Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effects of aerosolized DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA) (10(-4) M, 90 breaths), a specific inhibitor of carboxypeptidase B-type enzymes, on changes in total pulmonary resistance (RL) induced by aerosolized capsaicin (10(-7) to 10(-4) M; 10 breaths at each concentration) and vagus nerve stimulation (5 V, 5 ms, for 20 s at frequencies varying from 2 to 10 Hz) in anesthetized, atropinized, and ventilated guinea pigs. We also studied the effect of aerosolized MGTA on the bronchoconstrictor response to either aerosolized substance P, neurokinin A (10(-7) to 10(-4) M; 10 breaths at each concentration), and carbachol (10(-5) to 2 x 10(-4) M; 10 breaths at each concentration) or to i.v. administration of neurokinin A (10(-11) to 10(-8) mol/kg), bradykinin (10(-10) to 10(-7) mol/kg), and histamine (10(-8) to 10(-6) mol/kg). Although aerosolized MGTA caused no change in basal RL (P > 0.5), it did potentiate the noncholinergic bronchoconstrictor response to capsaicin (n = 5; P < 0.001) as well as to vagus nerve stimulation (n = 5; P = 0.001). In contrast, MGTA did not potentiate the bronchoconstrictor response to either aerosolized substance P, neurokinin A, and carbachol or to i.v. administration of neurokinin A, histamine, and bradykinin. Carboxypeptidase activity cleaving C-terminal arginine or lysine was found in the membrane preparations of trachea and lung from guinea pigs. The membrane-bound carboxypeptidase activity was maximal at pH 7.0 and was enhanced by the presence of CoCl2 (1 mM) in both the tracheal and lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Nov
PMID:Carboxypeptidase M-like enzyme modulates the noncholinergic bronchoconstrictor response in guinea pig. 138 81

Cobalt, a metal with numerous industrial applications, has been associated with lung disease, an extreme form of which is an interstitial fibrosis. The biochemical mechanisms underlying this toxicity are not understood. In vitro studies have suggested that cobalt(II) ions are able to generate reactive oxidant species (possibly hydroxyl radical) in a reaction with hydrogen peroxide, and we have hypothesized that the occurrence of such an event in lung tissue, and the subsequent development of oxidative damage, may contribute to this pulmonary toxicity. The intratracheal instillation of CoCl2 into hamster lungs resulted after 3 h in decreased levels of reduced glutathione and increases in levels of oxidized glutathione and in the activity of the pentose phosphate pathway. These changes, which are compatible with the generation of oxidative stress, were reversed by 48 h at low Co2+ doses (1.0 to 1,000 micrograms/kg). Irreversible changes at higher doses coincided with the onset of pulmonary edema. Incubation of lung slices with CoCl2 (0.1 to 10 mM) resulted in time- and Co2+ concentration-dependent increases in levels of oxidized glutathione and protein-mixed disulfides and a decrease in reduced glutathione. A concentration-dependent stimulation of the pentose phosphate pathway was also observed. These changes preceded the detection of overt cell toxicity, as assessed by various biochemical parameters. These data indicate that thiol oxidation constitutes an early event in the pulmonary toxicity of cobalt(II) ions and are compatible with the hypothesis that the generation of oxidative stress may be of significance to the toxic process.
Am J Respir Cell Mol Biol 1991 Aug
PMID:Indices of oxidative stress in hamster lung following exposure to cobalt(II) ions: in vivo and in vitro studies. 189 47

It has been observed that growth of Escherichia coli cells are inhibited when treated with cobalt chloride (300 microM). It has also been shown that CoCl2 preferentially inhibits translation without inhibiting the process of transcription (1, 2, 8). We report here, that during treatment of E. coli cells with CoCl2, both messenger RNA and stable RNA synthesis is slowed down about 2.5 folds. The rate of degradation of mRNA also decreases and both chemical and functional half-life of mRNA increases about 2.5 folds in Co-treated cells. This clearly shows that the process of transcription is also affected while translation is preferentially inhibited during CoCl2 treatment.
Mol Biol Rep 1981 Aug 14
PMID:RNA synthesis and degradation during preferential inhibition of protein synthesis by cobalt chloride in Escherichia coli K-12. 616 83

We have studied the effects of vasoactive intestinal peptide (VIP) on PRL secretion in a Bio-Gel column parafusion system containing rat pituitary tumour cells (GH4C1). A dose-dependent increase in PRL release was observed with half-maximal and maximal effect (2.1-fold) at 8 X 10(-8) and 5 X 10(-6) M, respectively. The PRL-stimulatory effect of VIP was instantaneous and maintained during the parafusion experiments (up to 60 min). On a molar basis VIP was always less effective than thyroliberin (THR), and the maximum stimulation of PRL release obtained with TRH was 1.2-3.0-fold higher (n = 12) than the maximum effect seen after VIP administration. The PRL-releasing effects of VIP, THR and high extracellular K+ were almost completely abolished in the presence of two inhibitors of voltage-sensitive Ca2+ channels, CoCl2 (10(-3) M) and verapamil (10(-4) M). In Ca2+-free buffer VIP, TRH and high extracellular K+ had only negligible effects, but the responses were fully restored in the presence of normal concentrations of extracellular Ca2+. In contrast to TRH, VIP had no demonstrable effect on the Ca2+-dependent action potentials of the GH4 cells.
Mol Cell Endocrinol 1984 Aug
PMID:Vasoactive intestinal peptide causes a calcium-dependent stimulation of prolactin secretion in GH4C1 cells. 643 4

Essential and non-essential metal ions were compared on the basis of their growth-inhibitory potency and their mediation of metallothionein induction in a Chinese hamster ovary cell line resistant to cadmium. Cadmium-resistant cells were found to be 20-fold and 6-fold more resistant than wild-type Chinese hamster ovary cells to the non-essential metals CdCl2 and HgCl2, respectively. In contrast, cadmium-resistant cells showed 2-fold or less resistance to growth inhibition due to the metals with known or possible biological essentiality, ZnCl2, CuSO4, CoCl2, and NiCl2. Resistance to either cadmium or mercury was not due to decreased uptake as measured isotopically or by X-ray fluorescence. At concentrations near the threshold of growth inhibition, CdCl2 and ZnCl2 induced metallothionein 8- to 10-fold above background levels in cadmium-resistant cells within 8-10 hr. A 2- to 3-fold induction of this protein was produced in resistant cells by levels of HgCl2, CuSO4, and CoCl2 near the threshold of growth inhibition whereas NiCl2 produced no measurable elevations of metallothionein at concentrations below, near, and above those that inhibit cell growth. Induction of metallothionein was measured by a modified 203Hg binding assay and by [35S]cysteine incorporation. No measurable induction of metallothionein was evident in wild-type cells with any metal treatment using a reasonable quantity of cells consistent with our assay. These results in cadmium-resistant cells demonstrate selective induction of metallothionein by various metals and suggest that induction of this protein alone is not solely responsible for differences in the growth-inhibitory potential of these elements.
Mol Pharmacol 1983 Jul
PMID:Growth inhibition and metallothionein induction in cadmium-resistant cells by essential and non-essential metals. 686 29

Subcutaneous administration of CoCl2, a well recognized inhibitor of hepatic heme synthesis, to rats results in the functional stimulation of total (holo- + apo) tryptophan 2,3 dioxygenase (TDO), a hemoprotein and the key rate-limiting enzyme in the oxidative metabolism of tryptophan to formylkynurenine. Because basal holo-TDO activity is not altered, TDO stimulation appears to be entirely due to CoCl2-mediated increase of its apoprotein. This apoTDO increase was blocked by conventional inhibitors of protein synthesis (actinomycin D, cycloheximide), thereby revealing that such CoCL2-mediated apoprotein increase truly reflected TDO induction. To determine whether the CoCl2-mediated TDO induction involved the action of its natural physiological inducers (glucocorticoids) or was due to direct CoCl2-regulation of the TDO gene, rats were adrenalectomized before CoCl2 administration. In adrenalectomized rats, CoCl2 failed to induce TDO, but induction was completely restored on administration of the glucocorticoid hydrocortisone, but not of adrenaline. These findings reveal that CoCl2-mediated TDO induction is indirect and entails glucocorticoid participation. In addition, because CoCl2 lowered the % heme saturation of TDO [= 100(holo TDO activity/total (apo+holo) TDO activity] largely by increasing the apoTDO protein levels rather than by affecting the basal holo-TDO levels (as expected from its inhibition of heme synthesis), these findings question the widely accepted use of the relative intrahepatic % heme saturation of TDO as a reporter of the hepatic "free" heme pool.
Cell Mol Biol (Noisy-le-grand) 1994 Nov
PMID:Cobaltous chloride-mediated induction of rat hepatic tryptophan 2,3-dioxygenase: implications for the use of the enzyme to probe the hepatic free heme pool. 784 55

The presence of high concentrations of membrane-bound carboxypeptidase M in human, baboon, dog, and rat lung was established by employing a variety of techniques. The activity of the enzyme in the membrane-enriched fractions of human, baboon, dog, and rat lung, measured with fluorescent dansyl substrate (DNS-Ala-Arg), was 198, 261, 484, and 153 nmol/h/mg protein, respectively. This activity in the lung was much higher than that found in the heart, liver, or kidney. The enzyme, optimally active around neutral pH, was completely inhibited by 10 microM 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and was activated by 1 mM CoCl2 to 170%. Antibody to human carboxypeptidase M immunoprecipitated the solubilized carboxypeptidase from human (98%), baboon (81%), and dog (88%) lung membrane fractions. Carboxypeptidase M is attached to lung membranes by a phosphatidylinositol glycan anchor; thus, it is released with bacterial phospholipase C. Membrane fractions from cultured human pulmonary arterial endothelial cells also contained high carboxypeptidase M activity (254 nmol/h/mg protein). A Northern blot of poly(A)+ RNA from various human tissues showed the presence of a high level of carboxypeptidase M mRNA in human lung and placenta. Finally, immunohistochemistry, employing purified antibody to the enzyme, revealed in fluorescent light microscopy that carboxypeptidase M is present in alveolar type I pneumocytes and in macrophages in apparently lower concentration. In contrast, type II alveolar epithelial cells gave negative results. Because carboxypeptidase M cleaves a variety of active peptides (e.g., bradykinin, anaphylatoxins), it may protect the alveolar surface from the effects of these peptides. In addition, carboxypeptidase M could be a marker enzyme for type I cells.
Am J Respir Cell Mol Biol 1993 Aug
PMID:High concentration of carboxypeptidase M in lungs: presence of the enzyme in alveolar type I cells. 833 89

In response to hypoxia, mammalian cells express multiple gene products [including erythropoietin (EPO) and vascular endothelial growth factor (VEGF)] that serve to increase O2 delivery, as well as glucose transporters and glycolytic enzymes (such as enolase 1) that allow metabolic adaptation to decreased O2 availability. Increased transcription of the genes encoding these proteins in hypoxic cells is mediated by hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. Expression of HIF-1 and downstream genes can also be induced by exposure of cells to divalent metals (such as CoCl2) or iron chelators [such as desferrioxamine (DFO)]. We report here that the organomercurial compound mersalyl induced expression of VEGF and enolase 1 mRNA, as well as HIF-1 activity, in cultured cells. Expression of reporter genes containing hypoxia response elements from the EPO and VEGF genes was also induced by mersalyl treatment. However, mersalyl inhibited endogenous EPO mRNA expression induced by hypoxia, CoCl2, or DFO. In cells lacking expression of the insulin-like growth factor-1 receptor, mersalyl did not induce HIF-1 activity or VEGF mRNA expression, whereas induction by hypoxia, CoCl2, or DFO was unaffected. The mitogen-activated protein kinase kinase inhibitor PD098059 markedly reduced induction of HIF-1 by mersalyl but not by hypoxia. These results indicate that mersalyl induces expression of HIF-1 and a subset of hypoxia-inducible genes by a mechanism, involving the insulin-like growth factor-1 receptor and mitogen-activated protein kinase activity, that is distinct from mechanisms of induction by hypoxia, CoCl2, or DFO.
Mol Pharmacol 1998 Nov
PMID:Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity. 980 9

Hypoxia is thought to be a common precursor of coronary artery disease and malignant tumors, both diseases representing the leading causes of death in industrial nations. So far, investigations of oxygen-regulated erythropoietin (EPO) gene expression in the human hepatoma cell lines Hep3B and HepG2 allowed many important insights into the mechanisms of oxygen-sensing, signalling and regulation of an increasing number of oxygen-responsive genes. To differentiate the various signalling pathways involved in EPO production by these two cell lines, we examined several factors that positively influenced EPO expression. The results demonstrate a keen differential effect of cell density and oxygen concentration on EPO induction in Hep3B compared to HepG2 cells. Using optimized cell culture conditions, EPO production rates as high as 1 U EPO per 10(6) Hep3B cells in 24 h could be achieved. We also found a moderate but reproducible positive effect of CoCl2 on hypoxia-induced EPO expression in Hep3B but a negative CoCl2 effect on hypoxic induction in HepG2 cells. CoCl2 inhibited cell growth in a concentration-dependent manner. Interleukin-6 was synergistic with hypoxia on EPO induction in Hep3B as well as HepG2 cells, and dexamethasone enhanced this effect in Hep3B but not in HepG2 cells. The moderate CoCl2-dependent increase of EPO production observed in hypoxic Hep3B cells might indicate that CoCl2 and hypoxia do not necessarily act via, identical signalling pathways.
Int J Mol Med 1998 Sep
PMID:Optimal erythropoietin expression in human hepatoma cell lines requires activation of multiple signalling pathways. 985 4

Histologic, ultrastructural and nick end labeling studies were made to evaluate the occurrence of apoptosis in the hearts of dogs with acute myocarditis due to experimental infection with T. cruzi. The best results for the detection of apoptosis by nick end labeling were obtained by a method combining the use of terminal deoxynucleotidyl transferase, CoCl2 and fluorescein-conjugated deoxyuridine triphosphate, followed by counterstaining of DNA with 4'6-diamidino-2-phenylindole (DAPI) and examination by laser scanning confocal fluorescence microscopy. Apoptosis was found in: (1) cardiac myocytes; (2) endothelial cells of capillaries and venules: (3) immune effector cells, including macrophages, interstitial dendritic cells (antigen-presenting cells) and granular and agranular lymphocytes, and (4) intra- and extracellular forms of T. cruzi. The apoptosis in myocytes and endothelial cells affected cells that were not infected by T. cruzi and was probably caused by the release of toxic mediators of inflammation. The apoptosis of immune effector cells could be related either to the subsidence of inflammation or to modulation (and even failure) of the immune response. The finding of apoptosis in T. cruzi confirms the results of other studies showing that this phenomenon occurs during the differentiation of trypomastigotes in vitro. Thus, apoptosis constitutes an important and multifactorial event in the pathogenesis of acute Chagasic myocarditis.
J Mol Cell Cardiol 1999 Mar
PMID:Apoptosis in a canine model of acute Chagasic myocarditis. 1019 89


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