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Results for “differential selection”

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PubMed1994

Transcriptional regulation of differentiation, selective toxicity and ATGCAAAT binding of bisbenzimidazole derivatives in human melanoma cells.

To study the relationship between the structure of minor groove ligands and their affinity for specific DNA sequences that regulate gene transcription, three analogues of the A-T-specific DNA minor groove ligands Hoechst 33258 and Hoechst 33342 were synthesized with 5, 8 or 12 carbons in an aliphatic chain attached to the phenolic oxygen of the molecule. There was a striking bimodal relationship between toxicity to HeLa cells and the lipophilicity of the five analogues, toxicity being low for the compounds with a free hydroxyl (Hoechst 33258) or a 12-carbon substituent, yet high for the 5-carbon analogue. Selective killing of human melanoma cells compared with normal fibroblasts was observed for the Hoechst analogue with a 12-carbon chain attached. Hoechst 33258 itself was selectively toxic for the MM96E melanoma cell line compared with other cell lines, induced a highly dendritic morphology, increased tyrosinase activity and tyrosinase mRNA but decreased the level of gp75 (TRP-1) mRNA; message for a third pigment gene, Pmel-17, was unchanged. Tyrosinase activity was decreased in the resistant A2058 melanoma cell line and transcription was affected to a lesser extent than in MM96E. Expression of gp75 protein and two intermediate filament proteins was inhibited by Hoechst 33258 in MM96E cells. There was no major difference in the amount of 125I-Hoechst 33258 taken up by sensitive and resistant cells. Of the five derivatives studied, the parent drug Hoechst 33258 and the 2-carbon analogue (Hoechst 33342) were found to have the most inhibitory effect on affinity of octamer binding proteins for the ATGCAAAT consensus sequence found in the promoter region of certain genes associated with proliferation and differentiation. In contrast to Distamycin A (also an A-T-specific minor groove ligand), Hoechst 33258 displaced proteins already bound to the octamer motif. The G-C ligand chromomycin A3 exhibited a different spectrum of cell toxicity and tyrosinase stimulation compared with Hoechst 33258. Chromomycin A3 but not Hoechst 33258, strongly inhibited the zinc-dependent transcriptional activity of the sheep metallothionein-Ia promoter in reporter gene assays of transfected cells. Since the six metal-responsive elements of the promoter are GC-rich, this provides independent evidence for the sequence-specificity of transcriptional inactivation by one of these drugs in melanoma cells. Overall, the results suggest that Hoechst 33258 acts by inhibiting the transcription of specific genes, cell lines evidently differing in the accessibility to drugs of certain A-T-rich sequences.

Base Sequence↗
PubMed1995

Stimulation of protein kinase C during Ca(2+)-induced keratinocyte differentiation. Selective blockade of MARCKS phosphorylation by calmodulin.

Raising the external Ca2+ concentration from 0.05 to 1.8 mM stimulated membrane-associated protein kinase Cs (PKCs) activity as strongly as the specific PKCs activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in BALB/MK mouse keratinocytes. This was indicated by the increased phosphorylation of a PKC-selective peptide substrate, Ac-FKKSFKL-NH2, by membranes isolated from the Ca(2+)- or TPA-stimulated keratinocytes. Raising the external Ca2+ concentration to 1.8 mM also triggered a 4-fold rise in the intracellular free Ca2+ concentration. As reported elsewhere (Moscat, J. Fleming, T. P., Molloy, C. J. Lopez-Barahona, M., and Aaronson, S. A. (1989) J. Biol. Chem. 264, 11228-11235), TPA stimulated the phosphorylation of the PKCs substrate, the 85-kDa myristoylated alanine-rich kinase C substrate (MARCKS) protein, in intact keratinocytes, but Ca2+ did not. Furthermore, Ca(2+)-pretreatment reduced the TPA-induced phosphorylation of the 85-kDa protein in intact cells. There was no significant increase in MARCKS phosphorylation when keratinocytes were treated with a Ca2+.CaM-dependent phosphatase inhibitor, cyclosporin A, before stimulation with 1.8 mM Ca2+.Ca2+.calmodulin suppressed the ability of isolated membranes to phosphorylate the 85-kDa MARCKS holoprotein in vitro in the presence of phosphatase inhibitors such as fluoride, pyrophosphate, and vanadate, and this inhibition was overcome by a calmodulin antagonist, the calmodulin-binding domain peptide. Thus, the ability of 1.8 mM Ca2+ to strongly stimulate the membrane PKCs activity without stimulating the phosphorylation of the MARCKS protein in keratinocytes is consistent with the possibility of Ca2+.calmodulin complexes, formed by the internal Ca2+ surge, binding to, and blocking the phosphorylation of, this PKC protein substrate.

Amino Acid Sequence↗
PubMed1998

Alpha-1 antitrypsin up-regulates human B cell differentiation selectively into IgE- and IgG4- secreting cells.

Numerous allergens have proteolytic activities. It has been speculated that this property may contribute to their allergenicity. Therefore, we have evaluated the effect of different physiological protease inhibitors (PI) on the regulation of human IgE synthesis. Unexpectedly, the serine PI, alpha-1 antitrypsin, also called alpha-1 protease inhibitor (alpha1PI), induced a potent and selective dose-dependent increase of IgE and IgG4 production by human tonsillar B cells stimulated with the IgE and IgG4 switch factors, IL-4 and anti-CD40 mAb. The other serine PI tested were inefficient. Furthermore, this effect of alpha1PI was accompanied by an increase in (1) germ-line and mature sigma mRNA transcription, (2) proliferation and (3) membrane CD23 and CD21 expression, while the expression of other molecules involved in the regulation of IgE synthesis was unchanged. Since CD23-CD21 pairing plays a crucial role in the up-regulation of IgE synthesis, we have tested whether blocking this interaction affected alpha1PI-increased IgE production. The neutralizing anti-CD23 mAb, Mab 25, partly reversed the IgE increase caused by alpha1PI. Moreover, alpha1PI potentiation of IgE synthesis was prevented by elastase, a natural substrate of alpha1PI, thereby suggesting that alpha1PI may inhibit endogenous B cell enzyme(s) involved in the down-regulation of IgE synthesis. Alpha1PI also potentiated IgE and IgG4 production by IL-4-stimulated peripheral blood mononuclear cells but was not a switch factor for IgE and IgG4 as it was unable to replace IL-4 or anti-CD40 mAb in inducing IgE and IgG4 production. In conclusion, this study shows that alpha1PI acts as a potent co-stimulus for IgE and IgG4 synthesis and suggests that the equilibrium between protease/ protease inhibitor participates in the control of human IgE and IgG4 synthesis.

Antibodies, Monoclonal↗
PubMed2002

Phylogenetic relationships and differential selection pressures among genotypes of dengue-2 virus.

To elucidate the processes controlling the emergence and spread of dengue-2 virus (DEN-2) we examined the evolution of viral isolates sampled from both local (Viet Nam) and global populations. Our phylogenetic analysis, incorporating envelope (E) glycoprotein sequences from 147 isolates of DEN-2, provided a more complete picture of viral diversity, with a newly defined "Cosmopolitan" genotype having a near global distribution and two other genotypes restricted to Asia. By analyzing rates of synonymous and nonsynonymous substitution we determined that genotypes have experienced different selection pressures, with some evidence of positive selection in the Cosmopolitan genotype and one of the two Asian genotypes, but that the transition from sylvatic to human transmission was not accompanied by adaptive evolution of the E gene. Although there was no association between selection pressures acting on the E gene and proposed virulence differences among genotypes, some putatively selected amino acid sites have previously been implicated in changing viral pathogenicity, most notably E-390, and may also affect transmittability. These findings have implications for the future spread of DEN-2.

Africa↗
PubMed1996

Non-psychostimulant drugs of abuse and anxiogenic drugs activate with differential selectivity dopamine transmission in the nucleus accumbens and in the medial prefrontal cortex of the rat.

In rats vertically implanted with concentric dialysis probes in the medial prefrontal cortex and in the medial nucleus accumbens, morphine, ethanol and nicotine failed to modify extracellular dopamine in the medial prefrontal cortex at doses that were fully effective in raising extracellular dopamine in the nucleus accumbens. Conversely, the aversive/anxiogenic drugs picrotoxin, pentylenetetrazol and FG 7142, administered at subconvulsant doses, increased extracellular dopamine in the medial prefrontal cortex but failed to do so in the nucleus accumbens. Systemic administration of low doses of the 5HT3 antagonist ICS 205930, previously reported to prevent the increase of extracellular dopamine in the nucleus accumbens elicited by morphine, nicotine, ethanol and haloperidol (Carboni et al. 1989) as well as by stress (Imperato et al. 1990), also prevented the increase of extracellular dopamine elicited in the prefrontal cortex by anxiogenic drugs. Therefore, mesocortical and mesolimbic dopamine neurons show clear-cut differences in the reactivity to drugs of abuse and to aversive drugs but are both modulated by a facilitatory serotonergic input mediated by 5HT3 receptors.

Animals↗
PubMed2001

Differential selectivity in carbamazepine-induced inactivation of cytochrome P450 enzymes in rat and human liver.

Oxidative metabolism of carbamazepine results in covalent binding of its reactive metabolite to liver microsomal proteins, which has been proposed as an important event in pathogenesis of the hypersensitivity reactions to this drug. Although the proposed reactive metabolites are produced by cytochrome P450 enzymes (P450 or CYP), the impact of the formation of unstable metabolites on the enzyme itself has not been elucidated. The present study examines the alteration of P450 enzyme activities during the metabolism of carbamazepine. Liver microsomes from rats and humans were preincubated with carbamazepine in the presence of NADPH, and subsequently assayed for monooxygenase activities representing several P450s. No evidence was obtained for inactivation of CYP2C11, CYP3A, CYP1A1/2 or CYP2B1/2 in rat liver microsomes during the carbamazepine metabolism, whereas the CYP2D enzyme was inactivated in a manner related to the preincubation time. Interestingly, under the same protocol human liver microsomes did not exhibit inactivation of CYP2D6, as well as there being no CYP2C8, CYP2C9 or CYP3A4 inactivation, whereas CYP1A2 was inactivated. Reduced glutathione could not protect against the observed inactivation of the P450s. These results suggest that CYP2D enzyme(s) in rats and CYP1A2 in humans biotransform carbamazepine into reactive metabolites, resulting in inactivation of the enzyme themselves, and raise the possibility that the P450 isoforms participate in toxicity induced by the drug in both animal species.

Animals↗
PubMed2005

Promotion of cell adherence and spreading: a novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells.

The receptor for advanced glycation endproducts (RAGE) is expressed under pathological conditions in many tissues and has been assigned many functions. We demonstrate, in normal human lung tissue, the preferential and highly abundant expression of RAGE by quantitative polymerase chain reaction. In addition, RAGE expression, as a specific differentiation marker of alveolar epithelial type I cells (AT I cells), and its localization to the basolateral plasma membrane have been confirmed by means of newly raised monoclonal antibodies. The physiological function of RAGE on AT I cells has previously remained elusive. By using HEK293 cells transfected with cDNA encoding for full-length RAGE, we show that RAGE enhances the adherence of epithelial cells to collagen-coated surfaces and has a striking capacity for inducing cell spreading. The preferential binding of RAGE to collagen has been confirmed by assaying the binding of soluble RAGE to various substrates. RAGE might thus assist AT I cells to acquire a spreading morphology, thereby ensuring effective gas exchange and alveolar stability.

Antigens, Differentiation↗
PubMed1985

Differential selectivities of RU 24969 and 8-OH-DPAT for the purported 5-HT1A and 5-HT1B binding sites. Correlation between 5-HT1A affinity and hypotensive activity.

RU 24969 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) inhibited the specific binding of [3H]5-HT (2 nM) to rat brain membranes with shallow displacement curves. The displacement data were best fitted with a model of two independent, high and low affinity binding sites. Following addition of spiperone (1 microM) as a selective ligand for the putative 5-HT1A recognition site of [3H]5-HT, the displacement curve of RU 24969 underwent a leftward shift, whereas spiperone induced a shift to the right for the displacement curve of 8-OH-DPAT. In contrast to spiperone, pindolol (1 microM) shifted the displacement curve of RU 24969 to the right. These results suggest that RU 24969 possesses preference for the purported 5-HT1B subtype of central 5-HT1 recognition site. The reported significant linear correlation between hypotensive activity following intravenous (i.v.) administration to anesthetized rats and affinity for the central 5-HT1 binding site could only be maintained by incorporation of the affinity of RU 24969 for its low and 8-OH-DPAT for its high affinity binding site. Based on the proposal that the 5-HT1A site corresponds to the high affinity site of 8-OH-DPAT and the low affinity site of RU 24969, it is hypothesized that the late depressor phase of 5-HT agonists in rats is mediated by activation of peripheral (vascular) 5-HT receptors which have similarities with the 5-HT1A subtype of central 5-HT1 recognition site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

(+) 3-[3-hydroxyphenyl-N-(1-propyl) piperidine] selectively differentiates effects of sigma ligands on neurochemical pathways modulated by sigma receptors: evidence for subtypes, in vivo.

The effects of sigma ligands, (+)3PPP 3-[3-hydroxyphenyl-N(1-propyl) piperidine] and (-)butaclamol, were evaluated in vivo on the metabolism of dopamine (DA) and in the striatum release of adrenocorticotrophic hormone (ACTH) and prolactin in the rat and changes in levels of cyclic guanosine monophosphate (cGMP) in the cerebellum of the mouse and compared with the effects of (+)NANM (N-allyl-normetazocine, SKF 10,047) and (+)pentazocine. Both (+)3PPP and (-) butaclamol decreased the release of prolactin and did not affect the metabolism of DA. N-Allyl-normetazocine and (+)pentazocine increased release of prolactin and have been shown previously to increase the metabolism of DA. All four ligands increased release of ACTH; however, only the increases caused by (+)NANM and (+)pentazocine were reversed by pretreatment with CPP, a N-methyl-D-aspartate (NMDA) receptor antagonist. (+)Pentazocine and (+)NANM inhibited the NMDA receptor-mediated changes in levels of cGMP in the cerebellum of the mouse, while (+)3PPP and (-)butaclamol did not attenuate the response to NMDA. In addition to further confirming a functional interaction between sigma receptors and NMDA receptors, these studies divide the observed effects of putative sigma ligands into two groups, characterized by benzomorphan compounds and non-benzomorphan compounds, suggesting the possibility of subtypes at sigma receptor in vivo.

Adrenocorticotropic Hormone↗
PubMed1999

Differential selectivity of CIITA promoter activation by IFN-gamma and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affected by TNF-alpha.

During demyelinating disease of the central nervous system (CNS), locally elevated cytokine levels may induce upregulation of MHC class II molecules on otherwise low expressing or negative cell types such as microglia and astrocytes, since IFN-gamma has been shown to induce MHC class II expression on these cell types in vitro. While many transcription factors are involved with MHC class II expression, only the class II transactivator (CIITA) is tightly coordinated with IFN-gamma-inducibility. Control of CIITA gene expression is complex, involving four distinct promoters, two of which (promoters III and IV) are IFN-gamma-inducible in certain cell types. Here we demonstrate that IFN-gamma treatment of rat astrocytes induces only CIITA promoter IV activity in contrast to the murine macrophage cell line RAW 264.7 that uses both IFN-gamma-inducible promoters. In contrast to previously published reports, promoter IV activation is completely dependent upon an intact interferon regulatory factor-1 (IRF-1) but not STAT binding site using promoter constructs specifically mutated at these positions. Importantly, while TNF-alpha is able to synergize with IFN-gamma to increase astrocyte MHC class II expression in vitro, we show that treatment of rat astrocytes with TNF-alpha has no effect on CIITA promoter activity. These data demonstrate that TNF-alpha augments MHC class II expression through a mechanism downstream or independent of CIITA induction.

Animals↗
PubMedDate not supplied

Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions.

The sulphonylurea receptor (SUR) subunits of K(ATP) channels are the targets for several classes of therapeutic drugs. Sulphonylureas close K(ATP) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes, whereas the K(ATP) channel opener nicorandil acts as an antianginal agent by opening K(ATP) channels in cardiac and vascular smooth muscle. The predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle. Sulphonylureas and related drugs exhibit differences in tissue specificity, as the drugs interact to varying degrees with different types of SUR. Gliclazide and tolbutamide are beta-cell selective and reversible. Glimepiride, glibenclamide, and repaglinide, however, inhibit cardiac and smooth muscle K(ATP) channels in addition to those in beta-cells and are only slowly reversible. Similar properties have been observed by recording K(ATP) channel activity in intact cells and in Xenopus oocytes expressing cloned K(ATP) channel subunits. While K(ATP) channels in cardiac and smooth muscle are largely closed under physiological conditions (but open during ischaemia), they are activated by antianginal agents such as nicorandil. Under these conditions, they may be inhibited by sulphonylureas that block SUR2-type K(ATP) channels (e.g., glibenclamide). Care should, therefore, be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K(ATP) channels are to be avoided.

ATP-Binding Cassette Transporters↗
PubMed2004

The similarity of the physical sign frequencies of bovine spongiform encephalopathy and selected differential diagnoses.

This paper describes a method which enables the similarity of diseases based upon their physical sign frequencies to be defined relative to bovine spongiform encephalopathy (BSE). The means of the absolute differences between the sign frequencies of BSE and the differential diagnoses were used as measure of similarity. Four sets of signs were compared. The most useful quantitative measurement of difference between the diseases was achieved when only the variant signs were used. Diseases that have a high similarity to BSE when the variant signs are compared are more likely to have case presentations that approximate to those found in BSE. These are the diseases that are most likely to be confused with BSE by clinicians. Previously published BSE differential diagnoses from clinical opinion and brain histopathology are reported and compared to the diseases used in this study.

Animals↗
PubMed2002

The fireside hypothesis: was there differential selection to tolerate air pollution during human evolution?

It is believed that sometime around 1.9 million years ago early hominid ancestors began to migrate out of Africa. Migration north and away from the equator would have forced early humans to encounter seasonal fluctuations in temperature. As a means of adapting to cold climates, the use of fire undoubtedly played an important role. We hypothesize that progressive exposure to toxic airborne particles produced from combustion created selective pressure to develop an adaptation to the inhalation of smoke. In this paper we test this hypothesis using archival data on the incidence of different cancers among geographically distinct human populations. As predicted from evolutionary theory, the incidence of lung cancer is inversely proportional to the ostensible reliance on fire of geographically different groups during human evolutionary history.

Adaptation, Physiological↗
PubMed2003

RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity.

Regulator of G-protein signaling (RGS) proteins are GTPase activating proteins (GAPs) of heterotrimeric G-proteins that alter the amplitude and kinetics of receptor-promoted signaling. In this study we defined the G-protein alpha-subunit selectivity of purified Sf9 cell-derived R7 proteins, a subfamily of RGS proteins (RGS6, -7, -9, and -11) containing a Ggamma-like (GGL) domain that mediates dimeric interaction with Gbeta(5). Gbeta(5)/R7 dimers stimulated steady state GTPase activity of Galpha-subunits of the G(i) family, but not of Galpha(q) or Galpha(11), when added to proteoliposomes containing M2 or M1 muscarinic receptor-coupled G-protein heterotrimers. Concentration effect curves of the Gbeta(5)/R7 proteins revealed differences in potencies and efficacies toward Galpha-subunits of the G(i) family. Although all four Gbeta(5)/R7 proteins exhibited similar potencies toward Galpha(o), Gbeta(5)/RGS9 and Gbeta(5)/RGS11 were more potent GAPs of Galpha(i1), Galpha(i2), and Galpha(i3) than were Gbeta(5)/RGS6 and Gbeta(5)/RGS7. The maximal GAP activity exhibited by Gbeta(5)/RGS11 was 2- to 4-fold higher than that of Gbeta(5)/RGS7 and Gbeta(5)/RGS9, with Gbeta(5)/RGS6 exhibiting an intermediate maximal GAP activity. Moreover, the less efficacious Gbeta(5)/RGS7 and Gbeta(5)/RGS9 inhibited Gbeta(5)/RGS11-stimulated GTPase activity of Galpha(o). Therefore, R7 family RGS proteins are G(i) family-selective GAPs with potentially important differences in activities.

Animals↗
PubMed1995

Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes.

The differentiation potential of putative intermediates between CD4+8+ thymocytes and mature T cells has been examined. Such intermediate populations were sorted, in parallel with CD4+8+ thymocytes, from three types of C57BL/6 mice: major histocompatibility complex (MHC) class II-deficient mice, mice transgenic for an alpha/beta T cell receptor (TCR) restricted by class I MHC and normal mice. The sorted populations were then transferred into the thymus of nonirradiated C57BL/Ka mice differing in Thy 1 allotype, and the progeny of the transferred cells were analyzed 2 d later. Surprisingly, with all three types of donor mice, a major proportion of the CD4+8intTCRint-derived progeny were found to be CD4-8+TCRhi cells, thus delineating a new alternative pathway for development of the CD8 lineage. In contrast, the transfer of CD4int8+TCRint thymocytes produced CD4-8+TCRhi cells but no significant proportion of CD4+8-TCRhi cells, suggesting that there is no equivalent alternative pathway for the CD4 lineage. The results negate some of the evidence for a stochastic/selective model of lineage commitment, and point to an asymmetry in the steps leading to CD4-8+ versus CD4+8- T cells.

Animals↗