduction of intracellular signals associated with adhesion, migration, cell proliferation, differentiation, and apoptosis. Molecules targeting integrins that lead to cancer cell death have been developed. The most advanced molecules studied in clinical trials are abituzumab, intetumumab and cilengitide. There are different groups of anti-integrin drugs: monoclonal antibodies (e.g., abituzumab) and other such as cilengitide, E7820 and MK-0429. These drugs have been evaluated in various cancer types. However, they have shown modest efficacy, and none of them have yet been approved for cancer treatment. Studies have shown that patient selection using biomarkers might improve the efficacy of anti-integrin cancer treatment. Many preclinical models have demonstrated promising results using integrin visualization for cancer detection and treatment efficacy monitoring; however, these strategies require further evaluation in humans., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) more...
- Published
- 2019
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8. Ammonium trichloro [1,2-ethanediolato-O,O']-tellurate cures experimental visceral leishmaniasis by redox modulation of Leishmania donovani trypanothione reductase and inhibiting host integrin linked PI3K/Akt pathway.
- Author
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Vishwakarma P, Parmar N, Chandrakar P, Sharma T, Kathuria M, Agnihotri PK, Siddiqi MI, Mitra K, and Kar S
- Subjects
- Animals, Cells, Cultured, Cricetinae, Disease Models, Animal, Ethylenes pharmacology, Female, Host-Parasite Interactions drug effects, Integrins drug effects, Leishmania donovani drug effects, Leishmania donovani metabolism, Leishmaniasis, Visceral metabolism, Leishmaniasis, Visceral pathology, Male, Mice, Mice, Inbred BALB C, NADH, NADPH Oxidoreductases metabolism, Oxidation-Reduction drug effects, Phosphatidylinositol 3-Kinases drug effects, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt drug effects, Signal Transduction drug effects, Ethylenes therapeutic use, Integrins antagonists & inhibitors, Leishmania donovani enzymology, Leishmaniasis, Visceral drug therapy, NADH, NADPH Oxidoreductases drug effects
- Abstract
In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O']-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking α4β7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-κB for Th1 response. In silico docking and biochemical assays revealed AS101's affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca
2+ level, loss of ATP and mitochondrial membrane potential along with metacaspase activation. Our findings provide the first evidence for the mechanism of action of AS101 with excellent safety profile and suggest its promising therapeutic potential against experimental visceral leishmaniasis. more...- Published
- 2018
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9. D-mannose induces regulatory T cells and suppresses immunopathology.
- Author
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Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R, Konkel JE, Nakatsukasa H, Zanvit P, Goldberg N, Chen Q, Sun L, Chen ZJ, and Chen W
- Subjects
- Adoptive Transfer, Animals, Colon drug effects, Dietary Supplements, Disease Models, Animal, Fatty Acids metabolism, Flow Cytometry, Forkhead Transcription Factors metabolism, Humans, In Vitro Techniques, Inflammation, Integrins drug effects, Integrins immunology, Lipid Metabolism drug effects, Lung immunology, Lung Diseases chemically induced, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Ovalbumin adverse effects, Oxidation-Reduction drug effects, Pancreas immunology, Reactive Oxygen Species metabolism, Real-Time Polymerase Chain Reaction, Respiratory Hypersensitivity chemically induced, Reverse Transcriptase Polymerase Chain Reaction, Spleen drug effects, Spleen immunology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Transforming Growth Factor beta immunology, Up-Regulation, Colitis immunology, Diabetes Mellitus, Type 1 immunology, Lung drug effects, Lung Diseases immunology, Mannose pharmacology, Pancreas drug effects, Respiratory Hypersensitivity immunology, T-Lymphocytes, Regulatory drug effects, Transforming Growth Factor beta drug effects
- Abstract
D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3
+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αv β8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology. more...- Published
- 2017
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10. Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling.
- Author
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Wei Z and Shaikh ZA
- Subjects
- Cell Adhesion drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cytoskeleton drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, MCF-7 Cells, Phenotype, Wound Healing drug effects, Cadmium toxicity, Integrins drug effects, Neoplasm Metastasis pathology, Signal Transduction drug effects, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, beta Catenin drug effects
- Abstract
Cadmium (Cd) is a carcinogenic heavy metal which is implicated in breast cancer development. While the mechanisms of Cd-induced breast cancer initiation and promotion have been studied, the molecular processes involved in breast cancer progression remain to be investigated. The purpose of the present study was to evaluate the influence of Cd on metastasis-associated phenotypes, such as cell adhesion, migration, and invasion in triple-negative breast cancer cells. Treatment of MDA-MB-231 cells with 1μM Cd increased cell spreading and cell migration. This was associated with the activation of integrin β1, FAK, Src, and Rac1. Treatment with Cd also inhibited GSK3β activity and induced T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription, indicating the involvement of β-catenin signaling. Furthermore, treatment with 3μM Cd for 4weeks increased the expression of β-catenin and enhanced TCF/LEF-mediated transcription. Furthermore, enhanced expressions of integrins α5 and β1, paxillin, and vimentin indicated that prolonged Cd treatment reorganized the cytoskeleton, which aided malignancy, as evidenced by enhanced matrix metalloprotease 2/9 (MMP2/9) secretion and cell invasion. Prolonged Cd treatment also caused an increase in cell growth. Together, these results indicate that Cd alters key signaling processes involved in the regulation of cytoskeleton to enhance cancer cell migration, invasion, adhesion, and proliferation., (Copyright © 2017 Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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11. Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases.
- Author
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Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, Cleland T, and Xavier RJ
- Subjects
- Butyrates metabolism, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Feces chemistry, Feces microbiology, Humans, Integrins drug effects, Metagenome, Prospective Studies, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Biological Therapy, Gastrointestinal Microbiome physiology, Inflammatory Bowel Diseases therapy
- Abstract
The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn's disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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12. Novel Insights into the Mechanisms of Gut Homing and Antiadhesion Therapies in Inflammatory Bowel Diseases.
- Author
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Zundler S and Neurath MF
- Subjects
- Animals, Humans, Inflammatory Bowel Diseases immunology, Integrins drug effects, Intestines immunology, Antibodies, Monoclonal, Humanized pharmacology, Gastrointestinal Agents pharmacology, Inflammatory Bowel Diseases drug therapy, Integrins immunology, T-Lymphocytes immunology
- Abstract
Therapeutic compounds interfering with T cell trafficking are a new column of inflammatory bowel disease (IBD) treatment. Currently, the anti-α4β7 integrin antibody vedolizumab is successfully used in the clinic and further drugs are likely to follow. Despite these clinical advances, the precise mechanistic background of their action is only gradually elucidated and still a matter of intensive research. Only recently, advances made with the help of new in vivo models and human studies have contributed to shape our concept of T cell trafficking in IBD by deciphering some important and so far unanswered questions. At the same time, basic and clinical data have generated new issues to be addressed on the way toward a clear perception of trafficking mechanisms and toward elucidation of the action of compounds interfering with this process. In this review, we will give a comprehensive outline of all components of T cell trafficking in regard to IBD before discussing the current knowledge concerning targeted interference with integrins in this complex network. Moreover, we will summarize remaining ambiguity and give an outlook on potential future targets. more...
- Published
- 2017
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13. Targeting Integrin α4β7 in Steroid-Refractory Intestinal Graft-versus-Host Disease.
- Author
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Fløisand Y, Lundin KEA, Lazarevic V, Kristiansen JD, Osnes LTN, Tjønnfjord GE, Reims HM, and Gedde-Dahl T
- Subjects
- Adult, Female, Gastrointestinal Agents therapeutic use, Graft vs Host Disease pathology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Male, Middle Aged, Salvage Therapy methods, Steroids therapeutic use, Transplantation, Homologous, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Graft vs Host Disease drug therapy, Integrins drug effects, Intestinal Diseases drug therapy
- Abstract
Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin α4β7, in 6 patients. All patients responded, and 4 of 6 patients are alive with a median follow-up of 10 months., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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14. Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats.
- Author
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Wu J, Zhang Y, Yang P, Enkhjargal B, Manaenko A, Tang J, Pearce WJ, Hartman R, Obenaus A, Chen G, and Zhang JH
- Subjects
- Animals, Disease Models, Animal, Male, Neuroprotective Agents administration & dosage, Osteopontin administration & dosage, Phenotype, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Cerebral Arteries drug effects, Integrins drug effects, Muscle, Smooth, Vascular drug effects, Myocytes, Smooth Muscle drug effects, Neuroprotective Agents pharmacology, Osteopontin pharmacology, Protein Serine-Threonine Kinases drug effects, Subarachnoid Hemorrhage drug therapy, rac1 GTP-Binding Protein drug effects
- Abstract
Background and Purpose: Recombinant osteopontin (rOPN) has been reported to be neuroprotective in stroke animal models. The purpose of this study is to investigate a potential role and mechanism of nasal administration of rOPN on preserving the vascular smooth muscle phenotype in early brain injury after subarachnoid hemorrhage (SAH)., Methods: One hundred and ninety-two male adult Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Integrin-linked kinase small interfering RNA was intracerebroventricularly injected 48 hours before SAH. The integrin receptor antagonist fibronectin-derived peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP), focal adhesion kinase inhibitor Fib-14, and Rac-1 inhibitor NSC23766 were administered 1 hour before SAH induction. rOPN was administered via the intracerebroventricular and nasal route after SAH. SAH grade, neurological scores, brain water content, brain swelling, hematoxylin and eosin staining, India ink angiography, Western blots, and immunofluorescence were used to study the mechanisms of rOPN on the vascular smooth muscle phenotypic transformation., Results: The marker proteins of vascular smooth muscle phenotypic transformation α-smooth muscle actin decreased and embryonic smooth muscle myosin heavy chain (SMemb) increased significantly at 24 and 72 hours in the cerebral arteries after SAH. rOPN prevented the changes of α-smooth muscle actin and SMemb and significantly alleviated neurobehavioral dysfunction, increased the cross-sectional area and the lumen diameter of the cerebral arteries, reduced the brain water content and brain swelling, and improved the wall thickness of cerebral arteries. These effects of rOPN were abolished by GRGDSP, integrin-linked kinase small interfering RNA, and NSC23766. Intranasal application of rOPN at 3 hours after SAH also reduced neurological deficits., Conclusions: rOPN prevented the vascular smooth muscle phenotypic transformation and improved the neurological outcome, which was possibly mediated by the integrin receptor/integrin-linked kinase/Rac-1 pathway., (© 2016 American Heart Association, Inc.) more...
- Published
- 2016
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15. MAP4K4 regulates integrin-FERM binding to control endothelial cell motility.
- Author
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Vitorino P, Yeung S, Crow A, Bakke J, Smyczek T, West K, McNamara E, Eastham-Anderson J, Gould S, Harris SF, Ndubaku C, and Ye W
- Subjects
- Amino Acid Motifs, Animals, Cell Membrane drug effects, Cell Membrane metabolism, Cell Shape drug effects, Endothelial Cells drug effects, Epistasis, Genetic, Focal Adhesions metabolism, Humans, Integrin alpha1 drug effects, Integrin alpha1 metabolism, Integrin beta1 chemistry, Integrin beta1 drug effects, Integrin beta1 metabolism, Integrins drug effects, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Male, Mice, Microfilament Proteins deficiency, Microfilament Proteins genetics, Microfilament Proteins metabolism, Neovascularization, Pathologic, Phosphorylation, Protein Binding, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Protein Structure, Tertiary, Talin chemistry, Talin metabolism, Cell Movement, Endothelial Cells cytology, Endothelial Cells metabolism, Integrins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-β1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to β1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α5β1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target. more...
- Published
- 2015
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16. Enhancement of antifungal activity by integrin-targeting of branched histidine rich peptides.
- Author
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Scaria PV, Liu Y, Leng Q, Chou ST, Mixson AJ, and Woodle MC
- Subjects
- Candida albicans drug effects, Microbial Sensitivity Tests, Peptides chemistry, Polyethylene Glycols chemistry, Antifungal Agents pharmacology, Drug Delivery Systems, Histidine analysis, Integrins drug effects, Peptides pharmacology
- Abstract
The treatment of invasive candidiasis associated with growing numbers of immunocompromised patients remains a major challenge complicated by increasing drug resistance. A novel class of branched histidine-lysine (bHK) peptides has promising antifungal activity, and exhibits a mechanism similar to natural histatins, and thus may avoid drug resistance. The present studies evaluate ligand targeting of bHK peptides to fungal surface integrins by determining whether a cyclic RGD (cRGD) peptide with a large PEG linker could enhance bHK peptide antifungal activity. Whereas conjugates containing only the PEG linker reduced bHK peptide activity, conjugates with the cRGD-PEG ligand resulted in marked enhancement of activity against Candida albicans. This study provides the first demonstration of benefit from ligand targeting of antifungal agents to fungal surface receptors. more...
- Published
- 2014
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17. Therapeutic targeting of integrin αvβ6 in breast cancer.
- Author
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Moore KM, Thomas GJ, Duffy SW, Warwick J, Gabe R, Chou P, Ellis IO, Green AR, Haider S, Brouilette K, Saha A, Vallath S, Bowen R, Chelala C, Eccles D, Tapper WJ, Thompson AM, Quinlan P, Jordan L, Gillett C, Brentnall A, Violette S, Weinreb PH, Kendrew J, Barry ST, Hart IR, Jones JL, and Marshall JF more...
- Subjects
- Animals, Antigens, Neoplasm genetics, Antineoplastic Combined Chemotherapy Protocols pharmacology, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Immunohistochemistry, Integrins genetics, Kaplan-Meier Estimate, Mice, Mice, SCID, Receptor, ErbB-2 genetics, Trastuzumab, Treatment Outcome, Xenograft Model Antitumor Assays, Antibodies, Monoclonal, Humanized pharmacology, Antigens, Neoplasm drug effects, Antigens, Neoplasm metabolism, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Integrins drug effects, Integrins metabolism, Molecular Targeted Therapy methods, Receptor, ErbB-2 metabolism
- Abstract
Background: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer., Methods: Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided., Results: High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts., Conclusions: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients., (© The Author 2014. Published by Oxford University Press.) more...
- Published
- 2014
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18. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma.
- Author
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Gerber EE, Gallo EM, Fontana SC, Davis EC, Wigley FM, Huso DL, and Dietz HC
- Subjects
- Amino Acid Motifs genetics, Amino Acid Substitution genetics, Animals, Antibodies, Antinuclear immunology, Antibodies, Neutralizing immunology, Antibodies, Neutralizing pharmacology, Antibodies, Neutralizing therapeutic use, Autoimmunity immunology, Contracture immunology, Contracture prevention & control, Dendritic Cells drug effects, Female, Fibrillin-1, Fibrillins, Fibrosis drug therapy, Fibrosis pathology, Fibrosis prevention & control, Male, Mice, Microfilament Proteins chemistry, Microfilament Proteins genetics, Microfilament Proteins metabolism, Mutation, Missense genetics, Plasma Cells drug effects, Scleroderma, Systemic immunology, Scleroderma, Systemic prevention & control, Skin Diseases, Genetic immunology, Skin Diseases, Genetic prevention & control, T-Lymphocytes, Helper-Inducer drug effects, Transforming Growth Factor beta antagonists & inhibitors, Transforming Growth Factor beta immunology, Autoimmunity drug effects, Contracture drug therapy, Contracture pathology, Integrins drug effects, Integrins metabolism, Scleroderma, Systemic drug therapy, Scleroderma, Systemic pathology, Skin Diseases, Genetic drug therapy, Skin Diseases, Genetic pathology
- Abstract
In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies. more...
- Published
- 2013
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19. Connective tissue diseases: Integrins crucial for the onset of fibrosis in systemic sclerosis--a new therapeutic target?
- Author
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Ray K
- Subjects
- Animals, Female, Male, Autoimmunity drug effects, Contracture drug therapy, Contracture pathology, Integrins drug effects, Integrins metabolism, Scleroderma, Systemic drug therapy, Scleroderma, Systemic pathology, Skin Diseases, Genetic drug therapy, Skin Diseases, Genetic pathology
- Published
- 2013
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20. Integrin modulators: a patent review.
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Kapp TG, Rechenmacher F, Sobahi TR, and Kessler H
- Subjects
- Animals, Humans, Integrins agonists, Integrins antagonists & inhibitors, Integrins metabolism, Neovascularization, Pathologic, Patents as Topic, Protein Binding, Structure-Activity Relationship, Integrins drug effects
- Abstract
Introduction: Integrins are heterodimeric cell surface receptors, which enable adhesion, proliferation, and migration of cells by recognizing binding motifs in extracellular matrix (ECM) proteins. As transmembrane linkers between the cytoskeleton and the ECM, they are able to recruit a huge variety of proteins and to influence signaling pathways bidirectionally, thereby regulating gene expression and cell survival. Hence, integrins play a key role in various physiological as well as pathological processes, which has turned them into an attractive target for pharmaceutical research., Areas Covered: In this review, the latest therapeutic developments of drug candidates and recently patented integrin ligands are summarized., Expert Opinion: Integrins have been proven to be valuable therapeutic targets in the treatment of several inflammatory and autoimmune diseases, where leukocyte adhesion processes are regulated by them. Furthermore, they play an important role in pathological angiogenesis and tumor metastasis, being a promising target for cancer therapy. more...
- Published
- 2013
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21. Hydrogen sulfide-releasing aspirin derivative ACS14 exerts strong antithrombotic effects in vitro and in vivo.
- Author
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Pircher J, Fochler F, Czermak T, Mannell H, Kraemer BF, Wörnle M, Sparatore A, Del Soldato P, Pohl U, and Krötz F
- Subjects
- Animals, Aspirin analogs & derivatives, Bleeding Time, Blood Platelets metabolism, Cyclic AMP metabolism, Disulfides pharmacology, Humans, In Vitro Techniques, Integrins drug effects, Integrins metabolism, Mice, Mice, Inbred C57BL, Models, Animal, Platelet Activation drug effects, Platelet Activation physiology, Platelet Aggregation physiology, Prostaglandin-Endoperoxide Synthases drug effects, Prostaglandin-Endoperoxide Synthases metabolism, Thrombosis metabolism, Thrombosis prevention & control, Aspirin metabolism, Aspirin pharmacology, Blood Platelets drug effects, Fibrinolytic Agents pharmacology, Hydrogen Sulfide metabolism, Platelet Aggregation drug effects
- Abstract
Objective: Hydrogen sulfide (H(2)S)-releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H(2)S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets., Methods and Results: In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid-induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led to a significantly longer arterial occlusion time after light-dye-induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25-500 µmol/L) inhibited arachidonic acid-induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor-activating peptide-, ADP-, and collagen-dependent aggregation. In washed human platelets, ACS14 (500 µmol/L) attenuated αIIbβ3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation., Conclusions: The H(2)S-releasing aspirin derivative ACS14 exerts strong antiaggregatory effects by impairing the activation of the fibrinogen receptor by mechanisms involving increased intracellular cyclic nucleotides. These additional antithrombotic properties result in a more efficient inhibition of thrombus formation in vivo as achieved with aspirin alone. more...
- Published
- 2012
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22. Cigarette smoke extract induces select matrix metalloproteinases and integrin expression in periodontal ligament fibroblasts.
- Author
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Bulmanski Z, Brady M, Stoute D, and Lallier TE
- Subjects
- Cell Adhesion drug effects, Cell Culture Techniques, Cell Death drug effects, Cell Shape drug effects, Cell Survival drug effects, Collagen drug effects, Collagen metabolism, Collagen Type I drug effects, Collagen Type I metabolism, Collagen Type V drug effects, Collagen Type XI antagonists & inhibitors, Fibroblasts enzymology, Gels, Humans, Integrin alpha Chains drug effects, Integrin alpha1 drug effects, Integrin alpha2 drug effects, Matrix Metalloproteinase 1 drug effects, Matrix Metalloproteinase 2 drug effects, Matrix Metalloproteinase 3 drug effects, Matrix Metalloproteinase 8 drug effects, Periodontal Ligament cytology, Complex Mixtures pharmacology, Fibroblasts drug effects, Integrins drug effects, Matrix Metalloproteinases drug effects, Periodontal Ligament drug effects, Smoke, Nicotiana
- Abstract
Background: The periodontal ligament (PDL) is the connective tissue that anchors the cementum of the teeth to the alveolar bone. PDL fibroblasts are responsible for the production of collagen and remodeling of the PDL. Periodontal disease is increased among smokers in both incidence and severity. This study examines the direct effect of smoking on PDL fibroblasts and their production of various matrix components and remodeling enzymes., Methods: PDL cells were plated for 1 day and then treated with various concentrations of cigarette smoke extract (CSE). Survival of PDL cells was quantified after exposure to CSE, and their ability to contract three-dimensional collagen gels was examined. Changes in transcript expression after CSE treatment was compared using reverse transcription-polymerase chain reaction analysis for matrix metalloproteinases (MMPs), collagens, and integrins., Results: Treatment with CSE-induced cell death at concentrations of ≥5%. PDL-cell-induced collagen gel contraction was reduced at concentrations of 1.5% CSE. Treatment with CSE selectively increased the expression of collagen Vα3 and decreased collagen XIα1. CSE increased the expression of MMP1 and MMP3 and, to a lesser extent, MMP2 and MMP8. CSE also increased the expression of integrins α1, α2, and α10 (collagen receptors) and α9 (a tenascin receptor)., Conclusions: This study shows that cigarette smoking has local effects on the cells of the PDL. CSE reduced survival of PDL cells and their ability to contract collagen matrices. CSE also altered the expression of molecules known to provide the structural integrity of the ligament by altering collagen synthesis and remodeling as well as cell adhesion. more...
- Published
- 2012
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23. The influence of different implant materials on human gingival fibroblast morphology, proliferation, and gene expression.
- Author
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Yamano S, Ma AK, Shanti RM, Kim SW, Wada K, and Sukotjo C
- Subjects
- Cell Adhesion drug effects, Cell Proliferation drug effects, Cell Shape drug effects, Cells, Cultured, Collagen drug effects, Dental Alloys chemistry, Fibroblasts cytology, Fibroblasts metabolism, Gene Expression Regulation drug effects, Gingiva cytology, Gingiva drug effects, Gingiva metabolism, Humans, Integrins drug effects, Microscopy, Atomic Force, Microscopy, Electron, Scanning, Surface Properties, Titanium chemistry, Titanium pharmacology, Zirconium chemistry, Zirconium pharmacology, Collagen metabolism, Dental Alloys pharmacology, Dental Implants, Fibroblasts drug effects, Integrins metabolism
- Abstract
Purpose: The aim of this study was to investigate the cellular response of human gingival fibroblasts (HGFs) cultured on smooth or rough zirconia (Zr) or titanium (Ti) disks., Materials and Methods: Disks fabricated from four different materials--smooth Zr (Zr-S), rough Zr (Zr-R), smooth Ti (Ti-S), and rough Ti (Ti-R)--were used, and surface roughness was analyzed by atomic force microscopy. After HGFs were cultured on these disks, cell morphology was examined by scanning electron microscopy, cell proliferation activity was evaluated by a monotetrazolium assay, and gene expression levels of various collagens and integrins were measured by real-time polymerase chain reaction., Results: The Ti-R disks were the roughest, followed by Zr-R, Ti-S, and Zr-S, in that order. The cells cultured on the Zr-S and Ti-S disks appeared to be more aligned with the fine irregularities at later time points, whereas the cells cultured on the Zr-S showed the weakest spreading compared to the other surfaces after 3 hours of culture. With respect to proliferation, cells proliferated significantly faster on the Zr-S surface than on the other surfaces. Gene expression of integrin α2 at 3 hours and integrin α5 and type I collagen at 48 hours on Zr-S was significantly up-regulated compared to Ti. Conversely, the expression of integrins β1 and β3 and type III collagen was significantly decreased on Zr-S at 1 hour compared to the other materials., Conclusion: These data indicate that different surface materials and topographies may induce a distinct HGF morphology, proliferation, and gene expression. more...
- Published
- 2011
24. Non-RGD-containing snake venom disintegrins, functional and structural relations.
- Author
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Walsh EM and Marcinkiewicz C
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Animals, Catalytic Domain, Disintegrins pharmacology, Humans, Integrins antagonists & inhibitors, Integrins drug effects, Molecular Sequence Data, Disintegrins chemistry, Snake Venoms chemistry
- Abstract
Snake venom disintegrins are present in a variety of species and are functionally divided into three families: RGD, MLD and R/KTS. The RGD family of disintegrins, which bind and inhibit the physiological functions of RGD-dependent integrins, constitute the largest and most investigated family. This review will be focused on characterization of two relatively new families of snake venom disintegrins, expressing in their active site MLD and R/KTS motifs. The MLD motif, present only in heterodimeric disintegrins, mediates binding of these disintegrins to α4β1, α4β7 and α9β1 integrins, whereas the presence of a KTS or RTS sequence in the active site selectively directs activity of disintegrins to the collagen receptor α1β1 integrin. Structurally, KTS-disintegrins are short, monomeric molecules containing 41 amino acids in its polypeptide chain. Biological activities of MLD and KTS-disintegrins were investigated in many systems in vitro and in vivo. Purified disintegrins are non-toxic in therapeutic doses in rodent and avian models. Their modulatory properties were observed in investigations of cancer angiogenesis and metastasis, immunosuppression of IDDM (insulin-dependent diabetes mellitus) and asthma, as well as in neurodegenerative assays and cell apoptosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.) more...
- Published
- 2011
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25. Inhibitory effects of novel integrin-targeting peptides on angiogenesis activity in HUVEC cells in vitro.
- Author
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Liu Y, Li Y, and Xu Y
- Subjects
- Actins drug effects, Amino Acid Motifs, Angiogenesis Inhibitors chemistry, Binding Sites, Cell Adhesion drug effects, Cell Line, Cell Migration Assays, Cell Movement drug effects, Cytoskeleton drug effects, Endothelial Cells drug effects, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Extracellular Matrix drug effects, Focal Adhesions drug effects, Humans, Integrins metabolism, Neoplasm Invasiveness, Neovascularization, Pathologic drug therapy, Peptides, Cyclic chemistry, Stress Fibers drug effects, Umbilical Veins cytology, Umbilical Veins metabolism, Angiogenesis Inhibitors pharmacology, Integrins drug effects, Peptides, Cyclic pharmacology
- Abstract
Integrins are critically involved in many tumour-promoting activities. The development of inhibitors against integrins may suppress tumour growth by inhibiting tumour angiogenic signalling. In this study, we investigated the effects of two novel peptides containing the integrin binding arginine-glycine-aspartic acid-motif on inhibiting diverse cell behaviours, including cell adhesion, motility, invasion, tube formation and cell cytoskeleton. Cell adhesion and motility assays demonstrated that cyclopeptides c-Gly and c-Lys might inhibit the adhesive and motile activity at the concentration of 25 μM. There was no significant effect on cell invasion, indicating the importance of extracellular matrix degradation in modulating the anti-invasive effect of human umbilical vein endothelial cells (HUVECs). More importantly, the tubular network formation of HUVECs was significantly inhibited by cyclopeptide c-Lys besides causing a remarkable inhibition of cytoskeletal organization, disrupting the focal adhesion and actin stress fibres formation. In conclusion, this study results indicated that the novel peptide c-Lys has the ability to inhibit diverse cell behaviours of HUVECs, and the effects may be mediated at different levels of the tumour growth. Therefore, c-Lys is perhaps proposed to be a potent anti-angiogenic drug candidate., (Copyright © 2011 John Wiley & Sons, Ltd.) more...
- Published
- 2011
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26. Self-assembly of elastin-based peptides into the ECM: the importance of integrins and the elastin binding protein in elastic fiber assembly.
- Author
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Patel D, Menon R, and Taite LJ
- Subjects
- Cell Adhesion drug effects, Cells, Cultured, Elastic Tissue chemistry, Elastic Tissue drug effects, Elastin antagonists & inhibitors, Elastin chemistry, Extracellular Matrix chemistry, Extracellular Matrix drug effects, Humans, Hydrogels chemistry, Hydrogels metabolism, Integrins chemistry, Integrins drug effects, Models, Biological, Muscle, Smooth cytology, Muscle, Smooth drug effects, Muscle, Smooth metabolism, Oligopeptides chemistry, Oligopeptides pharmacology, Polyethylene Glycols chemistry, Polyethylene Glycols metabolism, Receptors, Cell Surface chemistry, Receptors, Cell Surface drug effects, Tissue Engineering, Elastic Tissue metabolism, Elastin metabolism, Extracellular Matrix metabolism, Integrins metabolism, Oligopeptides metabolism, Receptors, Cell Surface metabolism
- Abstract
The formation of a suitable extracellular matrix (ECM) that promotes cell adhesion, organization, and proliferation is essential within biomaterial scaffolds for tissue engineering applications. In this work, short elastin mimetic peptide sequences, EM-19 and EM-23, were engineered to mimic the active motifs of human elastin in hopes that they can stimulate ECM development in synthetic polymer scaffolds. Each peptide was incubated with human aortic smooth muscle cells (SMCs) and elastin and desmosine production were quantified after 48 h. EM-19 inhibited elastin production through competitive binding phenomena with the elastin binding protein (EBP), whereas EM-23, which contains an RGDS domain, induces recovery of elastin production at higher concentrations, alluding to a higher binding affinity for the integrins than for the EBP and the involvement of integrins in elastin production. Colocalization of each peptide with the elastin matrix was confirmed using immunofluorescent techniques. Our data suggest that with appropriate cell-binding motifs, we can simulate the cross-linking of tropoelastin into the developing elastin matrix using short peptide sequences. The potential for increased cell adhesion and the incorporation of elastin chains into tissue engineering scaffolds make these peptides attractive bioactive moieties that can easily be incorporated into synthetic biomaterials to induce ECM formation. more...
- Published
- 2011
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27. Bone morphogenetic protein-7 enhances cementoblast function in vitro.
- Author
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Hakki SS, Foster BL, Nagatomo KJ, Bozkurt SB, Hakki EE, Somerman MJ, and Nohutcu RM
- Subjects
- Animals, Calcification, Physiologic drug effects, Cell Adhesion Molecules drug effects, Cell Differentiation drug effects, Cell Line, Collagen drug effects, Core Binding Factor Alpha 1 Subunit drug effects, Dental Cementum cytology, Extracellular Matrix Proteins drug effects, Gene Expression Profiling, Gene Expression Regulation drug effects, Integrins drug effects, Matrix Metalloproteinase 3 drug effects, Matrix Metalloproteinases drug effects, Mice, Osteocalcin drug effects, Osteopontin drug effects, Protein Array Analysis, Time Factors, Tissue Inhibitor of Metalloproteinase-2 drug effects, Tissue Inhibitor of Metalloproteinases drug effects, Tooth Root cytology, Tooth Root drug effects, Up-Regulation, Bone Morphogenetic Protein 7 pharmacology, Dental Cementum drug effects
- Abstract
Background: Bone morphogenetic protein (BMP)-7 is a potent bone-inducing factor and was shown to promote periodontal regeneration in vivo and in vitro; however, to our knowledge, the specific effect of BMP-7 on cementoblasts has not been defined. We aimed to investigate the effects of BMP-7 on cementoblasts, which are cells responsible for tooth root-cementum formation. We hypothesized that BMP-7 would regulate mineralized tissue-associated genes in cementoblasts and influence the expression profile of genes associated with cementoblast extracellular matrix (ECM) and cell adhesion molecules (CAMs)., Methods: A murine immortalized cementoblast cell line (OCCM.30) was cultured with and without 50 ng/ml BMP-7. After 72 hours, total RNA was isolated, and mRNA levels for bone/cementum markers, including bone sialoprotein (BSP), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor-2 (Runx2), were investigated by real-time quantitative reverse transcription-polymerase chain reaction (Q-PCR). In vitro mineral nodule formation was assayed on day 8 using von Kossa staining. A pathway-specific gene-expression array was used to determine BMP-7-responsive ECM and CAM genes in cementoblasts., Results: Mineralized tissue markers were strongly regulated by BMP-7, with an almost three-fold increase in BSP and OCN transcripts and significant increases in OPN and Runx2 mRNA expressions. BMP-7 treatment markedly stimulated cementoblast-mediated biomineralization in vitro compared to untreated cells at day 8. BMP-7 treatment altered the OCCM.30 expression profile for ECM and CAM functional gene groups. BMP-7 tended to increase the expression of collagens and matrix metalloproteinases (MMPs), mildly decreased tissue inhibitors of MMPs (TIMPs), and had mixed regulatory effects on integrins. Using Q-PCR, selected array results were confirmed, including a significant BMP-7-induced increase in MMP-3 and a decrease in TIMP-2 mRNA expression., Conclusion: These results support the promising applications of BMP-7 in therapies aimed at regenerating periodontal tissues lost as a consequence of disease. more...
- Published
- 2010
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28. Integrins as target: first phase III trial launches, but questions remain.
- Author
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Carter A
- Subjects
- Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors adverse effects, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Brain Neoplasms metabolism, Clinical Trials, Phase III as Topic, Dose-Response Relationship, Drug, Drug Administration Schedule, Glioblastoma metabolism, Humans, Integrins metabolism, Neoplasms drug therapy, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Integrins drug effects, Neoplasms chemically induced, Snake Venoms administration & dosage, Snake Venoms adverse effects
- Published
- 2010
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29. CC-PLA2-1 and CC-PLA2-2, two Cerastes cerastes venom-derived phospholipases A2, inhibit angiogenesis both in vitro and in vivo.
- Author
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Kessentini-Zouari R, Jebali J, Taboubi S, Srairi-Abid N, Morjen M, Kallech-Ziri O, Bezzine S, Marvaldi J, El Ayeb M, Marrakchi N, and Luis J
- Subjects
- Animals, Chorioallantoic Membrane drug effects, Endothelial Cells, Focal Adhesions drug effects, Group I Phospholipases A2 chemistry, Group II Phospholipases A2 chemistry, Humans, In Vitro Techniques, Models, Structural, Static Electricity, Viper Venoms chemistry, Angiogenesis Inhibitors pharmacology, Group I Phospholipases A2 pharmacology, Group II Phospholipases A2 pharmacology, Integrins drug effects, Viper Venoms enzymology
- Abstract
Integrins are essential in the complex multistep process of angiogenesis and are thus attractive targets for the development of antiangiogenic therapies. Integrins are antagonized by disintegrins and C-type lectin-like proteins, two protein families from snake venom. Here, we report that CC-PLA2-1 and CC-PLA2-2, two novel secreted phospholipases A(2) (PLA(2)) isolated from Cerastes cerastes venom, also showed anti-integrin activity. Indeed, both PLA(2)s efficiently inhibited human brain microvascular endothelial cell adhesion and migration to fibrinogen and fibronectin in a dose-dependent manner. Interestingly, we show that this anti-adhesive effect was mediated by alpha5beta1 and alphav-containing integrins. CC-PLA2s also impaired in vitro human brain microvascular endothelial cell tubulogenesis on Matrigel and showed antiangiogenic activity in vivo in chicken chorioallantoic membrane assay. The complete PLA(2) cDNAs were cloned from a venom gland cDNA library. Mature CC-PLA2-1 and CC-PLA2-2 contain 121 and 120 amino acids, respectively, including 14 cysteines each and showed 83% identity. Tertiary model structures of CC-PLA2-1 and CC-PLA2-2 were generated by homology modeling. This is thus the first study describing an antiangiogenic effect for snake venom PLA(2)s and reporting first clues to their mechanism of action on endothelial cells. more...
- Published
- 2010
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30. Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex.
- Author
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Song H, Cha MJ, Song BW, Kim IK, Chang W, Lim S, Choi EJ, Ham O, Lee SY, Chung N, Jang Y, and Hwang KC
- Subjects
- Acetylcysteine pharmacology, Animals, Cell Adhesion drug effects, Cell Adhesion physiology, Cell Adhesion Molecules drug effects, Cell Differentiation physiology, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Focal Adhesion Kinase 1 drug effects, Focal Adhesion Kinase 1 metabolism, Focal Adhesions drug effects, Focal Adhesions metabolism, Free Radical Scavengers pharmacology, Gene Knock-In Techniques, Graft Survival physiology, Hydrogen Peroxide pharmacology, Integrins drug effects, Integrins metabolism, Male, Myocardial Ischemia physiopathology, Oxidants pharmacology, Oxidative Stress drug effects, Oxidative Stress physiology, Rats, Rats, Sprague-Dawley, Regeneration physiology, src-Family Kinases drug effects, src-Family Kinases metabolism, Cell Adhesion Molecules metabolism, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells metabolism, Myocardial Ischemia metabolism, Myocardial Ischemia surgery, Reactive Oxygen Species metabolism
- Abstract
The integrity of transplanted mesenchymal stem cells (MSCs) for cardiac regeneration is dependent on cell-cell or cell-matrix adhesion, which is inhibited by reactive oxygen species (ROS) generated in ischemic surroundings after myocardial infarction. Intracellular ROS play a key role in the regulation of cell adhesion, migration, and proliferation. This study was designed to investigate the role of ROS on MSC adhesion. In H(2)O(2) treated MSCs, adhesion and spreading were inhibited and detachment was increased in a dose-dependent manner, and these effects were significantly rescued by co-treatment with the free radical scavenger, N-acetyl-L-cysteine (NAC, 1 mM). A similar pattern was observed on plates coated with different matrices such as fibronectin and cardiogel. Hydrogen peroxide treatment resulted in a marked decrease in the level of focal adhesion-related molecules, such as phospho-FAK and p-Src in MSCs. We also observed a significant decrease in the integrin-related adhesion molecules, alpha V and beta1, in H(2)O(2) treated MSCs. When injected into infarcted hearts, the adhesion of MSCs co-injected with NAC to the border region was significantly improved. Consequently, we observed that fibrosis and infarct size were reduced in MSC and NAC-injected rat hearts compared to in MSC-only injected hearts. These results indicate that ROS inhibit cellular adhesion of engrafted MSCs and provide evidence that the elimination of ROS might be a novel strategy for improving the survival of engrafted MSCs. more...
- Published
- 2010
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31. Integrins in bone metastasis formation and potential therapeutic implications.
- Author
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Clëzardin P
- Subjects
- Bone Neoplasms physiopathology, Drug Delivery Systems, Humans, Integrins drug effects, Models, Biological, Neoplasm Invasiveness physiopathology, Protein Structure, Quaternary, Antineoplastic Agents therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms secondary, Integrins physiology
- Abstract
Integrins constitute a family of cell surface receptors that are heterodimers composed of noncovalently associated alpha and beta subunits. Integrins bind to extracellular matrix proteins and immunogobulin superfamily molecules. They exert a stringent control on cell migration, survival and proliferation. However, their expression and functions are often deregulated in cancer, and many lines of evidence implicate them as key regulators during progression from primary tumor growth to metastasis. Here, we review the role of integrins in bone metastasis formation and present evidence that the use of integrin-targeted therapeutic agents may be an efficient strategy to block tumor metastasis. more...
- Published
- 2009
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32. S-1 mediates the inhibition of lymph node metastasis in oral cancer cells.
- Author
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Sato H, Hatori M, Ando Y, Kurihara Y, Takayama S, Shirota T, Tachikawa T, and Shintani S
- Subjects
- Animals, Blotting, Western, Carcinoma, Squamous Cell drug therapy, Cell Line, Tumor, Drug Combinations, Gene Expression drug effects, Green Fluorescent Proteins, Humans, Integrins biosynthesis, Integrins drug effects, Mice, Mice, Nude, Mouth Neoplasms drug therapy, Xenograft Model Antitumor Assays, Antimetabolites, Antineoplastic pharmacology, Carcinoma, Squamous Cell pathology, Lymphatic Metastasis prevention & control, Mouth Neoplasms pathology, Oxonic Acid pharmacology, Signal Transduction drug effects, Tegafur pharmacology
- Abstract
S-1, an oral fluorouracil antitumor drug, is composed of three agents: tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo). Approximately 50% of oral squamous cell carcinomas (OSCC) exhibit cervical lymph node metastasis. The extent of lymph node involvement is a major determinant in both staging and prognosis of the majority of OSCC. The purpose of this study was to examine the effect of S-1 on the metastatic potential of OSCC cells. We used orthotopic green fluorescence protein (GFP) SAS-L1, in BALB/c nu/nu mice. Mice received oral doses of either 5% hydroxypropylmethylcellulose (HPMC) for control or S-1 (20 mg/kg) and were autopsied at 2 weeks. We also performed in vitro experiments using concomitant 5-fluorouracil (5-FU) and CDHP as a drug model of S-1 to determine the effect of S-1 on OSCC invasion and metastasis. Although 100% (11 of 11) of mice not treated with S-1 showed cervical lymph node metastasis, only 54.4% (6 of 11) of S-1 treated mice demonstrated metastasis. In in vitro experiments, OSCC cells treated with 5-FU and CDHP showed a marked reduction in invasiveness and in adhesion to laminin coated plates. Western blot analysis revealed that treatment with 5-FU and CDHP suppressed expression of integrins alphav, alpha3, alpha6, beta1, beta3, beta4, beta5, and beta6. These results suggest that S-1 inhibits tumor proliferation and lymph node metastasis in OSCC cells. Moreover, expression of integrin subunits and the integrin signal transduction pathway may be closely related to metastasis suppression. more...
- Published
- 2009
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33. Conformational mAb as a tool for integrin ligand discovery.
- Author
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Njus BH, Chigaev A, Waller A, Wlodek D, Ostopovici-Halip L, Ursu O, Wang W, Oprea TI, Bologa CG, and Sklar LA
- Subjects
- Binding, Competitive, Epitopes, Flow Cytometry, Fluorescein-5-isothiocyanate, Fluorescent Dyes, Humans, Integrin beta1 drug effects, Kinetics, Ligands, Protein Conformation, U937 Cells, Antibodies, Monoclonal chemistry, Integrins drug effects
- Abstract
alpha(4)beta(1)-Integrin (very late antigen-4 (VLA-4)) mediates cell adhesion to cell surface ligands (VCAM-1). Binding of VLA-4 to VCAM-1 initiates rolling and firm adhesion of leukocytes to vascular endothelium followed by the extravasation into the tissue. VLA-4-dependent adhesion plays a key role in controlling leukocyte adhesive events. Small molecules that bind to the integrin ligand-binding site and block its interaction with natural ligands represent promising candidates for treatment of several diseases. Following a flow cytometric screen for small molecule discovery, we took advantage of a conformationally sensitive anti-beta(1)-integrin antibody (HUTS-21) and a small LDV-containing ligand (LDV-FITC) with known affinity to study binding affinities of several known and recently discovered integrin ligands. We found that binding of the LDV-containing small molecule induced exposure of HUTS-21 epitope and that the EC(50) for antibody binding was equal to previously reported K(d) for fluorescent LDV (LDV-FITC). Thus, binding of HUTS-21 can be used to report ligand-binding site occupancy. We studied binding of two known integrin ligands (YLDV and TR14035), as well as of two novel compounds. EC(50) values for HUTS-21 binding showed good correlation with K(i)s determined in the competition assay with LDV-FITC for all ligands. A docking model suggests a common mode of binding for the small molecule VLA-4 ligands. This novel approach described here can be used to determine ligand-binding affinities for unlabeled integrin ligands, and can be adapted to a high-throughput screening format for identification of unknown integrin ligands. more...
- Published
- 2009
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34. Inhibition of TGF-beta1 suppresses motility and invasiveness of oral squamous cell carcinoma cell lines via modulation of integrins and down-regulation of matrix-metalloproteinases.
- Author
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Takayama S, Hatori M, Kurihara Y, Kinugasa Y, Shirota T, and Shintani S
- Subjects
- Blotting, Western, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Down-Regulation, Enzyme Inhibitors pharmacology, Humans, Integrins drug effects, Matrix Metalloproteinases drug effects, Neoplasm Invasiveness pathology, Carcinoma, Squamous Cell metabolism, Cell Movement physiology, Integrins metabolism, Matrix Metalloproteinases metabolism, Mouth Neoplasms metabolism, Transforming Growth Factor beta1 antagonists & inhibitors
- Abstract
Transforming growth factor (TGF)-beta1 is a multifunctional polypeptide that regulates a variety of cellular processes. Several studies have indicated that it is associated with epithelial-mesenchymal transition, angiogenesis, migration and metastases in many types of malignant tumors. We have used a wound-healing assay and a Matrigel invasion assay to evaluate the effects of TGF-beta1 and TGF-beta receptor I kinase inhibitor (TRI) on the cell motility and invasiveness of the human oral squamous cell carcinoma (OSCC) cell lines SAS-L1 and HSC-3. While TGF-beta1 enhanced the migration and invasion of OSCC cells, TRI significantly suppressed the migration and invasion of these cells. Exogenous TGF-beta1 up-regulated the activity of type IV collagenase (gelatinase A and gelatinase B), whereas TRI down-regulated the activity of these matrix metalloproteinases. Western blot analysis revealed that TGF-beta1 enhanced the expression of alpha5, alphav, beta1, beta6 and alphavbeta3 integrin subunits, and these enhanced integrins were down-regulated by treatment with TRI. These results suggest that the inhibition of TGF-beta1 suppresses motility and invasiveness of OSCC cells via modulation of integrins and matrix-metalloproteinases. Therefore, targeting the TGF-beta1 signaling pathway could be beneficial in the treatment of patients with OSCC. more...
- Published
- 2009
35. In vivo positron emission tomography (PET) imaging with an alphavbeta6 specific peptide radiolabeled using 18F-"click" chemistry: evaluation and comparison with the corresponding 4-[18F]fluorobenzoyl- and 2-[18F]fluoropropionyl-peptides.
- Author
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Hausner SH, Marik J, Gagnon MK, and Sutcliffe JL
- Subjects
- Animals, Antigens, Neoplasm chemistry, Antigens, Neoplasm metabolism, Cell Line, Tumor, Fluorine Radioisotopes, Humans, Integrins chemistry, Integrins metabolism, Male, Mice, Mice, Nude, Molecular Structure, Sensitivity and Specificity, Stereoisomerism, Tissue Distribution, Xenograft Model Antitumor Assays, Antigens, Neoplasm drug effects, Benzoates chemistry, Integrins drug effects, Neoplasms diagnosis, Peptides chemistry, Peptides pharmacokinetics, Positron-Emission Tomography methods, Propionates chemistry, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics
- Abstract
Numerous radiolabeled peptides have been utilized for in vivo imaging of a variety of cell surface receptors. For applications in PET using [(18)F]fluorine, peptides are radiolabeled via a prosthetic group approach. We previously developed solution-phase (18)F-"click" radiolabeling and solid-phase radiolabeling using 4-[(18)F]fluorobenzoic and 2-[(18)F]fluoropropionic acids. Here we compare the three different radiolabeling approaches and report the effects on PET imaging and pharmacokinetics. The prosthetic groups did have an effect; metabolites with significantly different polarities were observed. more...
- Published
- 2008
- Full Text
- View/download PDF
36. A potent integrin antagonist from a small library of cyclic RGD pentapeptide mimics including benzyl-substituted azabicycloalkane amino acids.
- Author
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Arosio D, Belvisi L, Colombo L, Colombo M, Invernizzi D, Manzoni L, Potenza D, Serra M, Castorina M, Pisano C, and Scolastico C
- Subjects
- Azabicyclo Compounds metabolism, Binding Sites, Cell Adhesion drug effects, Cells, Cultured, Endothelial Cells, Humans, Inhibitory Concentration 50, Integrins drug effects, Integrins metabolism, Magnetic Resonance Spectroscopy, Peptides, Cyclic metabolism, Small Molecule Libraries, Azabicyclo Compounds chemistry, Azabicyclo Compounds pharmacology, Integrins antagonists & inhibitors, Peptides, Cyclic chemistry
- Abstract
A small library of cyclic RGD pentapeptide mimics, including benzyl-substituted azabicycloalkane amino acids, was synthesized with the aim of developing active and selective integrin antagonists. In vitro binding assays established one particular compound with affinity for both the alpha(v)beta(3) and the alpha(v)beta(5) integrins. The synthesis in solution and the in vitro screening of these RGD derivatives, as well as the determination of the conformational properties of the integrin ligands by spectroscopic and computational methods are described. more...
- Published
- 2008
- Full Text
- View/download PDF
37. Integrins in angiogenesis and lymphangiogenesis.
- Author
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Avraamides CJ, Garmy-Susini B, and Varner JA
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Humans, Integrins drug effects, Neoplasms therapy, Integrins physiology, Lymphangiogenesis physiology, Neoplasms blood supply, Neoplasms pathology, Neovascularization, Pathologic etiology
- Abstract
Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis. more...
- Published
- 2008
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- View/download PDF
38. Discovery of subnanomolar arginine-glycine-aspartate-based alphaVbeta3/alphaVbeta5 integrin binders embedding 4-aminoproline residues.
- Author
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Zanardi F, Burreddu P, Rassu G, Auzzas L, Battistini L, Curti C, Sartori A, Nicastro G, Menchi G, Cini N, Bottoncetti A, Raspanti S, and Casiraghi G
- Subjects
- Binding Sites, Crystallography, X-Ray, Humans, Integrin alphaVbeta3 chemistry, Integrins chemistry, Magnetic Resonance Spectroscopy methods, Models, Molecular, Molecular Structure, Oligopeptides chemistry, Receptors, Vitronectin chemistry, Stereoisomerism, Structure-Activity Relationship, Integrin alphaVbeta3 drug effects, Integrins drug effects, Oligopeptides pharmacology, Proline analogs & derivatives, Proline chemistry, Receptors, Vitronectin drug effects
- Abstract
The embodiment of 4-aminoproline residues (Amp) into the arginine-glycine-aspartate (RGD) sequence led to the discovery of a novel class of high-affinity alpha Vbeta 3/alpha Vbeta 5 integrin binders [IC 50 h (alpha Vbeta 3) 0.03-5.12 nM; IC 50 h (alpha Vbeta 5) 0.88-154 nM]. A total of eight cyclopeptides of type cyclo-[-Arg-Gly-Asp-Amp-], 5- 12, were assembled by a standard solid-phase peptide synthesis protocol that involved the C2-carboxyl and C4-amino functionalities of the proline scaffolds, leaving the N (alpha)-nuclear site untouched. Functionalization of this vacant proline site with either alkyl or acyl substituents proved feasible, with significant benefit to the integrin binding capabilities of the ligands. Notably, six out of eight cyclopeptide inhibitors, 5- 7 and 9- 11, showed moderate yet significant selectivity toward the alpha Vbeta 3 receptor. The three-dimensional structure in water was determined by NMR techniques and molecular dynamics calculations. Docking studies to the X-ray crystal structure of the extracellular segment of integrin alpha Vbeta 3 complexed with reference compound 1 were also performed on selected analogues to highlight the structural features required for potent ligand binding affinity. more...
- Published
- 2008
- Full Text
- View/download PDF
39. Novel therapeutic targets at the platelet vascular interface.
- Author
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Brass LF, Zhu L, and Stalker TJ
- Subjects
- Animals, Education, Medical, Continuing, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Humans, Integrins drug effects, Integrins metabolism, Platelet Activation drug effects, Platelet Activation physiology, Platelet Aggregation physiology, Platelet Aggregation Inhibitors pharmacology, Sensitivity and Specificity, Signal Transduction, Vascular Cell Adhesion Molecule-1 metabolism, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors therapeutic use, Thromboembolism prevention & control, Vascular Cell Adhesion Molecule-1 drug effects
- Abstract
Platelet activation in vivo can be part of the hemostatic response to injury or a pathological response to disease. In either setting, platelets adhere to the vessel wall and to each other, forming a closely packed mass interspersed with fibrin. Recent studies have identified new molecules on the platelet surface and within platelets that support and regulate thrombus growth and stability, ensuring that platelet accumulation after injury is sufficient to stop bleeding, but not so exuberant that vascular occlusion occurs. An understanding of how this balance is achieved helps to illuminate the events of platelet activation and, at the same time, provides potential targets for new classes of antiplatelet agents. more...
- Published
- 2008
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- View/download PDF
40. Cyclophilin B induces integrin-mediated cell adhesion by a mechanism involving CD98-dependent activation of protein kinase C-delta and p44/42 mitogen-activated protein kinases.
- Author
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Melchior A, Denys A, Deligny A, Mazurier J, and Allain F
- Subjects
- Antibodies pharmacology, Basigin metabolism, Cell Adhesion drug effects, Cell Adhesion physiology, Cell Line, Tumor, Cell Membrane drug effects, Cyclophilins genetics, Cyclophilins pharmacology, Enzyme Activation drug effects, Enzyme Activation physiology, Fibronectins metabolism, Fusion Regulatory Protein-1 antagonists & inhibitors, Fusion Regulatory Protein-1 genetics, Humans, Integrin beta1 metabolism, Integrins drug effects, Integrins genetics, Macromolecular Substances metabolism, Mitogen-Activated Protein Kinase 1 drug effects, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 drug effects, Peptidylprolyl Isomerase genetics, Peptidylprolyl Isomerase pharmacology, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase C-delta drug effects, RNA Interference physiology, Cell Membrane metabolism, Cyclophilins physiology, Fusion Regulatory Protein-1 metabolism, Integrins metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Peptidylprolyl Isomerase physiology, Protein Kinase C-delta metabolism
- Abstract
Initially identified as a cyclosporin-A binding protein, cyclophilin B (CyPB) is an inflammatory mediator that induces adhesion of T lymphocytes to fibronectin, by a mechanism dependent on CD147 and alpha 4 beta 1 integrins. Recent findings have suggested that another cell membrane protein, CD98, may cooperate with CD147 to regulate beta1 integrin functions. Based on these functional relationships, we examined the contribution of CD98 in the pro-adhesive activity of CyPB, by utilizing the responsive promonocyte cell line THP-1. We demonstrated that cross-linking CD98 with CD98-AHN-18 antibody mimicked the responses induced by CyPB, i.e. homotypic aggregation, integrin-mediated adhesion to fibronectin and activation of p44/42 MAPK. Consistent with previous data, immunoprecipitation confirmed the existence of a heterocomplex wherein CD147, CD98 and beta1 integrins were associated. We then demonstrated that CyPB-induced cell adhesion and p44/42 MAPK activation were dependent on the participation of phosphoinositide 3-kinase and subsequent activation of protein kinase C-delta. Finally, silencing the expression of CD98 by RNA interference potently reduced CyPB-induced cell responses, thus confirming the role of CD98 in the pro-adhesive activity of CyPB. Altogether, our results support a model whereby CyPB induces integrin-mediated adhesion via interaction with a multimolecular unit formed by the association between CD147, CD98 and beta1 integrins. more...
- Published
- 2008
- Full Text
- View/download PDF
41. Neural crest motility on fibronectin is regulated by integrin activation.
- Author
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Strachan LR and Condic ML
- Subjects
- Animals, Cell Differentiation drug effects, Cell Differentiation physiology, Cell Movement drug effects, Chick Embryo, Cranial Nerves cytology, Cranial Nerves embryology, Cranial Nerves metabolism, Dose-Response Relationship, Drug, Fibronectins pharmacology, Integrin beta1 drug effects, Integrin beta1 metabolism, Integrins drug effects, Manganese pharmacology, Neural Crest cytology, Neural Crest drug effects, Neurons cytology, Neurons drug effects, Neurons metabolism, Receptor Aggregation drug effects, Spinal Nerves cytology, Spinal Nerves embryology, Spinal Nerves metabolism, Stem Cells cytology, Stem Cells drug effects, Cell Movement physiology, Fibronectins metabolism, Integrins metabolism, Neural Crest metabolism, Receptor Aggregation physiology, Stem Cells metabolism
- Abstract
Cell migration is essential for proper development of numerous structures derived from embryonic neural crest cells (NCCs). Although recent work has shown that receptor recycling plays an important role in NCC motility on laminin, the molecular mechanisms regulating NCC motility on fibronectin remain unclear. One mechanism by which cells regulate motility is by modulating the affinity of integrin receptors. Here, we provide evidence that cranial and trunk NCCs rely on functional regulation of integrins to migrate efficiently on fibronectin (FN) in vitro. For NCCs cultured on fibronectin, velocity decreases after Mn2+ application (a treatment that activates all surface integrins) while velocity on laminin (LM) is not affected. The distribution of activated integrin beta 1 receptors on the surface of NCCs is also substratum-dependent. Integrin activation affects cranial and trunk NCCs differently when cultured on different concentrations of FN substrata; only cranial NCCs slow in a FN concentration-dependent manner. Furthermore, Mn2+ treatment alters the distribution and number of activated integrin beta 1 receptors on the surface of cranial and trunk NCCs in different ways. We provide a hypothesis whereby a combination of activated surface integrin levels and the degree to which those receptors are clustered determines NCC motility on fibronectin. more...
- Published
- 2008
- Full Text
- View/download PDF
42. Leukocyte and endothelial adhesion molecules in patients with hypercholesterolemia: the effect of atorvastatin treatment.
- Author
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Stulc T, Vrablík M, Kasalová Z, Marinov I, Svobodová H, and Ceska R
- Subjects
- Adult, Atorvastatin, Cell Adhesion Molecules blood, E-Selectin blood, E-Selectin drug effects, Endothelial Cells drug effects, Endothelial Cells metabolism, Female, Humans, Hypercholesterolemia drug therapy, Integrins blood, Intercellular Adhesion Molecule-1 blood, Intercellular Adhesion Molecule-1 drug effects, L-Selectin blood, L-Selectin drug effects, Leukocytes metabolism, Male, Matched-Pair Analysis, Middle Aged, Reference Values, Statistics, Nonparametric, von Willebrand Factor drug effects, von Willebrand Factor metabolism, Anticholesteremic Agents therapeutic use, Cell Adhesion Molecules drug effects, Heptanoic Acids therapeutic use, Hypercholesterolemia blood, Integrins drug effects, Leukocytes drug effects, Pyrroles therapeutic use
- Abstract
Atherogenesis involves the migration of leukocytes into vascular subendothelial space, a process mediated by endothelial and leukocyte cell adhesion molecules. Endothelial molecules are assessed indirectly via serum levels, but leukocyte molecules can be assessed directly. We have therefore hypothesized that leukocyte adhesion molecules are altered to a greater degree in hypercholesterolemia than serum endothelial adhesion molecules. We examined 29 subjects with hypercholesterolemia and 27 controls at baseline and after 12 weeks of atorvastatin treatment (20 mg/day). Expression of leukocyte integrins CD11a, CD11b, CD18, and CD49d and of L-selectin was measured by flow cytometry. Serum ICAM-1, E-selectin and von Willebrand factor were measured by ELISA. Expression of leukocyte adhesion molecules was significantly higher in patients at baseline than in the controls, except for CD11a. Expression significantly decreased after atorvastatin in most adhesion molecules except for CD11b. In contrast, there was no effect of hypercholesterolemia and/or atorvastatin on the serum endothelial molecules. Leukocyte but not endothelial adhesion molecules were influenced by hypercholesterolemia and by lipid lowering treatment. Leukocyte molecules may therefore be a more sensitive marker of atherogenesis than endothelial molecules. Our results support the role of increased leukocyte adhesiveness in atherogenesis. more...
- Published
- 2008
- Full Text
- View/download PDF
43. Cilostazol inhibits monocytic cell adhesion to vascular endothelium via upregulation of cAMP.
- Author
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Mori D, Ishii H, Kojima C, Nitta N, Nakajima K, and Yoshida M
- Subjects
- Cell Adhesion drug effects, Cells, Cultured, Cilostazol, Endothelial Cells drug effects, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Fetal Blood cytology, Flow Cytometry, Humans, Immunoassay, Integrins biosynthesis, Integrins drug effects, Leukocyte Rolling drug effects, Monocytes metabolism, Tumor Necrosis Factor-alpha metabolism, Up-Regulation, Cyclic AMP metabolism, Endothelial Cells metabolism, Monocytes drug effects, Platelet Aggregation Inhibitors pharmacology, Tetrazoles pharmacology
- Abstract
Aim: Cilostazol is clinically used as an inhibitor of platelet aggregation. Although several reports have demonstrated its anti-inflammatory effect, its effect on monocytes and their adhesive interaction to vascular endothelium remains unclear. We thus examined the potential role of cilostazol towards monocyte endothelial interaction under physiological flow conditions., Methods: THP-1 cells, a monocytic cell line, were pretreated with cilostazol (5 microM) for 48 hours. The cells were then perfused over TNF-alpha (5 microg/mL for 4 hours)-stimulated monolayers of human umbilical vein endothelial cells (HUVECs) at shear stress of 1.0 dyen/cm(2)., Results: TNF-alpha-activated HUVECs supported significantly more monocyte adhesion to HUVECs (7.32+/-1.25/HPF) compared to inactivated HUVECs (0.74+/-0.15/HPF), and the amount of adhesion to TNF-alpha-activated HUVECs was markedly reduced (3.63+/-0.55/HPF) when THP-1 cells were incubated in the presence of cilostazol at 5 microM. Interestingly, surface expressions of integrins were not dramatically changed after cilostazol treatment. Intracellular concentration of cAMP was significantly increased after cilostazol treatment, and treatment with Forskolin and Dibutyryl-cAMP, potent inducers of cAMP, dramatically increased THP-1 adhesion to HUVECs., Conclusion: These data suggest that cilostazol has a potential anti-inflammatory effect on monocyte-endothelial interactions via the upregulation of intracellular cAMP. more...
- Published
- 2007
- Full Text
- View/download PDF
44. The lipoxygenase inhibitor, baicalein, modulates cell adhesion and migration by up-regulation of integrins and vinculin in rat heart endothelial cells.
- Author
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Hsieh YC, Hsieh SJ, Chang YS, Hsueh CM, and Hsu SL
- Subjects
- Actins metabolism, Animals, Blotting, Western, Cell Movement drug effects, Dose-Response Relationship, Drug, Endothelial Cells, Enzyme Inhibitors administration & dosage, Fibronectins drug effects, Flavanones administration & dosage, Fluorescent Antibody Technique, Integrin alpha5beta1 drug effects, Integrin alpha5beta1 metabolism, Integrin alphaVbeta3 drug effects, Integrin alphaVbeta3 metabolism, Integrins drug effects, Integrins metabolism, Rats, Receptors, Vitronectin drug effects, Receptors, Vitronectin metabolism, Vinculin drug effects, Vinculin metabolism, Cell Adhesion drug effects, Enzyme Inhibitors pharmacology, Flavanones pharmacology, Up-Regulation drug effects
- Abstract
Background and Purpose: Endothelial cell proliferation, migration and adhesion are necessary for the formation of new blood vessels. We reported previously that baicalein strongly inhibited proliferation of rat heart endothelial cells and here we assess effects on migration and adhesion of these cells., Experimental Approach: Effects of baicalein on endothelial migration and adhesion were determined by in vitro wound assays and in modified Boyden chambers. Protein expression and subcellular distribution in rat heart endothelial cells were analysed by immunoblots and immunofluorescence staining., Results: Pretreatment with baicalein for 48 h resulted in a concentration-dependent inhibition of endothelial migration, with an IC(50) of approximately 20 microM. Adhesion assays revealed that baicalein stimulated endothelial cell adhesion to fibronectin and vitronectin, effects blocked by the synthetic peptide Arg-Gly-Asp (RGD). Moreover, treatment with a blocking antibody against integrin alpha5beta1 drastically attenuated baicalein-mediated endothelial adhesion to fibronectin, but not to vitronectin. Furthermore, baicalein-mediated anti-migration effect and adhesion promotion could be partially reversed by the addition of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Western blot analysis indicated that baicalein increased expression levels of integrin-alpha5beta1, -alphavbeta3 and vinculin proteins. Immunofluorescence staining showed that baicalein induced a marked reorganization of actin stress fibres and the recruitment of vinculin and integrins to focal adhesion plaques, with consequently increased formation of focal adhesion contacts., Conclusions and Implications: Baicalein markedly inhibited the migration and enhanced the adhesion of rat heart endothelial cells, possibly by up-regulation of the integrins (alpha5beta1 and alphavbeta3) and vinculin and by promotion of actin reorganization and focal adhesion contact formation. more...
- Published
- 2007
- Full Text
- View/download PDF
45. The extracellular matrix in wound healing: a closer look at therapeutics for chronic wounds.
- Author
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Agren MS and Werthén M
- Subjects
- Animals, Chronic Disease, Epithelium physiology, Extracellular Matrix physiology, Fibroblasts drug effects, Humans, Integrins drug effects, Soft Tissue Injuries drug therapy, Soft Tissue Injuries physiopathology, Wound Healing physiology, Epithelium drug effects, Extracellular Matrix drug effects, Granulation Tissue drug effects, Intercellular Signaling Peptides and Proteins pharmacology, Wound Healing drug effects
- Abstract
Disappointing results with the use of exogenous recombinant growth factors in chronic wounds have redirected the focus to the extracellular matrix (ECM). Newer research has clearly changed our view on the role of the ECM in tissue repair and dismissed the dogma that the sole function of ECM is a passive physical support for cells. It is now clear that intact or fragmented ECM molecules are capable of transducing signals pivotal for cell processes in wound healing primarily via integrin interactions in concert with growth factor activation. In addition, our knowledge about ECM molecules in minute concentrations with biological activity, but devoid of significant structural influence, is increasing. This article reviews the multifaceted molecular roles of ECM in the normal wound-healing process and some molecular abnormalities in chronic wounds, and touches on potential therapies based on the developments of tissue biology. more...
- Published
- 2007
- Full Text
- View/download PDF
46. Integrins: novel therapeutic targets for cardiovascular diseases.
- Author
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Lal H, Guleria RS, Foster DM, Lu G, Watson LE, Sanghi S, Smith M, and Dostal DE
- Subjects
- Cardiovascular Agents chemistry, Cardiovascular Physiological Phenomena, Endothelium, Vascular drug effects, Endothelium, Vascular growth & development, Extracellular Matrix drug effects, Humans, Randomized Controlled Trials as Topic, Signal Transduction drug effects, Signal Transduction physiology, Cardiovascular Agents pharmacology, Cardiovascular Diseases drug therapy, Endothelium, Vascular metabolism, Extracellular Matrix metabolism, Integrins antagonists & inhibitors, Integrins drug effects, Integrins metabolism
- Abstract
Integrins are the principle mediators of molecular dialog between a cell and its extracellular matrix environment. The unique combinations of integrin subunits determine which extracellular matrix molecules are recognized by a cell. Recent studies have demonstrated that remodeling in heart and vasculature is linked to alterations in extracellular matrix and integrin expression. The roles of integrins in controlling cellular behavior have made these molecules highly attractive drug targets. New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation and cardiac growth suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures such as cardiac transplantation. Therapeutic candidates include antibodies, cyclic peptides, peptidomimetics and small molecules. The integrin inhibitors Integrilin and ReoPro have been approved as blood thinners in cardiovascular disease, and newer agents are undergoing testing. Although integrin function is important in the cardiovascular system, there are wide gaps in knowledge. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these molecules in the cardiovascular system. more...
- Published
- 2007
- Full Text
- View/download PDF
47. Continuous requirement for pp60-Src and phospho-paxillin during fibronectin matrix assembly by transformed cells.
- Author
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Wierzbicka-Patynowski I, Mao Y, and Schwarzbauer JE
- Subjects
- Antineoplastic Agents, Hormonal pharmacology, Cell Line, Transformed, Cell Line, Tumor, Dexamethasone pharmacology, Fibrosarcoma pathology, Humans, Integrins drug effects, Integrins physiology, Phosphorylation, Fibronectins metabolism, Oncogene Protein pp60(v-src) physiology, Paxillin metabolism
- Abstract
Fibronectin (FN) matrix assembly is an integrin-mediated process that is regulated by both the extracellular environment and intracellular signaling pathways. The activity of Src-family kinases is important for initiation of FN assembly by normal fibroblasts. Here we report that in HT1080 fibrosarcoma cells, Src kinase activity is required not only for the assembly of FN matrix but also for the maintenance of FN matrix fibrils at the cell surface. Dexamethasone-induced FN fibril formation by these cells was completely blocked for at least 24 h when Src-family kinase activity was inhibited by either PP1 or SU6656. Inhibition of Src after significant matrix had already been assembled, resulted in an increased rate of loss of detergent-insoluble FN. Binding of activation-dependent integrin antibodies reveals a role for Src in maintaining integrin activity. The requirement for Src kinase activity appears to depend, in part, on phosphorylation of paxillin at tyrosine 118 (Y118). Phospho-paxillin co-localized with FN fibrils, and overexpression of GFP-paxillin but not of GFP-paxillinY118F enhanced cell-mediated assembly of FN. Our results indicate that Src maintains FN matrix at the cell surface through its effect on integrin activity and paxillin phosphorylation., (Copyright 2006 Wiley-Liss, Inc.) more...
- Published
- 2007
- Full Text
- View/download PDF
48. A protein kinase signal-responsive gene carrier modified RGD peptide.
- Author
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Oishi J, Ijuin M, Sonoda T, Kang JH, Kawamura K, Mori T, Niidome T, and Katayama Y
- Subjects
- Cell Line, Tumor, DNA genetics, DNA metabolism, Enzyme Activation, HeLa Cells, Humans, Integrins genetics, Integrins metabolism, Luciferases genetics, Luciferases metabolism, Oligopeptides chemical synthesis, Protein Kinases metabolism, Gene Expression Regulation drug effects, Genetic Therapy methods, Integrins drug effects, Oligopeptides pharmacology, Protein Kinases genetics, Signal Transduction drug effects
- Abstract
We have previously reported artificial gene-regulation systems responding to cyclic AMP-dependent protein kinase (PKA) using a cationic polymer. However, this polymer alone cannot deliver any gene into living cells. In the present work, we modified the signal-responsive polymer to the RGD peptide for the introduction of a polymer/DNA complex into living cells and succeeded in regulating the gene expression responding to intracellular PKA activation. more...
- Published
- 2006
- Full Text
- View/download PDF
49. Blockade of alpha v beta3 and alpha v beta5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells.
- Author
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Maubant S, Saint-Dizier D, Boutillon M, Perron-Sierra F, Casara PJ, Hickman JA, Tucker GC, and Van Obberghen-Schilling E
- Subjects
- Anoikis drug effects, Apoptosis drug effects, Cell Culture Techniques, Cell Death drug effects, Cell Death physiology, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Fetal Blood cytology, Humans, Integrin alphaVbeta3 drug effects, Integrin alphaVbeta3 genetics, Integrins drug effects, Integrins genetics, Neoplasms blood supply, Neovascularization, Pathologic, Receptors, Vitronectin drug effects, Receptors, Vitronectin genetics, Umbilical Veins, Vitronectin physiology, gamma-Aminobutyric Acid pharmacology, Anoikis physiology, Benzocycloheptenes pharmacology, Endothelium, Vascular physiology, Integrin alphaVbeta3 antagonists & inhibitors, Integrins antagonists & inhibitors, Oligopeptides pharmacology, Receptors, Vitronectin antagonists & inhibitors, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Alpha v integrins are thought to play an important role in tumor angiogenesis. However, discrepancies between findings with Arg-Gly-Asp (RGD) mimetics, which block angiogenesis in animal models, and knockout mice, in which loss of some alpha v integrins enhances tumor angiogenesis, raise questions concerning the function of these integrins and the precise role of alpha v substrate mimetics in antiangiogenic therapies. We have examined the effects of a novel non-peptide RGD mimetic, S 36578-2, on human endothelial cells to elucidate its antagonist activity and to identify possible agonist functions. S 36578-2 is highly selective for alpha v beta3 and alpha v beta5 integrins and induces detachment, caspase-8 activation, and apoptosis in human umbilical endothelial cells (HUVECs) plated on vitronectin. Importantly, the compound has no effect on the morphology or survival of cells plated on interstitial matrix components such as fibronectin, and it does not potentiate the apoptotic process in suspended cells. Identical results were obtained with a cyclic RGD peptide with similar target specificity. In microvascular endothelial cells, S 36578-2-induced death was also linked to its antiadhesive effect, with established lines markedly more resistant than primary cultures to the antiadhesive and proapoptotic effects. Altogether, these findings have important implications for the development of this class of antiangiogenics. more...
- Published
- 2006
- Full Text
- View/download PDF
50. Semaphorin 3C regulates endothelial cell function by increasing integrin activity.
- Author
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Banu N, Teichman J, Dunlap-Brown M, Villegas G, and Tufro A
- Subjects
- Animals, Cell Adhesion, Cell Movement, Cell Proliferation, Endothelial Cells cytology, Endothelium, Vascular cytology, Integrin beta1 metabolism, Integrins drug effects, Integrins metabolism, Kidney cytology, Mice, Neovascularization, Physiologic, Phosphorylation, Recombinant Proteins pharmacology, Semaphorins pharmacology, Vascular Endothelial Growth Factor A pharmacology, Endothelial Cells drug effects, Endothelial Cells physiology, Integrin beta1 drug effects, Semaphorins physiology
- Abstract
Class 3 semaphorins (sema 3) are secreted guidance proteins. Sema 3A expressed by endothelial cells controls vascular morphogenesis through integrin inhibition. Sema 3C is required for normal cardiovascular patterning. Here we examined the potential role of sema 3C as regulator of endothelial cell function in vitro using mouse glomerular endothelial cells (MGEC). We determined that MGEC express sema 3C mRNA and protein and its receptors mRNA. Recombinant sema 3C induced MGEC proliferation 18 +/- 2% above control, as assessed by bromodeoxyuridine (BrdU) incorporation, and reduced starvation-induced apoptosis by 46 +/- 3%, as indicated by an in situ marker of activated caspase 3. Sema 3C increased MGEC adhesion to fibronectin 79 +/- 13% and to collagen 55 +/- 12% as compared with control. Sema 3C-induced MGEC adhesion was prevented by integrin blocking antibodies and involved beta1 integrin serine phosphorylation. Sema 3C-induced MGEC adhesion and proliferation were similar to those induced by vascular endothelial growth factor (VEGF)-A. Sema 3C induced a 44 +/- 11% increase in MGEC directional migration and stimulated MGEC capillary-like network formation on collagen I gels. Collectively, our data indicate that sema 3C promotes glomerular endothelial cell proliferation, adhesion, directional migration, and tube formation in vitro by stimulating integrin phosphorylation and VEGF120 secretion, functions that are similar to VEGF-A and opposite to sema 3A. more...
- Published
- 2006
- Full Text
- View/download PDF
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