Leptin is an adipokine of pleiotropic effects linked to energy metabolism, satiety, the immune re... more Leptin is an adipokine of pleiotropic effects linked to energy metabolism, satiety, the immune response, and cardioprotection. We have recently shown that leptin causally conferred resistance to myocardial infarction-induced damage in long-lived transgenic αMUPA mice overexpressing leptin compared to their wild type (WT) ancestral mice FVB/N. Prompted by these findings, we have investigated here if leptin can counteract the inflammatory response triggered after LPS administration in tissues in vivo and in cardiomyocytes in culture. The results have shown that LPS upregulated in vivo and in vitro all genes examined here, both pro-inflammatory and antioxidant, as well as the leptin gene. Pretreating mice with leptin neutralizing antibodies, further upregulated the expression of TNFα and IL-1β in the adipose tissue of both mouse types, and in the αMUPA heart. The antibodies also increased the levels of serum markers for cell toxicity in both mouse types. These results indicate that under LPS, leptin actually reduced the levels of these inflammatory-related parameters. In addition, pretreatment with leptin antibodies reduced the levels of HIF-1α and VEGF mRNAs in the heart, indicating that under LPS leptin increased the levels of these mRNAs. In cardiomyocytes, pretreatment with exogenous leptin prior to LPS reduced the expression of both pro-inflammatory genes, enhanced the expression of the antioxidant genes HO-1, SOD2 and HIF-1α, and lowered ROS staining. In addition, results obtained with leptin antibodies and the SMLA leptin antagonist indicated that endogenous and exogenous leptin can inhibit leptin gene expression. Together, these findings have indicated that under LPS, leptin concomitantly downregulated pro-inflammatory genes, upregulated antioxidant genes, and lowered ROS levels. These results suggest that leptin can counteract inflammation in the heart and adipose tissue by modulating gene expression.
The wide use of low energy lasers in wound healing has led to great interest in the mechanism. Of... more The wide use of low energy lasers in wound healing has led to great interest in the mechanism. Of low energy laser-skin cells interaction. Realizing that low energy lasers in the visible and near infra-red stimulate fibroblast proliferation, we decided to measure intracellular Ca2+ concentration ([Ca2+]), in the irradiated cells.
Several laboratories have shown that phencyclidine (PCP) and analog drugs interact with the ionic... more Several laboratories have shown that phencyclidine (PCP) and analog drugs interact with the ionic channel of the nicotinic acetylcholine receptor (AChR). These studies were done on two separate preparations, animal organs for electrophysiological studies and membrane preparations for biochemical studies. This work, however, was performed with myotubes grown in culture: these provide a convenient experimental system for the study of PCP and analog drug effects on both receptor function and receptor binding properties. Moreover, the extent of PCP retention by these cells was studied on the same preparations. All experiments were performed on viable cells in petri dishes. PCP and four PCP analogs were found to inhibit carbamylcholine induced 22Na and 45Ca ion fluxes with 50% inhibition (I50) at 2–6 μM drug concentration. The I50 for carbamylcholine induced 42K efflux was 8–20 μM. Ketamine was less efficient with an I50 of 100 μM. 125 I-α-Bungarotoxin binding was not affected at drug concentrations that cause 100% inhibition of ion fluxes. Uptake of 3H-PCP by the myotubes was a saturable process with half maximal saturation at ~ 20 μM PCP. It was inhibited by PCP and by several tertiary PCP analogs, with an I50 of ~ 20 μM. The quaternary analog PCP-methiodide (PCPMeI) however, was much less effective with an I50 of 1 mM. The capacity for 3H-PCP retention by the cells was 4 nmol/mg protein. PCPMeI was as potent as PCP in its inhibition of the AChR function although the amount retained by the cells was 50-fold lower than that of PCP. These results are consistent with the theory that PCP and analog drugs affect AChR function at a site other than the α-Bungarotoxin binding site, possibly at the ionic channel of the nicotinic receptor.
The Schumann Resonances (ScR) are Extremely Low Frequency (ELF) electromagnetic resonances in the... more The Schumann Resonances (ScR) are Extremely Low Frequency (ELF) electromagnetic resonances in the Earth-ionosphere cavity excited by global lightning discharges. This natural electromagnetic noise has likely existed on the Earth ever since the Earth had an atmosphere and an ionosphere, hence surrounding us throughout our evolutionary history. The purpose of this study was to examine the influence of extremely weak magnetic fields in the ScR first mode frequency range on the spontaneous contractions, calcium transients and Creatine Kinase (CK) release of rat cardiac cell cultures. We show that applying 7.8 Hz, 90 nT magnetic fields (MF) causes a gradual decrease in the spontaneous calcium transients’ amplitude, reaching 28% of the initial amplitude after 40 minutes of MF application, and accompanied with a gradual decrease in the calcium transients’ rise time. The mechanical spontaneous contractions cease after the ScR fields have been applied for more than 30 minutes, when the calci...
Various studies on humans and experimental mammals showed that d-sotalol and tedisamil (class III... more Various studies on humans and experimental mammals showed that d-sotalol and tedisamil (class III antiarrhythmic drugs with positive inotropic effect) facilitate spontaneous ventricular defibrillation. Following our previous results, we summarized that spontaneous ventricular defibrillation requires high level of intercellular coupling and synchronization, both of which depends on intracellular free Ca2+ concentration. We hypothesized that any antiarrhythmic compound that facilitates spontaneous defibrillation, including d-sotalol and tedisamil, should prevent intracellular free Ca2+ overload most likely by elevating cAMP level and enhancing cAMP-related Ca2+ uptake of the sarcoplasmic reticulum (SR). The aim of the present study was to examine the role of the SR uptake function in their effect against Ca2+ overload. The effect of d-sotalol, tedisamil and dbcAMP on increased intracellular Ca2+ level were examined in cultured rat cardiomyocytes during blockade of SR Ca2+ uptake by ad...
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 prev...
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia e... more Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca2+ uptake to the sarcoplasmic reticulum and Ca2+-dependent inhibition of ryanodine channels, leading to diastolic Ca2+ leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 ± 5 vs. 51 ± 7% in controls, P < 0.05) and improved after training (43 ± 12 and 51 ± 9% in KO and contr...
Leptin is an adipokine of pleiotropic effects linked to energy metabolism, satiety, the immune re... more Leptin is an adipokine of pleiotropic effects linked to energy metabolism, satiety, the immune response, and cardioprotection. We have recently shown that leptin causally conferred resistance to myocardial infarction-induced damage in long-lived transgenic αMUPA mice overexpressing leptin compared to their wild type (WT) ancestral mice FVB/N. Prompted by these findings, we have investigated here if leptin can counteract the inflammatory response triggered after LPS administration in tissues in vivo and in cardiomyocytes in culture. The results have shown that LPS upregulated in vivo and in vitro all genes examined here, both pro-inflammatory and antioxidant, as well as the leptin gene. Pretreating mice with leptin neutralizing antibodies, further upregulated the expression of TNFα and IL-1β in the adipose tissue of both mouse types, and in the αMUPA heart. The antibodies also increased the levels of serum markers for cell toxicity in both mouse types. These results indicate that under LPS, leptin actually reduced the levels of these inflammatory-related parameters. In addition, pretreatment with leptin antibodies reduced the levels of HIF-1α and VEGF mRNAs in the heart, indicating that under LPS leptin increased the levels of these mRNAs. In cardiomyocytes, pretreatment with exogenous leptin prior to LPS reduced the expression of both pro-inflammatory genes, enhanced the expression of the antioxidant genes HO-1, SOD2 and HIF-1α, and lowered ROS staining. In addition, results obtained with leptin antibodies and the SMLA leptin antagonist indicated that endogenous and exogenous leptin can inhibit leptin gene expression. Together, these findings have indicated that under LPS, leptin concomitantly downregulated pro-inflammatory genes, upregulated antioxidant genes, and lowered ROS levels. These results suggest that leptin can counteract inflammation in the heart and adipose tissue by modulating gene expression.
The wide use of low energy lasers in wound healing has led to great interest in the mechanism. Of... more The wide use of low energy lasers in wound healing has led to great interest in the mechanism. Of low energy laser-skin cells interaction. Realizing that low energy lasers in the visible and near infra-red stimulate fibroblast proliferation, we decided to measure intracellular Ca2+ concentration ([Ca2+]), in the irradiated cells.
Several laboratories have shown that phencyclidine (PCP) and analog drugs interact with the ionic... more Several laboratories have shown that phencyclidine (PCP) and analog drugs interact with the ionic channel of the nicotinic acetylcholine receptor (AChR). These studies were done on two separate preparations, animal organs for electrophysiological studies and membrane preparations for biochemical studies. This work, however, was performed with myotubes grown in culture: these provide a convenient experimental system for the study of PCP and analog drug effects on both receptor function and receptor binding properties. Moreover, the extent of PCP retention by these cells was studied on the same preparations. All experiments were performed on viable cells in petri dishes. PCP and four PCP analogs were found to inhibit carbamylcholine induced 22Na and 45Ca ion fluxes with 50% inhibition (I50) at 2–6 μM drug concentration. The I50 for carbamylcholine induced 42K efflux was 8–20 μM. Ketamine was less efficient with an I50 of 100 μM. 125 I-α-Bungarotoxin binding was not affected at drug concentrations that cause 100% inhibition of ion fluxes. Uptake of 3H-PCP by the myotubes was a saturable process with half maximal saturation at ~ 20 μM PCP. It was inhibited by PCP and by several tertiary PCP analogs, with an I50 of ~ 20 μM. The quaternary analog PCP-methiodide (PCPMeI) however, was much less effective with an I50 of 1 mM. The capacity for 3H-PCP retention by the cells was 4 nmol/mg protein. PCPMeI was as potent as PCP in its inhibition of the AChR function although the amount retained by the cells was 50-fold lower than that of PCP. These results are consistent with the theory that PCP and analog drugs affect AChR function at a site other than the α-Bungarotoxin binding site, possibly at the ionic channel of the nicotinic receptor.
The Schumann Resonances (ScR) are Extremely Low Frequency (ELF) electromagnetic resonances in the... more The Schumann Resonances (ScR) are Extremely Low Frequency (ELF) electromagnetic resonances in the Earth-ionosphere cavity excited by global lightning discharges. This natural electromagnetic noise has likely existed on the Earth ever since the Earth had an atmosphere and an ionosphere, hence surrounding us throughout our evolutionary history. The purpose of this study was to examine the influence of extremely weak magnetic fields in the ScR first mode frequency range on the spontaneous contractions, calcium transients and Creatine Kinase (CK) release of rat cardiac cell cultures. We show that applying 7.8 Hz, 90 nT magnetic fields (MF) causes a gradual decrease in the spontaneous calcium transients’ amplitude, reaching 28% of the initial amplitude after 40 minutes of MF application, and accompanied with a gradual decrease in the calcium transients’ rise time. The mechanical spontaneous contractions cease after the ScR fields have been applied for more than 30 minutes, when the calci...
Various studies on humans and experimental mammals showed that d-sotalol and tedisamil (class III... more Various studies on humans and experimental mammals showed that d-sotalol and tedisamil (class III antiarrhythmic drugs with positive inotropic effect) facilitate spontaneous ventricular defibrillation. Following our previous results, we summarized that spontaneous ventricular defibrillation requires high level of intercellular coupling and synchronization, both of which depends on intracellular free Ca2+ concentration. We hypothesized that any antiarrhythmic compound that facilitates spontaneous defibrillation, including d-sotalol and tedisamil, should prevent intracellular free Ca2+ overload most likely by elevating cAMP level and enhancing cAMP-related Ca2+ uptake of the sarcoplasmic reticulum (SR). The aim of the present study was to examine the role of the SR uptake function in their effect against Ca2+ overload. The effect of d-sotalol, tedisamil and dbcAMP on increased intracellular Ca2+ level were examined in cultured rat cardiomyocytes during blockade of SR Ca2+ uptake by ad...
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 prev...
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia e... more Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca2+ uptake to the sarcoplasmic reticulum and Ca2+-dependent inhibition of ryanodine channels, leading to diastolic Ca2+ leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 ± 5 vs. 51 ± 7% in controls, P < 0.05) and improved after training (43 ± 12 and 51 ± 9% in KO and contr...
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Papers by Asher Shainberg