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The detection and successful treatment of cancers is dependent on timely presentation with abnormal and often subtle symptoms. In this article, we draw on research conducted with Australian immigrant women in 2001-02 who experienced delays in diagnosis of gynecological cancer. Data from in-depth interviews with women with gynecological cancer indicated a common trajectory of an "illness career" whereby the search for diagnosis was often painful and lengthy, either because women normalized the abnormal signs or because their experiences of bodily abnormality, pain, and dysfunction contrasted with medical explanations. This delay was sometimes exacerbated by structural barriers. As a result, diagnosis was often protracted, during which time women presented with symptoms that were dismissed or resulted in the misdiagnosis, with a resultant loss of confidence in clinical services. 相似文献
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Mehran Pashirzad Mojtaba Shafiee Majid Khazaei Hamid Fiuji Mikhail Ryzhikov Saman Soleimanpour AmirReza Hesari Amir Avan Seyed Mahdi Hassanian 《Journal of cellular physiology》2019,234(2):1237-1247
Prostate cancer is a major cause of cancer-related death in males. Wnt/β-catenin signaling plays a critical role in the pathogenesis of this disease by regulating angiogenesis, drug resistance, cell proliferation, and apoptosis. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease. 相似文献
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Conformational models of the active site of adenosine deaminase (ADA) and its complexes in the basic state with adenosine and 13-isosteric analogues of the aza, deaza, and azadeaza series were constructed. The optimization of the conformational energy of the active site and the nucleoside bound with it in the complex was achieved in the force field of the whole enzyme [the structure of ADA complex with 1-deazaadenosine (1ADD) was used] within the molecular mechanics model using the AMBER 99 potentials. The stable conformational states of each of the complexes, as well as the optimal conformation of ADA in the absence of ligand, were determined. It was proved that the conformational state that is close to the structure of the ADA complex with 1ADD known from X-ray study corresponds to one of the local minima of the potential surface. Another, a significantly deeper minimum was determined; it differs from the first minimum by the mutual orientation of side chains of amino acid residues. A similar conformational state is optimal for the ADA active site in the absence of bound ligand. A qualitative correlation exists between the values of potential energies of the complexes in this conformation and the enzymatic activity of ADA toward the corresponding nucleosides. The dynamics of conformational conversions of the active site after the binding of substrate or its analogues, as well as the possibility of the estimation of the inhibitory properties of nucleosides on the basis of calculations, are discussed. 相似文献
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Gessi S Varani K Merighi S Fogli E Sacchetto V Benini A Leung E Mac-Lennan S Borea PA 《Purinergic signalling》2007,3(1-2):109-116
Adenosine is a potent extracellular messenger that is produced in high concentrations under metabolically unfavourable conditions.
Tissue hypoxia, consequent to a compromised cellular energy status, is followed by the enhanced breakdown of ATP leading to
the release of adenosine. Through the interaction with A2 and A3 membrane receptors, adenosine is devoted to the restoration of tissue homeostasis, acting as a retaliatory metabolite. Several
aspects of the immune response have to be taken into consideration and even though in general it is very important to dampen
inflammation, in some circumstances, such as the case of cancer, it is also necessary to increase the activity of immune cells
against pathogens. Therefore, adenosine receptors that are defined as “sensors” of metabolic changes in the local tissue environment
may be very important targets for modulation of immune responses and drugs devoted to regulating the adenosinergic system
are promising in different clinical situations. 相似文献
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Atena Soleimani Farzad Rahmani Nikoo Saeedi Rana Ghaffarian Majid Khazaei Gordon A. Ferns Amir Avan Seyed Mahdi Hassanian 《Journal of cellular biochemistry》2019,120(12):19245-19253
Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease. 相似文献
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Zarubin Yu. P. Il'icheva I. A. Purygin P. P. Florent'ev V. L. 《Russian Journal of Bioorganic Chemistry》2002,28(5):404-411
Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a relationship between their molecular structures and the properties as substrates for the mammalian adenosine deaminase. The atomic charge distribution and maps of electrostatic potential around their van der Waals molecular surface were calculated using the ab initioSTO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The previously proposed mechanism of the substrate acceptance in the active site of mammalian adenosine deaminase was refined, and the potential substrate properties were predicted for two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3-deazaadenosine. 相似文献
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运用神经毒剂MPTP(1-methy-4-pheny-1,2,3,6-tetrahydropyridine)制作的ICR小鼠帕金森病模型,通过荧光测定方法和免疫组织化学方法,测定MPTP及腺甘A2a受体拮抗剂喹唑啉(Quinazoline,CP66713)对单胺类神经递质去甲肾上腺素(NA)、多巴胺(DA)、5-羟色胺(5-HT)及其代谢产物5-羟吲哚乙酸(5-HIAA)和氨基酸类神经递质γ-氨基 相似文献
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Adenosine in the central nervous system: release mechanisms and extracellular concentrations 总被引:23,自引:0,他引:23
Adenosine has several functions within the CNS that involve an inhibitory tone of neurotransmission and neuroprotective actions in pathological conditions. The understanding of adenosine production and release in the brain is therefore of fundamental importance and has been extensively studied. Conflicting results are often obtained regarding the cellular source of adenosine, the stimulus that induces release and the mechanism for release, in relation to different experimental approaches used to study adenosine production and release. A neuronal origin of adenosine has been demonstrated through electrophysiological approaches showing that neurones can release significant quantities of adenosine, sufficient to activate adenosine receptors and to modulate synaptic functions. Specific actions of adenosine are mediated by different receptor subtypes (A(1), A(2A), A(2B) and A(3)), which are activated by various ranges of adenosine concentrations. Another important issue is the measurement of adenosine concentrations in the extracellular fluid under different conditions in order to know the degree of receptor stimulation and understand adenosine central actions. For this purpose, several experimental approaches have been used both in vivo and in vitro, which provide an estimation of basal adenosine levels in the range of 50-200 nM. The purpose of this review is to describe pathways of adenosine production and metabolism, and to summarize characteristics of adenosine release in the brain in response to different stimuli. Finally, studies performed to evaluate adenosine concentrations under physiological and hypoxic/ischemic conditions will be described to evaluate the degree of adenosine receptor activation. 相似文献
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Villalobos Virginia Suárez Jacqueline Estévez Jesús Novo Ernesto Bonilla Ernesto 《Neurochemical research》2001,26(10):1157-1161
In the present study the effects of chronic manganese (Mn) treatment on adenosine A2a receptor binding in mouse brain have been assessed. Male albino mice were divided in two groups: In the Mn-treated group, the animals were injected intraperitoneally (i.p.) with MnCl2 (5 mg/kg/day) five days per week during 9 weeks; in the control group, they were injected likewise with a saline solution. A significant decrease of the Kd without alteration of Bmax in the cerebellum and, an increase of the Kd and Bmax in hippocampus of mice treated with Mn were found. Also, an increase of Kd in frontal cortex was observed. The binding parameters in caudate nucleus, olfactory bulb and hypothalamus were not altered by Mn. A significant decrease in the adenosine concentration in caudate nucleus, olfactory bulb and hypothalamus, without significant changes in hippocampus, frontal cortex and cerebellum was also detected. These findings suggest that chronic administration of Mn could affect adenosine receptor function and turnover, depending on the brain region analyzed. 相似文献
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Adenosine Measurement by a Rapid HPLC-Fluorometric Method: Induced Changes of Adenosine Content in Regions of Rat Brain 总被引:9,自引:5,他引:4
Abstract: We describe a rapid, sensitive method to determine brain adenosine content by HPLC. Adenosine is first reacted with chloroacetaldehyde to form fluorescent 1, N 6 -ethenoadenosine. The derivative is then separated from interfering compounds by HPLC on a C18 reverse-phase column and quantitated by fluorometry. We found that adenosine was rather uniformly distributed in nine brain regions of animals killed by microwave radiation. In contrast, there was an increase of adenosine in hippocampus, frontal cortex, and especially striatum of animals killed by decapitation. Moreover, adenosine content increased approximately 10-fold in the thalamus, mesencephalon, and pons-medulla if the animals were exposed to CO2 for 1 min before they were killed by microwave radiation. Our method should be a useful aid for providing new information about the metabolic and proposed transmitter roles of brain adenosine. 相似文献
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人血管内皮细胞中腺苷代谢的定量研究 总被引:4,自引:0,他引:4
目的:通过对人脐静脉内皮细胞腺苷分泌进行定性及定量研究,了解人类血管内皮细胞的腺苷代谢及机制.方法:收集并测定不同干预下细胞柱流出液中分离的人脐静脉内皮细胞分泌的腺苷量.结果:在无干预、抑制腺苷激酶及去氨酶、抑制细胞膜腺苷转运情况下,人脐静脉内皮细胞腺苷分泌率分别为13.5±7.1 pmol·min-1·mg-1、32.5±14.2 pmol·min-1·mg-1和20.8±15.7 pmol·min-1·mg-1.结论:人类血管内皮细胞内腺苷合成高于胞外,而细胞膜腺苷转运被抑制后的腺苷分泌率反而高于生理状态下分泌率,则表明腺苷在胞内分解代谢非常迅速,使部分腺苷反由胞外扩散入胞内. 相似文献
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The enzyme adenosine kinase (AK) plays a key role in the regulation of intracellular and extracellular concentration of adenosine
(Ado), which exhibits potent hormonal activity in cardiovascular, nervous and immune systems. In view of the pharmacological
effects of Ado, there is much interest in identifying inhibitors of AK, which can augment its tissue-protective effects. In
this study, we have screened 1040 compounds from a chemical library of putative kinase inhibitors for their effect on purified
human recombinant AK. These studies have identified 8 novel, non-nucleoside AK inhibitors. Four of these compounds (viz. 2-tert-butyl-4H-benzo[1,2,4]thiadiazine-3-thione
(2759–0749); N-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-yl)-propionamide (3998–0118); 3-[5,6-Bis-(4-methoxy-phenyl)-furo[2,3-d]pyrimidin-4-ylamino]-propan-1-ol
(4072–2732); and 2-[2-(3,4-dihydroxy-phenyl)-5-phenyl-1H-imidazol-4-yl]-fluoren-9-one (8008–6198)), which inhibited human
AK in a concentration-dependent manner in a low micromolar range (IC50 = 0.38 ∼ 1.98 μM) were further studied. Kinetic and structural studies on these compounds provide evidence that inhibition
of AK by these compounds was competitive with respect to Ado and non-competitive for ATP. All of these compounds also inhibited
uptake of Ado and its metabolism in cultured mammalian cells at comparable concentrations indicating their efficient cellular
penetrability. These AK inhibitors, whose chemical structures differ significantly from all previously known inhibitors, provide
useful lead compounds for identification of more potent but less toxic AK inhibitors that may prove useful for therapeutic
purposes. 相似文献
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腺苷对颈动脉窦压力感受器反射的易化作用 总被引:7,自引:3,他引:7
在27只隔离灌流颈动脉窦区的麻醉大鼠,观察了腺苷(adenosine,Ado)对颈动脉窦压力感受器反射的影响。所得结果如下:(1)以 Ado(125μmol/L)隔离灌流大鼠左侧颈动脉窦区时,压力感受器机能曲线向左下方移位,曲线最大斜率(PS)由0.37±0.02增至0 55±0.02kPa/KPa(P<0.001),反射性血压下降幅度(RD)由5.53±0.12增至7.76±0.36KPa;阈压(TP)、平衡压(EP)和饱和压(SP)则分别从8.60±0.27,12.53±0.30和23.69±0.15下降至5.63± 0.11kPa,10.89±0.29KPa和20.18±0.55KPa(P<0.01-0.001 )。其中RD,PS和TP的变化呈明显的剂量依赖性。(2)用腺苷选择性 A1受体拮抗剂(8-cyclopentyl-l,3-dipropylianthene,0.134mmol/L)预处理后,Ado的上述反射效应即被阻断。(3)先给予KATP通道阻断剂格列苯脲(glibenclamide.10μmol/L)亦可取消腺苷对压力感受器反射的影响。以上结果表明, Ado对大鼠颈动脉窦压力感受器活动有易化作用,这一作用似与腺苷A1受体介导的KATP通道开放有关。 相似文献