Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The use of Cyclophosphamide, an anti-cancer and immunosuppressant drug, is accompanied by a number of side effects. Rats injected with a single dose of cyclophosphamide (200 mg kg-1 body weight) showed an increase in the levels of serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase, glucose-6-phosphate dehydrogenase and creatine phosphokinase isoenzyme by 53, 24, 55 and 135%, respectively. Also the ability of heart or liver mitochondria to retain accumulated Ca2+ and tetraphenylphosphonium ion was sharply affected in treated rats. Rats injected with the same dose of cyclophosphamide plus cyclosporin A (500 micrograms kg-1 body weight) showed reduction in the levels of those enzymes by about 44, 21, 43 and 57%, respectively compared to cyclophosphamide-treated rats. Cyclosporin A treatment also restored mitochondrial ability to retain accumulated Ca2+ and tetraphenyl phosphonium ions nearly to the level of untreated rats. We suggest that cyclophosphamide induced cardio and hepatotoxicity by increasing heart and liver inner mitochondrial membrane permeability to Ca2+. The protective effect of cyclosporin A against cyclophosphamide-induced damage also support this suggestion.
Comp Biochem Physiol A Mol Integr Physiol 1998 Nov
PMID:In vivo prevention of cyclophosphamide-induced Ca2+ dependent damage of rat heart and liver mitochondria by cyclosporin A. 997 18

phi CTX is a cytotoxin-converting phage isolated from Pseudomonas aeruginosa. In this study, we determined the complete nucleotide sequence of the phi CTX phage genome. The precise genome size was 35,538 bp with 21 base 5'-extruding cohesive ends. Forty-seven open reading frames (ORFs) were identified on the phi CTX genome, including two previously identified genes, ctx and int. Among them, 15 gene products were identified in the phage particle by protein microsequencing. The most striking feature of the phi CTX genome was an extensive homology with the coliphage P2 and P2-related phages; more than half of the ORFs (25 ORFs) had marked homology to P2 genes with 28.9-65.8% identity. The gene arrangement on the genome was also highly conserved for the two phages, although the G + C content and codon usage of most phi CTX genes were similar to those of the host P. aeruginosa chromosome. In addition, phi CTX was found to share several common features with P2, including the morphology, non-inducibility, use of lipopolysaccharide core oligosaccharide as receptor and Ca(2+)-dependent receptor binding. These findings indicate that phi CTX is a P2-like phage well adapted to P. aeruginosa, and provide clear evidence of the intergeneric spread and evolution of bacteriophages. Furthermore, comparative analysis of genome structures of phi CTX, P2 and other P2 relatives revealed the presence of several hot-spots where foreign DNAs, including the cytotoxin gene, were inserted. They appear to be deeply concerned in the acquisition of various genes that are horizontally transferred by bacteriophage infection.
Mol Microbiol 1999 Jan
PMID:The complete nucleotide sequence of phi CTX, a cytotoxin-converting phage of Pseudomonas aeruginosa: implications for phage evolution and horizontal gene transfer via bacteriophages. 1002 59

Our laboratory has concentrated on the possible regulation the benzamides and nicotinamides may have on the processes of DNA repair and apoptosis. Recent reports have suggested that both apoptosis and inflammation are regulated by the transcription factor NF-kappaB. We have initiated studies regarding the hypothesis that the benzamides and nicotinamides could inhibit the production of tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as induce apoptosis via inhibition of NF-kappaB. Our data have shown that nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was prevented in the rat by 3 x 50 mg/kg doses of 3-CPA or MCA, and 100-200 microM doses of MCA could also inhibit NF-kappaB in Hela cells. Taken together these data strongly support the notion that benzamides and nicotinamides have potent anti-inflammatory and antitumor properties, because their primary mechanism of action is regulated by inhibition at the gene transcription level of NF-kappaB, which in turn inhibits TNFalpha and induces apoptosis.
Mol Cell Biochem 1999 Mar
PMID:Newly discovered anti-inflammatory properties of the benzamides and nicotinamides. 1033 48

Reviews modern data on the genetic control of the key factors of Vibrio cholerae pathogenicity: cholera toxin and toxin-coregulated adhesion pili. Pays special attention to the temperate filamentous CTX bacteriophage, whose genome contains structural genes of cholera toxin, and the "pathogenicity island" carrying tcp genes responsible for the most important factor of the human small intestine colonization with V. cholerae. Discusses the mechanism of coordinated regulation of the activity of the main genes of V. cholerae pathogenicity genes.
Mol Gen Mikrobiol Virusol 1999
PMID:[Genetic control of Vibrio cholerae pathogenicity: the temperate filamentous phage CTX, coding for cholera toxin and the "island of pathogenicity"]. 1062 31

The toxin-co-regulated pilus (TCP), a type 4 pilus that is expressed by epidemic strains of Vibrio cholerae O1 and O139, is required for colonization of the human intestine. The TCP structure is assembled as a polymer of repeating subunits of TcpA pilin that form long fibres, which laterally associate into bundles. Previous passive immunization studies have suggested that the C-terminal region of TcpA is exposed on the surface of the pilus fibre and has a critical role in mediating the colonization functions of TCP. In the present study, we have used site-directed mutagenesis to delineate two domains within the C-terminal region that contribute to TCP structure and function. Alterations in the first domain, termed the structural domain, result in altered pilus stability or morphology. Alterations in the second domain, termed the interaction domain, affect colonization and/or infection by CTX-bacteriophage without affecting pilus morphology. In vitro and in vivo analyses of the tcpA mutants revealed that a major function of TCP is to mediate bacterial interaction through direct pilus-pilus contact required for microcolony formation and productive intestinal colonization. The importance of this function is supported by the finding that intragenic suppressor mutations that restore colonization ability to colonization-deficient mutants simultaneously restore pilus-mediated bacterial interactions. The alterations resulting from the suppressor mutations also provide insight into the molecular interactions between pilin subunits within and between pilus fibres.
Mol Microbiol 2000 Feb
PMID:Delineation of pilin domains required for bacterial association into microcolonies and intestinal colonization by Vibrio cholerae. 1069 66

To determine whether the measurement of repeat number mutations at a minisatellite locus could detect human germline mutations induced by chemotherapy, we performed a longitudinal study of the mutation frequencies in sperm from 10 patients treated for Hodgkin's disease. Polymerase chain reaction on small pools of DNA equivalent to 100 sperm and Southern blotting were used to screen at least 7900 sperm in each sample to quantify the mutation frequency at the minisatellite MS205 locus. Pretreatment and posttreatment semen samples were obtained at least 2 months after completion of therapy from 4 patients treated with a regimen (Novantrone, Oncovin, vinblastine and prednisone [NOVP]) that lacks alkylating agents and from three patients treated with regimens (Cytoxan, vinblastine, procarbazine and prednisone/Adriamycin, bleomycin, dacarbazine, lomustine, and prednisone [CVPP/ABDIC] or mechlorethamine, Oncovin, procarbazine and prednisone [MOPP]) containing alkylating agents. There were no effects of NOVP or CVPP/ABDIC on the mutation frequencies. In the 1 patient treated with MOPP, the treatment with the highest dose of gonadotoxic alkylating agents, there was a statistically significant increase in mutation frequency from 0.79% pretreatment to 1.14% posttreatment, indicating induction of mutations in stem spermatogonia. During-treatment semen samples obtained from 2 patients treated with ABVD, which does not contain gonadotoxic alkylating agents, and 1 with NOVP also did not show any increases above the baseline mutation frequencies, indicating no increase in the minisatellite mutation frequency in spermatocytes. Thus, measurement of repeat number changes at minisatellite MS205 appears to be able to detect induced germline mutations in human sperm. However, most chemotherapy regimens do not significantly increase this class of mutations.
Environ Mol Mutagen 2000
PMID:Frequency of minisatellite repeat number changes at the MS205 locus in human sperm before and after cancer chemotherapy. 1101 12

A new Rayleigh light scattering (RLS) assay of protein was conducted in this paper. At the optimum pH conditions, and in the presence of Tween-20, the weak RLS of dibromomethylchlorophosphonazo (DBM-CPA) can be enhanced greatly by the addition of proteins. Based on this, the reactions of DBM-CPA and proteins were studied. A new quantitative determination method for proteins has been developed. The method is simple, practical and relatively free from interference from coexisting substances, as well as much more sensitive (the dynamic ranges of 0.065-40.05 microg ml(-1) and detection limit of 30 ng ml(-1) for bovine serum albumin (BSA)) than most of the existing assays. The determination results of human body serum samples are identical to those by the CBB method, with relative S.D. of six determination of 0.5-2.2%.
Spectrochim Acta A Mol Biomol Spectrosc 2000 Nov 01
PMID:Determination of proteins at nanogram levels based on their enhancement effects of Rayleigh light scattering on dibromomethylchlorophosphonazo. 1107 89

Adenosine is a potent vasodilator of the coronary microvessels and is implicated in the regulation of coronary blood flow during metabolic stress. However, the receptor subtypes and the vasodilatory mechanism responsible for the dilation of coronary microvessels to adenosine remain unclear. In the present study, using an isolated-vessel preparation we demonstrated that porcine coronary arterioles (50-100 microm) dilated concentration-dependently to adenosine, CPA (adenosine A1 receptor agonist) and CGS21680 (adenosine A2A receptor agonist). These vasodilations were not altered by the A1 receptor antagonist CPX, but were abolished by the selective A2A receptor antagonist ZM241385, indicating that activation of A2A receptors mediates these vasodilatory responses. The protein kinase A inhibitor Rp-8-Br-cAMPS abolished coronary arteriolar dilations to adenylyl cyclase activator forskolin and cAMP analog 8-Br-cAMP, but failed to inhibit adenosine- and CGS21680-induced dilations. The calcium-activated potassium channel inhibitor iberiotoxin also did not affect vasodilations to adenosine and CGS21680. In contrast, the ATP-sensitive potassium (K(ATP)) channel inhibitor glibenclamide abolished vasodilations to adenosine and CGS21680 but did not affect vasodilations to forskolin and 8-Br-cAMP. In addition, the cAMP level in coronary microvessels was not increased by adenosine or CGS21680. The results from RT/PCR and in situ hybridization indicated that adenosine A2A receptor mRNA was encoded in coronary arterioles and the left anterior descending (LAD) artery but not in cardiomyocytes, whereas the A1 receptor transcript was detected in the LAD artery and cardiomyocytes but not in arterioles. Similarly, adenosine A1 and A2A proteins were expressed in the LAD artery, but only A2A receptors were expressed in coronary arterioles. Collectively, these functional data suggest that coronary arteriolar dilation to adenosine is primarily mediated by the opening of K(ATP) channels through activation of A2A receptors. This conclusion is corroborated by the molecular data showing that coronary arterioles only express adenosine A2A receptors. Furthermore, the dilation of coronary microvessels to adenosine A2A receptor activation appears to be independent of cAMP signaling.
J Mol Cell Cardiol 2001 Feb
PMID:Functional and molecular characterization of receptor subtypes mediating coronary microvascular dilation to adenosine. 1116 32

The genetic transfer of drug resistance to hematopoietic cells is an attractive approach to overcoming myelosuppression caused by high-dose chemotherapy. Because cyclophosphamide (CTX) and methotrexate (MTX) are commonly used non-cross-resistant drugs, generation of dual drug resistance in hematopoietic cells that allows dose intensification may increase anti-tumor effects and circumvent the emergence of drug-resistant tumors. We constructed a retroviral vector containing both a human cytosolic ALDH-1 cDNA and a human doubly mutated DHFR cDNA (Phe22/Ser31; termed F/S in the description of constructs) to generate increased resistance to both CTX and MTX. Infection of NIH3T3 cells resulted in increased resistance to both 4-hydroperoxycyclophosphamide (4HC) (1.9 +/- 0.1-fold) and MTX (73 +/- 2.8-fold). Transduced human CD34(+) enriched hematopoietic progenitor cells were also resistant to both 4HC and MTX by CFU-GM readout. Lethally irradiated mice transplanted with SFG-ALDH-IRES-F/S or mock-transduced bone marrow cells were treated with high-dose pulse CTX or high-dose CTX/MTX. Animals receiving marrow not transduced with ALDH-1 or mutated DHFR cDNA died from CTX or CTX/MTX toxicity, whereas mice transduced with ALDH-1 and mutated DHFR cDNA-containing marrow were able to tolerate the same doses of CTX or CTX/MTX treatment posttransplant. These data taken together indicate that ALDH-1 overexpression and mutant DHFR increased both 4HC and MTX resistance in vitro and in the in vivo mouse model. This construct may be useful for protecting patients from high-dose CTX- and MTX-induced myelosuppression.
Mol Ther 2001 Jan
PMID:Generation of dual resistance to 4-hydroperoxycyclophosphamide and methotrexate by retroviral transfer of the human aldehyde dehydrogenase class 1 gene and a mutated dihydrofolate reductase gene. 1116 15

Ca2+ signals regulate many cellular functions, including hormone secretion. Agonist-specific Ca2+ signaling may arise from the differential mobilization of multiple Ca2+ stores. Although they act through the same receptor subtype, two gonadotropin-releasing hormones (sGnRH and cGnRH-II) generate quantifiably different Ca2+ signals in goldfish gonadotropes, suggesting that their Ca2+-dependent signaling cascades may differ. We combined electrophysiology, Ca2+ imaging, and radioimmunoassay detection of gonadotropin (GTH-II) secretion to determine the role of intracellular Ca2+ stores in GnRH-stimulated exocytosis. Our findings suggest that voltage-gated Ca2+ channels do not mediate acute GnRH-signaling. Instead, both sGnRH- and cGnRH-II-stimulated GTH-II releases are dependent on Ca2+ mobilized from TMB-8/CPA-sensitive compartments. However, sGnRH, but not cGnRH-II, utilizes intracellular stores sensitive to caffeine and xestospongin C. We also identified a homeostatic mechanism where reduced extracellular Ca2+ availability increase GTH-II release by mobilizing Ca2+ stores. Our results are the first to suggest that several classes of intracellular Ca2+ stores differentially participate in agonist signaling and homeostasis in gonadotropes.
Mol Cell Endocrinol 2000 Dec 22
PMID:Agonist-specific Ca2+ signaling systems, composed of multiple intracellular Ca2+ stores, regulate gonadotropin secretion. 1116 87


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