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At least 271 records · Page 15Linked to original sources
PubMed1997

A highly conserved DNA replication module from Streptococcus thermophilus phages is similar in sequence and topology to a module from Lactococcus lactis phages.

A highly conserved DNA region extending over 5 kb was observed in Streptococcus thermophilus bacteriophages. Comparative sequencing of one temperate and 26 virulent phages demonstrated in the most extreme case an 18% aa difference for a predicted protein, while the majority of the phages showed fewer, if any aa changes. The relative degree of aa conservation was not homogeneous over the DNA segment investigated. Sequence analysis of the conserved segment revealed genes possibly involved in DNA transactions. Three predicted proteins (orf 233, 443, and 382 gene product (gp)) showed nucleoside triphosphate binding motifs. Orf 443 gp showed in addition a DEAH box motif, characteristically found in a subgroup of helicases, and a variant zinc finger motif known from a phage T7 helicase/primase. Tree analysis classified orf 443 gp as a distant member of the helicase superfamily. Orf 382 gp showed similarity to putative plasmid DNA primases. Downstream of orf 382 a noncoding repeat region was identified that showed similarity to a putative minus origin from a cryptic S. thermophilus plasmid. Four predicted proteins showed not only high degrees of aa identity (34 to 63%) with proteins from Lactococcus lactis phages, but their genes showed a similar topological organization. We interpret this as evidence for a horizontal gene transfer event between phages of the two bacterial genera in the distant past.

Amino Acid Sequence↗
PubMed1982

3-Hydroxy-3-methylglutaryl-coenzyme A reductase. The difference in the mechanism of the in vitro modulation by phosphorylation and dephosphorylation to modulation of enzyme activity by non-esterified cholesterol.

Incubation of rat liver microsomal fraction in the presence of increasing concentration of a serum preparation and the re-isolation of the treated microsomal vesicles resulted in a progressive increase in the concentration of non-esterified cholesterol, a progressive decrease in the activity of hydroxymethylglutaryl-CoA reductase and progressive changes in the characteristics of the Arrhenius plots of the enzyme. The changes in the characteristics of the Arrhenius plots of the enzyme in the serum-treated preparations are consistent with a progressive increase in the concentration of non-esterified cholesterol in the environment of the hydroxymethylglutaryl-CoA reductase in endoplasmic reiticulum vesicles. The serum-treated preparations with high non-esterified cholesterol content showed a constant activation energy between 37 and 20 degrees C, whereas the enzyme in the non-treated microsomal fraction, the buffer-treated and the lipoprotein-deficient serum-treated preparations showed breaks in the activation energy at about 29 degrees C. The microsomal fraction from rats fed on the standard, cholesterol- or cholestyramine-supplemented diet showed considerable differences in the activity of hydroxymethylglutaryl-CoA reductase and differences in the characteristics of their Arrhenius plots. However, the incubation of the microsomal fraction from the rats in the three experimental conditions with ATP and Mg2+ and the further incubation of the inactivated enzyme with a preparation of cytosolic phosphoprotein phosphatase resulted in Arrhenius plots with similar characteristics to those of the corresponding original microsomal fraction. These results suggest that changes in the concentration of non-esterified cholesterol in the endoplasmic reticular membrane are responsible for the differences in the activity of hydroxymethylglutaryl-CoA reductase in the microsomal fraction from the rats in these dietary conditions.

Animals↗
PubMed1996

Modulation of cocaine intravenous self-administration in drug-naive animals by dihydropyridine Ca2+ channel modulators.

The dihydropyridine Ca2+ channel blocker nimodipine and the dihydropyridine Ca2+ channel activator BayK 8644 (1,4-dihydropyridine-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-py ridine- 5-carboxylate) were administered to drug-naive mice and rats that were tested for intravenous cocaine self-administration. A range of cocaine doses was tested to investigate the nature of the effect. The results indicate that nimodipine and BayK 8644 shifted the dose-response curve for cocaine's reinforcing action to the right and left, respectively. Thus, the Ca2+ channel blocker nimodipine decreases the sensitivity of mice and rats to the reinforcing effects of cocaine while the Ca2+ channel activator BayK 8644 makes the animals more sensitive to cocaine reward. The results suggest that a dihydropyridine-sensitive mechanism is implicated in the initiation of cocaine self-administration.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Modulation of AP-1 activity by nitric oxide (NO) in vitro: NO-mediated modulation of AP-1.

To understand the role of nitric oxide (NO) in controlling the specific DNA-binding activities of transcriptional factors, we investigated the in vitro effect of the NO-donor sodium nitroprusside (SNP) on the AP-1 activity of cultured mouse cerebellar granule cells. A gel-mobility assay showed that SNP inhibited AP-1 activity in the presence, but not the absence of dithiothreitol (DTT). This DTT-dependent inhibition of AP-1 activity by SNP corresponded with the activation of the chemical reactivity of SNP with DTT, which can be monitored by the production of nitrite (NO2-). In contrast, diamide, a typical sulfhydryl oxidizing agent, inhibited AP-1 activity in the absence of DTT and its inhibitory effect was reversed competitively by DTT. Studies using structurally or functionally related analogues of SNP demonstrated that S-nitrosylation of the AP-1 moiety mediated by some NO-carriers but not by free NO, which can be produced by the chemical reaction of SNP with DTT, was responsible for the inhibition of AP-1 activity, suggesting NO-mediated regulation of the AP-1 transcriptional factor.

3T3 Cells↗
PubMed1996

In vivo modulated N-acyl side chain of N-acetylneuraminic acid modulates the cell contact-dependent inhibition of growth.

Sialylation of plasma membrane glycoproteins is thought to be involved in the regulation of differentiation and in the process of tumorigenesis. Here we show that sialylation also affects cell-cell contact-dependent growth regulation. When cultured in the presence of non-physiological synthetic sialic acid precursors, human diploid fibroblasts no longer exhibited density-dependent inhibition of growth. Concomitantly, increased sialylation of contactinhibin, a glycoprotein involved in density-dependent inhibition of growth, was observed. These results indicate that sialidase-resistant sialic acid modifications lead to dysregulated growth control. The modifications have been induced by N-propanoyl and other N-acyl derivatives of D-mannosamine.

Cell Division↗
PubMed1987

Cell surface oligosaccharide modulation during differentiation. I. Modulation of lectin binding.

IMR-90 human lung fibroblasts exhibit quantitative and qualitative changes in their cell surface oligosaccharide expression as a result of low-density growth, contact inhibition of growth and changes in population doubling level (PDL). Binding of Concanavalin-A (CON-A), wheat germ agglutinin (WGA) and Ricinus communis (RCA-120) was shown to decrease by 20-40% as the cells advanced through their lifespan (but significantly before morphological manifestations commonly associated with senescence, which occur at approximately PDL 45). The binding of Dolichos biflorus agglutinin (DBA) increased by 100% over the same time interval. These changes were detected by quantitation of FITC conjugated lectins on single cells and the use of a sensitive analytical biotin-avidin-enzyme amplification assay on whole populations of cells. These studies were performed on randomly growing cultures. These results suggest an important and dynamic role for the cell surface oligosaccharide in growth control and cellular senescence.

Cell Differentiation↗
PubMed1980

Doxorubicin and daunorubicin modulation of macrophages, T and B lymphocytes (anthracycline lymphocyte modulation).

Mouse spleen cells were cloned in the presence of phytohemagglutinin or lipopolysaccharide. The effects in vitro of doxorubicin or daunorubicin on colony formation were examined. At certain concentrations these drugs stimulated B lymphocytes and suppressed T lymphocytes. These were the opposite of the effects observed with in vivo drug administration. It was observed that soluble factors from drug-treated monocytes produced these effects. It was not clear whether the disparate effects were the result of two different monocytic populations or differences in the in vivo versus in vitro microenvironment present during drug administration.

Animals↗
PubMedDate not supplied

The modulation of intracellular glutathione level modulates the mitochondrial response in proliferating rat splenocytes.

We have investigated the effect of intracellular reduced glutathione (GSH) levels on the mitochondrial parameters of proliferating rat splenocytes. The intracellular GSH content of the cells was altered by continuous culture with buthionine-S, R-sulfoximine (BSO), a specific inhibitor of GSH synthesis. BSO decreased the GSH levels, inhibited DNA synthesis and caused depolarization of mitochondria in 52% of cells stimulated to proliferate for 72 h. These data support the proposition that GSH influences the lymphocyte proliferation at more than one site, one of which is the energy producing machinery.

Journal Article↗
PubMed2005

Modulation of effector affinity by hinge region mutations also modulates switching activity in an engineered allosteric TEM1 beta-lactamase switch.

RG13 is an engineered allosteric beta-lactamase (BLA) for which maltose is a positive effector. RG13 is a hybrid protein between TEM1 BLA and maltose-binding protein (MBP). Maltose binding to MBP is known to convert the open form of the protein to the closed form through conformational changes about the hinge region. We have constructed and genetically selected several variants of RG13 modified in the hinge region of the MBP domain and explored their effect on beta-lactam hydrolysis, maltose affinity and maltose-induced switching. Hinge mutations that increased maltose affinity the most (and thus presumably close the apo-MBP domain the most) also abrogated switching the most. We provide evidence for a model of RG13 switching in which there exists a threshold conformation between the open to closed form of the MBP domain that divides states that catalyze beta-lactam hydrolysis with different relative rates of acylation and deacylation.

Acylation↗
PubMed1999

Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes.

Recent metabolic studies have demonstrated the importance of reactive intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p.). Dietary BHA markedly suppressed the hepatotoxicity caused by both BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity.

Alanine Transaminase↗
PubMed2003

Modulation of CD(4)(+) and CD(8)(+) tumor infiltrating lymphocytes by a fraction isolated from shark cartilage: shark cartilage modulates anti-tumor immunity.

Shark cartilage has proven to have some inhibitory effects on angiogenesis, metastasis, cell adhesion and proteolysis. In this study, we wanted to study some of the effects of shark cartilage on tumor immune response. Firstly, by means of chromatographic methods and delayed type hypersensitivity (DTH) test, we optimized a procedure for isolation and purification of a shark cartilage protein fraction with most immunostimulatory effects. Then, we examined its effect on the infiltration of CD(4)(+) and CD(8)(+) lymphocytes into a murine tumor model. Our fraction was composed of two major proteins with molecular weights (MWs) of about 14 and 15 kDa. This fraction highly increases DTH response against sRBC in mice. Furthermore, intraperitoneal injection of this fraction to tumor-bearing mice could increase T-cell infiltration into the tumor. Also, there was a significant increase in the CD(4)/CD(8) ratio in tumor infiltrating lymphocytes, but no such changes were found in the peripheral blood lymphocytes. According to these results, we suppose that this fraction is a good candidate for further studies in cancer therapy. Also, we concluded that this fraction, with previously proven anti-angiogenic effects, can augment cellular immune response and T-cell infiltration into the tumor and thus, there may be a direct relationship between angiogenesis inhibition and T-cell infiltration.

Adenocarcinoma↗
PubMed2004

N-Terminal domain linkage modulates the folding properties of protein S epidermal growth factor-like modules.

Protein S interacts with activated protein C to play a crucial role in blood anticoagulation, and protein S deficiency is associated with increased risk of thrombosis. Despite the large volume of functional data available for this protein, no atomic resolution structure data have yet been reported. This is due at least in part to difficulties encountered when trying to produce fragments dissected from the intact protein; however, a few successful strategies have been described. In this research we have expressed a number of constructs containing protein S epidermal growth factor-like (EGF) domains 1 and 2 in Escherichia coli and Pichia pastoris. None of the proteins produced was stably folded as assayed by solution nuclear magnetic resonance spectroscopy. We therefore constructed a series of non-native protein S EGF concatemers to investigate the role of pairwise domain linkage in domain folding. Our results demonstrate that N-terminal domain linkage can either positively or negatively impact on the refolding of an adjacent domain. Furthermore, analysis of the NMR data for EGF3-4 reveals the expected interdomain NOEs that are characteristic of an extended arrangement of calcium-binding EGF domains and a similar average [(1)H]-(15)N heteronuclear NOE value for each of the two domains. These results provide the first data in support of protein S EGF3-4 adopting the same extended domain orientation as observed for the functionally distinct proteins fibrillin-1 and the low-density lipoprotein receptor. The results also have important implications for future studies, particularly when a dissection approach is used, of tandem EGF domains from protein S and other proteins.

Amino Acid Sequence↗
PubMed2001

Modulation of BzATP and formalin induced nociception: attenuation by the P2X receptor antagonist, TNP-ATP and enhancement by the P2X(3) allosteric modulator, cibacron blue.

1. Exogenous ATP produces acute and localized pain in humans, and P2X receptor agonists elicit acute nociceptive behaviours in rodents following intradermal administration to the hindpaw. The predominant localization of P2X(3) mRNA in sensory neurones has led to the hypothesis that activation of P2X(3) and/or P2X(2/3) receptors contributes to nociception. 2. The local administration of the P2X receptor agonist, BzATP (100--1000 nmol paw(-1), s.c.) into the rat hindpaw produced an acute (<15 min) paw flinching response that was similar to that observed in the acute phase of the formalin (5%) test. 3. The co-administration of the potent P2X receptor antagonist, TNP-ATP (30--300 nmol paw(-1)), but not an inactive analogue, TNP-AMP, with BzATP into the rat hindpaw attenuated BzATP-induced nociception. Similarly, co-administration of TNP-ATP, but not TNP-AMP, with 5% formalin reduced both acute and persistent nociception in this test. 4. Co-administration of cibacron blue (30 and 100 nmol paw(-1)), a selective allosteric enhancer of P2X(3) and P2X(2/3) receptor activation, with BzATP (30 and 100 nmol paw(-1)) into the rat hindpaw produced significantly greater nociception as compared to the algogenic effects of BzATP alone. Intradermal co-administration of cibacron blue (30 and 100 nmol paw(-1)) with formalin (1 and 2.5%) into the rat hindpaw also produced significantly greater nociceptive behaviour as compared to formalin alone. 5. The ability of TNP-ATP and cibacron blue to respectively attenuate and enhance nociceptive responses elicited by exogenous BzATP and formalin provide further support for the hypothesis that activation of peripheral P2X(3) containing channels contributes specifically to both acute and persistent nociception in the rat.

Adenosine Triphosphate↗
PubMed1980

3-hydroxy-3-methylglutaryl-coenzyme A reductase A comparison of the modulation in vitro by phosphorylation and dephosphorylation to modulation of enzyme activity by feeding cholesterol- or cholestryamine-supplemented diets.

The activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hydroxymethylglutaryl-CoA reductase) was considerably inhibited during incubation with ATP+Mg(2+). The inactivated enzyme was reactivated on further incubation with partially purified cytosolic phosphoprotein phosphatase. The inactivation was associated with a decrease in the apparent K(m) of the reductase for hydroxymethylglutaryl-CoA, and this was reversed on reactivation. The slight increase in activity observed during incubation of microsomal fraction without ATP was not associated with a change in apparent K(m) and, unlike the effect of the phosphatase, was not inhibited by NaF. Liver microsomal fraction from rats given cholesterol exhibited a low activity of hydroxymethylglutaryl-CoA reductase with a low apparent K(m) for hydroxymethylglutaryl-CoA. Mícrosomal fraction from rats fed cholestyramine exhibited a high activity with a high K(m). To discover whether these changes had resulted from phosphorylation and dephosphorylation of the reductase, microsomal fraction from rats fed the supplemented diets and the standard diet were inactivated with ATP and reactivated with phosphoprotein phosphatase. Inactivation reduced the maximal activity of the reductase in each microsomal preparation and also reduced the apparent K(m) for hydroxymethylglutaryl-CoA. There was no difference between the preparations in the degree of inactivation produced by ATP. Treatment with phosphatase restored both the maximal activity and the apparent K(m) of each preparation, but never significantly increased the activity above that observed with untreated microsomal fraction. It is concluded that hydroxymethylglutaryl-CoA reductase in microsomal fraction prepared by standard procedures is almost entirely in the dephosphorylated form, and that the difference in kinetic properties in untreated microsomal fraction from rats fed the three diets cannot be explained by differences in the degree of phosphorylation of the enzyme.

Adenosine Triphosphate↗