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D R Edwards

Publications and source records attributed to D R Edwards.

At least 55 records · Page 3Linked to original sources
PubMed1998

Matrix metalloproteinases and diseases of the CNS.

Matrix metalloproteinases (MMPs) are increasingly being implicated in the pathogenesis of several CNS diseases. In multiple sclerosis, MMPs could be responsible for the influx of inflammatory mononuclear cells into the CNS, contribute to myelin destruction and disrupt the integrity of the blood-brain barrier; in Alzheimer's disease, MMPs might mediate the deposition of amyloid beta-proteins; and MMPs are known to contribute to the invasiveness of malignant glioma cells and might regulate their angiogenic capacity. Nonetheless, MMPs could also have beneficial roles in recovery from CNS injury.Therefore, both the identity of the MMP and its cellular origin could determine whether disease pathogenesis or regeneration occurs, and thus synthetic MMP inhibitors might be valuable for treating some CNS diseases.

Animals↗
PubMed1998

High levels of gelatinase-B and active gelatinase-A in metastatic glioblastoma.

PURPOSE: Extra-neural metastases from glioblastoma multiforme (GBM) are rare. Because gelatinases-A and -B have been implicated in tumor invasion/metastasis in non-neural tumors, we compared the expression of gelatinase-A and -B in 2 patients (both had a prior craniotomy performed) with extraneural metastases from GBM to expression levels in 24 other gliomas; 15 non-metastatic GBMs, 9 other lower grade gliomas, and 7 normal brain tissues. METHODS: The intracerebral tumor from both patients, patient # 1's extraneural metastases, 24 other gliomas, 1 sample of reactive astrocytes and 7 normal brain tissues were studied using gelatin zymography. The active form of gelatinases was confirmed by co-migration after activation with APMA. RESULTS: Expression of the latent form of gelatinase-A correlated with glioma grade (r = 0.486; p = 0.0053). Active gelatinase-A was found only in the 2 GBMs with extraneural metastases and patient # 1's cervical metastases. In contrast, latent gelatinase-B levels correlated more strongly with histologic grade (r = 0.577; p = 0.0009) (higher levels with higher grades). Very high levels of gelatinase-B were seen in both GBMs with extraneural metastases, a cervical extraneural metastases, and 2 GBMs without metastases. CONCLUSIONS: We observed that gelatinases-A and -B are present in most gliomas but we found active gelatinase-A only in the GBMs with extraneural metastases suggesting that the active form of this enzyme may determine the metastatic potential of GBMs. We propose that high levels of gelatinolytic activities are associated with intracerebral invasion and rarely, metastases of GBMs.

Adult↗
PubMed1998

Proteolytic activity of human non-Hodgkin's lymphomas.

This study was conducted to assess the net proteolytic activity of human non-Hodgkin's lymphomas (NHLs). We have compared the extracellular matrix (ECM)-degradative abilities of human NHLs, reactive lymphoid hyperplasias, and established lymphoid cell lines using Matrigel invasion and elastin degradation assays. The inhibition studies allowed identification of the classes of proteinases involved in ECM degradation. Our results indicate that lymphocytes and other leukocytes derived from both human NHLs and reactive lymphoid hyperplasias are capable of Matrigel penetration, but only cells derived from the high-grade human NHLs degrade elastin in vitro. Established lymphoid cell lines (both malignant and Epstein-Barr virus immortalized) do not produce MMP-9, do not penetrate the Matrigel, and do not degrade elastin. Moreover, in human NHLs, elastolytic activity is blocked by metalloproteinase inhibitors, while inhibitors of the other classes of proteolytic enzymes have only minor effects. This study identifies metalloproteinases as the most important class of proteinases involved in ECM degradation by NHLs. The previous studies suggest that, within this class, MMP-9 represents the key enzyme that plays a role in the biological aggressiveness of human NHLs.

Cell Line↗
PubMed1997

Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia.

Matrix metalloproteinases (MMPs) are involved in remodelling extracellular matrix. Gelatinase B (MMP-9) is an inducible 92 kDa MMP expressed by neutrophils, microglia, and endothelial cells. Gelatinase A (MMP-2) is a 72 kDa MMP, constitutively expressed in brain. Elevated MMP activity has been linked to various pathologic conditions, and the therapeutic benefit of MMP inhibitors is under study in a few experimental models. Using gelatin zymography, we have compared activities of these MMPs in infarcted and matched non-infarcted cerebral tissue from eight subjects dying at intervals of less than 2 h to several years after a stroke. Gelatinase B activity was markedly elevated in the infarcted tissue at two days post-infarction, and remained elevated in cases dying months after the event. Increases in gelatinase A activity were subtle at 2-5 days; they were marked and significant in cases dying at 4 months and later. The findings indicate distinct temporal profiles of post-ischemic gelatinase activity in human brain, with earlier but equally persistent elevation in gelatinase B when compared to gelatinase A.

Aged↗
PubMed1997

Transcriptional activity of the human tissue inhibitor of metalloproteinases 1 (TIMP-1) gene in fibroblasts involves elements in the promoter, exon 1 and intron 1.

The active forms of all of the matrix metalloproteinases (MMPs) are inhibited by a family of specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Inhibition represents a major level of control of MMP activity. A detailed knowledge of the mechanisms controlling TIMP gene expression is therefore important. We have isolated a genomic clone of the human TIMP-1 gene. A 3 kbp XbaI fragment has been sequenced; this fragment contains 1718 bp 5' flanking sequences, exon 1, a 929 bp intron 1 and part of exon 2. Computer analysis reveals 10 consensus sequences for Sp1, six for activating protein 1 (AP-1), six for polyoma enhancer A3 (PEA3), 12 for AP-2 and five CCAAT boxes. The region hybridizing with a murine TIMP-1 promoter fragment has been subcloned and analysed further. RNase protection identifies six transcription start points, making exon 1 up to 48 bp in length. Transient transfection of promoter-chloramphenicol O-acetyltransferase reporter constructs into primary human connective tissue fibroblasts shows that a 904 bp fragment that hybridizes to a murine TIMP-1 promoter fragment contains a functional promoter. Constructs of -738/+95 to -194/+21 are inducible with serum or phorbol ester to a similar extent to the endogenous TIMP-1 gene. These results and further mapping with 5' deletion mutants from the -738/+95 region have demonstrated that an AP-1 site at -92/-86 is essential for basal expression of the gene. Point mutations within this region have further confirmed the role of this site, along with a more minor role for a neighbouring PEA3 site, in basal expression. Deletions from the 3' end also implicate a region across the exon 1/intron 1 boundary and especially +21 to +58 in basal expression. The +21/+58 region contains a putative binding site for the transcription factor leader-binding protein 1 (LBP-1). Gel-shift analysis shows that protein binds specifically to this region, but competition studies suggest that it is unlikely to be LBP-1.

Animals↗
PubMed1997

Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues.

We have isolated cDNA clones corresponding to a new member of the murine tissue inhibitor of metalloproteinase (TIMP) family, designated Timp-4. The nucleotide sequence predicts a protein of 22,609 Da that contains the characteristic 12 cysteine TIMP signature. TIMP-4 is more closely related to TIMP-2 and TIMP-3 than to TIMP-1 (48%, 45% and 38% identity, respectively). Analysis of Timp-4 mRNA expression in adult mouse tissues indicated a 1.2 kb transcript in brain, heart, ovary and skeletal muscle. This pattern of expression distinguishes Timp-4 from other Timps, suggesting that the TIMP-4 protein may be an important tissue-specific regulator of extracellular matrix remodelling.

Amino Acid Sequence↗
PubMed1997

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period.

The attachment of the blastocyst to the uterine luminal epithelium and the subsequent invasion by trophoblast cells through the stroma and deciduum occur in a highly regulated manner by remodeling of the extracellular matrix. We investigated the temporal and spatial expression of mRNAs for four matrix metalloproteinases (MMPs; MMP-2 [gelatinase A], MMP-3 [stromelysin 1], MMPs; MMP-2 [gelatinase B], and MMP-13 [collagenase 3]) and tissue inhibitors of metalloproteinases (TIMPs; TIMP-1, TIMP-2, and TIMP-3) in the mouse uterus from days 1 to 8 of pregnancy. Northern blot analyses showed the transcripts for MMP-2, MMP-3, RNA on these days. However, MMP-13 mRNA was not detected in the uterus, and only weak signals for MMP-3 mRNA were detected in the myometrium. Striking expression was observed with MMP-2 mRNA in the subepithelial stroma on days 3-5. With the progression of decidualization on day 6, signals were primarily in the secondary decidual zone. On day 8, MMP-2 mRNA was localized at the site of placenta formation in the mesometrial pole. Signals for MMP-9 mRNA were first detected in a small population of stromal cells exclusively at the site of implantation on day 5 at the antimesometrial pole. However, the most pronounced expressed was noted in trophoblast giant cells on day 8. TIMP-1 mRNA was present in the myometrium on day 1. On days 2-5, modest signals were detected in the stroma, and on days 6 and 8, they were in the secondary decidual zone. Localization of TIMP-2 mRNA was similar to that of TIMP-1 except it was restricted to the stroma on day 1. The regulation of TIMP-3 was more pronounced. While a gradual increase in signals was observed in stromal cells from days 1 to 4, strong signals were detected in antimesometrial stromal cells at the sites of blastocyst attachment on day 5. On days 6 and 7, even stronger signals were present in the primary decidual zone surrounding the embryo, and on day 8 signals were localized primarily in the mesometrial decidual bed. These results suggest that MMP-2 may participate in the early phase of decidualization and neovascularization required for placentation. The restricted MMP-9 expression in stromal cells on day 5 and in trophoblast giant cells on day 8, coupled with the expression of TIMP-3 in the stroma surrounding the embryo, suggests that a fine balance between MMP-9 and TIMP-3 may regulate trophoblast invasion in the uterus.

Animals↗
PubMed1997

Matrix metalloproteinase-9 maps to the distal end of chromosome 2 in the mouse.

The activity and expression of matrix metalloproteinase-9/gelatinase B (MMP-9), an enzyme implicated in the implantation process in mice, was investigated in normal and parthenogenetic blastocyst outgrowths. Conditioned media from parthenogenetic blastocysts after 4 days of culture had reduced levels of MMP-9 activity compared to conditioned medium from normal outgrowths. Levels of MMP-9 mRNA assayed by reverse transcription-polymerase chain reaction methods were also reduced in parthenogenetic blastocysts compared to normal outgrowths. Genetic mapping studies showed that Mmp9 maps to the distal end of chromosome 2 near the proximal boundary of a region affected by genomic imprinting. Both parental alleles of Mmp9, however, are expressed in 11.5-day embryos derived from interspecific crosses of Mus musculus and Mus spretus. Thus, loss of MMP-9 activity in parthenogenetic blastocysts does not appear to be due to imprinting but, rather, due to a defect of trophoblast giant cell proliferation and differentiation.

Animals↗
PubMed1996

Tissue inhibitor of metalloproteinases-3 is the major metalloproteinase inhibitor in the decidualizing murine uterus.

Embryo implantation in the mouse is a highly orchestrated process, a key aspect of which is the invasion of trophoblast cells of the blastocyst into the maternal uterine endometrium. Invasion is facilitated via proteinases expressed by trophoblast cells and balanced by expression of inhibitors of proteinases in the maternal decidua. The predominant proteinase expressed by trophectodermal derivatives of the implanting mouse embryo is matrix metalloproteinase-9 (MMP-9; gelatinase B). Using in situ hybridization, transcripts for MMP-9 were detected in trophoblast cells of the embryo from the earliest stage of decidual formation (day 6.0) examined. MMP-9 transcripts were localized to trophoblast giant cells at the periphery of the embryo at the egg cylinder stage (day 7.0). By the neural-fold stage (day 8.5), expression was restricted to giant cells adjacent to the maternal side of the developing placenta, and by day 9.5 few MMP-9-positive cells remained. The major tissue inhibitor of metalloproteinases (TIMP) produced during this period was TIMP-3. Transcripts encoding TIMP-3 were detected from day 6.0-7.0 in the maternal decidua immediately adjacent to embryonic cells expressing MMP-9. The intensity of TIMP-3 expression in later-stage embryos declined in parallel with MMP-9 expression. Maternal TIMP-3 expression also occurred in the absence of embryonic MMP-9 expression in decidual reactions induced by parthenogenetic embryos (where MMP-9 positive cells were not detected) or in oil-induced deciduomas. These results support the hypothesis that MMP-9 is an important mediator of cellular invasiveness during embryo implantation, and that TIMP-3 serves as a regulator within the uterus to restrict invasion to the site of implantation.

Animals↗
PubMed1996

Comparative analysis of the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin's lymphomas in humans.

Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) play essential roles in the remodelling of the extracellular matrix (ECM). Results of in vivo and in vitro studies suggest that the balance between MMPs and TIMPs is altered in neoplasia, contributing to the invasive and metastatic properties of malignant tumours. In this study we have analysed the expression of five MMP genes and TIMP-1 and TIMP-2 in 37 benign and malignant lesions of human breast using Northern blot analysis. MMP-9 (92 kDa gelatinase) and MMP-11 (stromelysin 3) were most consistently expressed by carcinomas. Based on detection of either MMP-9 or MMP-11 mRNAs, we were able to distinguish between malignant and benign disease with a predictive accuracy of 90% with 94% sensitivity and 85% specificity. Subsequently, these results were compared with results for carcinomas of colon and lung and malignant non-Hodgkin's lymphomas (NHL). Elevated MMP-9 and TIMP-1 expression was observed in all four systems. MMP-11 characterised all carcinomas as well as carcinomas in situ but was not detectable in NHL. Our data therefore argue that there are remarkably similar patterns of specific functions involved in ECM remodelling that correlate with malignancy in different human tumours of different histogenesis. However, MMP-11 expression is a characteristic of tumours of epithelial origin that is not found in lymphoid neoplasia. Thus it suggests that MMP-11 may play a regulatory role in the invasion and metastasis of carcinomas.

Adenofibroma↗
PubMed1996

Temporal and spatial expression of tissue inhibitors of metalloproteinases during the natural ovulatory cycle of the mouse.

The role of tissue inhibitors of metalloproteinases (TIMPs) in ovarian function has primarily been documented by studies that utilize hormone-primed animals. In this study, our objectives were to elucidate the spatiotemporal expression of individual TIMP genes during the natural ovulatory cycle, and to correlate these with specific biological events. Two models of spontaneous ovulation used were the murine estrous cycle and the first ovulation postpartum. Ovaries were collected from mice at diestrus, estrus, and metestrus, or at early and late proestrus, and from pregnant females on Days 17 and 18 of gestation (D17, D18) and within 24 or 48 h postpartum (PP1, PP2). We observed that TIMP-1 mRNA was elevated at early proestrus and D18 and was maximal at late proestrus and PP1. The TIMP-3 pattern was distinct from that of TIMP-1, maximal expression occurring at early proestrus and D17 and D18. In both models, TIMP-2 mRNA remained constant and at very low levels throughout ovulation. In situ hybridization localized TIMP-1 mRNA to the corpus luteum at D18 and PP1, and to oocytes at specific stages of follicular development. Expression of TIMP-1 in granulosa and thecal cells was not observed at any stage. Demonstrating a distinct distribution, TIMP-3 mRNA was localized to oocytes, thecal and granulosa cells of small and large follicles, and corpora lutea only at D17. These data suggest specific hormonal regulation of individual TIMP gene expression in the ovary associated with distinct physiological functions. We propose that in the natural ovulatory process, TIMP-1 is probably a factor that regulates corpus luteum regression while TIMP-3 is important in maintaining the structural integrity of the corpus luteum.

Animals↗
PubMed1996

Evaluation of chemical amendments to reduce ammonia volatilization from poultry litter.

Ammonia volatilization from poultry litter often causes high levels of atmospheric ammonia in poultry houses, which is detrimental to both farm workers and birds. Ammonia emissions from houses also aggravate environmental problems, such as acid rain, and result in a loss of fertilizer nitrogen. The objectives of this study were to determine the effect of litter amendments on ammonia volatilization and to determine the effect of these amendments on nitrogen and phosphorus content in litter. The results of this research indicate that alum [Al2(SO4)3.18H2O], ferrous sulfate (FeSO4.7H2O), and phosphoric acid (H3PO4) dramatically reduce ammonia volatilization form litter. The amount of ammonia lost from litter treated with sodium bisulfate (NaHSO4) and a proprietory product made of Ca-Fe silicate with a phosphoric acid coating was not different from the control (untreated litter). Aluminum sulfate (alum) and ferrous sulfate also reduced water soluble P concentrations in litter, whereas phosphoric acid greatly increased water-soluble P levels. The most effective compound evaluated with respect to reducing both ammonia loss and P solubility was alum.

Air Pollution↗
PubMed1996

The roles of tissue inhibitors of metalloproteinases in tissue remodelling and cell growth.

Tissue inhibitors of metalloproteinases (TIMPs) are secreted proteins that block the activities of the extracellular matrix (ECM)-degrading metalloproteinases (MMPs). As key determinants of ECM integrity and turnover, TIMPs are involved in the establishment and maintenance of tissue architecture and may indirectly influence ECM-dependent cells signaling. In addition, TIMPs exert both positive and negative effects on cell growth through mechanisms that are independent of MMP inhibition. The three members of the mammalian TIMP family differ in structure, biochemical properties and expression, suggesting that they have distinct physiological roles. Here, we review recent advances in our understanding of TIMP protein function and gene regulation. We discuss the potential relevance of MMPs and TIMPs in obesity with regard to effects on the processing of tumor necrosis factor-alpha.

Animals↗
PubMed1995

Predictors of response to amine-specific antidepressants.

Discriminant function analysis of data from a double-blind comparative trial of lofepramine (a noradrenaline-specific reuptake inhibitor) and fluoxetine (a serotonin-specific reuptake inhibitor), involving 183 patients was used to identify predictors of response. Psychic anxiety significantly predicted a positive response to antidepressant medication, whereas psychomotor retardation, observed sadness, subjective lassitude and somatic complaints were significant predictors of nonresponse. Age, gender, endogenicity, duration of illness and number of previous episodes were not predictive of response. Significant differences were found between predictors of response to fluoxetine and lofepramine (P < 0.001 all groups). Predictors of response to lofepramine were similar to overall predictors, i.e., psychic anxiety predicted responders whilst observed sadness, psychomotor retardation, lassitude, inability to feel and somatic complaints predicted nonresponders. In contrast, baseline weight loss predicted response to fluoxetine, whereas anxiety, reduced insight and a tendency to blame others significantly predicted nonresponse. Such findings have practical implications for the management of depressive illness.

Adult↗
PubMed1995

Tissue inhibitor of metalloproteinases-2 (TIMP-2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E2.

To explore the functional role of TIMP-2 in liver, we determined TIMP-2 mRNA levels in primary rat hepatocytes and in total rat liver. Rat hepatocytes constitutively express TIMP-2 mRNA at a low level. Incubation with dexamethasone, prostaglandin E2 and a combination of inflammatory cytokines leads to an up-regulation of TIMP-2 mRNA. In rats in vivo we found a dramatic increase of TIMP-2 expression after intraperitoneal injection of lipopolysaccharide. Compared to our previous findings on TIMP-1 we conclude that TIMP-2 mRNA expression is regulated in a distinct and partially opposite manner. Over-production of TIMP-2 could inhibit the activity of metalloproteinases and thus lead to matrix accumulation. Dysregulation of TIMP-2 synthesis might be involved in the development of liver fibrosis.

Animals↗
PubMed1995

Roles of growth factors during peri-implantation development.

Several growth factor ligand and receptor gene products have been shown to play roles during preimplantation mammalian development. Genes for insulin-like growth factors (IGFs), transforming growth factors (TGFs), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and receptors for insulin, IGF, PDGF, TGF alpha and epidermal growth factor (EGF) are expressed by early embryos of several species including mouse, rat, cow and sheep. Roles of growth factors during early development have been demonstrated by addition of purified growth factors to culture medium or by molecular genetic techniques that interfere with gene expression. In this way, it has been shown that successful development of the blastocyst is dependent on the action of epidermal growth factor (EGF) and leukaemia inhibitory factor (LIF). Recent experiments show that both LIF and EGF stimulate secretion of urokinase-type plasminogen activator (uPA) and gelatinase B/matrix metalloproteinase-9 (MMP-9) in day 7 mouse blastocyst outgrowths. At the same time, tissue inhibitors of MMPs (TIMPs) are also expressed by embryonic, decidual and uterine tissues during the implantation process. It appears that LIF may act directly or indirectly, by inducing the expression of other cytokines, to regulate the temporal and spatial production and activity of proteases and protease inhibitors to create a favourable environment for implantation.

Animals↗