Malka Cohen-Armon - Academia.edu (original) (raw)

Papers by Malka Cohen-Armon

Clinical Nephrology, Apr 1, 2016

Aminoglycosides (AG) cause nephrotoxicity in 10 - 20% of patients. One of the mechanisms is by ge... more Aminoglycosides (AG) cause nephrotoxicity in 10 - 20% of patients. One of the mechanisms is by generating reactive oxygen species (ROS), leading to DNA destruction and activation of poly(ADPribose) polymerase (PARP) causing necrotic tubular cell death. PARP inhibition on gentamicin-induced nephrotoxicity was studied. 19 female Wistar-Kyoto rats divided into 3 groups: control (3 rats receiving no treatment); gentamicin-treated group (8 rats); and 8 rats treated with gentamicin combined with 3-aminobenzamide (3 AB). Kidney functions, protein, and gentamicin levels as well as urinary trypsin inhibitory activity (TIA) were measured. Tissue microscopic examination and immunohistochemical study for proliferative cell nuclear antigen (PCNA) were determined. The effect of PARP inhibitor on the bactericidal activity of gentamicin was also assessed. The following results were statistically significant: urea (mg/dL) 39.9 ± 5.86, 88.3 ± 50.3, and 48.5 ± 12.7 (p = 0.048); serum creatinine (mg/dL): 0.6 ± 0.26, 1.05 ± 0.7, 0.6 ± 0.06 (p = 0.043); proteinuria (mg/24-hours): 7.27 ± 3.65, 41.2 ± 18.1, and 17.6 ± 13.9 (p = 0.050); the number of tubular macronuclei (per 10 mm2): 18.33 ± 16.07, 218 ± 101.8, 41.7 ± 36.2 (p = 0.012); the number of dilated tubes (per 10 mm2): 61.67 ± 12.58, 276.3 ± 112.7, 140.0 ± 90.9 (p = 0.04); and the number of PCNA positive nuclei (per 10 mm2): 223.3 ± 95.69, 3,585 ± 2,215.3, 626.7 ± 236.9 (p = 0.034) in the control, gentamicin, and gentamicin+3AB-treated groups, respectively. The following biochemical and histologic parameters were also examined, however, they showed no statistically significant difference: TIA (p = 0.055), mitoses (p = 0.14), mononuclear infiltrate (p = 0.188), and intratubular cast formation (p = 0.084). No effect on bactericidal activity was observed. This study illustrates that PARP inhibitor significantly attenuates gentamicininduced nephrotoxicity in rats with no effect on the bactericidal activity.

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Cells, May 7, 2022

Molecular Psychiatry, Sep 6, 2016

Reward-related memory is an important factor in cocaine seeking. One necessary signaling mechanis... more Reward-related memory is an important factor in cocaine seeking. One necessary signaling mechanism for long-term memory formation is the activation of poly(ADP-ribose) polymerase-1 (PARP-1), via poly(ADP-ribosyl)ation. We demonstrate herein that autopoly(ADP-ribosyl)ation of activated PARP-1 was significantly pronounced during retrieval of cocaine-associated contextual memory, in the central amygdala (CeA) of rats expressing cocaine-conditioned place preference (CPP). Intra-CeA pharmacological and short hairpin RNA depletion of PARP-1 activity during cocaine-associated memory retrieval abolished CPP. In contrast, PARP-1 inhibition after memory retrieval did not affect CPP reconsolidation process and subsequent retrievals. Chromatin immunoprecipitation sequencing revealed that PARP-1 binding in the CeA is highly enriched in genes involved in neuronal signaling. We identified among PARP targets in CeA a single gene, yet uncharacterized and encoding a putative transposase inhibitor, at which PARP-1 enrichment markedly increases during cocaine-associated memory retrieval and positively correlates with CPP. Our findings have important implications for understanding drug-related behaviors, and suggest possible future therapeutic targets for drug abuse.

Biochemical Journal, Aug 12, 2011

International Journal of Molecular Sciences, Apr 19, 2023

Neurochemistry & neuropharmacology, Aug 14, 2017

Scientific Reports, Apr 28, 2016

Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell resp... more Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PolyADP-ribose polymerases (PARPs) catalyze an abundant post-translational modification of nuclear proteins by polyADP-ribosylation. In this modification, NAD (Nicotinamide adenine dinucleotide) derived ADP-ribosyl moieties form ADP-ribose polymers on glutamate, lysine and aspartate residues of PARPs and their substrates 1,2. Binding of the most abundant nuclear polyADP-ribose polymerase PARP1 to DNA single-strand breaks activates the protein and thereby triggers DNA base-excision repair 1,2. Recent findings implicated PARP1 in additional processes in the chromatin, including gene expression regulated by chromatin remodeling, DNA methylation or recruitment of transcription factors 2-6. Moreover, alternative mechanisms of PARP1 activation in the absence of DNA damage were identified in a variety of cell types and cell-free systems. They include PARP1 activation by a variety of signal transduction mechanisms inducing intracellular Ca 2+ release and activation of phosphorylation cascades 2,7-9. Numerous findings implicated the phosphorylation of extracellular signal regulated kinase-2 (Erk2) in synaptic plasticity and long-term memory 10-12. Interestingly, recent in vivo experiments also revealed a pivotal role of PARP1 activation in long-term memory acquisition during learning 13-18 , but the explicit molecular mechanism underlying this unexpected role of PARP1 has not been identified. Here, we disclose a molecular mechanism in the chromatin of cerebral neurons, which is activated by stimulation-induced Erk-PARP1 binding and synergistic activity required for immediate early genes (IEG) expression implicated in long-term memory. Furthermore, identified intra-molecular rearrangements in DNA-bound PARP1 preventing its binding to phosphorylated Erk2, interfered with stimulation-induced IEG expression and LTP generation in the presence of DNA single-strand breaks, usually accumulated in aged irreplaceable cerebral neurons 19,20 .

Journal of Biological Chemistry, May 1, 1993

International Journal of Molecular Sciences

Unexpectedly, the affinity of the seven-transmembrane muscarinic acetylcholine receptors for thei... more Unexpectedly, the affinity of the seven-transmembrane muscarinic acetylcholine receptors for their agonists is modulated by membrane depolarization. Recent reports attribute this characteristic to an embedded charge movement in the muscarinic receptor, acting as a voltage sensor. However, this explanation is inconsistent with the results of experiments measuring acetylcholine binding to muscarinic receptors in brain synaptoneurosomes. According to these results, the gating of the voltage-dependent sodium channel (VDSC) acts as the voltage sensor, generating activation of Go-proteins in response to membrane depolarization, and this modulates the affinity of muscarinic receptors for their cholinergic agonists.

Israel journal of medical sciences, 1982

There is an inherent error in the voltage clamp, which is a major electrophysiological research t... more There is an inherent error in the voltage clamp, which is a major electrophysiological research tool. Current (I) flowing across the voltage-clamped membrane generates a drop in the resistance potential in series with the membrane (Rs) and thus an error in control of the potential. This error, which may be very significant, can only be partially corrected by electronic compensation during the experiment. Subsequent correction by computation is generally believed impossible for membrane potentials (Vm) for which the conductance parameters are voltage dependent. In the proposed method, which is based on the assumption that dI/dt is a function of I and Vm only, the reconstruction begins with very small sodium or potassium currents (for which the Rs error is negligible). The subsequent I value is calculated using a dI/dt value obtained under any set of conditions where Vm is known to have the desired value (as ensured by the experimental protocol) and where I equals the initial I value....

The Journal of Cell Biology, 2000

We present the first evidence for a fast activation of the nuclear protein poly(ADP-ribose) polym... more We present the first evidence for a fast activation of the nuclear protein poly(ADP-ribose) polymerase (PARP) by signals evoked in the cell membrane, constituting a novel mode of signaling to the cell nucleus. PARP, an abundant, highly conserved, chromatin-bound protein found only in eukaryotes, exclusively catalyzes polyADP-ribosylation of DNA-binding proteins, thereby modulating their activity. Activation of PARP, reportedly induced by formation of DNA breaks, is involved in DNA transcription, replication, and repair. Our findings demonstrate an alternative mechanism: a fast activation of PARP, evoked by inositol 1,4,5,-trisphosphate–Ca2+ mobilization, that does not involve DNA breaks. These findings identify PARP as a novel downstream target of phospholipase C, and unveil a novel fast signal–induced modification of DNA-binding proteins by polyADP-ribosylation.

Confocal images show polyADP-ribosylated nuclear proteins and pERKs in primary cultures of cortic... more Confocal images show polyADP-ribosylated nuclear proteins and pERKs in primary cultures of cortical neurons treated with BDNF (100 ng/ml, 5 min, 37oC) and with MEK inhibitors

Journal of Biological Chemistry, 1991

Journal of Biological Chemistry

ABSTRACT

Advances in second messenger and phosphoprotein research, 1988

Lupus, 1999

Antiphospholipid antibodies (aPL) are associated with neurological diseases such as stroke, migra... more Antiphospholipid antibodies (aPL) are associated with neurological diseases such as stroke, migraine, epilepsy and dementia and are thus associated with both vascular and non-vascular neurological disease. We have therefore examined the possibility that these antibodies interact directly with neuronal tissue by studying the electrophysiological effects of aPL on a brain synaptosoneurosome preparation. IgG from patients with high levels of aPL and neurological involvement was purified by protein-G affinity chromatography as was control IgG pooled from ten sera with low levels of aPL. Synaptoneurosomes were purified from perfused rat brain stem. IgG from the patient with the highest level of aPL at a concentration equivalent to 1:5 serum dilution caused significant depolarization of the synaptoneurosomes as determined by accumulation of the lipophylic cation [3H]-tetraphenylphosphonium. IgG from this patient as well as IgG from two elderly patients with high levels of aPL were subsequ...

Journal of Cardiovascular Pharmacology, 1984