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At least 235 records · Page 13Linked to original sources
PubMed2002

Development of one experimental module to study the modulation of the propagation velocity of chemical excitation waves in gel by weak external force (gravity).

Biological and chemical systems in which the pattern of flow of energy and matter imposes self-organization can be seen as examples of excitable media. One property of such media is the presence of excitation waves. The Belouzov-Zabotinsky(B-Z) reaction system and the retinal spreading depression wave are examples of experimental models of excitable media in which the influence of gravity can be studied. In this paper we describe one especial module constructed to test the influence of gravity in gels of the B-Z system. In the gel condition, convection effects are minimized. The results will be directly comparable to retinal experiments programmed by the same group and complete a series of investigations of systematic comparison of the modulation of chemical and biological excitation waves by weak external forces.

Journal Article↗
PubMed1984

Effects of 5-aza-2'-deoxycytidine in combination with the biochemical modulator thymidine or the immune modulator pyran copolymer on L1210 leukemia-bearing mice.

The purpose of these studies was to investigate the potential modulation by thymidine in vivo of the antitumor action of 5-aza-2'-deoxycytidine (DAC). During the course of these investigations it was observed that DAC given as a single dose to mice bearing late L1210 tumor resulted in cell kills estimated to be close to 6 logs. Because of the potentially large antigen load released by such a cell kill, the immune modulator pyran copolymer was also tested in combination with DAC. Thymidine increased the cytotoxicity of DAC but not in a selective fashion. Doses of DAC in combination with thymidine were more toxic to host mice than equivalent doses of DAC alone, but no therapeutic benefit was apparent with this combination at maximally tolerated doses. A single dose of pyran copolymer and DAC appears to result in an adjuvant action that eliminates the few remaining L1210 cells refractory to DAC chemotherapy. Doses of DAC alone that result in lengthy increases in survival times but no cures resulted in a substantial number of cures when used in combination with pyran copolymer.

Animals↗
PubMed1982

The probable binding between cations and stimulatory protein kinase modulator and subsequent stimulation on cerebellar modulator-dependent protein kinases.

The formation of complexes between cations and stimulatory protein kinase modulator (PKMs) were performed by preincubation and gel filtration. The stimulatory effects of Fe3+, Fe2+, Mg2+, and Co2+ complexes on cerebellar modulator-dependent protein kinases (M-PK) were similar to those without preformation of complexes by preincubation and gel filtration. Antagonism by Ca2+ on the stimulatory effect of Mg2+ was noted in spite of the ineffectiveness of Ca2+ when present alone.

Animals↗
PubMed2006

Chemical modification modulates estrogenic activity, oxidative reactivity, and metabolic stability in 4'F-DMA, a new benzothiophene selective estrogen receptor modulator.

The benzothiophene selective estrogen receptor modulators (SERMs), raloxifene and arzoxifene, in the clinic or clinical trials for treatment of breast cancer and postmenopausal symptoms, are highly susceptible to oxidative metabolism and formation of electrophilic metabolites. 4'F-DMA, fluoro-substituted desmethyl arzoxifene (DMA), showed attenuated oxidation to quinoids in incubation with rat hepatocytes as well as in rat and human liver microsomes. Incubations of 4'F-DMA with hepatocytes yielded only one glucuronide conjugate and no GSH conjugates, whereas DMA underwent greater metabolism giving two glucuronide conjugates, one sulfate conjugate, and two GSH conjugates. Phase I and phase II metabolism were further evaluated in human small intestine microsomes and in human intestinal Caco-2 cells. In comparison to DMA, 4'F-DMA formed significantly less glucuronide and sulfate conjugates. The formation of quinoids was further explored in hepatocytes in which DMA was observed to give concentration- and time-dependent depletion of GSH accompanied by damage to DNA, which showed inverse dependence on GSH; in contrast, GSH depletion and DNA damage were almost completely abrogated in incubations with 4'F-DMA. 4'F-DMA shows ligand binding affinity to estrogen receptor (ER)alpha and ERbeta with similarity to both raloxifene and to DMA. ER-mediated biological activity was measured with the ERE-luciferase reporter system in transfected MCF-7 cells and Ishikawa cells, and in MCF-7 cells, proliferation was measured. In all systems, 4'F-DMA exhibited anitestrogenic activity of comparable potency to raloxifene but did not manifest estrogenic properties, mirroring previous results on inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells. These results suggest that 4'F-DMA might be an improved benzothiophene SERM with similar antiestrogenic activity to raloxifene but improved metabolic stability and attenuated toxicity, showing that simple chemical modification can abrogate oxidative bioactivation to potentially toxic metabolites without loss of activity.

Animals↗
PubMed1995

Activating transcription factor 1 and cyclic AMP response element modulator can modulate the activity of the immunoglobulin kappa 3' enhancer.

Previously we determined that the immunoglobulin kappa 3' enhancer (kappa E3') contains at least two functional DNA sequences (PU.1/NF-EM5 and E2A) within its 132-base pair active core. We have determined that the activities of these two sequences are insufficient to account for the entire activity of the 132-base pair core. Using site-directed linker scan mutagenesis across the core fragment we identified several additional functional sequences. We used one of these functional sequences to screen a lambda gt11 cDNA expression library resulting in the isolation of cDNA clones encoding the transcription factors ATF-1 (activating transcription factor) and CREM (cyclic AMP response element modulator). Because ATF-1 and CREM are known to bind to cAMP response elements (CRE), this functional sequence was named the kappa E3'-CRE. We show that dibutyryl cAMP can increase kappa E3' enhancer activity, and in transient expression assays ATF-1 caused a 4-5-fold increase in the activity of the core enhancer while CREM-alpha expression resulted in repression of enhancer activity. RNA analyses showed increased levels of ATF-1 mRNA during B cell development and some changes in CREM transcript processing. By joining various fragments of the kappa E3' enhancer to the kappa E3'-CRE, we observed that the kappa E3'-CRE can synergistically increase transcription in association with the PU.1/NF-EM5 binding sites, suggesting a functional interaction between the proteins that bind to these DNA sequences. Consistent with this possibility, we found that ATF-1 and CREM can physically interact with PU.1. The isolation of activator and repressor proteins that bind to the kappa E3'-CRE may relate to previous conflicting results concerning the role of the cAMP signal transduction pathway in kappa gene transcription.

Activating Transcription Factor 1↗
PubMed2006

Estradiol-induced modulation of estrogen receptor-beta and GABA within the adult neocortex: a potential transsynaptic mechanism for estrogen modulation of BDNF.

Estrogen influences brain-derived neurotrophic factor (BDNF) expression in the neocortex. However, BDNF-producing cortical neurons do not express detectable levels of nuclear estrogen receptors; instead, the most abundant cortical nuclear estrogen receptor, ER-beta, is present in GABAergic neurons, prompting us to test the hypothesis that estrogen effects on BDNF are mediated via cortical inhibitory interneurons. Adult female ovariectomized rats were provided acute estrogen replacement and the number of cortical GABA, ER-beta, and ER-beta/GABA double-labeled neurons was examined. Within 48 hours of injection of 17-beta-estradiol, the number of perirhinal neurons double-labeled for ER-beta/GABA was reduced by 28% (P<0.01 compared to vehicle-treated ovariectomized controls), and all cells expressing detectable levels of GABA were reduced by 19% (P<0.01). To investigate potential relationships between estrogen receptors, GABAergic neurons, and BDNF-expressing cells, brain sections were double- or triple-labeled for ER-beta, GABAergic, and BDNF immunomarkers. The findings indicated that ER-beta-bearing inhibitory neurons project onto other GABAergic neurons that lack nuclear estrogen receptors; these inhibitory neurons in turn innervate BDNF-expressing excitatory cells. High estrogen states reduce cortical GABA levels, presumably releasing inhibition on BDNF-expressing neurons. This identifies a putative two-step transsynaptic mechanism whereby estrogen availability modulates expression of inhibitory transmitters, resulting in increased BDNF expression.

Animals↗
PubMed1994

Modulation of epidermal growth factor and keratinocyte growth factor effects on human keratinocyte growth by protein kinase C inhibitor, GF 109203X: comparison to fibroblast growth modulation.

In this study, epidermal growth factor (EGF), 20 ng/ml, and keratinocyte growth factor (KGF), 10 ng/ml, were able to stimulate human keratinocyte growth only in presence of GF 109203X 1 microM, a selective PKC inhibitor. This suggests that PKC negatively controls keratinocyte growth in response to EGF and KGF. On the other hand, EGF and KGF have no significant effect on PKC activity. In contrast, in human fibroblasts, EGF stimulated fibroblast growth in the presence or not of GF 109203X. Thus, EGF seems to stimulate fibroblast growth in a PKC independent manner. Moreover, EGF didn't modify significantly PKC activity in fibroblasts. KGF had no effect on fibroblasts. These results show differences in the interconnections between PKC and EGF transduction pathway in the modulation of human keratinocyte and fibroblast growth. Moreover, they especially demonstrate that PKC would negatively control human keratinocyte growth in response to EGF and also to KGF.

Adult↗
PubMed1993

Modulation of swimming behavior in the medicinal leech. II. Ionic conductances underlying serotonergic modulation of swim-gating cell 204.

In the previous paper we showed that serotonin had several effects on the electrical properties of swim-gating neurons (cells 204) of the leech. These included membrane potential depolarization, induction of a sag voltage response, and enhancement of rebound responses. Here we investigate the ionic basis of these changes by comparing responses of cell 204 to injected current pulses in experimental salines containing modified concentrations of Na+, K+, Ca2+, or Cl-. Our data indicate that serotonin modulates multiple conductances in cell 204. However, most effects of serotonin can be explained by enhancement of two Na(+)-dependent conductances, a Cs(+)-sensitive cation conductance (gh) and a persistent Na+ conductance (gNaS). Both conductances contribute to the resting potential depolarization and increased amplitude of postinhibitory rebound responses induced by serotonin. In addition, enhanced gh underlies a sag potential elicited by hyperpolarizing current pulses in serotonin-treated cells. Hyperpolarizing rebound responses following depolarizing current pulses are composed of Na(+)-dependent and Na(+)-independent components, both of which are enhanced by serotonin. Activation of an electrogenic Na+/K+ pump may underlie the prolonged Na(+)-dependent component. The Na(+)-independent component decays within 1 s and may be produced by a voltage- or Ca(2+)-activated K+ conductance.

Animals↗
PubMed1994

Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation.

Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase which is found in NIDDM appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

The agonists for nociceptors are ubiquitous, but the modulators are specific: P2X receptors in the sensory neurons are modulated by cannabinoids.

P2X2 and P2X3 receptors expressed in mammalian sensory neurons participate in nociception. Cannabinoid receptors modulate nociceptive processing in various models of pain. They are also expressed in nociceptive sensory neurons. We have examined the effect of cannabinoids on the slow P2X2 and P2X2/3 receptors in the cells isolated from nodosal and dorsal root ganglia of rat. The study was carried out by means of the whole-cell patch clamp and rapid superfusion methods. We have found that both endogenous and synthetic cannabinoids (anandamide, WIN55,212-2, and (R)-(+)-methanandamide) inhibit the slow response to ATP mediated by P2X2 and P2X2/3 receptors in a majority of tested neurons. This inhibition was significant but only partial: anandamide (0.5-1 microM) inhibited the response to 51+/-21% of control. In the remaining minority of tested neurons, the response was transiently facilitated. The effect of cannabinoids appears to be mediated via cannabinoid CB(1) receptors: it was reversibly inhibited by selective CB(1) antagonist, SR141716A (10 microM). Introduction of cyclic AMP (0.5 mM) into the cell potently facilitated the inhibitory effect of cannabinoids: the ATP-activated current was inhibited to 13+/-10% of control. These data indicate that cannabinoids may inhibit nociceptive responses produced by P2X receptors.

Adenosine Triphosphate↗
PubMed1991

The murine epsilon receptor modulating protein: a novel serine protease which modulates CD23 binding of IgE.

In our recent previous studies, we have identified and purified a murine 17-kDa protein which diminishes the avidity of binding between IgE and CD23 (low-affinity Fc receptor for IgE) without decreasing the quantitative expression of the CD23. The protein was thus designated epsilon receptor modulating protein (epsilon RMP). In this study, we have further characterized this protein and have found that (i) epsilon RMP is inactivated by phenylmethylsulfonyl fluoride and decomposes N,alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester, as well as N-succinyl-Ala-Ala-Pro-Phe p-nitroanilide; (ii) epsilon RMP does not work directly on B cells but requires CD4+ T cells to decrease functional expression of CD23 on B cells; and (iii) the partial internal amino acid sequence of epsilon RMP, obtained by using in situ cyanogen bromide cleavage on polyvinylidene difluoride membrane is unique. These data thus clearly demonstrate that epsilon RMP is a novel serine protease controlling the functional expression of CD23 through the participation of CD4+ T cells. Mechanisms of the involvement of CD4+ T cells are discussed.

14-3-3 Proteins↗
PubMed1988

Dorsal raphe stimulation modulates nociceptive responses in thalamic parafascicular neurons via an ascending pathway: further studies on ascending pain modulation pathways.

A study on the nociceptive responses of single cells within the nucleus parafascicularis (PF) thalami of the rat was undertaken to clarify the reported observations of a pain suppression pathway to this nucleus from the dorsal raphe (DR) nucleus. Two types of nociceptive neuron were identified in the PF which were classified as 'nociceptive-on' and 'nociceptive-off' neurons, respectively. DR stimulation exhibits a simple monophasic 'dose-dependent' relationship between the degree of the inhibition elicited and the stimulation intensity used on the 'nociceptive-off' cells. In contrast, biphasic effects following DR stimulation on the 'nociceptive-on' cells was obtained, with low intensities eliciting suppression while high intensities excited the cells. These effects of low intensity DR stimulation upon the responses of the 'nociceptive-on' cells were diminished but not prevented by transection of the well-known bulbospinal inhibitory fibers descending in the dorsal half of the spinal cord, while the effects of DR stimulation upon the 'nociceptive-off' cells remain unchanged following spinal transection. Thus, our results show that DR stimulation modulates the nociceptive responsiveness of the PF by way of supraspinal pathways in addition to the previously described descending paths.

Animals↗
PubMed2006

Modulation of peroxynitrite-induced fibroblast injury by hesperetin: a role for intracellular scavenging and modulation of ERK signalling.

Peroxynitrite is thought to contribute to the progression of many diseases including cardiovascular disease, cancer, and neurodegenerative disorders. We report that pre-treatment of fibroblasts with the citrus flavanone, hesperetin, prior to peroxynitrite exposure protects against peroxynitrite-mediated cytotoxicity. This protection was partially mediated by the intracellular scavenging of peroxynitrite by hesperetin as exposure of fibroblasts to peroxynitrite following hesperetin loading led to the formation of two intracellular nitro-hesperetin derivatives. In addition, protection appeared to be mediated by hesperetin-induced changes in MAP kinase signalling. Exposure of fibroblasts to hesperetin led to concentration-dependent increases in the phosphorylation of ERK1/2 and was observed to restore peroxynitrite-mediated decreases in ERK1/2 phosphorylation. We propose that the protective potential of hesperetin in fibroblasts may be mediated both by intracellular scavenging of peroxynitrite and by modulation of fibroblast signalling.

Cells, Cultured↗
PubMed2005

Intensity-modulated radiotherapy planning from limited anatomical information: is Sim-CT sufficient for planning women with breast cancer receiving intensity-modulated radiotherapy?

AIMS: To investigate intensity-modulated radiotherapy (IMRT) plans for women with carcinoma of the breast, using a small number of Sim-CT slices, thus avoiding changing the patient's position and potential problems with CT capacity. MATERIALS AND METHODS: Ten CT scans of women with breast cancer were obtained for use in the study. IMRT plans based on an open tangent pair and additional top-up segment fields were created using the full CT scan, and represented the gold standard treatment plan for comparison purposes. Five-slice CT simulator scans were artificially created by omitting intermediate slices from the full CT scans. Additionally, the intermediate CT slices were recreated via interpolation of the five slices using a standard interpolation algorithm. IMRT plans were created in the same way as for the full CT scans. To allow a suitable plan comparison to be made, the beam segments and monitor units were transferred to the full CT scans, and the dose distribution calculated. RESULTS: The interpolated five-slice plans showed no significant difference in the volume of tissue receiving dose outside the range 95-105%, compared with the IMRT plans created using the full CT data set (1.3 +/- 2.2%, P = 0.092). In contrast, the discrete slice CT simulator plans increased by 6.3 +/- 5.4%, P = 0.0054, showing a statistically significant difference in the dose distribution produced and a clinically inferior plan. CONCLUSIONS: Plans created using five discrete slice CT scans were inferior to full CT-derived IMRT treatment plans, and are therefore not acceptable for IMRT. However, interpolating five CT simulator slices provides adequate anatomical information to produce comparable IMRT plans to those created by full CT scans of the patient. This allows the introduction of IMRT for this patient group without the need to change treatment position to accommodate CT scanning.

Anatomy, Cross-Sectional↗
PubMed2026

The circadian clock proteins PRR modulate root hair development via the RHD6/RSL module in Arabidopsis.

Root hairs, derived from trichoblasts, are critical for plant growth and environmental adaptation. Although environmental cues are known to influence root hair development, how endogenous timing systems such as the circadian clock integrate into the core transcriptional network governing root hair formation remains unclear. Here, we show that the circadian clock-associated protein PSEUDO-RESPONSE REGULATOR5 (PRR5) physically interacts with ROOT HAIR DEFECTIVE6 (RHD6) and RHD6 LIKE1 (RSL1), two basic helix-loop-helix transcription factors essential for root hair initiation. Genetic analyses suggest that PRR proteins contribute to root hair development under long-day conditions in Arabidopsis thaliana. Simultaneous disruption of PRR5, PRR7, and PRR9 results in defective root hairs, whereas PRR5 overexpression markedly increases root hair density and length. Transcriptomic and RT-qPCR analyses reveal that PRRs enhance the expression of RHD6, RSL1, and multiple downstream root hair-responsive genes, while modulating their temporal expression patterns. Furthermore, PRR5-mediated root hair promotion requires RHD6/RSL1, and PRR proteins enhance RHD6-dependent activation of the RSL4 promoter. PRRs also contribute to root hair development under phosphate-deficient and salt-stress conditions. Together, these findings establish a molecular framework in which PRR proteins regulate the RHD6/RSL network to coordinate root hair development and environmental responses.

Arabidopsis↗
PubMed2000

Optimizing radiotherapy of orbital and paraorbital tumors: intensity-modulated X-ray beams vs. intensity-modulated proton beams.

PURPOSE: This study presents a dosimetric optimization effort aiming to compare intensity-modulated (IM) X-rays and IM protons in 4 different orbital and paraorbital tumors. These are most challenging targets for standard radiotherapy due to their close relationship with the eyes and related structures. METHODS AND MATERIALS: A primary orbital lymphoma, an optic nerve meningioma, a sphenoidal ridge meningioma protruding into the orbit, and a pediatric parameningeal paraorbital rhabdomyosarcoma were selected for the purpose of this study. Planning target volumes (PTVs) and organs at risk (OAR) were defined in each patient CT data set for each tumor site. IM X-ray and IM proton three-dimensional treatment plans were implemented. The following total tumor doses were prescribed: 30 Gy for the orbital lymphoma, 54 Gy for both meningiomas, and 50.4 Gy for the rhabdomyosarcoma case. Dose-volume histograms (DVHs) were obtained for all targets and OAR with both treatment techniques. DVHs were used to predict normal tissue complication probabilities (NTCPs) for the OAR in the vicinity of the tumor. RESULTS: The PTV coverage was optimal and equally homogeneous with both IM X-rays and IM proton plans in the 4 tumor sites. DVHs for most OAR were better with IM proton beams especially in the low- to mid-dose range region. The integral nontarget dose was lower with IM protons in every case (factor ranging from 1.5 to 1.9). However, predicted NTCPs (for severe late effects) were equally low for both treatment techniques in every tumor site. CONCLUSION: Although IM proton plans optimally decreased the dose to the OAR in all tumor sites, both optimized X-ray and proton beams equally succeeded to reduce severe-toxicity prediction risks to less than 5% while optimally treating the PTV.

Humans↗
PubMed1998

Sex steroid hormones modulate the activation of murine peritoneal macrophages: receptor mediated modulation.

The comparative dose and time-dependent effects of male and female sex steroid hormones on nitrite release by murine peritoneal macrophages (M phi) stimulated by LPS were studied. M phi from gonadectomized mice released larger amounts of nitrite on LPS stimulation than controls; although nitrite release was significantly greater in castrated males than in ovariectomized females, suggesting that sex hormone deprivation results in an increase in nitrite release. This was further confirmed by in vitro treatment of M phi with estradiol (E2), testosterone (T) and progesterone (P) at different doses and duration prior to, and during, stimulation of nitrite production by LPS. E2 (except at 10(-2) ng/ml), T and P significantly (P < 0.05) suppressed the nitrite release in a dose-dependent manner. Nitrite release from M phi increased with decreasing exposure time to E2, T and P. Preincubation of M phi with sex hormones prior to LPS treatment also reduced nitrite production. Sex steroid receptor antagonists tamoxifen citrate, cyproterone acetate/flutamide and RU486 markedly reduced the inhibitory effect of E2, T and P, respectively, suggesting that sex hormones modulate M phi nitrite release via a receptor-mediated system.

Animals↗
PubMed1998

Modulating the oxygen affinity of human fetal haemoglobin with synthetic allosteric modulators.

Improving the delivery of oxygen to the tissues by decreasing the oxygen affinity of haemoglobin has been a major aim of several laboratories over recent years because this may reduce the consequences of anaemia and/or improve tissue oxygenation in cases of decreased blood perfusion. Within the same context, lowering the oxygen affinity may prove valuable in the application of native or recombinant haemoglobin solutions as a blood substitute. The shift of the oxygen equilibrium curve to the right is obtained by various modulators. Among them, the bezafibrate derivatives are considered as a most interesting group. These principles are of the utmost importance in thalassaemia and other haemoglobinopathies where the beneficial effects of the compensatory synthesis of fetal haemoglobin are diminished by the increased oxygen affinity of this pigment. In this paper we present the results of a study initiated to determine whether a potent oxygen affinity modifier, RSR-4, could satisfactorily decrease the oxygen affinity of fetal haemoglobin, thus improving tissue oxygenation. The experiments were carried out on whole blood and on purified haemoglobin solutions and showed that the effector markedly decreased the oxygen affinity of HbF (from 18.7 to 3.73 mmHg in whole blood). At the same time the cooperativity index (n50) and the oxygen saturation levels remained within normal limits under the conditions of the main experiment. These observations have important implications for the potential application of oxygen affinity modifiers in vivo.

Aniline Compounds↗