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PubMed1982

Discrepancy between thyroid-stimulating and thyrotropin-binding inhibitory activities of Graves' immunoglobulin Gs assessed in the mouse.

TSH receptor binding-inhibiting (TBI) and thyroid-stimulating (TSI) activities of Graves' immunoglobulin Gs (IgGs) were measured using the murine TSH receptor (mTBI) and the McKenzie LATS bioassay. In contrast to the expectation that only the IgGs positive for LATS showed mTBI activity, mTBI activity was closely correlated with TBI activity measured at the human TSH receptor regardless of LATS potency (r = 0.79; P less than 0.01), indicating a lack of species specificity of IgG in this particular aspect. In 7 to 15 IgGs positive for both mTBI and LATS, there was a significant correlation between the 2 parameters (r = -0.89; P less than 0.01). However, 4 IgGs among the 15 were positive for mTBI but negative for LATS even when tested at 3- to 7-fold concentrations of IgG.

Animals↗
PubMed1990

Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein.

Activating mutations in the gene for the alpha-chain of Gs, the stimulatory regulator of adenylyl cyclase, have been identified in human GH-secreting pituitary tumors. Using the polymerase chain reaction and allele-specific oligonucleotide hybridization, we screened 25 GH-secreting tumors for the presence of the activating mutations. We also reviewed the clinical charts of the patients from whom the tumors were removed. Of 25 tumors, 10 (40%) contained activating mutations. Patients in the mutation-positive group came to surgery with smaller tumors and had lower GH levels. The activating mutations identify a subgroup of GH-secreting pituitary tumors that probably arise from a shared oncogenic mechanism.

Acromegaly↗
PubMed1993

In vitro modulation of growth hormone (GH) secretion from early to midgestation human fetal pituitaries by GH-releasing factor and somatostatin: role of Gs-adenylate cyclase-Gi complex and Ca2+ channels.

Using explant cultures of human fetal anterior pituitary glands (9-19 weeks fetal age) and an acute (3-h) test protocol, we investigated the role of two signal transduction pathways (Gs-adenylate cyclase-Gi, Ca2+ channels) in GH-releasing factor (GRF)/somatostatin (SRIF) regulation of GH secretion during the first half of gestation. Data have been analyzed for ontogenic changes using three age groups: 9-10, 12-13, and 15-19 weeks fetal age. The fetal somatotrope shows dose-related responses to forskolin (0.1-10 microM), dibutyryl cAMP (dBcAMP; 0.1-1 mM), and theophylline (0.01-1 mM), all factors that increase intracellular concentrations of cAMP; there is a significant age-related increase in the stimulatory effects of 1 mM dBcAMP and 1 mM theophylline. When any one of these three factors is added with 10 nM GRF, there are no significant additive or synergistic effects on GH secretion. Although 10 nM SRIF has no effect at 9-10 weeks, it is inhibitory in the 12-13 and 15-19 week groups, significantly suppressing the stimulatory effect of 1 microM forskolin and completely blocking the effects of 1 mM dBcAMP or theophylline. Pretreatment of cultures with pertussis toxin completely blocks SRIF inhibition of both basal and GRF-stimulated GH release. KCl (5-50 mM) and Bay K 8644 (0.1-10 microM), both activators of Ca2+ channels, have dose-related stimulatory effects on GH release; 50 mM KCl shows an age-related increase in stimulatory activity. If 10 nM GRF, 1 microM forskolin, 1 mM theophylline or 1 mM dBcAMP is added with either 50 mM KCl or 1 microM Bay K 8644, there is an additive response. SRIF (10 nM) completely blocks the stimulatory effects of 1 microM Bay K 8644 and markedly inhibits the effects of 50 mM KCl from as early as the ninth week of fetal age. The Ca2+ channel blocker nifedipine (1-10 microM) significantly inhibits basal as well as stimulated (GRF, forskolin, dBcAMP, theophylline, KCl, and Bay K) GH release from as early as 9 weeks fetal age; in contrast, the calmodulin blocker trifluoperazine (0.01-10 microM) has no effects on basal GH secretion and only slightly inhibits the stimulatory effects of KCl. Pretreatment with 10 nM GRF for 24 h significantly decreases a subsequent 3-h response to 10 nM GRF, but does not alter the subsequent response to 1 mM theophylline or 50 mM KCl.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1988

Developmental analysis of grandchildless (gs(1)N441) mutation in Drosophila melanogaster; abnormal formation of pole cells.

A detailed examination of the developmental features of abnormal formation of pole cells and a functional analysis of the germ plasma of gs(1)N441 embryos were carried out. The germ plasma is morphologically normal. Embryos in which cleavage nuclei show retarded migration to the posterior pole do not form pole cells. Pole cells, following formation, are abnormally segregated and then intermingled between the blastoderm cell layer but retaining normal morphology and differentiating into functional germ cells. The results of cytoplasmic transplantation experiments indicate the autonomous segregation ability of the mutant polar plasma to form pole cells to possibly be affected.

Animals↗
PubMed2006

Preventive administration of GS Imunostim as a protection against acute respiratory infections.

With respect to the fact that acute respiratory infections (hereafter ARI) are a world-wide serious social and economic problem, more and more attention is being paid to the development and application of oral bacterial immunomodulators. The preventive effect of GS Imunostim has been evaluated during the respiratory season 2005. The study took place at 10 outpatient sites of general practitioners and lung specialists in Prague, Pilsen and Brno in the respiratory season from January to April 2005. The comparison with the ARI morbidity reports in the studied period revealed statistically significant morbidity reduction in the study participants compared to the ARI morbidity in the Czech population in the studied period from January to April 2005. The morbidity rate in the studied group was 7%, whereas ARI morbidity 15.1% was reported in the general population. The morbidity in the study group was significantly lower that in the general population.

Administration, Oral↗
PubMed2000

Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor.

Rational drug design utilizing available X-ray crystal structures of sialic acid analogues bound to the active site of influenza virus neuraminidase has led to the discovery of a series of potent carbocyclic influenza neuraminidase inhibitors. From this series, GS 4104 (oseltamivir, TAMIFLU ) has emerged as a promising antiviral for the treatment and prophylaxis of human influenza infection. This article will summarize the design, discovery, and development of oseltamivir as an oral therapeutic to treat influenza infection.

Administration, Oral↗
PubMed1994

Amphiphilic property of chlorhexidine and its toxicity against Streptococcus mutans GS-5.

The toxicity of chlorhexidine digluconate against Streptococcus mutans GS-5 was comparatively determined by measuring its bactericidal activity, and its inhibitory effect on microbial dehydrogenases was studied by the resazurin reduction method. Both methods indicated that chlorhexidine within the range 0.75-5.00 mg/l was highly toxic to Streptococcus mutans, probably due to inhibition of dehydrogenase activity, and the extent of toxicity was closely associated with concentration. In an attempt to better understand the relationship between the amphiphilic nature of chlorhexidine and its toxicity against Streptococcus mutans, the effect of solvent polarity on dehydrogenase inhibition was investigated. A decrease in solvent polarity, induced by inclusion of 5% acetone in the reaction mixture, did not enhance the toxicity of chlorhexidine. This implies that the antimicrobial action of chlorhexidine is mainly attributable to its hydrophilicity, and that the nature of the lipophilic groups is only of secondary importance.

Acetone↗
PubMed1999

Potentiation of ATP calcium responses by A2B receptor stimulation and other signals coupled to Gs proteins in type-1 cerebellar astrocytes.

We have studied the interaction between P1 and P2 purinoceptors in purified type-1 astrocyte cultures from postnatal days 7-8 rat cerebella using single cell microfluorimetry with fura-2. The stimulation of astrocytes with ATP elicits rapid [Ca2+]i transients showing an EC50 value of 7.9 +/- 0.3 microM. Costimulation of type-1 astrocytes with adenosine and ineffective ATP concentrations (0.1 or 1 microM) evoked [Ca2+]i transients that correspond to 60% of the maximal ATP response. NECA (5'-N-ethylcarboxamidoadenosine) was the only agonist that mimicked the adenosine effect and showed an EC50 value of 0.17 +/- 0.01 microM. This value was identical to that obtained for the cAMP production stimulation, indicating that A2B receptors coupled to adenylate cyclase activation were involved. The presence of A2B adenosine receptors was also confirmed by immocytochemistry experiments. When astrocytes were costimulated with isoproterenol and ineffective ATP concentrations similar [Ca2+]i transients were observed. The treatment of astrocytes with cholera toxin potentiated ATP calcium signals, lowering the EC50 value for ATP to 1.5 +/- 0.2 microM. However, the pretreatment of cells with forskolin or a permeable cAMP analogue had no effect on ATP calcium responses. These results indicated that the potentiation mechanism was elicited before the adenylate cyclase activation. We could conclude that in type-1 astrocytes, the activation of A2B adenosine receptors or other signals positively coupled to adenylate cyclase stimulation strongly potentiate metabotropic calcium responses to ATP. The potentiation was parallel but independent on cAMP accumulation suggesting the involvement of beta gamma subunits released after Gs stimulation.

Adenosine↗
PubMed1997

[GS-MS analysis of essential oils from five species of Asarum].

This paper reports the result of GS-MS analysis of the essential oils from five species of Asarum, namely, A. heterotropoides var. mandshuricum (cultivated), A. sieboldii (cultivated), A. caudigerellum (from Sichuan), A. sieboldii(from Shandong) and A. sieboldii(wild). Ninety-two constituents were detected, of which 73 compounds were identified.

Drugs, Chinese Herbal↗
PubMed2001

Flk-1 specific kinase inhibitor (SU5416) inhibited the growth of GS-9L glioma in rat brain and prolonged the survival.

BACKGROUND: Accumulating evidences suggest that tumor growth and metastasis depend on angiogenesis. At present, plenty of efforts are made to discover a chemical compound that specifically inhibits tumor angiogenesis either by reducing pro-angiogenic factor or increasing anti-angiogenic factors. OBJECT: SU5416, a novel, synthetic, potential inhibitor of angiogenesis specifically blocks the Flk-1/KDR tyrosine kinase activity. In vivo effect of SU5416 in the treatment of intracranial tumors has not been previously described. METHODS: We transplanted GS-9L cells into the right caudate nucleus of male Fisher 344 rats and administrated SU5416 intraperitoneally (i.p.) to investigate the impact of SU5416 on tumor angiogenesis and growth in vivo. Starting on Day 1 or Day 8, forty-two animals were treated with SU5416 at three different doses (e.g. 12.5, 25.0 and 50.0 mg/kg body weight) via i.p. injection every day until the end-point. As a control, seven animals received no treatment and after implant fourteen animals were treated with vehicle (DMSO) only. RESULTS: SU5416 prolonged the survival in the treated groups without any significant systemic adverse effect. Median survival in the treated group started on Day.1 was statistically longer compared to that in the control groups (p<0.01). Histological analysis of the treated tumors showed an increase in necroses and reduced in vascularity compared to the control tumors. Furthermore, the number of apoptotic cells increased in the treated tumors on a TUNEL stain. CONCLUSION: Small molecular compounds, such as SU5416 may be useful therapeutics that specifically inhibits the enzymatic activity of Flk-1 kinase and downstream events of tumor angiogenesis.

Animals↗
PubMed1976

Efficacy of divided doses of GS-23654 against immature Echinococcus granulosus infections in dogs.

One hundred dogs were used to evaluate the efficacy of GS-23654 (4-nitro-4'-isothiocyano-diphenyl-ether) against immature Echinococcus granulosus. A 25% suspension of active ingredient was administered at dose rates of 100, 200, or 400 mg/kg of body weight on 1, 2, or 3 occasions. Anthelmintic efficacy was dosage dependent and increased with the number of times the dosage was repeated. At none of the treatment schedules tested were all worms eliminated from all dogs, although 92.6% of the expected number of worms were eliminated from dogs given 400 mg/kg on 3 occasions.

Animals↗
PubMed2003

Unaltered agonist potency upon inducible 5-HT7(a) but not 5-HT4(b) receptor expression indicates agonist-independent association of 5-HT7(a) receptor and Gs.

We compared adenylyl cyclase (AC) activation by the G protein-coupled human serotonin (5-HT) receptors 5-HT4(b) and 5-HT7(a) using an ecdysone-inducible expression system, which allowed for reproducible expression of increasing receptor densities in clonal HEK293 (EcR293) cell lines. Low constitutive expression of receptors (2-70 fmol/mg protein) was observed and could be titrated up to 50-200-fold (approximately 400-7000 fmol/mg protein) by the ecdysone analogue ponasterone A. Although 5-HT-stimulated AC activity increased with receptor density, interclonal variation precluded comparisons of coupling efficiency. Interestingly, the potency of 5-HT to stimulate AC increased with increasing receptor density only in clones expressing 5-HT4(b) receptors. The potency for 5-HT did not change in clones expressing 5-HT7(a) receptors, even though 5-HT-stimulated AC activity approached asymptotic levels. This indicates that potency of 5-HT for stimulation of AC through the 5-HT7(a) receptor is independent of receptor-Gs stoichiometry and is consistent with a model where the 5-HT7(a) receptors are tightly associated with G protein, independent of agonist binding. This supports the existence of a complex between inactive receptor and G protein, as predicted by the cubic ternary complex model. In such a system, spare receptors do not lead to increased potency of an agonist with increased receptor density.

Adenylyl Cyclases↗
PubMed1992

Pineal 'synaptic ribbons' and serum melatonin levels in the rat following the pulse action of 52-Gs (50-Hz) magnetic fields: an evolutive analysis over 21 days.

In continuation of earlier studies, we have investigated the influence of 52-Gs (50-Hz) magnetic fields on the evolution of pinealocyte 'synaptic ribbons' and serum melatonin levels in rats, following 30 min daily exposure. The animals were sacrificed after 1, 3, 7, 15 and 21 days. A significant decrease in the number of synaptic ribbons was observed after 15 and 21 days, together with a significant drop in serum melatonin concentrations after 15 days. The mediating role of the retina in these modifications and magnetic field effects is discussed.

Animals↗
PubMed1991

[Isolation of GTP-binding Gs-protein liberated from human erythrocyte membranes under the action of fluoride ions].

Human erythrocyte membranes were incubated in the presence of sodium fluoride. After centrifugation at 30,000 g for 30 min the supernatant was able to stimulate the catalytic subunit of adenylate cyclase. The stimulatory factor was purified from the supernatant of fluoride-treated membranes by three subsequent chromatographic steps including DEAE-Sephacel ion-exchange chromatography in the absence of detergent, gel-filtration on Ultrogel AcA 44 in the presence of 1% sodium cholate and phenyl-Sepharose CL/4B hydrophobic chromatography. The final preparation showed approximately 120-fold purification in stimulatory activity over the initial extract and contained two polypeptides (Mr 42 kDa and 36 kDa). The stimulator activity of the preparation was inhibited by 60% by beta gamma-subunits of the GTP-binding protein of bovine brain membranes, G0. The data obtained suggest that the regulatory GTP-binding stimulatory protein of adenylate cyclase, GS, dissociates from human erythrocyte membranes as a result of fluoride-ion treatment.

Adenylyl Cyclases↗
PubMedDate not supplied

The presence of complement fixing antibodies to the avian group-specific ("gs") sarcoma-leukosis antigen in the human population and in cancer patients.

Antibodies to the avian group-specific "gs" sarcoma-leukosis antigen were made evident by complement fixation reaction in human sera collected from apparently healthy subjects and from patients with different forms of cancer and non-neoplastic diseases. The number of sera investigated was of 2,123. The possible mechanisms that might account for this paraimmune response of the human organism and the prospects of developing prophylactic steps against cancer are discussed.

Agricultural Workers' Diseases↗
PubMed1990

Tubulin binds specifically to the signal-transducing proteins, Gs alpha and Gi alpha 1.

Participation of cytoskeletal elements in regulation of hormonal response and responsiveness has been suggested by several laboratories. Addition of dimeric tubulin to rat cerebral cortex synaptic membranes causes stable inhibition of adenylyl cyclase, and the molecular basis for this effect appears to require a direct interaction between tubulin and G proteins. To test whether such tubulin-G protein interaction occurred, several purified G proteins were bound to nitrocellulose, and 125I-tubulin overlay studies were performed. 125I-Tubulin bound to the alpha subunits of Gs and Gil with high specificity and an apparent Kd of approximately 130 nM. Other G protein alpha subunits (alpha i2, alpha i3, alpha 0, and transducin) displayed a much lower affinity for tubulin, despite the much closer relationship of those proteins to alpha il than to alpha s. Association of beta gamma subunits with alpha il or alpha s did not alter the binding of tubulin to these G protein heterotrimers, and the binding of a hydrolysis-resistant GTP analog to the alpha subunits was similarly without effect. These results suggest that tubulin forms complexes with specific G proteins and these complexes might provide a locus for the interaction of cytoskeletal components and signal transduction cascades. These results also provide evidence of a functional distinction among the closely related alpha i subtypes.

Animals↗
PubMed1990

A new constitutively activating mutation of the Gs protein alpha subunit-gsp oncogene is found in human pituitary tumours.

A new 227 Gln----Lys oncogenic mutation of the Gs alpha subunit (the GTP-binding protein that stimulates adenylyl cyclase) has been found in three out of eight human growth hormone-secreting pituitary tumours of the group 2, characterized by high cAMP and constitutively activated adenylyl cyclase. The additional five group 2 tumours expressed another, previously described mutation, 201 Arg----Cys, while the tumours of group 1, characterized by normal cAMP and adenylyl cyclase activity, expressed neither these nor the two other mutations of the same sites previously described in group 2. The Gln 227 site of alpha s corresponds to the Gln 61 site in the low Mw G protein, p21 ras, where the Leu substitution had already been shown to be oncogenic. The oncogenic potential (gsp oncogene) of the mutations so far observed depends on the reduced GTPase activity intrinsic to alpha s, with constitutive activation of the protein and marked elevation of cAMP. The latter is the intracellular messenger that stimulates growth of pituitary growth hormone-secreting cells and other cell types.

Adenylyl Cyclases↗