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Mechanism of taurine protection against endoplasmic reticulum stress induced by glutamate in primary cortical neurons
Title
Mechanism of taurine protection against endoplasmic reticulum stress induced by glutamate in primary cortical neurons.
Creator
Pan, Chunliu, Wu, Jang-Yen, Prentice, Howard, Graduate College
Date Issued
2011-04-08
PURL
http://purl.flvc.org/fcla/dt/3164675
Subject Headings
Taurine, Endoplasmic reticulum, Glutamates
Format
Document (PDF)
Role of taurine in the central nervous system
Title
Role of taurine in the central nervous system.
Creator
Wu, Jang-Yen, Prentice, Howard
Date Issued
2010-08-24
PURL
http://purl.flvc.org/fau/fd/FADT3327262
Subject Headings
Central Nervous System --metabolism, Glutamic Acid --metabolism, Homeostasis --physiology, Neuroprotective Agents --metabolism, Neurotransmitter Agents --metabolism, Proto-Oncogene Proteins c-bcl-2 --metabolism, Receptors, Neurotransmitter --metabolism, Signal Transduction --physiology, Taurine, Taurine --metabolism, Neuroprotective Agents, Neurotransmitter Agents
Format
Document (PDF)
Protection of taurine and granulocyte colony-stimulating factor against excitotoxicity induced by glutamate in primary cortical neurons
Title
Protection of taurine and granulocyte colony-stimulating factor against excitotoxicity induced by glutamate in primary cortical neurons.
Creator
Pan, Chunliu, Gupta, Amit, Prentice, Howard, Wu, Jang-Yen
Date Issued
2010-08-24
PURL
http://purl.flvc.org/fcla/dt/3329093
Format
Document (PDF)
Calpain Cleavage of Brain Glutamic Acid Decarboxylase 65 Is Pathological and Impairs GABA Neurotransmission
Title
Calpain Cleavage of Brain Glutamic Acid Decarboxylase 65 Is Pathological and Impairs GABA Neurotransmission.
Creator
Buddhala, Chandana, Suarez, Marjorie, Modi, Jigar P., Prentice, Howard, Ma, Zhiyuan, Tao, Rui, Wu, Jang-Yen, Smalheiser, Neil R.
Date Issued
2012-03-12
PURL
http://purl.flvc.org/fau/fd/FAUIR000097
Format
Citation
Calpain Cleavage of GAD65 is pathological and impairs gaba neurotransmission
Title
Calpain Cleavage of GAD65 is pathological and impairs gaba neurotransmission.
Creator
Buddhala, Chandana, Suarez, Marjorie, Alexandrescu, Anamaria, Pissaris, Adam, Modi, Jigar P., Wei, Jianning, Prentice, Howard, Wu, Jang-Yen, Graduate College
Date Issued
2011-04-08
PURL
http://purl.flvc.org/fcla/dt/3164511
Subject Headings
Nervous System Diseases, GABA --physiology, Gamma-aminoboterzuur
Format
Document (PDF)
Taurine protection of PC12 cells against endoplasmic reticulum stress induced by oxidative stress
Title
Taurine protection of PC12 cells against endoplasmic reticulum stress induced by oxidative stress.
Creator
Pan, Chunliu, Giraldo, Grace S., Prentice, Howard, Wu, Jang-Yen
Date Issued
2010-08-24
PURL
http://purl.flvc.org/fcla/dt/3327276
Subject Headings
Oxidative Stress, Oxidative Stress --drug effects, Oxidative Stress --physiology, Antioxidants --pharmacology, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-bcl-2, PC12 Cells --drug effects, Endoplasmic Reticulum --drug effects, Transcription Factor CHOP, Taurine
Format
Document (PDF)
GCSF GENE THERAPY FOR PARKINSON’S DISEASE
Title
GCSF GENE THERAPY FOR PARKINSON’S DISEASE.
Creator
Lee, Zachary, Wu, Jang-Yen, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Medicine
Abstract/Description
The kynurenine pathway plays a critical role in regulating immunological homeostasis in the brain. Evidence supporting the hypothesis that kynurenine pathway dysfunction may exacerbate progression of neurodegenerative diseases like Parkinson’s is growing. First, we investigate the effects of Interferon-γ, Lipopolysaccharide, and Interleukin-4 on several key kynurenine pathway metabolites using high performance liquid chromatography. We found that Interferon-γ had significant effects on the...
Show moreThe kynurenine pathway plays a critical role in regulating immunological homeostasis in the brain. Evidence supporting the hypothesis that kynurenine pathway dysfunction may exacerbate progression of neurodegenerative diseases like Parkinson’s is growing. First, we investigate the effects of Interferon-γ, Lipopolysaccharide, and Interleukin-4 on several key kynurenine pathway metabolites using high performance liquid chromatography. We found that Interferon-γ had significant effects on the extracellular concentration of kynurenine metabolites in astrocytes, microglia, and macrophage. GCSF gene therapy is previously demonstrated to exert neuroprotective effects on models of Parkinson’s and Alzheimer’s disease. Seven days after receiving GCSF gene therapy, A53T Parkinson’s mice were found to have increased levels of GCSF and tyrosine hydroxylase positive neurons. A concurrent increase in expression of the kynurenine pathway enzyme kynurenine aminotransferase 2 was observed. GCSF gene therapy may exhibit neuroprotective effects in a Parkinson’s disease mouse model by restoring this key kynurenine pathway enzyme.
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Date Issued
2021
PURL
http://purl.flvc.org/fau/fd/FA00013773
Subject Headings
Parkinson Disease, Gene therapy, Kynurenine
Format
Document (PDF)
Protective Mechanisms of Granulocyte-Colony Stimulating Factor Against Experimental Models of Stroke
Title
Protective Mechanisms of Granulocyte-Colony Stimulating Factor Against Experimental Models of Stroke.
Creator
Menzie-Suderam, Janet, Wu, Jang-Yen, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description
Ischemic stroke has a multiplicity of pathophysiological mechanisms. Granulocyte-colony stimulating factor (G-CSF) is an endogenous growth factor that exerts a diverse range of neuroprotection against ischemic stroke. Several lines of evidence demonstrated the contribution of endoplasmic reticulum (ER) in apoptotic cell death involving ischemia. Cell culture of undifferentiated PC12 cells were subjected to 10mM glutamate and selected doses of G-CSF (25ng/ml, 50ng/ml, 100ng/ml and 250ng/ml)...
Show moreIschemic stroke has a multiplicity of pathophysiological mechanisms. Granulocyte-colony stimulating factor (G-CSF) is an endogenous growth factor that exerts a diverse range of neuroprotection against ischemic stroke. Several lines of evidence demonstrated the contribution of endoplasmic reticulum (ER) in apoptotic cell death involving ischemia. Cell culture of undifferentiated PC12 cells were subjected to 10mM glutamate and selected doses of G-CSF (25ng/ml, 50ng/ml, 100ng/ml and 250ng/ml) for 24 hours. Cell viability, expression of the G-CSF receptor and expression level of CHOP were assessed in vitro. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Rats were subcutaneously injected with G-CSF (n= 15; 50ug/kg body weight) 24 hours post-MCAO for 4 days. Vehicle treated rats were administered 5% dextrose for 1 day (n=4) or 4 days (n=16). Sham-operated rats (n=9) were not subjected to MCAO. Neurological deficit and infarct volume were measured while expression levels of pAKT, Bcl2, Bax, Bak, cleaved caspase-3, GRP78, ATF4, ATF6, p-p38MAPK, pJNK, CHOP and HSP27 were analyzed by western blotting. In vitro G-CSF receptor was expressed on undifferentiated PC12 cell, and an optimal dose of 50 ng/ml G-CSF significantly protected these cells against glutamate-induced cytotoxicity (P < 0.05). G-CSF significantly down-regulated (P < 0.01) the ER stressinduced pro-apoptotic marker CHOP in vitro. In vivo, G-CSF reduced infarct volume to 50% while significantly improved neurological deficit compared to vehicle rats. G-CSF significantly (P < 0.05) up-regulated pro-survival proteins pAKT and Bcl2 while downregulating pro-apoptotic proteins Bax, Bak and cleaved caspase 3 in the ischemic brain. It also significantly (P < 0.05) downregulated the ER intraluminal stress sensor GRP78, proteins of ER stress induced intracellular pathway; ATF4, ATF6, p-p38MAPK, pJNK and the ER stress induced apoptotic marker CHOP, which suggests that ER stress is being ameliorated by G-CSF treatment. G-CSF also reduced the level of HSP27, providing additional evidence of cellular stress reduction. G-CSF treatment increased cell survival by attenuating both general pro-apoptotic proteins and specific effector proteins in the ER stress induced apoptotic pathways. Our data has provided new insight into the anti-apoptotic mechanism of G-CSF, especially as it relates to ER stress induced apoptosis in ischemia.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004795, http://purl.flvc.org/fau/fd/FA00004795
Subject Headings
Cerebral ischemia--Protection., Apoptosis., Rats as laboratory animals., Cellular signal transduction., Oxidation-reduction reaction.
Format
Document (PDF)
Mechanism of Carbamathione as a therapeutic agent for Stroke.
Title
Mechanism of Carbamathione as a therapeutic agent for Stroke.
Creator
Modi, Jigar P., Wu, Jang-Yen, Florida Atlantic University, Charles E. Schmidt College of Science, Center for Complex Systems and Brain Sciences
Abstract/Description
Stroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been shown completely effective in stroke treatment. Stroke may result in hypoxia, glutamate release and oxidative stress. One approach for protecting neurons from excitotoxic damage in stroke is to attenuate receptor activity with specific antagonists. Disulfiram requires bio-activation to S-methyl N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO). In vivo, DETC-MeSO is further...
Show moreStroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been shown completely effective in stroke treatment. Stroke may result in hypoxia, glutamate release and oxidative stress. One approach for protecting neurons from excitotoxic damage in stroke is to attenuate receptor activity with specific antagonists. Disulfiram requires bio-activation to S-methyl N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO). In vivo, DETC-MeSO is further oxidized to the sulfone which is carbamoylated forming Carbamathione, a glutathione adducts. Carbamathione proved to be useful as a pharmacological agent in the treatment of cocaine dependence with the advantage that it lacks ALDH2 inhibitory activity. Carbamathione is a partial NMDA glutamate antagonist. The purpose of this dissertation study is to evaluate the neuroprotective effects of Carbamathione drug on PC-12 cell line and to understand the protective mechanisms underlying in three stroke-related models: excessive glutamate, hypoxia/reoxygenation and bilateral carotid artery occlusion (BCAO). Carbamathione was administered 14 mg/kg subcutaneously for 4 days with the first injection occurring 30 min after occlusion in the mouse BCAO stroke model. Mice were subjected to the locomotor test, and the brain was analyzed for infarct size. Heat shock proteins, key proteins involved in apoptosis and endoplasmic reticulum (ER) stress, were analyzed by immunoblotting. Carbamathione reduced both cell death following hypoxia/reoxygenation and brain infarct size. It improved performance on the locomotor test. The level of pro-apoptotic proteins declined, and anti-apoptotic, P-AKT and HSP27 protein expressions were markedly increased. We found that Carbamathione suppresses the up- regulation of Caspase-12, Caspase-3 and significantly declined ER stress protein markers GRP 78, ATF4, XBP-1, and CHOP. Carbamathione can down- regulate ATF 4 and XBP1 expression, indicating that Carbamathione inhibits the ER stress induced by hypoxia/reoxygenation through suppressing PERK and IRE1 pathways. Carbamathione elicits neuroprotection through the preservation of ER resulting in reduction of apoptosis by increase of anti-apoptotic proteins and decrease of pro-apoptotic proteins. Carbamathione can suppress the activation of both PERK and IRE1 pathways in PC-12 cell cultures and has no inhibitory effect on ATF6 pathway. These findings provide promising and rational strategies for stroke therapy.
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Date Issued
2017
PURL
http://purl.flvc.org/fau/fd/FA00004979, http://purl.flvc.org/fau/fd/FA00004969
Subject Headings
Dissertations, Academic -- Florida Atlantic University, Stroke., Stroke--drug therapy., Carbamathione
Format
Document (PDF)
EFFECT OF G-CSF GENE THERAPY IN A MICROGLIA MODEL OF STROKE
Title
EFFECT OF G-CSF GENE THERAPY IN A MICROGLIA MODEL OF STROKE.
Creator
Velasquez Saldarriaga, Esteban, Wu, Jang-Yen, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Medicine
Abstract/Description
Cerebrovascular events (stroke) are a significant cause of morbidity and mortality worldwide. Ischemic stroke accounts for ~85% of all strokes and is caused by the blockade of blood flow to a certain area of the brain, resulting in oxygen and nutrient deprivation and ultimately cell death. Cerebral ischemia induces a strong neuroinflammatory response that contributes to tissue damage and is driven by changes in the gene expression profile and phenotype of brain cells including neurons,...
Show moreCerebrovascular events (stroke) are a significant cause of morbidity and mortality worldwide. Ischemic stroke accounts for ~85% of all strokes and is caused by the blockade of blood flow to a certain area of the brain, resulting in oxygen and nutrient deprivation and ultimately cell death. Cerebral ischemia induces a strong neuroinflammatory response that contributes to tissue damage and is driven by changes in the gene expression profile and phenotype of brain cells including neurons, astrocytes, and microglia. Microglia are the resident immune and phagocytic cells of the central nervous system. They rapidly respond to ischemia by migrating to the site of injury and modulating the inflammatory response there. Although microglia may play a deleterious role in the acute phase of stroke, evidence suggests that they play an important role in the reduction of excitotoxic injury as well as in neurogenesis during the tissue regeneration phase. Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that has shown beneficial effects in models of ischemic stroke. G-CSF exerts its neuroprotective effects through different mechanisms including mobilization of haemopoietic stem cells, angiogenesis, neurogenesis, anti-inflammation, and anti-apoptosis. However, its effect on microglia is not well understood yet. The main objective of this project was to evaluate the protective and anti-inflammatory effect of G-CSF gene therapy against glutamate cytotoxicity in the human microglial clone 3 cell line (HMC3). Our results show that although G-CSF gene therapy did not significantly protect HMC3 cells against glutamate induced cell death, it reduced the expression levels of pro-inflammatory proteins NF-κB p65, IL-1β and IL-6, while increasing the phosphorylation of Akt, a regulator of cell survival and proliferation.
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Date Issued
2021
PURL
http://purl.flvc.org/fau/fd/FA00013821
Subject Headings
Stroke, Granulocyte Colony-Stimulating Factor, Cerebrovascular disease, Microglia
Format
Document (PDF)
MULTIMODAL THERAPIES FOR ALZHEIMER’S DISEASE
Title
MULTIMODAL THERAPIES FOR ALZHEIMER’S DISEASE.
Creator
Bhandari, Subash, Wu, Jang-Yen, Florida Atlantic University, Department of Biological Sciences, Charles E. Schmidt College of Science
Abstract/Description
Alzheimer's disease (AD) is projected to triple by 2050, highlighting the urgent need for disease-modifying treatment strategies. Our gene therapy approach tackles three critical challenges: a) delivering drugs effectively to the brain and brain bioavailability of those delivered drugs, b) intervening early in the disease process to prevent progression into nonreversible stages, and c) managing the behavioral and psychological symptoms of dementia (BPSD) that significantly impact patients and...
Show moreAlzheimer's disease (AD) is projected to triple by 2050, highlighting the urgent need for disease-modifying treatment strategies. Our gene therapy approach tackles three critical challenges: a) delivering drugs effectively to the brain and brain bioavailability of those delivered drugs, b) intervening early in the disease process to prevent progression into nonreversible stages, and c) managing the behavioral and psychological symptoms of dementia (BPSD) that significantly impact patients and caregivers. Our non-invasive ocular delivery system effectively delivered therapies to CNS as indicated by the localization of those transcribed genes and translated protein products in different brain regions, including the hippocampus, cortex, dorsal lateral geniculate nucleus, red nucleus, and pontine nucleus This approach could overcome the limitations of traditional drug delivery methods for neurological diseases. In a 3xTg AD mouse model of AD, we evaluated the efficacy of Choline Acetyltransferase (ChAT) gene therapy on early disease progression. A single treatment improved impaired memory functions such as cognitive flexibility, memory extinction and working memory, reduced amyloid beta oligomers and phosphorylated tau protein levels, and enhanced mitochondrial dynamics through the regulation of fusion, fission and mitophagy. Additionally, ChAT gene therapy modulated apoptosis, inflammation and the activity of microglia and astrocytes in parts through the activation of AKT. These findings suggest ChAT gene therapy's potential to slow or prevent AD progression if administered early in the disease course.
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Date Issued
2024
PURL
http://purl.flvc.org/fau/fd/FA00014400
Subject Headings
Alzheimer's disease, Alzheimer's Disease--therapy, Gene therapy
Format
Document (PDF)
Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases
Title
Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases.
Creator
Prentice, Howard, Modi, Jigar P., Wu, Jang-Yen
Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FAUIR000111
Format
Citation