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Prof. Philip Lazarovici
Laboratory of Neuropharmacology, Neuro-oncology and Neural Engineering, School of Pharmacy-Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel

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0 Drug Development
0 neurodegenerative diseases
0 disintegrins
0 Animal Venoms
0 neurotoxins

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In vitro and in vivo model systems
disintegrins
Drug Development
neurodegenerative diseases
neurotoxins
Neurotoxicity and neuroprotection

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Review article
Published: 05 February 2021 in Cytokine & Growth Factor Reviews
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Although lung innervation has been described by many studies in humans and rodents, the regulation of the respiratory system induced by neurotrophins is not fully understood. Here, we review current knowledge on the role of neurotrophins and the expression and function of their receptors in neurogenesis, vasculogenesis and during the embryonic development of the respiratory tree and highlight key implications relevant to respiratory diseases.

ACS Style

Limor Rubin; Collin T. Stabler; Adi Schumacher-Klinger; Cezary Marcinkiewicz; Peter I. Lelkes; Philip Lazarovici. Neurotrophic factors and their receptors in lung development and implications in lung diseases. Cytokine & Growth Factor Reviews 2021, 59, 84 -94.

AMA Style

Limor Rubin, Collin T. Stabler, Adi Schumacher-Klinger, Cezary Marcinkiewicz, Peter I. Lelkes, Philip Lazarovici. Neurotrophic factors and their receptors in lung development and implications in lung diseases. Cytokine & Growth Factor Reviews. 2021; 59 ():84-94.

Chicago/Turabian Style

Limor Rubin; Collin T. Stabler; Adi Schumacher-Klinger; Cezary Marcinkiewicz; Peter I. Lelkes; Philip Lazarovici. 2021. "Neurotrophic factors and their receptors in lung development and implications in lung diseases." Cytokine & Growth Factor Reviews 59, no. : 84-94.

Journal article
Published: 01 September 2020 in Peptides
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Humanin (HN) is a 24-amino acid mitochondrial-derived peptide, best known for its ability to protect neurons from damage caused by ischemic stroke and neurodegenerative insults and cardiomyocytes from myocardial infarction or doxorubicin (Dox)-induced cardiotoxicity. This study examines the neuroprotective and myoprotective effects of HN novel synthetic analogs HUJInin and c(d-ser14)HN, prepared by solid-phase peptide synthesis. The cellular models employed were oxygen-glucose-deprivation (OGD) followed by reoxygenation (R)-induced neurotoxicity in PC12 and SH-SY5Y neuronal cell cultures and Dox-induced cardiotoxicity in H9c2 and C2C12 myoblast cell cultures, respectively. Necrotic and apoptotic cell death was measured by LDH release and caspase-3 activity. Erk 1/2 and AKT phosphorylations were examined by western blotting. Mitochondrial calcium and mitochondrial membrane potential were measured using the fluorescent dye tetramethylrhodamine-methyl ester. It was found that HUJInin and c(d-ser14)HN conferred significant dose-dependent neuroprotection, a phenomenon related to attenuation of OGD insult-induced Erk 1/2 phosphorylation, stimulation of AKT phosphorylation and improvement of mitochondrial functions. These peptides also conferred myoprotective effect towards (Dox)-induced apo-necrotic cell death insults. HUJInin and c(d-ser14)HN synthetic analogs may provide new lead compounds for the development of a potential candidate drug for stroke treatment and/or DOX-induced cardiotoxicity therapy in cancer patients.

ACS Style

Chaim Gilon; Agata Gitlin-Domagalska; Adi Lahiani; Shiran Yehoshua- Alshanski; Adi Shumacher-Klinger; Dan Gilon; Mahmoud Taha; Israel Sekler; Amnon Hoffman; Philip Lazarovici. Novel humanin analogs confer neuroprotection and myoprotection to neuronal and myoblast cell cultures exposed to ischemia-like and doxorubicin-induced cell death insults. Peptides 2020, 134, 170399 .

AMA Style

Chaim Gilon, Agata Gitlin-Domagalska, Adi Lahiani, Shiran Yehoshua- Alshanski, Adi Shumacher-Klinger, Dan Gilon, Mahmoud Taha, Israel Sekler, Amnon Hoffman, Philip Lazarovici. Novel humanin analogs confer neuroprotection and myoprotection to neuronal and myoblast cell cultures exposed to ischemia-like and doxorubicin-induced cell death insults. Peptides. 2020; 134 ():170399.

Chicago/Turabian Style

Chaim Gilon; Agata Gitlin-Domagalska; Adi Lahiani; Shiran Yehoshua- Alshanski; Adi Shumacher-Klinger; Dan Gilon; Mahmoud Taha; Israel Sekler; Amnon Hoffman; Philip Lazarovici. 2020. "Novel humanin analogs confer neuroprotection and myoprotection to neuronal and myoblast cell cultures exposed to ischemia-like and doxorubicin-induced cell death insults." Peptides 134, no. : 170399.

Research article
Published: 15 July 2020 in ACS Chemical Neuroscience
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Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro “off-target” pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, towards development of a clinically relevant neurotropic drug.

ACS Style

Adi Lahiani; Dikla Haham-Geula; David Lankri; Susan Cornell-Kennon; Erik M. Schaefer; Dmitry Tsvelikhovsky; Philip Lazarovici. Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid. ACS Chemical Neuroscience 2020, 11, 2577 -2589.

AMA Style

Adi Lahiani, Dikla Haham-Geula, David Lankri, Susan Cornell-Kennon, Erik M. Schaefer, Dmitry Tsvelikhovsky, Philip Lazarovici. Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid. ACS Chemical Neuroscience. 2020; 11 (17):2577-2589.

Chicago/Turabian Style

Adi Lahiani; Dikla Haham-Geula; David Lankri; Susan Cornell-Kennon; Erik M. Schaefer; Dmitry Tsvelikhovsky; Philip Lazarovici. 2020. "Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid." ACS Chemical Neuroscience 11, no. 17: 2577-2589.

Review
Published: 31 December 2019 in Cells
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Dietary restriction (DR), which is defined as a reduction of particular or total nutrient intake without causing malnutrition, has been proved to be a robust way to extend both lifespan and health-span in various species from yeast to mammal. However, the molecular mechanisms by which DR confers benefits on longevity were not yet fully elucidated. The forkhead box O transcription factors (FOXOs), identified as downstream regulators of the insulin/IGF-1 signaling pathway, control the expression of many genes regulating crucial biological processes such as metabolic homeostasis, redox balance, stress response and cell viability and proliferation. The activity of FOXOs is also mediated by AMP-activated protein kinase (AMPK), sirtuins and the mammalian target of rapamycin (mTOR). Therefore, the FOXO-related pathways form a complex network critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis and to support physiological aging. In this review, we will focus on the role of FOXOs in different DR interventions. As different DR regimens or calorie (energy) restriction mimetics (CRMs) can elicit both distinct and overlapped DR-related signaling pathways, the benefits of DR may be maximized by combining diverse forms of interventions. In addition, a better understanding of the precise role of FOXOs in different mechanistic aspects of DR response would provide clear cellular and molecular insights on DR-induced increase of lifespan and health-span.

ACS Style

Yizhou Jiang; Fengxia Yan; Zhongping Feng; Philip Lazarovici; Wenhua Zheng. Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction. Cells 2019, 9, 100 .

AMA Style

Yizhou Jiang, Fengxia Yan, Zhongping Feng, Philip Lazarovici, Wenhua Zheng. Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction. Cells. 2019; 9 (1):100.

Chicago/Turabian Style

Yizhou Jiang; Fengxia Yan; Zhongping Feng; Philip Lazarovici; Wenhua Zheng. 2019. "Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction." Cells 9, no. 1: 100.

Protocol
Published: 02 October 2019 in Methods in Molecular Biology™
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Snake venoms could lead to the development of new drugs to treat a range of life-threatening conditions like cardiovascular diseases. Most snake venoms contain a large variety of lethal toxins as well as anti-adhesive proteins such as disintegrins, which have evolved from the harmless compounds ADAMs (proteins with a disintegrin and a metalloprotease domain) and C-type lectin proteins which disturb connective tissue and cell-matrix interaction. These anti-adhesive proteins target and block integrin receptors and disrupt normal biological processes in snakes’ prey such as connective tissue physiology and blood clotting. This chapter provides the experimental details of a practical, cell-based adhesion protocol to help identify and isolate disintegrins and C-type lectin proteins from snake venoms, important tools in integrin research and lead compounds for drug discovery.

ACS Style

Philip Lazarovici; Cezary Marcinkiewicz; Peter I. Lelkes. Cell-Based Adhesion Assays for Isolation of Snake Venom’s Integrin Antagonists. Methods in Molecular Biology™ 2019, 2068, 205 -223.

AMA Style

Philip Lazarovici, Cezary Marcinkiewicz, Peter I. Lelkes. Cell-Based Adhesion Assays for Isolation of Snake Venom’s Integrin Antagonists. Methods in Molecular Biology™. 2019; 2068 ():205-223.

Chicago/Turabian Style

Philip Lazarovici; Cezary Marcinkiewicz; Peter I. Lelkes. 2019. "Cell-Based Adhesion Assays for Isolation of Snake Venom’s Integrin Antagonists." Methods in Molecular Biology™ 2068, no. : 205-223.

Protocol
Published: 02 October 2019 in Methods in Molecular Biology
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Snake and spider venoms have been developed by nature as a defense mechanism against predators or to immobilize their prey by blocking the cardiovascular, respiratory, and/or nervous systems. Consequently, predators are deterred from approaching their prey by painful sensations. At a molecular level, the targeted physiological systems are blocked or stimulated by peptide toxins which, once injected into the body, modulate, though not exclusively, important cell membrane ion channels and receptors. Millions of years of constant evolution have led to the evolvement of complex venom libraries of optimized protein toxins, making them more potent, more selective, resistant to proteases, less immunogenic, and improved in terms of pharmacokinetic (PK) properties. The resulting advantage is that they induce long-term and potent pharmacodynamic (PD) effects toward unique molecular targets of therapeutic importance such as coagulation cascade proteins, receptors, and ionic channels. This optimization process has been enabled by the diversification of peptide sequences (mainly by gene duplication) and an upscaling of the complexity of toxin peptide scaffold structures, through implementation of multiple disulfide bridges and sequence-active motif diversification, leading to a wide diversity of chemical structures. This combination of pharmaceutical properties has made venom toxins valuable both as pharmacological tools and as leads for drug development. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. This brief overview provides basic definitions, rules, and methodologies and describes successful examples of a few drugs developed from snake toxins that are currently used in the clinic for therapy of several diseases as well as new molecular entities in clinical development based on spider-venom-derived peptide toxins.

ACS Style

Philip Lazarovici. Snake- and Spider-Venom-Derived Toxins as Lead Compounds for Drug Development. Methods in Molecular Biology 2019, 2068, 3 -26.

AMA Style

Philip Lazarovici. Snake- and Spider-Venom-Derived Toxins as Lead Compounds for Drug Development. Methods in Molecular Biology. 2019; 2068 ():3-26.

Chicago/Turabian Style

Philip Lazarovici. 2019. "Snake- and Spider-Venom-Derived Toxins as Lead Compounds for Drug Development." Methods in Molecular Biology 2068, no. : 3-26.

Protocol
Published: 02 October 2019 in Methods in Molecular Biology
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Snake and spider envenomation have a considerable impact on public health. Their pathology is induced by a variety of toxins composing the venom which induce cytotoxicity to cells of different organs by several cell death pathways. Described in this chapter are methods in vitro used to assess venoms and toxin-induced cell death using mammalian cell cultures. The chapter is divided into five sections: (1) a brief overview of in vitro cytotoxicity and categories of cell death induced by venoms and toxins; (2) a common method to measure necrotic cell death using lactate dehydrogenase (LDH) release; (3) a flow cytometry method that simultaneously measures necrosis and apoptosis; (4) measurements of nuclear morphology; and (5) measurements of the autophagy following microtubule-associated protein light chain 3 (LC3) expression, by immunoblotting and by fluorescence microscopy of LC3-positive vesicles, to assess the levels of autophagosomes.

ACS Style

Yossi Maatuf; Avi Priel; Philip Lazarovici. Measurements of Cell Death Induced by Snake and Spider's Venoms and Derived Toxins. Methods in Molecular Biology 2019, 2068, 239 -268.

AMA Style

Yossi Maatuf, Avi Priel, Philip Lazarovici. Measurements of Cell Death Induced by Snake and Spider's Venoms and Derived Toxins. Methods in Molecular Biology. 2019; 2068 ():239-268.

Chicago/Turabian Style

Yossi Maatuf; Avi Priel; Philip Lazarovici. 2019. "Measurements of Cell Death Induced by Snake and Spider's Venoms and Derived Toxins." Methods in Molecular Biology 2068, no. : 239-268.

Reference work
Published: 29 May 2019 in Encyclopedia of Gerontology and Population Aging
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ACS Style

Philip Lazarovici. Stem Cells Aging. Encyclopedia of Gerontology and Population Aging 2019, 1 -8.

AMA Style

Philip Lazarovici. Stem Cells Aging. Encyclopedia of Gerontology and Population Aging. 2019; ():1-8.

Chicago/Turabian Style

Philip Lazarovici. 2019. "Stem Cells Aging." Encyclopedia of Gerontology and Population Aging , no. : 1-8.

Review
Published: 27 May 2019 in Toxins
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Snake venoms are attractive natural sources for drug discovery and development, with a number of substances either in clinical use or in research and development. These drugs were developed based on RGD-containing snake venom disintegrins, which efficiently antagonize fibrinogen activation of αIIbβ3 integrin (glycoprotein GP IIb/IIIa). Typical examples of anti-platelet drugs found in clinics are Integrilin (Eptifibatide), a heptapeptide derived from Barbourin, a protein found in the venom of the American Southeastern pygmy rattlesnake and Aggrastat (Tirofiban), a small molecule based on the structure of Echistatin, and a protein found in the venom of the saw-scaled viper. Using a similar drug discovery approach, linear and cyclic peptides containing the sequence K(R)TS derived from VP12, a C-type lectin protein found in the venom of Israeli viper venom, were used as a template to synthesize Vipegitide, a novel peptidomimetic antagonist of α2β1 integrin, with anti-platelet activity. This review focus on drug discovery of these anti-platelet agents, their indications for clinical use in acute coronary syndromes and percutaneous coronary intervention based on several clinical trials, as well as their adverse effects.

ACS Style

Philip Lazarovici; Cezary Marcinkiewicz; Peter I. Lelkes. From Snake Venom's Disintegrins and C-Type Lectins to Anti-Platelet Drugs. Toxins 2019, 11, 303 .

AMA Style

Philip Lazarovici, Cezary Marcinkiewicz, Peter I. Lelkes. From Snake Venom's Disintegrins and C-Type Lectins to Anti-Platelet Drugs. Toxins. 2019; 11 (5):303.

Chicago/Turabian Style

Philip Lazarovici; Cezary Marcinkiewicz; Peter I. Lelkes. 2019. "From Snake Venom's Disintegrins and C-Type Lectins to Anti-Platelet Drugs." Toxins 11, no. 5: 303.

Journal article
Published: 07 June 2018 in The FASEB Journal
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Glioblastoma is an aggressive and invasive brain malignancy with high mortality rates despite current treatment modalities. In this study, we show that a 7-gene signature, previously found to govern the switch of glioblastomas from dormancy to aggressive tumor growth, correlates with improved overall survival of patients with glioblastoma. Using glioblastoma dormancy models, we validated the role of 2 genes from the signature, thrombospondin-1 (TSP-1) and epidermal growth factor receptor (EGFR), as regulators of glioblastoma dormancy and explored their therapeutic potential. EGFR up-regulation was reversed using EGFR small interfering RNA polyplex, antibody, or small-molecule inhibitor. The diminished function of TSP-1 was augmented via a peptidomimetic. The combination of EGFR inhibition and TSP-1 restoration led to enhanced therapeutic efficacy in vitro, in 3-dimensional patient-derived spheroids, and in a subcutaneous human glioblastoma model in vivo. Systemic administration of the combination therapy to mice bearing intracranial murine glioblastoma resulted in marginal therapeutic outcomes, probably due to brain delivery challenges, p53 mutation status, and the aggressive nature of the selected cell line. Nevertheless, this study provides a proof of concept for exploiting regulators of tumor dormancy for glioblastoma therapy. This therapeutic strategy can be exploited for future investigations using a variety of therapeutic entities that manipulate the expression of dormancy-associated genes in glioblastoma as well as in other cancer types.—Tiram, G., Ferber, S., Ofek, P., Eldar-Boock, A., Ben-Shushan, D., Yeini, E., Krivitsky, A., Blatt, R., Almog, N., Henkin, J., Amsalem, O., Yavin, E., Cohen, G., Lazarovici, P., Lee, J. S., Ruppin, E., Milyavsky, M., Grossman, R., Ram, Z., Calderón, M., Haag, R., Satchi-Fainaro, R. Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma.

ACS Style

Galia Tiram; Shiran Ferber; Paula Ofek; Anat Eldar-Boock; Dikla Ben-Shushan; Eilam Yeini; Adva Krivitsky; Roni Blatt; Nava Almog; Jack Henkin; Orit Amsalem; Eylon Yavin; Gadi Cohen; Philip Lazarovici; Joo Sang Lee; Eytan Ruppin; Michael Milyavsky; Rachel Grossman; Zvi Ram; Marcelo Calderón; Rainer Haag; Ronit Satchi-Fainaro. Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma. The FASEB Journal 2018, 32, 5835 -5850.

AMA Style

Galia Tiram, Shiran Ferber, Paula Ofek, Anat Eldar-Boock, Dikla Ben-Shushan, Eilam Yeini, Adva Krivitsky, Roni Blatt, Nava Almog, Jack Henkin, Orit Amsalem, Eylon Yavin, Gadi Cohen, Philip Lazarovici, Joo Sang Lee, Eytan Ruppin, Michael Milyavsky, Rachel Grossman, Zvi Ram, Marcelo Calderón, Rainer Haag, Ronit Satchi-Fainaro. Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma. The FASEB Journal. 2018; 32 (11):5835-5850.

Chicago/Turabian Style

Galia Tiram; Shiran Ferber; Paula Ofek; Anat Eldar-Boock; Dikla Ben-Shushan; Eilam Yeini; Adva Krivitsky; Roni Blatt; Nava Almog; Jack Henkin; Orit Amsalem; Eylon Yavin; Gadi Cohen; Philip Lazarovici; Joo Sang Lee; Eytan Ruppin; Michael Milyavsky; Rachel Grossman; Zvi Ram; Marcelo Calderón; Rainer Haag; Ronit Satchi-Fainaro. 2018. "Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma." The FASEB Journal 32, no. 11: 5835-5850.

Review
Published: 08 February 2018 in Brain Sciences
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This review surveys the efforts taken to investigate in vitro neuroprotective features of synthetic compounds and cell-released growth factors on PC12 clonal cell line temporarily deprived of oxygen and glucose followed by reoxygenation (OGD/R). These cells have been used previously to mimic some of the properties of in vivo brain ischemia-reperfusion-injury (IRI) and have been instrumental in identifying common mechanisms such as calcium overload, redox potential, lipid peroxidation and MAPKs modulation. In addition, they were useful for establishing the role of certain membrane penetrable cocktails of antioxidants as well as potential growth factors which may act in neuroprotection. Pharmacological mechanisms of neuroprotection addressing modulation of the MAPK cascade and increased redox potential by natural products, drugs and growth factors secreted by stem cells, in either undifferentiated or nerve growth factor-differentiated PC12 cells exposed to ischemic conditions are discussed for future prospects in neuroprotection studies.

ACS Style

Adi Lahiani; Annette Brand-Yavin; Ephraim Yavin; Philip Lazarovici. Neuroprotective Effects of Bioactive Compounds and MAPK Pathway Modulation in “Ischemia”—Stressed PC12 Pheochromocytoma Cells. Brain Sciences 2018, 8, 32 .

AMA Style

Adi Lahiani, Annette Brand-Yavin, Ephraim Yavin, Philip Lazarovici. Neuroprotective Effects of Bioactive Compounds and MAPK Pathway Modulation in “Ischemia”—Stressed PC12 Pheochromocytoma Cells. Brain Sciences. 2018; 8 (2):32.

Chicago/Turabian Style

Adi Lahiani; Annette Brand-Yavin; Ephraim Yavin; Philip Lazarovici. 2018. "Neuroprotective Effects of Bioactive Compounds and MAPK Pathway Modulation in “Ischemia”—Stressed PC12 Pheochromocytoma Cells." Brain Sciences 8, no. 2: 32.

Journal article
Published: 01 February 2018 in Cytotherapy
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These findings strengthen the role of NGF and its TrkA receptor in the HUCB CD45 subpopulation's neurotherapeutic effect. The presence of neurotrophin receptors in the HUCB CD45 pan-hematopoietic subpopulation may explain the neuroprotective effect of cord blood in therapy of a variety of neurological disorders.

ACS Style

Galit Gincberg; Esther Shohami; Victoria Trembovler; Alexander G. Alexandrovich; Philip Lazarovici; Uriel Elchalal. Nerve growth factor plays a role in the neurotherapeutic effect of a CD45 + pan-hematopoietic subpopulation derived from human umbilical cord blood in a traumatic brain injury model. Cytotherapy 2018, 20, 245 -261.

AMA Style

Galit Gincberg, Esther Shohami, Victoria Trembovler, Alexander G. Alexandrovich, Philip Lazarovici, Uriel Elchalal. Nerve growth factor plays a role in the neurotherapeutic effect of a CD45 + pan-hematopoietic subpopulation derived from human umbilical cord blood in a traumatic brain injury model. Cytotherapy. 2018; 20 (2):245-261.

Chicago/Turabian Style

Galit Gincberg; Esther Shohami; Victoria Trembovler; Alexander G. Alexandrovich; Philip Lazarovici; Uriel Elchalal. 2018. "Nerve growth factor plays a role in the neurotherapeutic effect of a CD45 + pan-hematopoietic subpopulation derived from human umbilical cord blood in a traumatic brain injury model." Cytotherapy 20, no. 2: 245-261.

Research article
Published: 15 December 2017 in ACS Chemical Neuroscience
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One of the main symptoms in degenerative diseases is death of neuronal cell followed by the loss of neuronal pathways. In neuronal cultures, neurite outgrowths are cell sprouts capable of transforming into either axons or dendrites, to further form functional neuronal synaptic connections. Such connections have an important role in brain cognition, neuronal plasticity, neuronal survival and regeneration. Therefore, drugs that stimulate neurite outgrowth may be found beneficial in ameliorating neural degeneration. Here, we establish the existence of a unique family of methylene-cycloalkylacetate-based molecules (MCAs) that interface with neuronal cell properties, and operate as acceptable pharmacophores for a novel neurotropic (neurite outgrowth inducing) lead compounds. Using an established PC12 cell bioassay, we investigated the neurotropic effect of methylene-cycloalkylacetate compounds by comparison to NGF, a known neurotropic factor. Micrographs of the cells were collected by a light microscope camera, and digitized photographs were analyzed for compounds- induced neurotropic activity using NIH image protocol. The results indicate that the alkene element, integrated within the cycloalkylacetate core, is indispensable for neurotropic activity. The discovered lead compounds need further mechanistic investigation and may be improved towards development of a neurotropic drug.

ACS Style

David Lankri; Dikla Haham; Adi Lahiani; Philip Lazarovici; Dmitry Tsvelikhovsky. Methylene-Cycloalkylacetate (MCA) Scaffold-Based Compounds as Novel Neurotropic Agents. ACS Chemical Neuroscience 2017, 9, 691 -698.

AMA Style

David Lankri, Dikla Haham, Adi Lahiani, Philip Lazarovici, Dmitry Tsvelikhovsky. Methylene-Cycloalkylacetate (MCA) Scaffold-Based Compounds as Novel Neurotropic Agents. ACS Chemical Neuroscience. 2017; 9 (4):691-698.

Chicago/Turabian Style

David Lankri; Dikla Haham; Adi Lahiani; Philip Lazarovici; Dmitry Tsvelikhovsky. 2017. "Methylene-Cycloalkylacetate (MCA) Scaffold-Based Compounds as Novel Neurotropic Agents." ACS Chemical Neuroscience 9, no. 4: 691-698.

Protocol
Published: 09 December 2017 in Neurotrophic Factors
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Nerve growth factor (NGF) is a neurotrophin promoting survival, proliferation, differentiation, and neuroprotection in the embryonal and adult nervous system. NGF also induces angiogenic effects in the cardiovascular system, which may be beneficial in engineering new blood vessels and for developing novel anti-angiogenesis therapies for cancer. Angiogenesis is a cellular process characterized by a number of events, including endothelial cell migration, invasion, and assembly into capillaries. In vitro endothelial tube formation assays are performed using primary human umbilical vein endothelial cells, human aortic endothelial cells, and other human or rodent primary endothelial cells isolated from the vasculature of both tumors and normal tissues. Immortalized endothelial cell lines are also used for these assays. When seeded onto Matrigel, these cells reorganize to create tubelike structure, which may be used as models for studying some aspects of in vitro angiogenesis. Image acquisition by light and fluorescence microscopy and/or quantification of fluorescently labeled cells can be carried out manually or digitally, using commercial software and automated image processing. Here we detail materials, procedure, assay conditions, and cell labeling for quantification of endothelial cell tube formation. This model can be applied to study cellular and molecular mechanisms by which NGF or other neurotrophins promote angiogenesis. This model may also be useful for the development of potential angiogenic and/or anti-angiogenic drugs targeting NGF receptors.

ACS Style

Philip Lazarovici; Adi Lahiani; Galit Gincberg; Dikla Haham; Arnon Fluksman; Ofra Benny; Cezary Marcinkiewicz; Peter I. Lelkes. Nerve Growth Factor-Induced Angiogenesis: 1. Endothelial Cell Tube Formation Assay. Neurotrophic Factors 2017, 1727, 239 -250.

AMA Style

Philip Lazarovici, Adi Lahiani, Galit Gincberg, Dikla Haham, Arnon Fluksman, Ofra Benny, Cezary Marcinkiewicz, Peter I. Lelkes. Nerve Growth Factor-Induced Angiogenesis: 1. Endothelial Cell Tube Formation Assay. Neurotrophic Factors. 2017; 1727 ():239-250.

Chicago/Turabian Style

Philip Lazarovici; Adi Lahiani; Galit Gincberg; Dikla Haham; Arnon Fluksman; Ofra Benny; Cezary Marcinkiewicz; Peter I. Lelkes. 2017. "Nerve Growth Factor-Induced Angiogenesis: 1. Endothelial Cell Tube Formation Assay." Neurotrophic Factors 1727, no. : 239-250.

Protocol
Published: 09 December 2017 in Advanced Structural Safety Studies
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The avian chorioallantoic membrane (CAM) is a simple, highly vascularized extraembryonic membrane, which performs multiple functions during embryonic development. Therefore, the models of chicken and quail assays represent robust experimental platforms to study angiogenesis, which reflects perturbation of the entire vascular tree. This experimental approach, when combined with fractal morphometry, is sensitive to changes in vascular branching pattern and density. Nerve growth factor is a neurotrophin promoting angiogenesis in CAM models. Here, we provide a detailed protocol of the quail CAM, shell-less model, to study nerve growth factor effects on blood capillary sprouting. The quail CAM assay may be beneficial in investigations of cellular and molecular aspects of neurotrophin-induced angiogenesis and for developing novel anti-angiogenesis and anticancer therapies.

ACS Style

Philip Lazarovici; Adi Lahiani; Galit Gincberg; Dikla Haham; Cezary Marcinkiewicz; Peter I. Lelkes. Nerve Growth Factor-Induced Angiogenesis: 2. The Quail Chorioallantoic Membrane Assay. Advanced Structural Safety Studies 2017, 1727, 251 -259.

AMA Style

Philip Lazarovici, Adi Lahiani, Galit Gincberg, Dikla Haham, Cezary Marcinkiewicz, Peter I. Lelkes. Nerve Growth Factor-Induced Angiogenesis: 2. The Quail Chorioallantoic Membrane Assay. Advanced Structural Safety Studies. 2017; 1727 ():251-259.

Chicago/Turabian Style

Philip Lazarovici; Adi Lahiani; Galit Gincberg; Dikla Haham; Cezary Marcinkiewicz; Peter I. Lelkes. 2017. "Nerve Growth Factor-Induced Angiogenesis: 2. The Quail Chorioallantoic Membrane Assay." Advanced Structural Safety Studies 1727, no. : 251-259.

Review
Published: 22 September 2017 in International Journal of Molecular Sciences
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Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

ACS Style

Haitao Wang; Jiangping Xu; Philip Lazarovici; Wenhua Zheng. Dysbindin-1 Involvement in the Etiology of Schizophrenia. International Journal of Molecular Sciences 2017, 18, 2044 .

AMA Style

Haitao Wang, Jiangping Xu, Philip Lazarovici, Wenhua Zheng. Dysbindin-1 Involvement in the Etiology of Schizophrenia. International Journal of Molecular Sciences. 2017; 18 (10):2044.

Chicago/Turabian Style

Haitao Wang; Jiangping Xu; Philip Lazarovici; Wenhua Zheng. 2017. "Dysbindin-1 Involvement in the Etiology of Schizophrenia." International Journal of Molecular Sciences 18, no. 10: 2044.

Journal article
Published: 01 July 2017 in Journal of Controlled Release
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SiRNA-based therapeutics possess great potential to treat a wide variety of genetic disorders. However, they suffer from low cellular uptake and short half-lives in blood circulation; issues that remain to be addressed. This work is, to the best of our knowledge, the first to report the production of solid nano-in-nanoparticles, termed double nano carriers (DNCs) by means of the innovative technology of Nano Spray Drying. DNCs (with a median size of 580-770 nm) were produced by spraying at low temperatures (50 °C) to prevent damage to heat-sensitive biomacromolecules like siRNA. DNCs consisting of Poly (D,L-lactide co-glycolide) used as a wall material, encapsulating 20% human serum albumin primary nanoparticles (PNPs) loaded with siRNA, were obtained as a dry nanoparticulate powder with smooth spherical surfaces and a unique inner morphology. Incubation of pegylated or non-pegylated DNCs under sink conditions at 37 °C, elicited a controlled release profile of the siRNA for up to 12 or 24 h, respectively, with a minimal burst effect. Prolonged incubation of pegylated DNCs loaded with active siRNA (anti EGFR) in an A549 epithelial cell culture monolayer did not induce any apparent cytotoxicity. A slow degradation of the internalized DNCs by the cells was also observed resulting in the progressive release of the siRNA for up to 6 days, as corroborated by laser confocal microscopy. The structural integrity and silencing activity of the double encapsulated siRNA was fully preserved, as demonstrated by HPLC, gel electrophoresis, and potent RNAi activity of siRNA extracted from DNCs. These results demonstrate the potential use of DNCs as a nano drug delivery system for systemic administration and controlled release of siRNA and potentially other sensitive bioactive macromolecules. Graphical Nano in nanoparticles: SEM images of intact double nano carriers (DNCs) (left) and a fractured DNC (following freeze-fracture process), showing the inner structure (right). Left insert shows the general architecture of pegylated DNCs and right insert is a zoom-in of the inner matrix of the DNCs, composed of polymeric PLGA fibers with HSA PNPs (~ 100 nm) embedded within them.

ACS Style

Orit Amsalem; Taher Nassar; Sandrine Benhamron; Philip Lazarovici; Simon Benita; Eylon Yavin. Solid nano-in-nanoparticles for potential delivery of siRNA. Journal of Controlled Release 2017, 257, 144 -155.

AMA Style

Orit Amsalem, Taher Nassar, Sandrine Benhamron, Philip Lazarovici, Simon Benita, Eylon Yavin. Solid nano-in-nanoparticles for potential delivery of siRNA. Journal of Controlled Release. 2017; 257 ():144-155.

Chicago/Turabian Style

Orit Amsalem; Taher Nassar; Sandrine Benhamron; Philip Lazarovici; Simon Benita; Eylon Yavin. 2017. "Solid nano-in-nanoparticles for potential delivery of siRNA." Journal of Controlled Release 257, no. : 144-155.

Review
Published: 16 March 2017 in Toxins
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An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as portal, and the modulation of the different portal’s signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A2 (PLA2) or phospholipase C (PLC) act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different toxins with respect to the site of action and the secondary messengers and signaling cascades they trigger in the host. While the interaction with the initial portal is largely determined by the chemical nature of the toxin, once inside the cell, several ubiquitous second messengers and protein kinases/ phosphatases pathways are impaired, to attain toxicity. Therefore, toxins represent one of the most promising natural molecules for developing novel therapeutics that selectively target the major cellular portals involved in human physiology and diseases.

ACS Style

Adi Lahiani; Ephraim Yavin; Philip Lazarovici. The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals. Toxins 2017, 9, 107 .

AMA Style

Adi Lahiani, Ephraim Yavin, Philip Lazarovici. The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals. Toxins. 2017; 9 (3):107.

Chicago/Turabian Style

Adi Lahiani; Ephraim Yavin; Philip Lazarovici. 2017. "The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals." Toxins 9, no. 3: 107.

Journal article
Published: 01 March 2017 in Biochimica et Biophysica Acta (BBA) - General Subjects
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Peptide and protein toxins are essential tools to dissect and probe the biology of their target receptors. Venoms target vital physiological processes to evoke pain. Snake venoms contain various factors with the ability to evoke, enhance and sustain pain sensation. While a number of venom-derived toxins were shown to directly target TRPV1 channels expressed on somatosensory nerve terminals to evoke pain response, such toxins were yet to be identified in snake venoms. We screened Echis coloratus saw-scaled viper venom's protein fractions isolated by reversed phase HPLC for their ability to activate TRPV1 channels. To this end, we employed heterologous systems to analyze TRPV1 and NGF pathways by imaging and electrophysiology, combined with molecular biology, biochemical, and pharmacological tools. We identified TRPV1 activating proteins in the venom of Echis coloratus that produce a channel-dependent increase in intracellular calcium and outwardly rectifying currents in neurons and heterologous systems. Interestingly, channel activation was not mediated by any of its known toxin binding sites. Moreover, although NGF neurotropic activity was detected in this venom, TRPV1 activation was independent of NGF receptors. Echis coloratus venom contains proteins with the ability to directly activate TRPV1. This activity is independent of the NGF pathway and is not mediated by known TRPV1 toxins' binding sites. Our results could facilitate the discovery of new toxins targeting TRPV1 to enhance current understanding of this receptor activation mechanism. Furthermore, the findings of this study provide insight into the mechanism through which snakes' venom elicit pain.

ACS Style

Matan Geron; Rakesh Kumar; Henry Matzner; Adi Lahiani; Galit Gincberg; Gadi Cohen; Philip Lazarovici; Avi Priel. Protein toxins of the Echis coloratus viper venom directly activate TRPV1. Biochimica et Biophysica Acta (BBA) - General Subjects 2017, 1861, 615 -623.

AMA Style

Matan Geron, Rakesh Kumar, Henry Matzner, Adi Lahiani, Galit Gincberg, Gadi Cohen, Philip Lazarovici, Avi Priel. Protein toxins of the Echis coloratus viper venom directly activate TRPV1. Biochimica et Biophysica Acta (BBA) - General Subjects. 2017; 1861 (3):615-623.

Chicago/Turabian Style

Matan Geron; Rakesh Kumar; Henry Matzner; Adi Lahiani; Galit Gincberg; Gadi Cohen; Philip Lazarovici; Avi Priel. 2017. "Protein toxins of the Echis coloratus viper venom directly activate TRPV1." Biochimica et Biophysica Acta (BBA) - General Subjects 1861, no. 3: 615-623.

Research article
Published: 22 August 2016 in ACS Chemical Neuroscience
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α-Lipoic acid (α-LA), a natural thiol antioxidant and Tempol, a synthetic free radical scavenger are known to confer neuroprotection following ischemic insults both in in vivo and in vitro models. The aim of this study was to synthesize and characterize a conjugate of α-LA and Tempol linked by polyethylene glycol (PEG) in order to generate a more efficacious neuroprotectant molecule. AD3 (α-Tempol ester-ω-lipo ester PEG) was synthesized, purified and characterized by flash chromatography, reverse phase high pressure liquid chromatography and by 1H nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. AD3 conferred neuroprotection in a PC12 pheochromocytoma cell line of dopaminergic origin, exposed to oxygen and glucose deprivation (OGD) insult measured by LDH release. AD3 exhibited EC50 at 10 µM and showed a 2-3 fold higher efficacy compared to the precursor moieties, indicating an intrinsic potent neuroprotective activity. AD3 attenuated by 25% the intracellular redox potential, by 54% lipid peroxidation and prevented phosphorylation of ERK, JNK and p38 by 57%, 22% and 21%, respectively. Cumulatively, these findings indicate that AD3 is a novel conjugate that confers neuroprotection by attenuation of MAPK phosphorylation and by modulation of the redox potential of the cells.

ACS Style

Adi Lahiani; Adel Hidmi; Jehoshua Katzhendler; Ephraim Yavin; Philip Lazarovici. Novel Synthetic PEGylated Conjugate of α-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia. ACS Chemical Neuroscience 2016, 7, 1452 -1462.

AMA Style

Adi Lahiani, Adel Hidmi, Jehoshua Katzhendler, Ephraim Yavin, Philip Lazarovici. Novel Synthetic PEGylated Conjugate of α-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia. ACS Chemical Neuroscience. 2016; 7 (10):1452-1462.

Chicago/Turabian Style

Adi Lahiani; Adel Hidmi; Jehoshua Katzhendler; Ephraim Yavin; Philip Lazarovici. 2016. "Novel Synthetic PEGylated Conjugate of α-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia." ACS Chemical Neuroscience 7, no. 10: 1452-1462.