Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Integrin alpha4beta1”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 973 records · Page 54Linked to original sources
PubMed2003

Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells.

We have investigated the effects of Chlamydia pneumoniae on human brain endothelial cells (HBMECs) and human monocytes as a mechanism for breaching the blood-brain barrier (BBB) in Alzheimer's disease (AD). HBMECs and peripheral blood monocytes may be key components in controlling the entry of C. pneumoniae into the human brain. Our results indicate that C. pneumoniae infects blood vessels and monocytes in AD brain tissues compared with normal brain tissue. C. pneumoniae infection stimulates transendothelial entry of monocytes through HBMECs. This entry is facilitated by the up-regulation of VCAM-1 and ICAM-1 on HBMECs and a corresponding increase of LFA-1, VLA-4, and MAC-1 on monocytes. C. pneumoniae infection in HBMECs and THP-1 monocytes up-regulates monocyte transmigration threefold in an in vitro brain endothelial monolayer. In this way, C. pneumoniae infection in these cell types may contribute to increased monocyte migration and promote inflammation within the CNS resulting from infection at the level of the vasculature. Thus, infection at the level of the vasculature may be a key initiating factor in the pathogenesis of neurodegenerative diseases such as sporadic AD.

Alzheimer Disease↗
PubMed2004

Estrogen treatment induces a novel population of regulatory cells, which suppresses experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a debilitating neurological disease characterized by a progressive loss of motor and sensory function, eventually leading to paralysis and death. The primary cause of neurological impairment is demyelination of the central nervous system (CNS) caused by an inflammatory autoimmune response. Previous studies have shown that the severity of MS is reduced during pregnancy, suggesting that the increased level of sex hormones may reduce the autoimmune response. Recently, we have shown that estrogen treatment confers protection from experimental autoimmune encephalomyelitis (EAE), which is an animal model for MS. However, the cellular basis of estrogen's action remains unknown. In the current study, we demonstrate that estrogen treatment led to the induction of a novel subpopulation of regulatory cells in spleen and CNS, which also occurs naturally in pregnant mice. These previously uncharacterized cells display a low level expression of CD45 (CD45(dim)) and no detectable expression of many cell surface markers related to TCR signaling, including CD3 and TCR. However, these cells retained expression of VLA-4, an extracellular protein involved in cellular migration. Several lines of evidence suggest that these novel cells, defined as CD45(dim)VLA-4(+) cells, may play a role in the protective effects of estrogen in EAE. Injection of purified CD45(dim)VLA-4(+) cells conferred protection from spontaneous EAE (Sp-EAE). In contrast, injection of CD45(high)VLA-4(+) cells exacerbated the disease course. CD45(dim)VLA-4(+) cells also suppressed antigen-specific proliferation of primed lymphocytes in coculture. A better understanding of how CD45(dim)VLA-4(+) cells suppress the harmful immune response of EAE may help in explaining the induction of immune tolerance during pregnancy and lead to novel therapeutic approaches to combat MS and other autoimmune diseases.

Adjuvants, Immunologic↗
PubMed2003

VLA-4 antagonists: potent inhibitors of lymphocyte migration.

Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development.

Animals↗
PubMed2006

Association of CD45(dim)VLA-4 (+) cells with the NKT cell lineage and their selective expression of IL-13, IP-15, and CCR3 transcripts.

INTRODUCTION: Estrogen (E2) was shown to prevent experimental autoimmune encephalomyelitis (EAE) and to produce a novel population of regulatory CD45(dim)VLA-4(+) cells. Although their appearance was dependent upon an elevated hormonal level, E2 was not required for their production, as they also were induced by immunization with Mycobacterium tuberculosis as a component of complete Freund's adjuvant. MATERIALS AND METHODS: Molecular techniques, including ribonuclease protection assays and quantitative RT-PCR, were used to provide further characterization of CD45(dim)VLA-4(+) cells. Moreover, we determined the developmental requirements of the CD45(dim)VLA-4(+) cells using genetically modified mice and extensive flow cytometry analysis. RESULTS: Characterization of CD45(dim)VLA-4(+) mRNA profile revealed highly elevated levels of CD16, CD44, CCR3, IP-15, and IL-13 transcripts compared with their CD45(high)VLA-4(+) counterparts. Furthermore, we found up-regulation of anti-apoptotic bcl-w and bcl-xl genes and transcripts encoding the TCRalpha and CD8alpha homodimer. The production of CD45(dim)VLA-4(+) cells was evident in nude mice and in MHC class II- and beta2-microglobulin, but not in CD1-deficient mice, suggesting a crucial role for CD1 in their induction. CONCLUSIONS: These findings suggest that CD45(dim)VLA-4(+) cells might resemble natural killer T cells and imply possible roles for IL-13 and IP-15 in the protective function of CD45(dim)VLA-4(+) cells. A better understanding of how these cells, also occurring naturally during pregnancy, suppress the harmful immune response of EAE may lead to novel therapeutic approaches to combat multiple sclerosis and other autoimmune diseases.

Animals↗
PubMed2005

Microcirculation and venous ulcers: a review.

Recent histological and immunocytochemical analyses of venous leg ulcers suggest that lesions observed in the different stages of chronic venous insufficiency (CVI) may be related to an inflammatory process. This inflammatory process leads to fibrosclerotic remodeling of the skin and then to ulceration. The vascular network of the most superficial layers of the skin appears to be the target of the inflammatory reaction. Hemodynamic forces such as venous hypertension, circulatory stasis, and modified conditions of shear stress appear to play an important role in an inflammatory reaction accompanied by leukocyte activation which clinically leads to CVI: venous dermatitis and venous ulceration. The leukocyte activation is accompanied by the expression of integrins and by synthesis and release of many inflammatory molecules, including proteolytic enzymes, leukotrienes, prostaglandin, bradykinin, free oxygen radicals, cytokines, and possibly other classes of inflammatory mediators. The inflammatory reaction perpetuates itself, leading to liposclerotic skin and subcutaneous tissue remodeling. In light of the mechanisms of venous ulcer formation cited above, therapy in the future might be directed against leukocyte activation in order to diminish the magnitude of the inflammatory response. With this in mind, the attention of many investigators has been drawn to two different drugs with an anti-inflammatory effect: pentoxifylline and flavonoids.

Endothelium, Vascular↗
PubMed2005

Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists.

A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).

Acetates↗
PubMed2006

Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists.

A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL=18.5 ml/min/kg,F=28%; rats, CL=5.2 ml/min/kg,F=36%; dogs, CL=3.6 ml/min/kg,F=55%). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.

Administration, Oral↗
PubMed2004

Synthesis, characterization and evaluation of pro-drugs of VLA-4 antagonists.

A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.

Animals↗
PubMed2004

Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4.

We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).

Anilides↗
PubMed2004

Amidines as amide bond replacements in VLA-4 antagonists.

VLA-4 (alpha(4)beta(1), very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biological evaluation of amidines as small molecule antagonists of VLA-4.

Amides↗
PubMed2005

2,3-Diphenylpropionic acids as potent VLA-4 antagonists.

The discovery and SAR of 2,3-diphenylpropionic acid derivatives as highly potent VLA-4 antagonists are described. One representative compound, 9cc has inhibited intercellular adhesion by a VCAM-1/VLA-4 interaction with an IC(50) of 1.7 nM, and has good pharmacokinetics and oral bioavailability.

Administration, Oral↗
PubMed2005

Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist.

An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.

Administration, Oral↗
PubMed2005

Influence of acid surrogates toward potency of VLA-4 antagonist.

A series of VLA-4 antagonist were synthesized wherein carboxylic acid was replaced by various acid surrogates. The effect of these acid surrogates toward potency was evaluated in a binding assay. A number of acid surrogates were potent antagonist of VLA-4, albeit significantly less potent than the corresponding carboxylic acid. Heterocyclic acid surrogate, oxadiazolidinone 3, demonstrated an improved pharmacokinetic property when dosed intravenously.

Acids↗
PubMed2004

Apoptotic and anti-adhesion effect of ajoene, a garlic derived compound, on the murine melanoma B16F10 cells: possible role of caspase-3 and the alpha(4)beta(1) integrin.

In this study we evaluated the hypothesis that the antitumor activity of ajoene could be associated with its apoptosis-inducing effect, and with its ability to block the expression of the alpha(4)beta(1) integrin, in the murine melanoma B16F10 cells. Ajoene induced a significant reduction in B16F10 viability (IC(50)=62 microM), in a dose-dependent manner. Flow cytometric analysis showed that the cytotoxic effect of this compound was associated with caspase-3 activation. Ajoene at 25 microM altered the alpha(4)beta(1) integrin expression on B16F10, and induced a significant reduction in the adhesion of these cells to an endothelial cell monolayer.

Animals↗
PubMed2005

Neutralisation of TGF beta or binding of VLA-4 to fibronectin prevents rat tendon adhesion following transection.

Following tendon injury, severe loss of function often occurs either as a result of obliteration of the synovial canal with fibrous scar tissue or from rupture of the repaired tendon. The role of cell engineering in tendon repair is to promote strong and rapid healing of tendon whilst at the same time facilitating rapid reconstitution of the synovial canal. Modification of the immediate inflammatory response around healing tendon has been found to be of value. Experimentally this has been achieved by neutralisation of transforming growth factor-beta over the first 3 days following injury, or by blockade of inflammatory cell binding to the CS-1 locus on fibronectin with an anti-VLA-4 antibody, or with the synthetic VLA-4 inhibitor, CS-1 peptide, in a rat model of tendon transection. It is concluded from this pilot study that the treatments described hold promise in improving outcomes of the common clinical problem of tendon injury in man.

Animals↗