Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A hitherto unknown function for transglutaminase (TGase; R-glutaminyl-peptide: amine gamma-glutamyltransferase, EC 2.3.2.13) was found in the conversion of latent transforming growth factor-beta (LTGF-beta) to active TGF-beta by bovine aortic endothelial cells (BAECs). The cell-associated, plasmin-mediated activation of LTGF-beta to TGF-beta induced either by treatment of BAECs with retinoids or by cocultures of BAECs and bovine smooth muscle cells (BSMCs) was blocked by seven different inhibitors of TGase as well as a neutralizing antibody to bovine endothelial cell type II TGase. Control experiments indicated that TGase inhibitors and/or a neutralizing antibody to TGase did not interfere with the direct action of TGF-beta, the release of LTGF-beta from cells, or the activation of LTGF-beta by plasmin or by transient acidification. After treatment with retinoids, BAECs expressed increased levels of TGase coordinate with the generation of TGF-beta, whereas BSMCs and bovine embryonic skin fibroblasts, which did not activate LTGF-beta after treatment with retinoids, did not. Furthermore, both TGase inhibitors and a neutralizing antibody to TGase potentiated the effect of retinol in enhancing plasminogen activator (PA) levels in cultures of BAECs by suppressing the TGF-beta-mediated enhancement of PA inhibitor-1 (PAI-1) expression. These results indicate that type II TGase is a component required for cell surface, plasmin-mediated LTGF-beta activation process and that increased expression of TGase accompanies retinoid-induced activation of LTGF-beta.
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PMID:Requirement for transglutaminase in the activation of latent transforming growth factor-beta in bovine endothelial cells. 809 47

Cell-associated plasmin is a putative physiological activator of latent transforming growth factor-beta (LTGF-beta). Since retinoids enhance the production of plasminogen activator (PA) and thereby increase cell-associated plasmin activity, we tested the possibility that retinoids might induce the activation of LTGF-beta using bovine endothelial cells (ECs) as a model system. ECs treated with physiological concentrations of retinol or retinoic acid formed active TGF-beta in the culture media in a dose- and time-dependent fashion. Cells were treated with 2 microM retinol for 24 h, and the amount of TGF-beta produced during a subsequent 12-h incubation period was measured. Out of a total of 14 pM LTGF-beta secreted, 0.7 pM was converted to active TGF-beta. Northern blot analyses showed that mRNA levels for TGF-beta 2 but not for TGF-beta 1 increased in cells treated with retinol. Inclusion of either inhibitors of PA or of plasmin or antibody against PA in the culture medium as well as depletion of plasminogen from the serum blocked the formation of TGF-beta, suggesting that PA, plasminogen, and the resulting plasmin are essential for activation of LTGF-beta in retinoid-stimulated cells. Antibody against the LTGF-beta binding protein blocked activation implying that localization of LTGF-beta through its binding protein may be important. However, inhibition of binding of LTGF-beta to the cell surface mannose 6-phosphate receptor did not prevent activation. These data indicate that retinoids up-regulate the production of LTGF-beta in ECs and induce activation of LTGF-beta, perhaps, by increasing PA and plasmin levels. Thus, TGF-beta might be a local mediator of some of the biological activities of retinoids both in vivo and in vitro.
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PMID:Mechanism of retinoid-induced activation of latent transforming growth factor-beta in bovine endothelial cells. 848 24

The multifunctional cytokine, transforming growth factor-beta (TGF beta), is found in many tissues in a latent or inactive form. The nature and composition of the latent complex can vary depending on tissue type. The release of active TGF beta from its latent complex is a potentially important mechanism for regulation of TGF beta activity. We have shown previously that osteoclasts activate latent TGF beta produced by bone and that bone cells produce a 100-kDa latent complex that lacks the latent TGF beta-binding protein. Here we investigated the effects of retinol on osteoclast activation of various forms of latent TGF beta. Two sources of osteoclasts were used that provide either mature avian osteoclasts or avian osteoclast precursors. Whereas both cell populations activate latent TGF beta, only mature osteoclasts respond to retinol with an increase in activation of latent TGF beta over basal levels. Activation could not be ascribed to pH changes in conditioned medium. Nonacid-dissociable 100-kDa latent complex, which is also produced by bone cells, was added to mature osteoclasts and to osteoclast precursors, but no activation was observed. Platelet latent TGF beta, which contains the 130-kDa latent TGF beta-binding protein, was activated by both osteoclast populations. Conditioned medium from the precursor population activated latent complex, whereas conditioned medium from mature cells did not. Activation of latent TGF beta by retinol-treated mature cells was not blocked by inhibitors of plasmin, nor was activation by conditioned medium from precursor cells. These data suggest that retinol-induced activation of latent TGF beta by osteoclasts is dependent on the stage of differentiation of these cells and the presence of other cell types, and that unlike other cell systems, the plasmin-plasminogen activator mechanism is not involved.
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PMID:Effects of retinol on activation of latent transforming growth factor-beta by isolated osteoclasts. 900

Myofibroblasts (MF) are a major effector cell type in liver fibrogenesis, where they are thought to derive from the activation of hepatic stellate cells. Cultured human MF, grown from liver explants, retain most of the in vivo characteristics of liver MF but are in limited supply. A continuous MF cell line would therefore be valuable in studying human liver fibrogenesis. For this purpose, we sought to immortalize human liver MF with polyoma virus large T antigen. MF were obtained from explants of human liver and transfected with a plasmid containing the coding sequence of polyoma virus large T antigen. This procedure yielded an activity growing cell line, designated GREF-X, which did not express large T antigen. Nevertheless, this cell line has been passaged repeatedly for almost 1 year and is thus likely immortalized. The morphology of GREF-X resembles that of primary liver MF. These cells have a doubling time of approximately 72 hours and are density-inhibited, and their growth is serum-dependent. Moreover, GREF-X cells do not grow in soft agar or induce tumors in nude mice, suggesting that they are not transformed. They stain positively for MF markers, such as smooth muscle alpha-actin and vimentin; express collagens type I, IV, V, and VI, fibronectin, and laminin: and secrete matrix-metalloproteinase-2. In addition, GREF-X cells are able to take up and esterify [3H]retinol, suggesting that they actually derive from hepatic stellate cells. Finally, these cells respond to transforming growth factor-beta 1, a major mediator of liver fibrogenesis, by increasing secretion of fibronectin and plasminogen activator-inhibitor type 1. Transient transfection experiments showed that plasminogen activator-inhibitor type 1 regulation, by transforming growth factor-beta 1, was transcriptional. We believe, therefore, that GREF-X would be a useful tool for studying the pathophysiology and pharmacology of liver fibrogenesis.
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PMID:Characterization of a new human liver myofibroblast cell line: transcriptional regulation of plasminogen activator inhibitor type I by transforming growth factor beta 1. 925 79

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in patients previously operated on for T1-T2 N-M0 breast cancer. During the trial, blood samples were collected at baseline and on a yearly basis from most of the patients. Evaluation of drug and retinol concentrations by HPLC assay has been performed for all the samples to obtain 4-HPR pharmacokinetic information as well as information on the effect of 4-HPR in lowering retinol plasma levels. The most important criteria for validation and quality control of the HPLC assay are summarized in order to provide a guide and practical recommendations for analytical procedures to be performed during prevention trials. Studies have been performed on subsets of patients participating in the trial in order to identify circulating biomarkers predictive of breast cancer. Evidence has been obtained on a lowering effect of 4-HPR on biologically active IGF-I only in premenopausal women. This was due to a decrease of IGF-I, associated with a trend to an increase in IGF-I binding protein 3 (IGFBP-3). An interim analysis of the ongoing trial indicates that 4-HPR reduces the incidence of contralateral breast cancer only in premenopausal women. Analyses of total and unbound IGF-I are being performed on plasma samples collected at baseline and during intervention from women < or = 50 years old. The relationship between the incidence of a second breast cancer and the changes in IGF-I plasma levels will be assessed in order to validate IGF-I as a surrogate end point of contralateral breast cancer. The preliminary results of other studies on the effects of 4-HPR on tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), and urokinase plasminogen activator (uk-PA) and on the relevance of circulating p53 antibodies with relapse will be also presented.
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PMID:Quality control for HPLC assay and surrogate end point biomarkers from the fenretinide (4-HPR) breast cancer prevention trial. 1076 18

Vitamin A and its active metabolite retinoic acid (RA) modulate host-pathogen interactions by interfering with the host immune and inflammatory response including prostaglandin (PG) biosynthesis. The effects of RA on phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) isoforms in vitro are controversial, and few in vivo studies exist. We investigated the in vivo effects of RA on PG biosynthesis in the presence or absence of lipopolysaccharide (LPS) in rats. RA alone [10 mg/(kg. d) for 5 d] increased plasma and liver PG concentrations by increasing COX-1 protein expression (twofold that of control rats). RA acted synergistically with LPS to increase plasma (400-fold) and liver (15-fold) concentrations of prostaglandin E(2) (PGE(2)) and significantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA(2) expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA + LPS-mediated increase in PGE(2) was significantly attenuated (97%) by aminoguanidine (AG), a relatively specific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LPS on NOS2 expression and activity. In addition, RA and LPS induced the expression of the microsomal isoform of PGE synthase (mPGES). In conclusion, in vivo, RA and LPS increased PG and especially PGE(2) concentrations. The PGE(2) increase was associated with NOS2-mediated activation of COX and induction of mPGES. These results contribute to the characterization of the effects of vitamin A on the host inflammatory response.
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PMID:Retinoic acid and lipopolysaccharide act synergistically to increase prostanoid concentrations in rats in vivo. 1158 82

This study was conducted to examine whether the inhibition of intestinal lipid absorption by green tea is associated with the inhibitory effect of its catechins on pancreatic phospholipase A(2) (PLA(2)). PLA(2) activity was assayed by using 1,2-dioleoylphosphatidylcholine (DOPC), porcine pancreatic PLA(2) and catechins at varying concentrations (0.075-1.80 micromol/L). The amount of 1-oleoyl-2-hydroxyphosphatidylcholine liberated was determined by HPLC. The percentage of inhibition of PLA(2) by catechins at 0.6 micromol increased in the order of (-)-epicatechin (23.3%), (+)-catechin (CAT; 24.8%), (-)-epigallocatechin (25.7%), (-)-epicatechin gallate (39.7%) and (-)-epigallocatechin gallate (EGCG; 64.9%). In an in vivo study, ovariectomized rats with lymph cannula were infused intraduodenally for 8 h with a triolein emulsion containing [dioleoyl-1-(14)C]-phosphatidylcholine, DOPC, alpha-tocopherol (alphaTOH) and retinol (ROH) without (CAT0) or with CAT or EGCG. The lymphatic total (14)C-radioactivity was significantly lowered by EGCG (45.5+/-4.9% dose) compared with CAT (56.2+/-5.2% dose) and CAT0 (64.7+/-2.0% dose). The (14)C-radioactivity remaining in the small intestinal lumen and cecum was higher in EGCG (24.1% dose) than in CAT (9.5% dose) and CAT0 rats (9.0% dose). Significantly less (14)C radioactivity was incorporated into lymph triacylglycerol and cholesteryl ester in EGCG rats. The absorption of alphaTOH, used as a marker of extremely hydrophobic lipids, was significantly lower in EGCG (7.8+/-1.7 micromol) than in CAT (14.4+/-2.8 micromol) and CAT0 rats (16.8+/-2.1 micromol). The absorption of ROH was unaffected, whereas oleic acid output was lower in EGCG rats. The results show that EGCG inhibits the intestinal absorption of lipids, which is in part associated with its inhibition of phosphatidylcholine hydrolysis. Data suggest that EGCG may inhibit the absorption of other highly lipophilic organic compounds.
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PMID:Green tea catechins inhibit pancreatic phospholipase A(2) and intestinal absorption of lipids in ovariectomized rats. 1671 29

Block copolymer nanoparticles often referred to as "block copolymer micelles" have been assessed as carriers for skin delivery of hydrophobic drugs. Such carriers are based on organic biocompatible and biodegradable materials loaded with hydrophobic drugs: poly(lactide)-block-poly(ethylene glycol) copolymer (PLA-b-PEG) nanoparticles that have a solid hydrophobic core made of glassy poly(d,l-lactide), and poly(caprolactone)-block-poly(ethylene glycol) copolymer (PCL-b-PEG) nanoparticles having a liquid core of polycaprolactone. In vitro skin absorption of all-trans retinol showed a large accumulation of retinol in stratum corneum from both block copolymer nanoparticles, higher by a factor 20 than Polysorbate 80 surfactant micelles and by a factor 80 than oil solution. Additionally, skin absorption from PLA-b-PEG nanoparticles was higher by one order of magnitude than PCL-b-PEG, although their sizes (65nm) and external surface (water-swollen PEG layer) were identical as revealed by detailed structural characterizations. Fluorescence microscopy of histological skin sections provided a non-destructive picture of the storage of Nile Red inside stratum corneum, epidermis and dermis. Though particle cores had a different physical states (solid or liquid as measured by (1)H NMR), the ability of nanoparticles for solubilization of the drug assessed from their Hildebrand solubility parameters appeared the parameter of best relevance regarding skin absorption.
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PMID:Skin delivery by block copolymer nanoparticles (block copolymer micelles). 2660 93

Surfactant-free biocompatible and biodegradable Pickering emulsions were investigated as vehicles for skin delivery of hydrophobic drugs. O/w emulsions of medium-chain triglyceride (MCT) oil droplets loaded with all-trans retinol as a model hydrophobic drug were stabilized by block copolymer nanoparticles: either poly(lactide)-block-poly(ethylene glycol) (PLA-b-PEG) or poly(caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG). Those innovative emulsions were prepared using two different processes allowing drug loading either inside oil droplets or inside both oil droplets and non-adsorbed block copolymer nanoparticles. Skin absorption of retinol was investigated in vitro on pig skin biopsies using the Franz cell method. Supplementary experiments by confocal fluorescence microscopy allowed the visualization of skin absorption of the Nile Red dye on histological sections. Retinol and Nile Red absorption experiments showed the large accumulation of hydrophobic drugs in the stratum corneum for the Pickering emulsions compared to the surfactant-based emulsion and an oil solution. Loading drug inside both oil droplets and block copolymer nanoparticles enhanced again skin absorption of drugs, which was ascribed to the supplementary contribution of free block copolymer nanoparticles loaded with drug. Such effect allowed tuning drug delivery to skin over a wide range by means of a suitable selection of either the formulation or the drug loading process.
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PMID:Pickering emulsions stabilized by biodegradable block copolymer micelles for controlled topical drug delivery. 2880 93

The detection of phospholipase A2 receptor (PLA2R) and thrombospondin domain containing 7A THSD7A among primary membranous glomerulonephritis (MGN) patients transformed the diagnosis, treatment monitoring, and prognosis. Anti-PLA2R can be detected in 70-90% of primary MGN patients while anti-THSD7A in 2-3% of anti-PLA2R negative primary MGN patients depending on the technique used. Serum and urine samples are less invasive and non-invasive, respectively, and thus can detect the presence of anti-PLA2R and anti-THSD7A with higher sensitivity and specificity, which is significant in patient monitoring and prognosis. It is better than exposing patients to a frequent biopsy, which is an invasive procedure. Different techniques of detection of PLA2R and THSD7A in patients' urine and sera were reviewed to provide newer and alternative techniques. We proposed the use of biomarkers (PLA2R and THSD7A) in the diagnosis, treatment decision, and follow-up of patients with primary MGN. In addition, other prognostic renal biomarkers like retinol binding protein (RBP) and beta-2 microglobulin were reviewed to detect the progression of renal damage for early intervention.
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PMID:Primary Membranous Glomerulonephritis: The Role of Serum and Urine Biomarkers in Patient Management. 3168 74


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