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81.
The absence or low levels of adenosine deaminase (ADA) in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion and autoimmunity. Deficiency of ADA causes increased levels of both intracellular and extracellular adenosine, although only the intracellular lymphotoxicity of accumulated adenosine is considered in the pathogenesis of ADA SCID. It is shown that extracellular but not intracellular adenosine selectively inhibits TCR-triggered up-regulation of activation markers and apoptotic events in thymocytes under conditions of ADA deficiency. The effects of intracellular adenosine are dissociated from effects of extracellular adenosine in experiments using an adenosine transporter blocker. We found that prevention of toxicity of intracellular adenosine led to survival of TCR-cross-linked thymocytes in long-term (4 days) assays, but it was not sufficient for normal T cell differentiation under conditions of inhibited ADA. Surviving TCR-cross-linked thymocytes had a non-activated phenotype due to extracellular adenosine-mediated, TCR-antagonizing signaling. Taken together the data suggest that both intracellular toxicity and signaling by extracellular adenosine may contribute to pathogenesis of ADA SCID. Accordingly, extracellular adenosine may act on thymocytes, which survived intracellular toxicity of adenosine during ADA deficiency by counteracting TCR signaling. This, in turn, could lead to failure of positive and negative selection of thymocytes, and to additional elimination of thymocytes or autoimmunity of surviving T cells. 相似文献
82.
为观察腺苷心肌保护液对大鼠心肌ATP及离子含量的影响, 采用离体大鼠工作心脏缺氧停搏120 m in, 采用高钾、高钾+ 腺苷及腺苷停搏液进行心肌保护。发现停搏末含腺苷的两组ATP含量明显高于高钾组, 且复灌后进一步恢复; 各离子含量均能保持平稳。高钾组复灌后细胞内Na+ 、Ca2+ 明显增高伴Mg2+ 的减少。结果表明: 腺苷心肌保护液能够改善心肌能量代谢, 维持停搏期间及复灌后细胞内离子含量的稳定, 对缺氧心肌发挥保护作用 相似文献
83.
研究双丁酰环磷酸腺苷(dbcAMP)和全反式维甲酸(ATRA)两种分化诱导剂对人肝癌细胞株SMMC-7721亚细胞组分中酪氨酸蛋白激酶(TPK)的早期(24h内)效应。方法用超离心等法制备胞液(c),胞核(n)和膜性(m)TPK酶液,以聚谷氨酸∶酪氨酸(po1yE.Y)4∶l及γ-32P-ATP为底物测定TPK活力。结果对照和dbcAMP处理1h使cTPK和nTPK升高,以后对照降至原有水平,而dbcAMP处理细胞的nTPK在12~24h略低于对照细胞,但mTPK在1h反而降低,在3h(对照)或6h(dbcAMP)升至高峰,12h后dbcAMP使mTPK活力低于对照。ATRA作用于SMMC-7721细胞后,1h可使三类TPK活力均升至高峰,12h后cTPK和nTPK活力低于对照细胞,但mTPK活力在24h才低于对照。结论dbcAMP和ATRA对不同亚细胞组分TPK有不同的时相效应。一般说来,早期(1~6h)有升高作用,而在12~24h则有一下降作用,呈现双相效应 相似文献
84.
In an in vitro preparation of the intact carotid body (CB) of the rabbit, adenosine (100 microM) inhibited hypoxia-induced catecholamine release by 25%. The specific A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 microM) prevented the inhibition and increased the response to hypoxia further. In isolated chemoreceptor cells from the same species, adenosine inhibited voltage-dependent Ca2+ currents by 29% at 1 microM (concentration producing half-maximal inhibition, IC50 = 50 nM). This inhibition was mimicked by R(-)N6-(2-phenylisopropyl)-adenosine and 2-chloroadenosine (1 microM), two purinergic agonists poorly active at the intracellular ('P') site, and persisted in the presence of dipyridamole (a blocker of adenosine uptake; 1 microM) and was fully inhibited by 8-phenyltheophylline (10 microM). The A1 antagonists DPCPX (10 microM) and 8-cyclopentyl-1,3-dimethylxantine (0.1 microM) inhibited the effect of adenosine by 93% (IC50 = 0.14 microM) and 59%, respectively. The inhibition of the Ca2+ current (I(Ca)) was reduced by nisoldipine (an L-type Ca2+ channel antagonist) by nearly 50%, and was unaltered by omega-conotoxin GVIA, a blocker of N-type Ca2+ channels. Adenosine did not affect the voltage-dependent Na+ current (I(Na)) or K+ current (I(K)). We conclude that adenosine A1 receptors are located in chemoreceptor cells and mediate the inhibition of L-type Ca2+ channels and thereby the release of catecholamines produced by hypoxia. The data also indicate that endogenous adenosine acts as a physiological negative modulator of the chemoreceptor cell function. The previously reported excitatory action of adenosine on the activity of the sensory nerve of the CB is discussed in terms of a balance between the inhibition mediated by A1 receptors and the excitation mediated by A2 receptors. 相似文献
85.
E. Ongini Silvio Dionisotti Stefania Gessi E. Irenius Bertil B. Fredholm 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(1):7-10
Three structurally related non-xanthine compounds, CGS 15943, ZM 241385 and SCH 58261, are potent A2A adenosine receptor antagonists and have been used as tools in many pharmacological studies. We have now characterized their
affinity and selectivity profile on human adenosine receptors stably transfected into either CHO cells (A1 and A2B receptors) or HEK-293 cells (A2A and A3 receptors). In binding studies using [3H]SCH 58261 as a radioligand, the three compounds were equally potent at A2A receptors, their K
i value being less than 1 nM. Affinity for A1 and A3 receptors was measured using [3H]DPCPX and [125I]AB-MECA as radioligands. Given the lack of selective ligands, interaction with A2B receptors was assessed using the cAMP accumulation assay following stimulation by the adenosine receptor agonist N-ethylcarboxamidoadenosine (NECA). CGS 15943 was almost as potent at A1 receptors (K
i 3.5 nM) as at A2A receptors, showed moderate affinity for A3 receptors (K
i 95 nM) and also interacted with A2B receptors (K
i 44 nM; pA2 7.5). ZM 241385 showed little affinity for A1 receptors (K
i 255 nM), and did not interact with A3 receptors (K
i>10 μM); however, it displayed moderate affinity for A2B receptors (K
i 50 nM; pA2 7.3). SCH 58261 had weak affinity for A1 receptors (K
i 287 nM), no interaction with A3 receptors (K
i>10 μM), and showed negligible interaction with A2B receptors (K
i 5 μM; pA2 6.0). These data indicate that SCH 58261 is the most selective A2A antagonist currently available. Moreover, the different receptor selectivity of these three chemically related compounds
provides useful information to progress with structure-activity relationship studies.
Received: 2 July 1998 / Accepted: 6 October 1998 相似文献
86.
Noriyuki Masuda Shunichi Negoro Kouji Takeda Nobuhide Takifuji Tomonori Hirashima Takashi Yana Noriaki Kurata Takashi Kuwabara Satoshi Kobayashi Shinzoh Kudoh Kaoru Matsui Minoru Takada Masahiro Fukuoka 《Investigational new drugs》1999,16(3):245-254
(E)-2-deoxy-2-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3–4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC. 相似文献
87.
Charles M. Haskell Evelyn Mendoza Katherine M.W. Pisters Frank V. Fossella Robert A. Figlin 《Investigational new drugs》1999,16(1):81-85
Fifteen patients with Stage IIIB or IV non-small cell lung cancer gave informed consent to receive three or more 96-hour infusions of ATP at a dose of 50 mcg/kg/min or higher to determine whether ATP has antineoplastic activity against this tumor type and to better define the spectrum of toxicity for ATP given as a single agent. There were no objective complete or partial responses observed. The median survival of the overall group was 187 days and the median time to tumor progression was 113 days. The major toxic side effects were chest pain and dyspnea, leading to the cessation of treatment in 5 patients. We conclude that ATP at this dose and schedule of administration is an inactive agent in patients with advanced non-small cell lung cancer. 相似文献
88.
K. O. Schwab H. Bartels C. Martin E. -M. Leichtenschlag 《European journal of pediatrics》1993,152(10):797-801
Little is known about the receptor and post receptor mechanisms of sympathoadrenal signal transmission in type I diabetes mellitus. Therefore, we examined the maximum binding of granulocyte 2-adrenoceptors and the in vitro c-AMP accumulation in lymphocytes of 24 children and adolescents with diabetes mellitus and 14 similarly aged healthy subjects. The number of high affinity 2-adrenoceptors on granulocytes correlated significantly with unstimulated (r=0.6,P<0.004) and with isoproterenol stimulated c-AMP values in lymphocytes (r=0.68,P<0.0007) showing the proportional changes of 2-adrenoceptors and c-AMP in two different cells. The number of 2-adrenoceptors on granulocytes was significantly reduced in diabetic as compared to healthy children (median 1397, range 599–3405 vs. 2205, 825–3200 2-adrenoceptors per granulocyte,P=0.014). Moreover, the percentage in vitro stimulation of c-AMP by isoproterenol in lymphocytes was significantly reduced in diabetic children as compared to healthy individuals (120%, 39%–278% vs. 225%, 66%–500%,P=0.012). These results indicate a decreased sympathoadrenergic signal transmission in peripheral blood cells as a model for the liver probably contributing to severe hypoglycaemia in diabetic children. 相似文献
89.
Summary Cyclic adenosine 3,5monophosphate (cAMP) was assayed in CSF and plasma obtained from patients with multiple sclerosis. Decreased CSF cAMP levels were found in more than half of the patients while plasma cAMP was normal. The decrease is correlated significantly with the disability of the patient and with the progression of the disease. A low CSF cAMP level can be considered as prognostically unfavorable, particularly in the early stage of the disease. There was no correlation between the cAMP levels and the duration of the disease or with bouts and remissions. ACTH therapy did not normalize the decreased values. Obviously the decrease of CSF cAMP is related to the demyelination and not to the intensity of the pathological immunoreactions.
Zusammenfassung Es wurde das cyclische Adenosin-3,5monophosphat im Liquor von Patienten mit multipler Sklerose untersucht. Bei einem Teil der Patienten wurden auch die Vergleichswerte im Blutplasma bestimmt. Es zeigte sich bei mehr als der Hälfte der Patienten eine Verminderung der cAMP-Konzentration im Liquor bei normalem Plasmaspiegel. Diese cAMP-Verminderung erwies sich als signifikant abhängig von dem Schweregrad der Erkrankung bzw. der Erkrankungsprogredienz und ist besonders in frühen Erkrankungsfällen als prognostisch ungünstiges Zeichen anzusehen. Es fand sich kein Zusammenhang mit dem Krankheitsstadium, d.h. Schub bzw. Intervall, und mit der Erkrankungsdauer. Eine ACTH-Behandlung vermochte diese Verminderung der Werte nicht auszugleichen. Es wird die Wertigkeit dieser Befunde diskutiert.相似文献
90.
E. Leung K. A. Jacobson R. D. Green 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(6):639-644
Summary While G protein-coupled receptors are often studied by analyzing antagonist radioligand: cold agonist inhibition curves using an independent site model, it is now clear that KL and KH values determined in these analyses are not reliable estimates of the affinities of the agonists for free and G protein-coupled forms of the receptor. Thus, such experiments cannot be used to contrast the characteristics of a given type of receptor in different tissues, i.e., to probe for the existence of receptor subtypes. Since treatment with N-ethylmaleimide treatment blocks receptor: Gi/G0 protein interactions, such analyses on N-ethylmaleimide-pretreated membranes should allow direct assessment of the affinities of competing ligands for the free receptor or for multiple receptor subtypes.As A1 adenosine receptors couple to Gi, and perhaps to Go, we have performed A1 adenosine receptor radio-ligand competition studies first on control, then on N-ethylmaleimide-pretreated bovine cardiac and cerebral cortical membranes. Results of experiments with the antagonist radioligand [3H]xanthine amine congener appeared to be confounded by ligand binding to A2 adenosine receptors present in the cardiac membrane preparations. Further experiments utilized the A1-specific radioligand [3H] 1,3-dipropyl-8-cyclopentylxanthine. These experiments confirmed once more that the KL values determined by computer analysis of competition curves performed on control membranes are not reliable estimates of the affinities of the competing ligand for free receptors. Furthermore the results supported the hypothesis that similar analyses on NEM-treated membranes provide reliable estimates of the affinity(s) of competing ligands for free receptors. Lastly, the results suggest that cardiac membranes contain two subtypes of A1 adenosine receptors that are differentiated by 5-modified but not N6-modified adenosine analogs. One of these receptor subtypes appears to be the same as the A1 receptor detected in cortical membranes.Abbreviations [125I]ABA
[1251](N6-p-aminobenzyl)adenosine
- [3H]CPX
[3H]8-cyclopentyl-1,3-dipropylxanthine
- [3H]R-PIA
[3H]N6-R-phenylisopropyladenosine
- [6H]XAC
[6H]xanthine amine congener
- CHA
N6-cyclohexyladenosine
- EDTA
ethylenediaminetetraacetic acid
- [125I]BW-A844U
[125I]3-(4-amino)phenethyl-l-propyl-8-cyclopentylxanthine
- NCCA
5-N-cyclopropylcarboxamide adenosine
- NECA
5-N-ethylcarboxamide adenosine
- PMSF
phenylmethylsulphonyl fluoride
- NEM
N-ethylmaleimide
Recipient of a Postdoctoral Fellowship from the Chicago Heart Association 相似文献