Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.36 (hyaluronidase)
 4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chondrogenesis, the differentiation of mesenchyme into cartilage, results in a change in composition of the extracellular matrix. The cartilage matrix contains several unique components, including type II collagen and chondroitin sulfate proteoglycan; it also contains fibronectin, a glycoprotein that mediates the interaction of cells with their matrix. We show that chick cartilage fibronectin mRNA contains an unusual pattern of alternatively spliced exons. Specifically, it contains exon IIIB but does not contain exon IIIA whereas fibronectin mRNA from mesenchyme contains both exons IIIB and IIIA. Thus the splicing pattern of the fibronectin mRNA must change from B+A+ to B+A- during chondrogenesis. Most fibronectin mRNA in other mesenchymal tissues contains exon IIIA but little exon IIIB (B-A+). Culturing of chondrocytes (cartilage-producing cells) results in loss of exon IIIB from fibronectin mRNA (B-A-). Manipulation of culture conditions to produce more adhesive chondrocytes (treatment with hyaluronidase, transformation with Rous sarcoma virus, and treatment with retinoic acid) increases the amount of fibronectin mRNA containing exon IIIA. These results suggest that exon IIIB may mediate the interactions of chondrocytes with the unique components of the cartilage matrix and exon IIIA may play a role in chondrocyte adhesion.
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PMID:The splicing pattern of fibronectin mRNA changes during chondrogenesis resulting in an unusual form of the mRNA in cartilage. 200 28

The effects of all-trans retinoic acid on glycosaminoglycan (GAG) accumulation were determined in cultured primary human skin fibroblasts. Confluent cultures treated with retinoic acid accumulated less [3H]GAG than those without the compound, an effect with an apparent threshold of 10 nM which was dose dependent in the concentration range tested (0-10 microM). At 10 microM, the inhibition was 54%. Greater than 80% of the labeled macromolecular material was streptomyces hyaluronidase digestible in cultures labeled with [3H]acetate. The incorporation of H2[35S]O4 into chondroitin sulfate and dermatan sulfate was unaffected, as was total protein synthesis. Retinol also inhibited accumulation of [3H]GAG, but was far less potent. T3 and dexamethasone can inhibit [3H]hyaluronate synthesis. When retinoic acid was added to cultures treated with either of these hormones at concentrations that maximally inhibit [3H] GAG accumulation, there was a further decrease in the rate of macromolecular accumulation. The retinoic acid effect evolved over 24-48 h after addition to the culture medium. A pulse-chase study failed to demonstrate any effect on [3H]GAG degradation.
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PMID:Retinoic acid inhibition of hyaluronate synthesis in cultured human skin fibroblasts. 230 23

Several years of clinical chemotherapy have shown that, despite modern refinements, cytotoxic agents are not able to eradicate metastases of most adult solid tumors but only to prolong survival by achieving a cell kill that is not 100 per cent. Among the possible causes of this phenomenon, two are discussed in detail. The first one is cell autonomy. It is shown that the numbers of generations reached by a metastatic clone until clinical detection is largely in excess of 100, which allows for a considerable number of mutations, and that in addition genetic destabilization leading to autonomy proceeds much more rapidly than anticipated by a random mutation process. Adaptative changes by genetic amplification in response to toxic injury add to this acceleration effect, accounting for the fact that most metastatic cells are totally resistant very early in the natural history of a human tumor. On the other hand, it is shown that dormant metastatic cells do exist, due either to lack of autocrine growth factors or to inhibiting agents secreted by other metastases. These cells can survive chemotherapy and then re-enter a proliferative state due to some mechanisms that are analyzed, accounting for semi-late and late failures. These obstacles call for other strategies of metastases management, such as arresting or differentiating agents, some of which have been successfully tested by the author's group, such as antiprostaglandins, antithrombin, somatostatin, hyaluronidase, and retinoic acid. It remains to study their optimal combinations, and the appropriate timing, in order to achieve, if not eradication, growth suppression for very long periods without toxicity.
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PMID:Accelerated genetic destabilization and dormancy: two distinct causes of resistance in metastatic cells; clinical magnitude, therapeutic approaches. 240 88

The distribution of cell surface negatively-charged macromolecules was determined electron microscopically on untreated and on retinoic acid (RA)-treated cultured human osteosarcoma Hs791 and chondrosarcoma Hs705 cells using cationized ferritin (CF), an electron-dense marker of anionic sites. Labeling on the surface of prefixed cells was continuous and uniform whether they were grown in the absence or presence of RA. In contrast, CF distribution on unfixed cells was markedly affected by RA; CF labeling of untreated cells occurred in patches and clusters whereas the label on RA-treated cells was continuous, as on prefixed cells. CF labeling of unfixed cells decreased considerably after incubation of the cells either with hyaluronidase or neuraminidase. There was also a reduction in patching and clustering. Changes induced by RA in the apparent membrane microviscosity, in neuraminidase-releasable sialic acid, or in transglutaminase activity could not be related to the effect of RA on CF-induced anionic site redistribution since these characteristics were modulated differently in the two cell lines. In contrast, RA increased the sialylation of specific cell surface membrane glycoproteins on both cell types. These results suggest that RA prevents redistribution of cell surface sialoglycoconjugates and glycosaminoglycans by CF. This effect may be the result of increased sialylation of specific surface components and may be related causally to the suppression of the transformed phenotype in the sarcoma cells.
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PMID:Prevention by retinoic acid of anionic site redistribution on the surface of cultured human sarcoma cells. 615 8

The effect of beta-all-trans-retinoic acid (RA) on the synthesis of cellular, cell surface, and secreted glycoconjugates by human Hs705 chondrosarcoma and Hs791 osteosarcoma cells was investigated in vitro. Untreated and RA-treated cells were labeled either metabolically with radioactive precursors or by oxidation of externally exposed cell membrane glycoprotein(s) (GP) by treatment with NalO4 or neuraminidase and galactose oxidase followed by reduction with NaB[3H]4. The cells were solubilized and analyzed by polyacrylamide gel electrophoresis followed by fluorography. RA enhanced the labeling of sialic acid and galactose residues on the GP of relative molecular weight(s) (Mr) in the range 95,000-300,000 on the surfaces of both cell types. [3H]glycosamine incorporation into GP with Mr of 100,000, 150,000, and 190,000 in both cell lines was also stimulated. In the Hs705 cells there was also an increase in the labeling of a 290,000-Mr GP. In contrast, [3H]glucosamine incorporation into glycoconjugates greater than 400,000 Mr in both the cells and the conditioned medium of Hs705 cells decreased. The latter glycoconjugates were susceptible to hyaluronidase and chondroitinases. [3H]glucosamine incorporation into a secreted 230,000-Mr GP, identified as fibronectin, was also reduced. Analyses of conditioned media of cells labeled with [35S]methionine or [14C]proline demonstrated that RA decreased the secretion of procollagen chains and fibronectin. Immunofluorescence revealed that RA alters the distribution of cell-associated fibronectin. These results demonstrated that RA increases the glycosylation of specific cellular and cell surface GP and decreases the production of secreted GP and glycosaminoglycans by the sarcoma cells.
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PMID:Modulation by retinoic acid of cellular, surface-exposed, and secreted glycoconjugates in cultured human sarcoma cells. 658 9

Teratocarcinoma cells (F9) were induced to differentiate by retinoic acid and then labelled with [3H]-glucosamine and [35S]-sulphate. Proteoglycans were then isolated from the plasma membranes and the culture medium by mild, dissociative, non-shear-dependent techniques. The undifferentiated cells were devoid of hyaluronic acid and contained negligible quantities of heparan sulphate, dermatan sulphate and chondroitin sulphate. Upon differentiation, the cells synthesized large amounts of hyaluronic acid and there was a threefold increase in the amount of membrane-bound sulphated proteoglycans. The differentiated cells also synthesized a proteoglycan (PGM-2) which was shed completely into the medium. It consisted of a large protein core with covalently linked sugar chains which were sulphated and had an approximate molecular weight of 12000. These sugar chains consisted of glucosamine and galactose in a molar ratio of 1:1 and contained a small quantity of mannose. Upon differentiation of the cells the amount of this molecule increased by threefold. This molecule was distinct from other proteoglycans since it was resistant to degradation by heparanase, chondroitinases, hyaluronidase and neuraminidase, but could be degraded by keratanase. Structurally it was very similar to keratan sulphate, consisting of alternating residues of (-Gal-GlcNAc-) in chains of approximately 20 such disaccharide units.
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PMID:Changes in proteoglycan composition of F9 teratocarcinoma cells upon differentiation. 666 12

In vitro culture conditions enabling rat tracheal epithelial (RTE) cells to differentiate to mucociliary, mucous, or squamous phenotypes are described. Medium composition for rapid cell growth to confluence in membrane insert cultures was determined, and the effects of major modifiers of differentiation were tested. Retinoic acid (RA), collagen gel substratum, and an air-liquid interface at the level of the cell layer were required for expression of a mucociliary phenotype which most closely approximated the morphology of the tracheal epithelium in vivo. Large quantities of high molecular weight, hyaluronidase-resistant glycoconjugates, most likely mucin glycoproteins, were produced in the presence of RA when the cells were grown with or without a collagen gel and in submerged as well as in interface cultures. However, extensive ciliagenesis was dependent on the simultaneous presence of RA, collagen gel, and an air-liquid interface. When RA was omitted from the media, the cells became stratified squamous and developed a cornified apical layer in air-liquid interface cultures. This phenotype was accompanied by loss of transglutaminase (TGase) type II and keratin 18 and expression of the squamous markers TGase type I and keratin 13. The ability to modulate RTE cell phenotypes in culture will facilitate future studies investigating molecular regulation of tracheal cell proliferation, differentiation, and function.
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PMID:Rat tracheal epithelial cell differentiation in vitro. 768 43

In the presence of 4 mM inorganic phosphate, differentiating chick limb-bud mesenchymal cells plated in micromass cultures form a mineralized matrix resembling that of chick calcified cartilage. To test the hypothesis that cartilage proteoglycans are inhibitors of cell mediated mineralization, the synthesis, content, and turnover of proteoglycans were altered in this system, and the extent of mineralization and properties of the mineral crystals examined. In all cases where the proteoglycan synthesis or proteoglycans present were modified to provide fewer or smaller molecules, mineralization was enhanced. Specifically, when proteoglycan synthesis was blocked by treatment with 10(-10) M retinoic acid, extensive mineral deposition occurred on a matrix devoid of both proteoglycans and cartilage nodules. The crystals, which formed rapidly, were relatively large in size based on analysis by X-ray diffraction or FT-1R microspectroscopy, and were more abundant than in controls. When 2.5 or 5 mM xylosides were used to cause the synthesis of smaller proteoglycans, the extent of mineral accretion was also increased relative to controls; however, the matrix was less affected, and the extent of mineral deposition and the size of the crystals were not as markedly altered as in the case of retinoic acid. Modification of existing proteoglycans by either chondroinase ABC or hyaluronidase treatment similarly resulted in increased mineral accretion (based on 45Ca uptake or total Ca uptake) relative to cultures in which the proteoglycan content was not manipulated. Crystals were more abundant and larger than in control mineralizing cultures. In contrast, when proteoglycan degradation by metalloproteases was inhibited by metal chelation with o-phenanthroline, the Ca accretion at early time points was increased, but as mineralization progressed, Ca accumulation decreased. These data provide evidence that in this culture system, proteoglycans are inhibitors of mineralization.
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PMID:Effects of proteoglycan modification on mineral formation in a differentiating chick limb-bud mesenchymal cell culture system. 909 12

p-Dodecylaminophenol (p-DDAP) was designed on the basis of structure-activity relationship studies on N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR), a synthetic derivative of retinoic acid (RA). p-DDAP exhibits antioxidative activities greater than those of RA and 4-HPR. RA shows biological effects in epidermal cells that include the inhibition of differentiation to the squamous phenotype. In the current study, we examined the effects of topical p-DDAP treatment on the skin of hairless mice as compared with those of RA treatment. p-DDAP caused an increase in epidermal thickness and decreased matrix metalloprotease and hyaluronidase activities in mouse skin tissues to the same extent that RA did. p-DDAP did not induce desquamation, erythema, or inflammatory cytokine expression as observed with RA treatment. Two-dimensional polyacrylamide gel electrophoresis patterns of proteins from skin treated with p-DDAP were distinct from those treated with RA. A protein induced by both p-DDAP and RA was identified as cytokeratin 16. p-DDAP did not elevate transcriptional activities of RA nuclear receptors. These results suggest that p-DDAP improves skin as potently as RA without causing the desquamation and erythema that the latter does. An increase in cytokeratin 16 expression might be essential for the effects of both p-DDAP and RA in skin healing and maintenance.
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PMID:Effects of the aminophenol analogue p-Dodecylaminophenol on mouse skin. 2003 91

To treat cancer cells overexpressing P-glycoprotein (P-gp), we propose a new concept using a nanodrug. The nanodrug was prepared from polyethyleneimine (PEI)/all-trans retinoic acid (ATRA) conjugates (PRA) and covered with hyaluronic acid (HA) to control the cytotoxicity of PRA (yielding PRA-H). The size distribution of PRA-H was narrow, with an average particle size of approximately 143 nm. Its superior stability in phosphate-buffered saline (PBS) was verified by monitoring changes in particle size and zeta potential for 24 h, which were negligible. In contrast, PEI-H (not conjugated with ATRA) exhibited a significant change in particle size and zeta potential. Although PRA was highly cytotoxic against HCT-8 and SNU-484 cancer cells, both of which overexpress P-gp, the cytotoxicity was significantly reduced by shielding with HA. The cytotoxicity of PRA-H was recovered by treatment with hyaluronidase (HAase), which degrades HA and is present in tumors at high concentrations. These results were confirmed by optical microscopy, fluorescence-activated cell sorting (FACs) analysis, and confocal microscopy. The cytotoxic mechanism of PRA was revealed as a type of necrotic lysis by FACs analysis with propidium iodide (PI) staining. Furthermore, PRA increased HCT-8 cell (colon cancer) permeability to doxorubicin (DOX). Therefore, we concluded that PRA-H is a promising new candidate for the treatment of cells with multidrug resistance (MDR) induced by overexpression of P-gp and cancer stem cells.
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PMID:Polycationic nanodrug covered with hyaluronic acid for treatment of P-glycoprotein overexpressing cancer cells. 2068 38


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