Increased intracellular cyclic AMP levels suppress the mitogenic responses of human astrocytoma cells to growth factors

Summary It has been shown that the intracellular cAMP levels were decreased in human malignant astrocytomas. On the other hand, various growth factors and their receptors were found to be overexpressed in these tumors. It is therefore intriguing as to whether there is interplay between the two phenomena in the modulation of the astrocytoma cell growth. In a basal medium consisting of 75% DMEM, 25% Ham's F-12 supplemented with 2% FBS, we show that the mitogenic effects of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) on human astrocytoma cells were suppressed by dibutyryl-cAMP. Dibutyryl-cAMP alone neither potentiated nor inhibited the tumor cell growth. Further studies show that PDGF-induced receptor autophosphorylation in human astrocytoma cells is suppressed by increased intracellular cAMP levels as measured by immunoprecipitation with anti-PDGF receptor and antiphosphotyrosine antibodies. Our results indicate that there is antagonistic interplay between the receptor tyrosine kinase pathway and cAMP-dependent protein kinase pathway in the control of the malignantly transformed glial cells. A reduced cAMP level seen in many human astrocytoma cells may favor their response to growth factor mitogenesis.     

Reevaluating the role of phosphodiesterase inhibitors in the treatment of cardiovascular disease

First developed for clinical use in the late 1980s, the phosphodiesterase inhibitors were found to increase the levels of the ubiquitous second messenger cyclic adenosine monophosphate and could effect changes in vascular tone, cardiac function, and other cellular events. After several early studies using high doses of phosphodiesterase inhibitors in patients with severe heart failure suggested adverse consequences, they fell out of favor. However, recent investigations of phosphodiesterase inhibitors in patients with intermittent claudication have demonstrated profound benefits. Furthermore, these agents have proven useful in prevention of cerebral infarction and coronary restenosis, and their use in the treatment of heart failure is being reevaluated. The reemergence of phosphodiesterase inhibitors can be attributed to a better understanding of dosing and drug-specific pharmacology, the use of concomitant medications, and a recognition of unique ancillary properties; however, their use still requires caution.     

血红素氧合酶-CO-cGMP通路在体外培养人眼小梁细胞中的表达

目的 探讨体外培养人眼小梁细胞是否存在血红素氧合酶（HO）-一氧化碳（CO）-环磷酸鸟苷（cGMP）通路以及氯化血红素（hemin）对其的诱导作崩。方法 应用RT-PCR和免疫组织化学方法检测体外培养人眼小梁细胞中HO-1和HO-2 mRNA及蛋白的表达。向细胞培养液中加入氯化血红素，RT-PCR检测小梁细胞HO-1 mRNA，分光光度法检测培养上清液中碳氧血红蛋白（HbCO）浓度，并用放射免疫法检测细胞中cGMP浓度。结果 体外培养人眼小梁细胞存在HO-1和HO-2 mRNA及蛋白。氯化IffL红素对小梁细胞HO-1 mRNA、HbCO和cGMP浓度的诱导呈浓度依赖性。结论 人眼小梁细胞存在HO-CO-cGMP通路，并受氯化血红素诱导。药理诱导这一通路，可能为青光眼的治疗提供一个有效的新方法。     

Wernicke-encephalopathy in children with cancer

In the last 4 years, 24 cases of neuroblastoma were treated in the Pediatric Hematology-Oncology Unit at the Chaim Sheba Medical Center, 8 of whom were under 1 year of age. Four of them were the product of a pregnancy-induced or preserved by gonadotropins, clomiphene citrate, or progestational hormones. These drugs are known to produce a higher than normal level of estradiol or progestrone in the early stages of pregnancy. Our observation led to the hypothesis that high levels of progestational hormones given during pregnancy are a risk factor for neuroblastoma in infancy. © 1994 Wiley-Liss, Inc.     

cAMP信号途径和基因表达调控

环腺苷酸(cAMP)是细胞内广泛存在的第二信使，其含量取决于影响其合成与降解的多种酶与蚩白质的活性。cAMP途径可通过调控转录因子来调节细胞的增殖、分化和凋亡。本文就cAMP信号途径以及该途径所影响的部分转录因子加以综述。     

Comparative aspects of purine metabolism in some African trypanosomes

Some enzymes of purine salvage were detected in the cell-free preparations from bloodstream forms of African trypanosomes: Trypanosoma vivax; T. brucei and T. congolense. Extracts of trypanosomes cleave adenosine and inosine hydrolytically except in T. congolense where adenosine cleavage was mediated by a phosphorylase. All the trypanosomes apparently lacked adenosine deaminase. Adenine aminohydrolase was found only in T. vivax while adenosine monophosphate deaminase was detected in T. brucei and T. congolense. There was no detectable adenosine kinase activity in T. brucei. A pathway is proposed for the metabolism of purines in these trypanosomes.     

Further studies on the role of calcium in the depolarization-induced activation of tryptophan hydroxylase: Effect of verapamil,tetracaine, haloperidol and fluphenazine

Tryptophan hydroxylase becomes activated by a calcium-dependent process following depolarization of slices of rat brain stem in a potassium-enriched medium. The present study shows that the mechanism responsible for raising enzyme activity is sensitive to increasing concentrations of calcium in the depolarizing medium. Enzyme activity increased progressively as the calcium concentration in the medium was raised from 0.1 to 5.0 mM. The depolarization-induced activation was fully reversible and could be blocked by verapamil, a calcium channel blocking agent, tetracaine, a local anesthetic, and two antipsychotic drugs, haloperidol and fluphenazine, which bind calmodulin. Unlike verapamil and tetracaine, the antipsychotics appeared to have an intracellular site of action, for they blocked the increase in enzyme activity induced when brain stem slices were incubated in a calcium-free medium in the presence of a metabolic inhibitor, such as guanidine. This activation is presumed to be due to the increase in intracellular free calcium that occurs in the presence of such poisons. The inhibitory effects of haloperidol and fluphenazine on the depolarization-induced activation of tryptophan hydroxylase, taken together with published evidence that supernatant preparations of the enzyme are activated when incubated under phosphorylating conditions by a calcium-calmodulin-dependent process, suggest that calmodulin may mediate the calcium-dependent activation induced by depolarization.     

Activation of a nitric-oxide-sensitive cAMP pathway with phencyclidine: elevated hippocampal cAMP levels are temporally associated with deficits in prepulse inhibition

Rationale Schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP.Objective The aim of the present study was to investigate the effects of PCP on cAMP production in the ventral hippocampus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in cAMP levels in the ventral hippocampus.Results Significant increases in cAMP levels were observed in the ventral hippocampus following both local infusion (10^–4 mol/l and 10^–3 mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in the hippocampus. Furthermore, systemic administration of the NO synthase inhibitor, l-NAME (10 mg/kg), blocked both the changes in cAMP levels and the behavioural responses induced by PCP.Conclusions These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in cAMP levels in the ventral hippocampus, and that this change in cAMP response may be linked to the production of NO.