Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential evaluation of angiotensin II (Ang II) receptors (AT1A, AT1B and AT2) expression was performed in dispersed adenohypophyseal cells fractionated by unit gravity sedimentation. Binding of [125I-Sar1-Ile8]-Ang II and its displacement by specific nonpeptidic AT1 (DuP753) and AT2 (PD123319) antagonists was monitored throughout the gradient. Quantification of mRNA levels corresponding to both AT1 receptor subtypes (AT1A and AT1B) was achieved by reverse transcriptase polymerase chain reaction (RT-PCR) amplification in the presence of an AT1 receptor mutant cRNA as internal standard. Fractions were characterised by radioimmunoassay for the five major anterior pituitary hormones and by counting immunocytochemically labelled cells. Quantification of AT1 receptor subtype mRNA levels was also performed in four hypophyseal cell lines secreting prolactin, growth hormone, corticotropin and a gonadotropin subunit. As already described for the whole pituitary, AT1B receptor mRNA is predominantly expressed (80% of total AT1A + AT1B receptor mRNA content), whereas AT1A is expressed at lower level (20%) in dispersed pituitary cells. Most AT1 receptor mRNA and binding co-elute with fractions enriched in lactotropes and corticotropes. In contrast to AT1B, AT1A receptor mRNA is not present in heavier populations of lactotropes or in somatomammotropes. Low AT1B mRNA levels are detected in GH4C1 and in GC cells, two clones which secrete respectively prolactin and growth hormone. In contrast, no AT1 receptor mRNA expression was found in two other cell lines, AtT20 and alphaT3-1, which produce pro-opiomelanocortin and gonadotropin. It is concluded that expression of AT1 receptor subtypes is heterogeneous in different populations of lactotropes and corticotropes.
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PMID:Expression of angiotensin II receptor subtypes AT(1A) and AT(1B) in enriched fractions of dispersed rat pituitary cells. 943 Apr 47

Validity of measurement of somatic cell mutation frequency (Mf) at the hprt locus for evaluating cancer risk of the given individual was determined in pediatric patients. Peripheral lymphocytes (PL) from patients with various diseases, including acute lymphoblastic leukemia (ALL) and Hodgkin's disease (HD), DNA repair deficient syndromes or short stature receiving growth hormone (GH), were isolated through Ficoll-Hypaque sedimentation with informed consent. Mf at the hprt locus of PL was determined by limiting dilution assay using 6-thioguanine (6-TG). Results were as follows. (1) ALL patients after chemotherapy had higher Mf than that of age-matched controls. (2) Patients with HD tended to have higher Mf after chemotherapy. (3) Among DNA-repair deficient syndromes, diseases which are susceptible to cancer (Xeroderma pigmentosum, Ataxia telangiectasia) have high Mf, but those without any cancer disposition (Cockayne syndrome, Rothmund-Thomson syndrome) have normal Mf. (4) GH-receiving patients have normal Mf, regardless of total doses of GH. Measurement of Mf at HPRT locus may be useful for evaluating cancer risk of pediatric patients.
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PMID:Measurement of mutation frequency at the HPRT locus in peripheral lymphocytes. Is this a good method to evaluate a cancer risk in pediatric patients? 959 52

This study was performed in order to determine whether the stimulatory effect of plasma angiotensin II (ANG II) on Adrenocorticotropic hormone (ACTH) and growth hormone (GH) secretion in humans is mediated by AT1 subtype receptors. For this purpose, the effects of the administration of the AT1 receptor antagonist, losartan (50 mg p.o.) or a placebo on the ACTH and GH responses to ANG II (i.v. infusion for 60 min of successively increasing doses (4, 8 and 16 ng/kg/min); each dose for 20 min) were evaluated in eight normal men. ANG II infusion induced significant increases in both serum ACTH and GH levels (mean peaks were 1.6- and four-times higher than baseline, respectively). The ACTH response to ANG II was completely abolished by pretreatment with losartan. Also, the ANG II-induced GH rise was reduced by administration of losartan, but the GH response was still significantly higher than the basal value (mean peak was twice as high as the baseline). These data provide evidence of AT1 receptor involvement in mediation of the ANG-II stimulating effect on ACTH and GH secretion.
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PMID:Stimulation of ACTH and GH release by angiotensin II in normal men is mediated by the AT1 receptor subtype. 965 55

Angiotensin II (AT2) has been implicated in the growth and/or differentiation of its target tissues. In the present study, testicular AT2 receptor and its subtypes in hypophysectomized rats were examined using quantitative in vitro autoradiography and Northern blot analysis in an attempt to determine possible involvement of pituitary hormones in their expression. Prepubescent (3 weeks of age) male Sprague-Dawley rats underwent hypophysectomy or sham operation. From 10 days thereafter, they were treated with vehicle, growth hormone, human chorionic gonadotrophin or human menopausal gonadotrophin for 10 days. Testicular AT2 receptors were labelled with 125I-[Sar1,Ile8] AT2 and differentiated into its subtypes (AT1 and FAT2) according to their susceptibility to AT1 (losartan, 5 microM) and AT2 (CGP42112B, 1 microM) antagonists. Hypophysectomy led to a marked increase in AT2 receptor concentration (sham-operated rats: 0.7 +/- 0.2 fmol/mg protein, hypophysectomized rats: 2.5 +/- 0.6 fmol/mg protein, mean +/- SEM, n = 11-12, p < 0.01) with predominant occurrence of AT1 receptors. Both human chorionic gonadotrophin and human menopausal gonadotrophin decreased testicular AT2 receptor concentration, whereas growth hormone did not affect AT2 receptor expression. Northern blot analysis revealed both testicular AT1 and AT2 receptor mRNA expression to be significantly increased after hypophysectomy and reduced by gonadotrophin treatment. These results suggest that the expression of testicular AT2 receptors is regulated by pituitary gonadotrophins and that AT2 may play a role in testicular growth and/or differentiation.
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PMID:Pituitary-dependent expression of the testicular angiotensin II receptor and its subtypes in rats. 974 47

Cardiac hypertrophy can be caused in different ways, and the effect of hypertrophy on prognosis depends on whether it is concentric or eccentric in nature. It is simplistic to ascribe hypertrophy purely to workload, and it is a complex interaction between workload, wall stress, and the local and humoral environment. In rats, acute elevation of BP occurring during the rats' sleep cycle causes cardiac hypertrophy, and reduction of BP in hypertensive rats during the sleep cycle causes reversal of left ventricular hypertrophy. This may be due to secretion of growth hormone and renin during sleep. Experimental evidence indicates that angiotensin II possibly formed and acting locally may be implicated in the genesis of cardiac hypertrophy; however, angiotensin II by itself causes relatively minor hypertrophy, but this becomes intensified if there is a high sodium intake and a high angiotensin II level. Blockade of the angiotensin system with angiotensin-converting enzyme inhibitors causes reversal of cardiac hypertrophy and similar results are achieved with AT1 receptor blocking drugs, suggesting that bradykinin may be of relatively minor importance. Clinically, the AT1 receptor blocking drugs have few side effects and appear to have similar beneficial effects to angiotensin-converting enzyme inhibitors, making them suitable to treat many people with hypertension.
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PMID:Angiotensin blocking drugs and the heart beyond 2000. 989 72

The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts. We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue--probably due to metalloproteinase activation--could be the initial event. As a consequence, wall stress is increased triggering deleterious adaptation processes, such as: - intracardiac angiotensin II generation; - cardiac endothelin formation and release; - pro-apoptotic signals for cardiomyocytes; - hypertrophic signals for fibroblasts and cardiomyocytes. This cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure. Therapeutic principles therefore are similar in both conditions: - reduction of wall stress (pharmacological or mechanical unloading of the heart); - blockade of angiotensin II generation or of AT1-receptors (ACE-inhibitors or AT1 antagonists); - blockade of endothelin receptors (ET(A)-blockers); - blockade of adrenergic receptors (preferably beta1-adrenergic receptor blockers). Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade.
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PMID:Ventricular remodeling after acute myocardial infarction. 1069 91

Ataxia-telangiectasia (AT) syndrome (cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, susceptibility to infections, and neoplasia) is associated with cyto- and nucleomegaly in several organ systems. Our aim was to determine (1) whether such cellular abnormalities in the pituitary selectively involve specific cell types, and (2) the proliferation and DNA ploidy status of such cells. Three AT autopsy pituitaries were studied by histology, immunohistochemistry (pituitary hormones, MIB-1, p53 protein), in situ hybridization (pituitary hormones), and Feulgen stain image analysis for ploidy. Results indicated that, in adenohypophyses the scattered pleomorphic, bizarre nuclei were mainly those of somatotrophs and corticotrophs, growth hormone (GH), or adrenocorticotropic hormone (ACm) immunoreactive and expressing the GH or ACTH gene, respectively. Cyto- and nucleomegaly were less frequent in other secretory cells but were also noted in pituicytes of the posterior lobe. Affected cells were immunonegative for MIB-1 and for p53 protein. Image morphometric DNA analysis showed the bizarre cells to be aneuploid with complex histogram patterns, including many nuclei with DNA contents >8 n. No adenomas were found. We conclude that in AT adenohypophyseal cells with cyto- and nucleomegaly, as well as pleomorphism, synthesize and store adenohypophyseal hormones, mainly GH or ACTH. They and affected pituicytes are nonproliferative and are aneuploid.
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PMID:Pituitary Changes in Ataxia-Telangiectasia Syndrome: An Immunocytochemical, In Situ Hybridization, and DNA Cytometric Study of Three Cases. 1211 23

Genetic interventions that accelerate or retard aging in mice are crucial in advancing our knowledge over mammalian aging. Yet determining if a given intervention affects the aging process is not straightforward since, for instance, many disease-causing mutations may decrease life span without affecting aging. In this work, we employed the Gompertz model to determine whether several published interventions previously claimed to affect aging in mice do indeed alter the aging process. First, we constructed age-specific mortality tables for a number of mouse cohorts used in longevity experiments and calculated the rate at which mortality increases with age. Estimates of age-independent mortality were also calculated. We found no statistical evidence that GHRHR, IGF1R, INSR, PROP1, or TRX delay or that ATM + TERC, BubR1, klotho, LMNA, PRDX1, p53, WRN + TERC, or TOP3B accelerate mouse aging. Often, changes in the expression of these genes affected age-independent mortality and so they may prove useful to other aspects of medicine. We found statistical evidence that C/EBP, MSRA, SHC1, growth hormone, GHR, PIT1, and PolgA may influence aging in mice. These results were interpreted together with age-related physiological and pathological changes and provide novel insights regarding the role of several genes in the mammalian aging process.
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PMID:The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. 1546 29

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive ataxia, neurodegeneration, immunodeficiency, and cancer predisposition. Pathoanatomical studies reported a degeneration of cerebellar Purkinje cells as the striking feature of the disease. Although recent studies suggested the involvement of extracerebellar structures such as the brainstem and basal ganglia, this has rarely been studied in human AT. Thus, we performed a detailed cliniconeuroradiological investigation of 11 AT patients, aged 8 to 26 years by collecting clinical neurological data, ataxia scores, growth status, body mass index (BMI), growth hormone (GH), and insulin-like-growth factor 1 (IGF-1) and correlated them to extracerebellar neuroimaging findings in human AT. Neuroimaging was done by cranial and spine magnetic resonance imaging (MRI) with T1- and T2-weighted spin-echo and fluid attenuated inversion recovery sequences. We compared clinical and neuroradiological findings of six patients with IGF-1 levels and BMI below the third percentile to five patients with normal IGF-1 serum levels and BMI above the third percentile. Three of the six first mentioned patients older than 20 years and two patients older than 12 years showed noticeable high Klockgether ataxia scores above 25 points. Three of these patients presented with marked hyperintense lesions in the cerebral white matter of T2-weighted MR images. Interestingly, all six patients suffered from marked spinal atrophy. Two of the patients presented with severe extra-pyramidal symptoms, but only one patient showed associated MRI abnormalities of the basal ganglia. MRI in patients with normal IGF-1 levels showed the expected cerebellar lesions in four patients, whereas spinal atrophy was found only in two patients. There was no affection of the cerebral white matter or basal ganglia in this group. We conclude that central cerebral white matter affection, spinal atrophy, and extrapyramidal symptoms are more often present in patients with pronounced deficiency of the GH/IGF-1 axis accompanied by markedly reduced body weight and high ataxia scores. This may point to a major role of IGF-1 and nutritional status in neuroprotective signaling.
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PMID:Extracerebellar MRI-lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age. 1989 15

Acromegaly is associated with increased morbidity and mortality related to cardiovascular disease. Hypertension is one of the most common cardiovascular risk factors in acromegalic patients. The aim of this study was to investigate association between the frequencies of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and the angiotensin II type 1 receptor (AT1-R) A/C1166 gene polymorphisms and some clinical parameters of acromegalic patients. Total of 33 acromegalic patients and 63 controls were enrolled to study. We determined the ACE I/D, AGT M235T and AT1-R A/C1166 gene polymorphisms. Serum insulin, glucose, triglyceride, HDL-cholesterol, LDL-cholesterol, growth hormone and Insulin-like growth factor I (IGF-I) levels of subjects were analyzed. The frequencies of ACE and M235T AGT genotype were not significantly different between control and patients. The distribution of AT1R A/C1166 genotypes was significantly different between patients and control subjects (P=0.016). None of the three ACE genotypes, DD, ID and II displayed significant difference in acromegalic patients. A significant difference in systolic blood pressure and the serum IGF-I levels among the three AGT genotype, MM, MT and TT genotypes was found in patient group. Individuals with MT genotypes had significantly higher serum IGF-I levels and systolic blood pressure than MM and TT genotype subjects, P<0.05. In addition, serum triglyceride and HDL levels differed significantly between MM and MT genotypes, P<0.05. However, systolic blood pressure of patients with CC genotypes was found to be significantly higher than AA genotypes individuals in acromegaly group, P<0.05. It can be said that the angiotensinogen MT and AT1R CC1166 genotype carriers may have more risk than other genotypes in the development of hypertension in acromegaly.
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PMID:Angiotensin converting enzyme I/D, angiotensinogen M235T and AT1-R A/C1166 gene polymorphisms in patients with acromegaly. 2036 Dec 61


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