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Biomedical subjects

A Israel

Publications and source records attributed to A Israel.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of NEMO, the regulatory subunit of the IKK complex, induces apoptosis in high-risk myelodysplastic syndrome and acute myeloid leukemia.

In high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), blasts constitutively activate the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB). Here, we show that this NF-kappaB activation relies on the constitutive activation of the IkappaB kinase (IKK) complex, which is formed by the IKKalpha, IKKbeta and IKKgamma/NF-kappaB essential modulator (NEMO) subunits. A cell-permeable peptide that mimics the leucine zipper subdomain of IKKgamma, thus preventing its oligomerization, inhibited the constitutive NF-kappaB activation and induced apoptotic cell death in a panel of human MDS and AML cell lines (P39, MOLM13, THP1 and MV4-11). Small interfering RNA-mediated knockdown of the p65 NF-kappaB subunit or the three IKK subunits including IKKgamma/NEMO also induced apoptotic cell death in P39 cells. Cell death induced by the IKKgamma/NEMO-antagonistic peptide involved the caspase-independent loss of the mitochondrial transmembrane potential as well as signs of outer mitochondrial membrane permeabilization with the consequent release of cytochrome c, apoptosis-inducing factor and endonuclease G. Primary bone marrow CD34(+) cells from high-risk MDS and AML patients also succumbed to the IKKgamma/NEMO-antagonistic peptide, but not to a mutated control peptide. Altogether, these data indicate that malignant cells in high-risk MDS and AML cells critically depend on IKKgamma/NEMO to survive. Moreover, our data delineate a novel procedure for their therapeutic removal, through inhibition of IKKgamma/NEMO oligomerization.

Acute Disease↗
PubMed2004

Anti-inflammatory activity of leaf extract and fractions of Bursera simaruba (L.) Sarg (Burseraceae).

Seeking for new medicinal compounds in plants used in traditional medicine, which grow in Venezuela, we investigated the anti-inflammatory activity of the leaf hexane extract (HE) and several fractions obtained from sp. Bursera simaruba (L.) Sarg. (Indio desnudo) using carrageenan-induced paw edema inflammation. Oral administration of leaf HE as well I (91-100) fraction, and compounds VIII 25-26 and VIII 29, inhibited the carrageenan-induced paw edema with different capacity and time course, over a period of 7h. The anti-inflammatory effect was comparable to that of the reference drug phenylbutazone (80 mg/kg, p.o.). Included in fraction I (91-100), Vitamin E was identified as one of its components and compound VIII 29 was identified as a methyl-beta-peltatin A. The comparison of the anti-inflammatory activity of VIII 29 fraction with the corresponding standard of methyl-beta-peltatin A, suggest that this compound could be one of the active principles involved in the anti-inflammatory activity of Bursera simaruba (L.) Sarg. leave. Our results contribute to the pharmacological support of the use of Bursera simaruba (L.) Sarg. as anti-inflammatory in the ethnomedicinal practice.

Administration, Oral↗
PubMed2002

Role of endothelin in stress-induced hypertension.

In this study we investigated the role of endogenous endothelin in the cardiovascular response to acute stress, ie mild footshocks in conscious rats. Footshock-stress significantly increased mean arterial pressure and heart rate (P < 0.05). Peripheral or intracerebroventricular (IVT) administration of BQ 788, a selective antagonist of ET(B) receptor, did not alter pressor response to footshocks. Intraperitoneal injections of BQ 123 (1 mg/kg), a selective antagonist of the ET(A)-receptor, had a tendency to decrease, while BQ 123 (203 ng/5 microl) IVT administration significantly reduced the pressor response to footshocks (-12 mm Hg, P < 0.001). Neither ET(A) nor ET(B) antagonists, when injected centrally or peripherally, altered basal blood pressure or heart rate. Our results may indicate a role of brain endothelin in the sympathetic mediated cardiovascular response to stress, via stimulation of ET(A) receptor.

Analysis of Variance↗
PubMed2002

Angiotensin II supports sympathetically mediated vasopressor response to footshock-stress.

The present study was carried out to assess whether endogenous angiotensin II (Ang II) supports sympathetically mediated cardiovascular response to stress in conscious unrestrained rats, using experimental models in which the renin-angiotensin-system was reduced or blocked. Footshock-stress increased mean arterial pressure (MAP) and heart rate (HR). Inhibition of angiotensin-converting enzyme with captopril or blockade of AT(1)angiotensin receptor with losartan, attenuated vasopressor responses to footshocks, while heart rate response was not altered. Bilateral nephrectomy suppressed vasopressor response as well the elevation of plasma noradrenaline and adrenaline induced by footshocks, and reduced heart rate response. Cardiovascular response to stress in nephrectomised rats was restored by exogenous administration of a subpressor dose of Ang II. Our results demonstrate that in conscious rats cardiovascular response to footshocks is dependent on an active renin-angiotensin system and they indicate that endogenous Ang II supports the sympathetically mediated vasopressor response to footshocks.

Analysis of Variance↗
PubMed2001

Modelling perspectives on aging: can mathematics help us stay young?

We survey several types of mathematical models that keep track of age distributions in a population, or follow some aspects of aging, such as loss of replicative potential of stem cells. The properties of a class of linear models of this type are discussed and compared. We illustrate the applicability of such models with a simple example based on hypothetical stem cell dynamics developed to address age-related telomere loss in the human granulocyte pool. We then describe the contrasting behaviour of nonlinear systems. Examples are drawn from the class of "dynamical diseases" to illustrate some of the aspects of nonlinear systems. Applications of these, and other models to the problems of aging and replicative aging are discussed.

Age Distribution↗
PubMed2001

Effect of adrenomedullin receptor and calcitonin gene-related peptide receptor antagonists on centrally mediated adrenomedullin renal action.

To determine pharmacological specificity of intracerebroventricular (IVT) administration of adrenomedullin (AM) on water and sodium excretion, studies were performed in rats pretreated with AM (22-52), a putative AM-receptor antagonist or CGRP(8-37), a ligand that preferentially antagonizes the CGRP(1)-receptor subtype. In addition, the effects of IVT injection of calcitonin-gene-related peptide (CGRP) on urinary water and electrolyte excretion was assessed. Intracerebroventricular administration of rat adrenomedullin to conscious hydrated rats resulted in a significant increase in urinary volume and sodium excretion during the 6-h period of urine collection and was most effective at 3 and 6 h. Although less effective than AM, central administration of CGRP induced diuresis and natriuresis. Pretreatment with AM (22-52) or CGRP(8-37) significantly suppressed the diuretic and natriuretic effect of IVT-AM. These data suggest that both CGRP(1) and AM receptors are involved in the centrally mediated diuretic and natriuretic action of the AM. Our results provide evidence supporting the hypothesis that endogenous AM plays a role in the central nervous control of fluid and electrolyte homeostasis.

Adrenomedullin↗
PubMed2000

Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation.

NF-kappaB activity is induced by cytokines, stress, and pathogens. IKK1 and IKK2 are critical IkappaB kinases in NF-kappaB activation. In this study mice lacking IKK1 and IKK2 died at E12. Additional defect in neurulation associated with enhanced apoptosis in the neuroepithelium was also observed. MEF cells from IKK1(-/-)/IKK2(-/-) embryos did not respond to NF-kappaB inducers. Upon crossing with kappaB-lacZ transgenic mice, double-deficient embryos also lost lacZ transgene expression in vascular endothelial cells during development. Our data suggest that IKK1 and IKK2 are essential for NF-kappaB activation in vivo and have an important role in protecting neurons against excessive apoptosis during development.

Alleles↗
PubMed2000

Diuretic and natriuretic action of adrenomedullin administered intracerebroventricularly in conscious rats.

Intracerebroventricular administration of rat adrenomedullin (AM) to conscious hydrated or salt-loaded rats, resulted in a significant increase in urinary volume. The diuretic effect of adrenomedullin occurred during the 6-h period of urine collection and was most effective during the 3 and 6 h. Most remarkably, AM given IVT induced a dose-related increase in urinary sodium excretion at all periods of urine collection. In addition, AM induced significant kaliuresis. Our results strongly suggest that AM may play a significant role in the central regulation of fluid and electrolyte homeostasis, and that its diuretic and natriuretic effect may be, at least in part, centrally mediated.

Adrenomedullin↗
PubMed2000

Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation.

NF-kappaB is regulated by inhibitor proteins (IkappaBs), which retain NF-kappaB in the cytoplasm. Signal-induced phosphorylation by the IkappaB-kinase complex containing the IkappaB-kinases 1 and 2 (IKK-1/2 or IKK-alpha/beta) and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation. Many signals induce NF-kappaB, one of them being oncogenic Raf kinase. We investigated whether NF-kappaB induction is critical for Raf-mediated transformation. Here, we demonstrate that inhibition of NF-kappaB interferes with transformation by the Raf-oncogene, and we characterized the mechanism of NF-kappaB induction by activated Raf kinase and the tumor promoter phorbol 12-myristate 13-acetate (PMA). NF-kappaB activation by PMA and Raf critically depends on the IkappaB-kinase complex, most notably on IKK-2. A major signaling pathway induced by Raf is the mitogenic cytoplasmic kinase cascade. However, different inhibitors of this cascade do not affect PMA- and Raf-mediated NF-kappaB activation. Raf does not phosphorylate the IkappaB-kinase proteins directly. Raf rather synergizes with another membrane shuttle kinase MEKK1, and Raf-mediated activation of NF-kappaB is blocked by a dominant negative form of MEKK1. These results suggest that Raf induction of NF-kappaB is relayed by MEKK1, but not by the classical mitogenic cytoplasmic kinase cascade.

Animals↗
PubMed2000

Angiotensin AT(2) receptors mediate vasodepressor response to footshock in rats. Role of kinins, nitric oxide and prostaglandins.

Footshocks increased mean arterial pressure and heart rate. Systemic administration of losartan, a specific angiotensin AT(1) receptor antagonist, not only inhibited the pressor response to footshocks, but also resulted in vasodepression. Administration of 1-[[4-(dimethylamino)3-methylphenyl]methyl]-5 (diphenylacetyl)-4,5,6, 7-tetrahydro-1H imidazol (4,5-c] pyridine-6-carboxilic acid, ditrifluoro acetatemonohydrate (PD 123319), a specific angiotensin AT(2) receptor antagonist, did not alter the hemodynamic response to footshocks. Simultaneous blockade of angiotensin AT(1) and AT(2) receptors by combined administration of losartan and PD 123319, eliminated the vasodepressor response to footshocks unmasked in losartan-pretreated rats. Saralasin, a non-specific angiotensin receptor antagonist, abolished the cardiovascular response to footshocks similarly like the losartan+PD 123319 treatment. Our data suggest that the vasodepressor response to footshocks in the presence of an angiotensin AT(1) receptor antagonist is triggered by activation of angiotensin AT(2) receptors. We studied the role of kinins, nitric oxide and prostaglandins in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan-treated rats was blunted by icatibant (HOE 140), N(G)-nitro-L-arginine-methyl ester (L-NAME) or indomethacin, indicating that kinins, nitric oxide and prostaglandins appear to be involved in the pressure response to footshocks during angiotensin AT(1) receptor blockade.

Animals↗
PubMed2000

Brain AT(2) receptor mediate vasodepressor response to footshocks: role of kinins and nitric oxide.

In the present study the role of brain AT(2) receptor in the cardiovascular response to stress was investigated in conscious rats. Footshock-stress increased mean arterial pressure (MAP) and heart rate (p < 0.0001). Intracerebroventricular (i.c.v.) administration of losartan (100 microg/5 microl), a specific angiotensin AT(1) receptor antagonist, not only attenuated the pressor response to footshocks, but also resulted in a consistent vasodepressor response (-10 mmHg, p < 0.02). Meanwhile, heart rate response was not altered. Given alone, PD 123319 (3 microg/5 microl, i.c.v.), a specific angiotensin AT(2) receptor antagonist, did not alter the hemodynamic response to footshocks. However, simultaneous block of brain AT(1) and AT(2) receptors by combined administration of losartan and PD 12319, eliminated the vasodepressor response unmasked after footshocks in rats i.c.v.-pretreated with losartan alone. In addition, we studied the role of brain kinins and nitric oxide (NO) in the vasodepressor response observed after footshocks in losartan i.c.v.-treated rats. Intracerebroventricular administration of icatibant (20 pmol/5 microl), a selective B(2) receptor antagonist, or N(G)-nitro-L-arginine methyl ester (100 microg/5 microl), a selective NO-synthase inhibitor, abolished the vasodepressor response to footshocks in losartan-treated rats. Our data suggest that the vasodepressor response to footshocks in the presence of AT(1) antagonist is triggered by activation of AT(2) receptor. Brain NO and kinins appear to contribute in this effect.

Angiotensin II↗
PubMed2000

Renin-angiotensin-aldosterone system in pregnancy-induced hypertension.

Angiotensin-converting enzyme (ACE) and aldosterone concentration were measured in the plasma of 32 pregnant women with normal blood pressure or with pregnancy-induced hypertension (PIH). Mean arterial pressure (MAP) in PIH women was significantly higher than in normotensive pregnant women. Plasma ACE activity and aldosterone concentration in 17 PIH patients was significantly lower than their normotensive counterparts (15 cases). Mean arterial pressure was negatively correlated with the level of plasma ACE activity and with plasma aldosterone concentration in all pregnant women. Our results indicate that the circulating renin-angiotensin-aldosterone system is suppressed in pregnancy-induced hypertension.

Adult↗
PubMed2000

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension.

Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT1 and AT2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT2 receptor mediated the vasodepressor response to footshocks in the presence of angiotensin AT1 receptor antagonist. We studied the role of kinins and nitric oxide in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan treated rats was blunted by systemic or IVT administration of icatibant (HOE 140) or N(G)-nitro-L-arginine-methyl ester, indicating that peripheral or brain kinins and nitric oxide are involved in the hypotensor response to footshocks during angiotensin AT1 receptor blockade. Our results suggest a role for angiotensin AT2 receptor in the regulation of arterial blood pressure, possibly through the release of vasodilator autacoids such as bradykinins and nitric oxide.

Adrenergic beta-Antagonists↗
PubMed2000

A prospective comparison of three heat preservation methods for patients undergoing hypothermic cardiopulmonary bypass.

OBJECTIVE: To prospectively compare 3 methods of body heat preservation in patients undergoing surgery requiring the use of hypothermic cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, and nonblinded. SETTING: University teaching hospital. PARTICIPANTS: Adult cardiac surgery patients (n = 101). INTERVENTIONS: Subjects were randomly assigned to 1 of 3 treatment groups: Group 1 (n = 33) used a fluid-filled warming blanket, group 2 (n = 31) used a heated and humidified breathing circuit, and group 3 (n = 37) used intravenous fluid warmers for the administration of all fluids. Treatments started on separation from CPB and concluded at the end of the intraoperative experience. Anesthetic technique, minute ventilation, conduct of CPB, and room temperature in the operating room were standardized. MEASUREMENTS AND MAIN RESULTS: Blood temperature was measured at its nadir on CPB, on separation from CPB, and just before departure from the operating room. No differences were found among groups for CPB duration, coldest venous temperature on CPB, rewarming time, rate of rewarming, room temperature, or blood temperature on separation from CPB. There were no significant differences found in post-CPB temperature afterdrop among groups. CONCLUSIONS: This study suggests that there is no statistically significant disparity in the effectiveness of these 3 intraoperative heat preservation methods. Ease of use and cost-effectiveness should guide the choice of warming method post-CPB.

Adult↗
PubMed1999

Listeriolysin O-dependent activation of endothelial cells during infection with Listeria monocytogenes: activation of NF-kappa B and upregulation of adhesion molecules and chemokines.

The facultative intracellular bacterium Listeria monocytogenes is an invasive pathogen that crosses the vascular endothelium and disseminates to the placenta and the central nervous system. Its interaction with endothelial cells is crucial for the pathogenesis of listeriosis. By infecting in vitro human umbilical vein endothelial cells (HUVEC) with L. monocytogenes, we found that wild-type bacteria induced the expression of the adhesion molecules (ICAM-1 and E-selectin), chemokine secretion (IL-8 and monocyte chemotactic protein-1) and NF-kappa B nuclear translocation. The activation of HUVEC required viable bacteria and was abolished in prfA-deficient mutants of L. monocytogenes, suggesting that virulence genes are associated with endothelial cell activation. Using a genetic approach with mutants of virulence genes, we found that listeriolysin O (LLO)-deficient mutants inactivated in the hly gene did not induce HUVEC activation, as opposed to mutants inactivated in the other virulence genes. Adhesion molecule expression, chemokine secretion and NF-kappa B activation were fully restored by a strain of Listeria innocua transformed with the hly gene encoding LLO. The relevance in vivo of endothelial cell activation for listerial pathogenesis was investigated in transgenic mice carrying an NF-kappa B-responsive lacZ reporter gene. NF-kappa B activation was visualized by a strong lacZ expression in endothelial cells of capillaries of mice infected with a virulent haemolytic strain, but was not seen in those infected with a non-haemolytic isogenic mutant. Direct evidence that LLO is involved in NF-kappa B activation in transgenic mice was provided by injecting intravenously purified LLO, thus inducing stimulation of NF-kappa B in endothelial cells of blood capillaries. Our results demonstrate that functional listeriolysin O secreted by bacteria contributes as a potent inflammatory stimulus to inducing endothelial cell activation during the infectious process.

Ampicillin↗
PubMed1999

Nitric oxide/cGMP mediates the spasmolytic action of 3,4'-dihydroxy-5,5'-dimethoxybibenzyl from Scaphyglottis livida.

Five aromatic compounds, 3,4'-dihydroxy-5,5'-dimethoxybibenzyl (1), batatasin III (2), coelonin (3), 3,7-dihydroxy-2,4-dimethoxyphenanthrene (4), and 3,7-dihydroxy-2,4,8-trimethoxyphenanthrene (5) were isolated from the orchid Scaphyglottis livida (Lindley) Schltr. Compounds 1-5 induced a concentration-dependent inhibition of the spontaneous contractions of the rat ileum with potencies comparable or higher to that of papaverine. The relaxation evoked by compounds 1-4 was blocked by L-NAME, an inhibitor of nitric oxide synthase. It was also demonstrated that 1 increased cyclic GMP content in rat ileum rings. Compound 1-induced elevation of cGMP was inhibited by L-NAME and ODQ, inhibitors of nitric oxide synthase and soluble guanylyl cyclase, respectively. These results indicate that nitric oxide/cGMP formation constitute the signaling pathway in the spasmolytic action of compound 1.

Animals↗
PubMed1999

Endothelin-1 stimulates phosphoinositide hydrolysis in the rat pineal gland.

The presence of functional endothelin receptors and their signal transduction mechanism has not been determined so far in the pineal gland. We examined the effect of endothelin-1 (ET-1) on phosphoinositide turnover in whole pineal gland. Endothelin-1 increased monophosphate accumulation in a dose-dependent manner. The phosphoinositide (PI) response elicited by ET-1 was dependent on the presence of extracellular Ca (++) since its chelation resulted in a marked decrease in ET-1-stimulated InsP(1) accumulation. On the contrary, phosphoinositide hydrolysis was not changed by the calcium blocker amlodipine. ET-1 induced PI breakdown was inhibited by neomycin, an inhibitor of phospholipase C. However, mastoparan 7, a G protein activator via Gi/Go s timulation, did not alter ET-1-induced InsP(1) accumulation. Our data indicate that stimulation of PI turnover constitutes one of the signaling pathways of ET in rat pineal gland through the stimulation of a receptor-coupled phospholipase C. And they demonstrate, for the first time, the presence of functional binding sites for endothelin in the pineal gland.

Amlodipine↗