Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovulation, recurring every midcycle of the mammalian female and triggered by a surge of luteinizing hormone (LH) released from the pituitary, is an essential prerequisite for fertilization and subsequent embryonic development. Here we shall describe two of the biological components of the ovulatory response, cumulus expansion (frequently denoted as cumulus maturation) and the rupture of follicular wall, both crucial for the release of a fertilizable ovum. The role of a proteolytic cascade and its regulation by eicosanoids will be emphasized in relation to follicle rupture. The new data implicating cumulus maturation as an essential step for the release of the ovum and the apparent mediatory role of interleukin-1 in this process will be presented. LH/hCG stimulates, in the preovulatory follicles, a cascade of proteolytic enzymes, including plasminogen activator (PA), plasmin and matrix metalloproteinase 1 (MMP-1). These enzymes bring about the degradation of perifollicular matrix and, most notably, the decomposition of the meshwork of collagen fibers which provides the strength to follicular wall. Furthermore, pharmacological blockage of any of these enzymes resulted in inhibition of follicle rupture. LH/hCG stimulates, in addition, an increase in ovarian production of eicosanoids. These include prostaglandins, obtained from arachidonic acid via the cyclooxygenase pathway and leukotrienes, the products of lipoxygenase. Previous studies from our and other laboratories have demonstrated the ability of inhibitors of cyclooxygenase and of lipoxygenases to suppress ovulation in several mammalian species. MK-886, which inhibits the translocation of 5-lipoxygenase (5-LO) from the cytosol and its binding to the membranal 5-LO activating enzyme, suppressed dose-dependently follicular rupture from the treated ovary. Zymographic analysis of ovarian extracts from PMSG/hCG-stimulated rats revealed a band of collagenolytic activity at 52kD, corresponding to human MMP-1 and at 72kD, corresponding to human MMP-2. Both activities were markedly stimulated by administration of hCG and were significantly inhibited by indomethacin, NDGA or MK-886. Thus, eicosanoids seem to mediate LH stimulation of follicular collagenase. Interleukin-1 (IL-1) has been recently implicated in ovulation. The ability of an IL-1 receptor antagonist (ra) to block ovulation in vivo and in vitro has been demonstrated recently. Morphological examination of the ovulatory follicles failing to ovulate suggests that this effect is exerted by inhibiting cumulus oophorus expansion and detachment from mural granulosa cells. In vitro, IL-1ra attenuated the action of hCG and FSH on cumulus expansion and follicular hyaluronic acid synthesis. Thus, IL-1 seems to mediate and/or facilitate gonadotropin action on cumulus expansion, and hence on ovulation.
 ...
PMID:Ovulation as a tissue remodelling process. Proteolysis and cumulus expansion. 748 19

Inhibition of angiogenesis shows considerable promise as a strategy for treating solid malignancies. Induction of collagenase by protein kinase C plays an important role in the angiogenic process as well as in metastasis. Lipoxygenase products are required for endothelial cell mitosis, and also promote collagenase production. By down-regulating hormonal activation of protein kinase C and modulating eicosanoid metabolism, ingestion of omega-3-rich fish oils may impede angiogenesis and reduce tumor invasiveness-thus rationalizing the growth-retardant and anti-metastatic effects of fish oil feeding almost invariably seen in animal tumour models. Certain other anti-inflammatory agents-including cromolyn (an inhibitor of protein kinase C activation) and gamma-linolenic acid (which indirectly inhibits lipoxygenase) may have analogous tumour-retardant activity. Clinical application of supplemental fish oil in cancer therapy is long overdue.
 ...
PMID:Fish oil may impede tumour angiogenesis and invasiveness by down-regulating protein kinase C and modulating eicosanoid production. 869 33

Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.
 ...
PMID:Identification of arachidonic acid pathways required for the invasive and metastatic activity of malignant tumor cells. 890 Apr 40

We have previously reported that hydrogen peroxide, an active oxygen species and a cellular oxidant, induces c-Fos and c-Jun mRNA expression and DNA synthesis in vascular smooth muscle cells and that these events require arachidonic acid release and metabolism through the lipoxygenase pathway. Here we have identified the eicosanoids that mediate the hydrogen peroxide-induced growth-related events in these cells. Hydrogen peroxide stimulated the production of 12- and 15-hydroperoxyeicosatetraenoic acids in vascular smooth muscle cells. Both 12- and 15-hydroperoxyeicosatetraenoic acids induced the expression of c-Fos and c-Jun protein and increased activating protein 1 (AP-1) activity, as measured by AP-1-DNA binding and AP-1-dependent human collagenase promoter-driven chloramphenicol acetyltransferase reporter gene transcription. Hydrogen peroxide and arachidonic acid also induced the expression of c-Fos and c-Jun protein and AP-1 activity. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, significantly inhibited both hydrogen peroxide and arachidonic acid-stimulated c-Fos and c-Jun protein expression and AP-1 activity. Together, these findings suggest that hydrogen peroxide induces the production of eicosanoids and that the eicosanoids are potential mediators of the oxidative stress-stimulated growth-related events in vascular smooth muscle cells.
 ...
PMID:Role of hydroperoxyeicosatetraenoic acids in oxidative stress-induced activating protein 1 (AP-1) activity. 891 Mar 70

Endothelins (ETs) are a family of 21-amino acid hypertensive peptides, which together with their receptors ETA and ETB are expressed in human adrenal cortex. Evidence has been provided that ETs exert a potent secretagogue effect on human adrenocortical cells, acting through both ETA and ETB receptors. Therefore, it seemed worthwhile to study the signaling cascades mediating the cortisol secretagogue effect of the two receptor subtypes. Normal adrenal glands were obtained from consenting patients undergoing unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. Dispersed zona fasciculata-reticularis (ZF/R) cells were obtained by collagenase digestion and mechanical disaggregation. The selective activation of ETA and ETB receptors was obtained by exposing dispersed cells to ET-1 plus the ETB receptor antagonist BQ-788 and to the selective ETB receptor agonist BQ-3020, respectively. ETA and ETB receptors about equally contributed to the cortisol response of dispersed ZF/R cells to ETs. The phospholipase (PL) C inhibitor U-73122 abolished ETA-mediated secretory response, but only partially prevented the ETB-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes, while the Ca(2+)-channel blocker nifedipine was ineffective. The ETB receptor-, but not the ETA receptor-mediated cortisol response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. The inhibitors of adenylate cyclase, PKA, tyrosine kinase and lipoxygenase did not affect the secretory response to the activation of either receptor subtype. ETA-receptor activation raised inositol triphosphate (IP3) production from dispersed ZF/R cells, while ETB-receptor stimulation enhanced both IP3 and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate cortisol secretion from human ZF/R cells, acting through ETA receptors exclusively coupled with PLC/PKC-dependent pathway and ETB receptors coupled with both PLC/PKC- and COX-dependent cascades.
 ...
PMID:Signaling pathways involved in the A and B receptor-mediated cortisol secretagogue effect of endothelins in the human adrenal cortex. 1117 11

Antioxidant activities of flavonoids were decreased in the order of flavonols > flavanones > flavones. Inhibitory intensities for hyaluronidase and collagenase reaction differed clearly according to flavonoid subclasses. Kaempferol, quercetin, myricetin, and rutin in flavonols inhibited hyaluronidase reaction specifically, while apigenin, luteolin, baicalin, and baicalein in flavones showed specific inhibition to collagenase reaction. In addition, the flavonoids, except baicalin and catechin, inhibited potently LPS-induced nitrite production in a dose-dependent manner, which might be mainly due to the suppression of inducible nitric oxide (NO) synthase. Quercetin and luteolin showed the strongest inhibitory activities on 15-lipoxygenase (LOX), and quercetin showed relatively potent inhibition on cyclooxygenase-1 (COX-1) reaction. Otherwise, all tested flavonoids possessed the inhibitory activity to COX-2 reaction, and especially luteolin, kaempferol, hesperetin, and naringin showed relatively the potent inhibition on COX-2 reaction. This report elucidated the anti-inflammatory activities, such as the antioxidant property, inhibition of NO production, and inhibition of inflammatory enzymes (hyaluronidase, collagenase, LOX, and COXs) of several subclass flavonoids.
 ...
PMID:Evaluation of antioxidant and inhibitory activities for different subclasses flavonoids on enzymes for rheumatoid arthritis. 2153 45


<< Previous 1 2