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 1,009 records · Page 56Linked to original sources
PubMed2003

Monocytes initiate a cycle of leukocyte recruitment when cocultured with endothelial cells.

During the development of atherosclerotic plaque, monocytes and T-lymphocytes are recruited to the arterial intima by endothelial cells (EC) lining the vessel. This process is associated with chronic arterial inflammation and requires the activation-dependent expression of adhesion receptors and chemokines on EC. Here we show that monocytes can activate cocultured EC so that they support the adhesion, activation and transmigration of a secondary bolus of flowing peripheral blood monocytes or lymphocytes. The number of adherent leukocytes and their behaviour was comparable to that seen on EC activated with tumour necrosis factor-alpha (TNF-alpha). Depending upon the duration of endothelial cell/monocyte coculture different patterns of adhesion receptors were utilised by leukocytes. After 4 h coculture, antibodies against E-selectin, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) reduced mononuclear leukocyte adhesion. After 24 h coculture, antibodies against E-selectin and VCAM-1 but not P-selectin were effective. Immunofluorescence analysis confirmed that monocyte coculture induced endothelial expression of E-selectin and VCAM-1, while P-selectin was at the limit of detection. We conclude that EC stimulated by monocytes can support the adhesion of flowing mononuclear leukocytes. We hypothesise that this mode of EC activation and leukocyte recruitment could initiate a self-perpetuating cycle of inflammation that could be relevant to atherogenesis and other chronic inflammatory disease states.

Antibodies, Monoclonal↗
PubMed2003

Early pregnancy factor treatment suppresses the inflammatory response and adhesion molecule expression in the spinal cord of SJL/J mice with experimental autoimmune encephalomyelitis and the delayed-type hypersensitivity reaction to trinitrochlorobenzene in normal BALB/c mice.

Early pregnancy factor (EPF) is a secreted protein, present in serum during early pregnancy and essential for maintaining viability of the embryo. It is a homologue of chaperonin 10 (Cpn10) but, unlike Cpn10, it has an extracellular role. EPF has immunosuppressive and growth regulatory properties. Previously we have reported the preparation of recombinant EPF (rEPF) and shown that treatment with rEPF will suppress clinical signs of MBP-EAE in Lewis rats and PLP-EAE in SJL/J mice. In the present study, these findings have been extended to investigate possible mechanisms involved in the action of EPF. Following treatment of mice with rEPF from the day of inoculation, there were fewer infiltrating CD3+ and CD4+ cells in the parenchyma of the spinal cord during the onset of disease and after the initial episode, compared with mice treated with vehicle. Expression of the integrins LFA-1, VLA-4 and Mac-1 and of members of the immunoglobulin superfamily of adhesion molecules ICAM-1 and VCAM-1 was suppressed in the central nervous system (CNS) following rEPF treatment. The expression of PECAM-1 was not affected. To determine if rEPF suppressed T cell activation in the periphery, the delayed-type hypersensitivity (DTH) reaction of normal BALB/c mice to trinitrochlorobenzene (TNCB) following treatment with rEPF was studied. The results showed that treatment with rEPF suppressed the DTH reaction, demonstrating the ability of EPF to downregulate the cell-mediated immune response. These results indicate that suppression of immunological mechanisms by rEPF plays a major role in the reduction of clinical signs of disease in experimental autoimmune encephalomyelitis (EAE).

Animals↗
PubMed2003

Temporal variations of adhesion molecules and matrix metalloproteinases in the course of MS.

Thirty patients with clinically isolated syndromes (CIS) were evaluated at the onset of neurological symptoms and when they developed clinically definite MS (CDMS). Surface expression of LFA-1alpha, VLA-4 and intercellular adhesion molecule-1 (ICAM-1) on PBMC and CSF cells was evaluated using flow cytometry. Serum and CSF concentrations of soluble vascular cell adhesion molecules-1 (VCAM-1), ICAM-1 and E-Selectin, as well as MMP-9 and MMP-2 serum concentrations were assayed using ELISA. Surface expression of LFA-1alpha and VLA-4 molecules on peripheral blood and CSF T cells and monocytes from CIS and CDMS was significantly increased compared with control subjects. Moreover, LFA-1alpha and VLA-4 expression was significantly higher in patients who developed CDMS compared with those with CIS. Similar changes were observed in the serum levels of MMP-9. Furthermore, patients with CIS and CDMS had significantly higher levels of CSF sVCAM and s-E-Selectin than control subjects. These data suggest that VLA-4, LFA-1alpha and MMP-9 play a leading role in the evolution of inflammatory demyelinating lesions in patients with CIS who develop CDMS.

Adult↗
PubMed2003

Essential role of VLA-4/VCAM-1 pathway in the establishment of CD8+ T-cell-mediated Trypanosoma cruzi-elicited meningoencephalitis.

Central nervous system (CNS) damage can occur during Trypanosoma cruzi infection, especially in immunosuppressed patients. The enhanced susceptibility of C3H/He mice to CD8-mediated acute meningoencephalitis is associated with higher up-regulation of vascular cell adhesion molecule-1 (VCAM-1) on CNS vascular endothelia than in the less susceptible C57BL/6. Further, in vitro adhesion of activated peripheral blood cells to CNS blood vessels was abrogated by anti-VLA-4 antibodies that also inhibited cell migration into the CNS of T. cruzi-infected mice. Lastly, the reactivation of meningoencephalitis in immunosuppressed chronically infected mice was associated with VCAM-1 up-regulation. Therefore, we hypothesize that VLA-4/VCAM-1 pathway plays a pivotal role in the establishment of T. cruzi-elicited encephalitis.

Animals↗
PubMed2002

Inhibition of cancer growth by resveratrol is related to its low bioavailability.

The relationship between resveratrol (RES) bioavalability and its effect on tumor growth was investigated. Tissue levels of RES were studied after i.v. and oral administration of trans-resveratrol (t-RES) to rabbits, rats, and mice. Half-life of RES in plasma, after i.v. administration of 20 mg t-RES/kg b.wt., was very short (e.g., 14.4 min in rabbits). The highest concentration of RES in plasma, either after i.v. or oral administration (e.g., 2.6 +/- 1.0 microM in mice 2.5 min after receiving 20 mg t-RES/kg orally), was reached within the first 5 min in all animals studied. Extravascular levels (brain, lung, liver, and kidney) of RES, which paralleled those in plasma, were always < 1 nmol/g fresh tissue. RES measured in plasma or tissues was in the trans form (at least 99%). Hepatocytes metabolized t-RES in a dose-dependent fashion (e.g., 43 nmol of t-RES/g x min in the presence of 20 microM tRES), which means that the liver can remove circulating RES very rapidly. In vitro B16 melanoma (B16M) cell proliferation and generation of reactive oxygen species (ROS) was inhibited by t-RES in a concentration-dependent fashion (100% inhibition of tumor growth was found in the presence of 5 microM t-RES). Addition of 10 microM H(2)O(2) to B16M cells, cultured in the presence of 5 microM t-RES, reactivated cell growth. Oral administration of t-RES (20 mg/kg twice per day; or included in the drinking water at 23 mg/l) did not inhibit growth of B16M inoculated into the footpad of mice (solid growth). However, oral administration of t-RES (as above) decreased hepatic metastatic invasion of B16M cells inoculated intrasplenically. The antimetastatic mechanism involves a t-RES (1 microM)-induced inhibition of vascular adhesion molecule 1 (VCAM-1) expression in the hepatic sinusoidal endothelium (HSE), which consequently decreased in vitro B16M cell adhesion to the endothelium via very late activation antigen 4 (VLA-4).

Animals↗
PubMed2002

Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists.

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.

Animals↗
PubMed2002

Identification of unique VLA-4 antagonists from a combinatorial library.

A combinatorial library of 28 pools of 180 compounds (345 diastereomers) was designed and prepared in support of the delineation of the SAR of two prototypical VLA-4 antagonists. Deconvolution of the active pools led to the identification of three novel series of VLA-4 antagonists with low nanomolar potencies.

Anti-Inflammatory Agents↗
PubMed2002

N-Tetrahydrofuroyl-(L)-phenylalanine derivatives as potent VLA-4 antagonists.

Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability.

Administration, Oral↗
PubMed2002

Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists.

A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.

Administration, Oral↗
PubMed2002

N-aryl-prolyl-dipeptides as potent antagonists of VLA-4.

The design, synthesis, and biological evaluation of N-arylprolyl-dipeptide derivatives as small molecule VLA-4 antagonists is described. Potency against VLA-4 and alpha(4)beta(7) and rat pharmacokinetic evaluation revealed some advantages over the related N-(arylsulfonyl)-prolyl-dipeptide analogues.

Animals↗
PubMed2002

N-(arylacetyl)-biphenylalanines as potent VLA-4 antagonists.

A series of potent N-(aralkyl-, arylcycloalkyl-, and heteroaryl-acyl)-4-biphenylalanine VLA-4 antagonists was prepared by rapid analogue methods using solid-phase chemistry. Further optimization led to several highly potent compounds (IC(50) <1 nM). Evaluation of rat pharmacokinetic revealed generally high clearance.

Animals↗
PubMed2002

N-Cycloalkanoyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.

Crystallography, X-Ray↗
PubMed2002

N-Aroyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A series of N-benzoyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine derivatives was prepared in order to optimize the substitution on the N-benzoyl moiety for VCAM/VLA-4 antagonist activity. Disubstitution in the 2- and 6-positions is favored and a range of small alkyl and halogen are tolerated. A model of the bioactive conformation of these compounds is proposed.

Heterocyclic Compounds↗
PubMed2002

Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists.

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl- and (L)-azetidyl-beta-biaryl beta-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins.

Administration, Oral↗