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)

Radiotherapy plays an important role in the management of breast cancer. Whilst its role in achieving local control following surgery in patients with early stage cancer is well established, there is still unclear evidence to explain the factors governing radioresistance in patients who develop recurrences both in the breast and axilla. Radiotherapy induces damage to the DNA. Various cell cycle damage check points and DNA damage repair pathways have been demonstrated. Ataxia telangiectasia mutant (ATM) kinase, which is a member of phosphatidylinositol-3 kinase (PI-3K) family appears to play a central role in DNA damage check point pathways. Over-expression of Insulin like growth factor-I receptor (IGF-IR), Human Epidermal Growth factor receptors (HERS), Vascular Endothelial growth factor (VEGF) on the cell surface and increased concentration of Epidermal Growth factor in the extracellular fluid have been associated with radioresistance. Specific genes such as p53, BRCA, Bcl-2 and chromosomal characteristics like telomere lengths have also been identified as playing significant roles in radiation responsiveness of a cell. This article reviews the current data on general principles of radiotherapy, the cellular mechanisms that operate in response to radiation damage and various molecular markers, intranuclear and extranuclear which have been demonstrated to influence radiation sensitivity in breast cancer cells.
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PMID:Radioresistance in carcinoma of the breast. 1556 51

Most individuals with arterial hypertension or congestive heart failure are insulin-resistant and at a higher risk of developing type 2 diabetes (T2DM). The inhibition of the renin-angiotensin system (RAS), using an angiotensin converting enzyme inhibitor (ACEI) or a selective angiotensin receptor AT1 blocker (ARB), may exert favourable metabolic effects capable of preventing T2DM in high risk individuals. We performed a meta-analysis of randomised clinical trials (RCTs) assessing the effects of RAS inhibition on the incidence of new cases of T2DM in patients with arterial hypertension or congestive heart failure. Ten RCTs with cardiovascular prognosis as primary endpoints analysed the incidence of T2DM as secondary endpoints or as post-hoc analysis after a mean follow-up of 1 to 6 years: five with an ACEI and five with an ARB, compared with a placebo (n=4) or a reference drug (beta-blocker or diuretic: n=5; amlodipine: n=2). Eight RCTs concerned hypertensive patients: STOP Hypertension-2 (lisinopril or enalapril vs beta-blocker or diuretic), CAPPP (captopril vs thiazide or beta-blocker), HOPE (ramipril vs placebo), ALLHAT (lisinopril vs chlorthalidone and lisinopril vs amlodipine), LIFE (losartan vs atenolol), SCOPE (candesartan vs placebo), ALPINE (candesartan vs placebo) and VALUE (valsartan vs amlodipine). Two RCTs concerned patients with congestive heart failure: SOLVD (enalapril vs placebo) and CHARM-overall programme (candesartan vs placebo). Overall, 2 675 new cases of T2DM (7.40%) were observed in the group of 36 167 patients receiving a treatment with ACEI or ARA as compared with 3 842 events (9.63%) in the group of 39 902 control patients. A mean weighed relative risk reduction of new T2DM of 22% (95% CI: 18, 26; p<0.00001) was observed after RAS inhibition. The beneficial effect was similar with ACEIs and with ARBs as well as in patients with hypertension and in those with heart failure, and was also present whatever the comparator (placebo or beta-blockers/diuretics or amlodipine). The number needed-to-treat to avoid one new case of T2DM averaged 45 patients over 4-5 years. In conclusion, RAS inhibition consistently and significantly reduces the incidence of T2DM in individuals with arterial hypertension or with congestive heart failure. Considering the pandemic of T2DM, such pharmacological approach deserves further attention among the strategies aiming at preventing T2DM.
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PMID:Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. 1567 18

The inhibition of the renin-angiotensin system (RAS) with either angiotensin converting enzyme inhibitors (ACEIs) or AT1 angiotensin receptor blockers (ARBs) consistently and significantly reduces the incidence of type 2 diabetes in patients with hypertension or congestive heart failure. The mechanisms underlying this protective effect appear to be complex and may involve an improvement of both insulin sensitivity and insulin secretion. These two effects may result, at least in part, from the well known effects of these pharmacological agents on the vascular system on the one hand, on the ionic balance on the other hand. Indeed, the vasodilation induced by ACEIs or ARBs could improve the blood circulation in skeletal muscles, thus favouring peripheral insulin action, but also in the pancreas, thus promoting insulin secretion. Preserving cellular potassium and magnesium pools by blocking the aldosterone effects could also improve both cellular insulin action and insulin secretion. However, besides these classical effects, new mechanisms have been recently suggested. A direct effect of the inhibition of angiotensin and/or of the enhancement of bradykinin on various steps of the insulin cascade signalling has been described as well an increase in GLUT4 glucose transporters after RAS inhibition. Furthermore, it has been demonstrated that angiotensin II inhibits adipogenic differentiation of human adipocytes via A1 receptors and, therefore, it has been hypothesised that RAS blockade may prevent diabetes by promoting the recruitment and differentiation of adipocytes. Finally, some lipophilic ARBs appear to induce PPAR-gamma activity in the adipose tissue. Hence, the protection against type 2 diabetes observed after RAS inhibition may be partially linked to a thiazolidinedione-like effect. In conclusion, numerous physiological and biochemical mechanisms could explain the protective effect of RAS inhibition against the development of type 2 diabetes in individuals with arterial hypertension or congestive heart failure. What might be the main mechanism in the overall protection effect of ACEIs or ARBs remains an open question.
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PMID:Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. 1567 19

The present study was performed to evaluate the potential role and functional interaction of angiotensin II AT1 and AT2 receptors (AT1R and AT2R) in the regulation of blood pressure and glucose homeostasis in fructose-induced insulin-resistant, hypertensive rats. Male Sprague-Dawley rats on fructose-enriched or regular diets for 4 weeks were subjected to 2-step euglycemic euinsulinemic (EEI) and euglycemic hyperinsulinemic (EHI) clamp studies with [3-3H]glucose infusion. After a 40-minute basal period, selective AT1R and AT2R antagonists, losartan (LOS, 10 mg/kg IV bolus) and PD123319 (PD, 50 microg/kg/min), alone or in combination were separately given to control and fructose-fed groups in the 2 clamp periods. The results showed that during the EEI period, LOS significantly reduced the elevated blood pressure in fructose-fed rats, whereas PD further increased fructose-induced high blood pressure. Coadministration of LOS and PD did not alter the elevated blood pressure in fructose-fed rats. Administration of LOS and/or PD failed to change the blood pressure in control rats. During the EHI period, blockade of both AT1R and AT2R eliminated the insulin-induced blood pressure elevation in control and fructose-fed rats. Hepatic glucose production (HGP) did not alter among groups in the basal and EEI periods. Insulin infusion (EHI period) markedly suppressed HGP in control rats, but this suppressive effect was significantly attenuated in fructose-fed rats. LOS administration further reduced the insulin-induced suppression of HGP in fructose-fed rats. The whole-body glucose uptakes (rates of glucose disappearance, Rd) during the basal and EEI periods were similar among groups. During the EHI period, Rd was markedly increased in all groups and the magnitude of increase was significantly greater in control rats than in fructose-fed rats except those with LOS treatment. LOS treatment also redirected Rd in favor of glycolysis in fructose rats, but not in control rats, during the EEI and EHI periods. The effects of LOS on glycolysis during the 2 clamp periods and on HGP during the EHI period were reversed when PD was concomitantly administered, but PD alone did not alter glucose metabolism throughout the experiment in fructose-fed rats. Administration of LOS and/or PD did not change the glucose metabolism in control rats. Our data suggest that AT2R can counterbalance the AT1R-mediated effects on blood pressure and glucose metabolism in fructose-induced insulin-resistant, hypertensive rats. Furthermore, AT1R- and AT2R-mediated effects on blood pressure are disassociated with their actions on glucose metabolism in this hypertensive model.
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PMID:Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats. 1569 Mar 8

The renin-angiotensin system plays a critical role in the pathogenesis of obesity, obesity-associated hypertension, and insulin resistance. However, the biological actions of angiotensin II (AII) on insulin sensitivity remain controversial. Because angiotensinogen and AII receptors are expressed on adipose tissue, we investigated the effect of AII on the insulin sensitivity of isolated rat adipocytes. The results of a receptor binding assay showed the maximal AII binding capacity of adipocytes to be 8.3 +/- 0.9 fmol/7 x 10(6) cells and the dissociation constant to be 2.72 +/- 0.11 nM. Substantial expression of both type 1 and 2 AII (AT1 and AT2) receptors was detected by RT-PCR. AII had no effect on basal glucose uptake, but significantly potentiated insulin-stimulated glucose uptake; this effect was abolished by the AT1 antagonist, losartan. In addition, AII did not alter the insulin binding capacity of adipocytes, but increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, Akt phosphorylation, and translocation of glucose transporter 4 to the plasma membrane. AII potentiated insulin-stimulated glucose uptake through the AT1 receptor and by alteration of the intracellular signaling of insulin. Intraperitoneal injection of Sprague Dawley rats with AII increased insulin sensitivity in vivo. In conclusion, we have shown that AII enhances insulin sensitivity both in vitro and in vivo, suggesting that dysregulation of the insulin-sensitizing effect of AII may be involved in the development of insulin resistance.
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PMID:Angiotensin II enhances insulin sensitivity in vitro and in vivo. 1570 82

Increased renal sodium retention is considered a major risk factor contributing to hypertension associated with chronic hyperinsulinemia and obesity. However, the molecular mechanism involved is not understood. The present study investigates the effect of insulin treatment on AT1 receptor expression and ANG II-induced stimulation of Na/H exchanger (NHE) and Na-K-ATPase (NKA) in opossum kidney (OK) cells, a proximal tubule cell line. The presence of the AT1 receptors in OK cells was confirmed by the specific binding of 125I-sar-ANG II and by detecting approximately 43-kDa protein on Western blot analysis with AT1 receptor antibody and blocking peptide as well as by expression of AT1 receptor mRNA as determined by RT-PCR. Insulin treatment (100 nM for 24 h) caused an increase in 125I-sar-ANG II binding, AT1 receptor protein content, and mRNA levels. The whole cell lysate and membrane showed similar insulin-induced increase in the AT1 receptor protein expression, which was blocked by genistein (100 nM), a tyrosine kinase inhibitor, and cycloheximide (1.5 microg/ml), a protein synthesis inhibitor. Determination of ethyl isopropyl amiloride-sensitive 22Na+ uptake, a measure of the NHE activity, revealed that ANG II (1-100 pM)-induced stimulation of NHE in insulin-treated cells was significantly greater than in the control cells. Similarly, ANG II (1-100 pM)-induced stimulation of ouabain-sensitive 86Rb+ uptake, a measure of NKA activity in insulin-treated cells, was significantly greater than in the control cells. ANG II stimulation of both the transporters was blocked by AT1 receptor antagonist losartan, suggesting the involvement of AT1 receptors. Thus chronic insulin treatment causes upregulation of AT1 receptors, which evoked ANG II-induced stimulation of NHE and NKA. We propose that insulin-induced increase in the renal AT1 receptor function serves as a mechanism responsible for the increased renal sodium reabsorption and thus may contribute to development of hypertension in conditions associated with hyperinsulinemia.
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PMID:Insulin treatment enhances AT1 receptor function in OK cells. 1571 8

There is experimental evidence of an interaction between the angiotensin system and lipid metabolism. The aim of this study was to evaluate whether a block of the angiotensin system achieved both by ACE inhibition and angiotensin II-AT1 receptor blockade could affect the plasma lipid profile and, if so, what relationship exists between these possible changes and glucose metabolism and blood pressure. In 50 patients with type 2 diabetes and hypertension, treated with diabetes drugs and enalapril, we evaluated the glycemic and lipid profile together with the HOMA insulin-resistance index, blood pressure and microalbuminuria at baseline and 3 months after the addition of valsartan. At the second evaluation, blood pressure was reduced as expected, whereas the glycemic profile, the HOMA index, and the body mass index were unchanged. Total cholesterol, LDL-c, and apoprotein B were reduced during combination therapy (P = 0.003, P = 0.001, and P = 0.004, respectively), plasma HDL-c was slightly though significantly increased (P = 0.024), whereas apoprotein A and triglyceride levels did not change. After adjustment for the insulin resistance index and for blood pressure, the reduction of LDL-c and apoprotein B and the increase in HDL-c remained significant. The variation in lipid profile was not related to the changes in blood pressure. Moreover, the addition of valsartan to enalapril was associated with a reduction in microalbuminuria, which remained significant after adjustment for LDL-c or blood pressure changes. Thus, the greater degree of renin-angiotensin system blockade or specific pharmacodynamic effects of valsartan could account for the changes in plasma lipid profile observed in this study.
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PMID:Changes in plasma lipids during renin-angiotensin system blockade by combination therapy (enalapril plus valsartan) in patients with diabetes and hypertension. 1577 26

PPARs ("Peroxisome Proliferator-Activated Receptors") belong to a superfamily of nuclear receptors with several isoforms, among which PPAR-alpha mainly located in the liver and PPAR-gamma mainly located in the adipose tissue. These receptors are considered as major pharmacological targets since the discovery of their activation by specific agonists, which lead to various favourable metabolic effects. Improvement of lipid profile by fibrates is explained by the activation of liver PPAR-alpha receptors. However, PPAR-gamma receptors have focused most fundamental and clinical research in recent years after the demonstration of their activation by thiazolidinediones (pioglitazone, rosiglitazone), a new class of antidiabetic agents. Beyond their effects on insulin sensitivity, glitazones exert pleiotropic effects that may result in cardiovascular protection in high risk patients. It has been recently demonstrated that certain angiotensin AT1 receptor blockers (sartans) can also exert a partial agonist activity on PPAR-gamma. Among the molecules of this class, telmisartan appears to exert this effect at the lower concentrations. Thus, PPAR-y, as common pharmacological target, may, at least partially, explain some of the effects observed with both thiazolidinediones and inhibitors of the renin-angiotensin system, in particular the improvement in insulin sensitivity (in particular via an increase in adiponectin levels), the protection against type 2 diabetes, the reduction in arterial blood pressure and the prevention of cardiovascular complications. There is currently a major interest from the pharmaceutical industry in the development of new molecules able to activate both PPAR-alpha and PPAR-gamma.
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PMID:[PPAR-gamma receptors, new therapeutic target in metabolic and cardiovascular diseases]. 1581 71

Type 2 diabetes is a cardiovascular disease equivalent that is associated with accelerated atherosclerosis and significant mortality. However, the metabolic syndrome and prediabetes are associated with increased cardiovascular mortality, indicating that atherogenic vascular changes begin prior to the onset of overt diabetes. At the core of diabetes and the metabolic syndrome is insulin resistance (IR), which sets the stage for dyslipidemia, hypertension, and inflammation. Endothelial dysfunction is the first stage of the atherosclerosis process and results from exposure to cardiovascular risk factors, such as IR and diabetes. IR and atherosclerosis follow parallel paths as they progress in severity. Thiazolidinediones, angiotensin-converting enzyme inhibitors, angiotensin receptor-AT1 blockers, and statins are widely used in the treatment of diabetes. Emerging evidence indicates that these pharmacologic agents have added mechanisms of action, especially on the endothelium and in the prevention of diabetes.
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PMID:Insulin resistance and the endothelium. 1603 73

Ataxia telangiectasia (AT) is an infrequent condition, which is difficult to diagnose in children. The objective was to describe the evolution of all affected patients controlled in our hospital and to highlight the keys for an early diagnosis considering the variability of immunological disorders. The present study is a retrospective review of all patients diagnosed and controlled of AT in our hospital. Twelve patients were found, including two couples of siblings. The most frequent reason for consultation was unstable gait. Seven patients suffered repeated infections, being pneumonia the most frequent cause of infection, followed by sinusitis. One of the patients developed Burkitt's lymphoma, and another patient, Hodgkin's lymphoma, which caused the death of the patient at the age of 11. A couple of siblings aged 17 and 22 years developed insulin-resistant diabetes mellitus. The most frequent immunity disorders were the IgG deficiency and the decrease of T lymphocytes. Seven patients were treated with non-specific gamma-globulin. By the end of the follow-up, 8 patients (ages ranged 7 to 12 years) lost gait. Molecular genetic testing was conducted in patients who are still cared for in our hospital. Clinical suspicion of this entity will lead to an early diagnosis, the treatment of complications, and to provide genetic counselling for the families.
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PMID:Variability of immunodeficiency associated with ataxia telangiectasia and clinical evolution in 12 affected patients. 1623 88


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