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Wei L, Chen Y, Wu M, Ma P, Wang H, Jiang Y, Aschner M, Zhou J, Lu G, Zhao L, Huang X. MEK1 inhibition ameliorates mitochondrial-dependent apoptosis induced by deltamethrin in mouse hippocampal neuron HT22 cells. Toxicol In Vitro 2025; 106:106047. [PMID: 40058615 DOI: 10.1016/j.tiv.2025.106047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/28/2025] [Accepted: 03/05/2025] [Indexed: 03/14/2025]
Abstract
Deltamethrin (DM), a widely used pyrethroid insecticide, has been increasingly recognized as a risk factor for neurodegeneration. However, the underlying mechanism is still far from clear. In this study, we investigated whether MEK1 is involved in DM-induced neurotoxicity and mediated mitochondrial-dependent apoptosis. In mouse hippocampal neuron HT22 cells model, DM (2,10,50 μM) dose-dependently increased apoptotic cells rate and impaired mitochondrial membrane potential (MMP), as well as significantly upregulated of apoptotic related proteins Bax, cytochrome c (Cyt-c) and Caspase-3 were observed. RNA-sequencing analysis further revealed that the MEK/ERK signal pathway was remarkably enriched and activated after DM exposure. In particularly, upregulation of MEK1, other than ERK1/2, was detected at both transcriptional and translational levels. Inhibition of MEK1 can effectively result in the recovery of mitochondrial morphology and MMP in DM-treated HT22 cells. And that further alleviated apoptosis by reversing the overexpression of Bax, Cyt-c and Caspase-3. Collectively, these findings demonstrate the critical role of MEK1 in regulating mitochondrial-dependent apoptosis induced by DM, providing a novel understanding of the neurotoxicity of DM.
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Affiliation(s)
- Lexing Wei
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Yang Chen
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Minjia Wu
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Peixuan Ma
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Huan Wang
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China
| | - Yueming Jiang
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Michael Aschner
- Department of Molecular Pharmacology at Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Jing Zhou
- School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Guodong Lu
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; School of Public Health, Fudan University, Shanghai 200032, China
| | - Lina Zhao
- School of Public Health, Wuhan University, Wuhan 430071, China
| | - Xiaowei Huang
- Department of Toxicology, School of Public Health, Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China.
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Khandayataray P, Murthy MK. Dietary interventions in mitigating the impact of environmental pollutants on Alzheimer's disease - A review. Neuroscience 2024; 563:148-166. [PMID: 39542342 DOI: 10.1016/j.neuroscience.2024.11.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/23/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
Numerous studies linking environmental pollutants to oxidative stress, inflammation, and neurotoxicity have assigned pollutants to several neurodegenerative disorders, including Alzheimer's disease (AD). Heavy metals, pesticides, air pollutants, and endocrine disruptor chemicals have been shown to play important roles in AD development, with some traditional functions in amyloid-β formation, tau kinase action, and neuronal degeneration. However, pharmacological management and supplementation have resulted in limited improvement. This raises the interesting possibility that activities usually considered preventive, including diet, exercise, or mental activity, might be more similar to treatment or therapy for AD. This review focuses on the effects of diet on the effects of environmental pollutants on AD. One of the primary issues addressed in this review is a group of specific diets, including the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH intervention for Neurodegenerative Delay (MIND), which prevent exposure to these toxins. Such diets have been proven to decrease oxidative stress and inflammation, which are unfavorable for neuronal growth. Furthermore, they contribute to positive changes in the composition of the human gut microbiota and thus encourage interactions in the Gut-Brain Axis, reducing inflammation caused by pollutants. This review emphasizes a multi-professional approach with reference to nutritional activities that would lower the neurotoxic load in populations with a high level of exposure to pollutants. Future studies focusing on diet and environment association plans may help identify preventive measures aimed at enhancing current disease deceleration.
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Affiliation(s)
- Pratima Khandayataray
- Department of Biotechnology, Academy of Management and Information Technology, Utkal University, Bhubaneswar, Odisha 752057, India
| | - Meesala Krishna Murthy
- Department of Allied Health Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab 140401, India.
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Saferin N, Haseeb I, Taha AM, Beecroft SE, Pillai S, Neifer AE, Lakkuru R, Kistler BP, Nawor CN, Malik I, Hasan D, Carlson JA, Zade KK, Dressel SP, Carney EM, Shah R, Gautam S, Vergis J, Neifer KL, Johnson ZV, Gustison ML, Hall FS, Burkett JP. Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.25.625285. [PMID: 39651146 PMCID: PMC11623627 DOI: 10.1101/2024.11.25.625285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and neurodevelopmental disorders. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams chronically to vehicle or low-dose deltamethrin (3 mg/kg/3 days) with or without high-dose folate supplementation (methylfolate, 5 mg/kg/3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to neurodevelopmental disorders (including the social domain); increased plasma folate concentrations; and increased neural expression of SHMT1, a folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotypes (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two folate-related proteins. We conclude that DPE causes neurodevelopmental disorder-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.
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Affiliation(s)
- Nilanjana Saferin
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Ibrahim Haseeb
- College of Natural Sciences and Mathematics, University of Toledo, Toledo, OH 43606
| | - Adam M. Taha
- Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA
| | - Sarah E. Beecroft
- Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA
| | - Sangeetha Pillai
- College of Natural Sciences and Mathematics, University of Toledo, Toledo, OH 43606
| | - Asha E. Neifer
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Rudhasri Lakkuru
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Brian P. Kistler
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Charlotte N. Nawor
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Isa Malik
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Dena Hasan
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jonathan A. Carlson
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Kareem K. Zade
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Sydnee P. Dressel
- Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA
| | - Eileen M. Carney
- Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA
| | - Radha Shah
- College of Natural Sciences and Mathematics, University of Toledo, Toledo, OH 43606
| | - Shudhant Gautam
- College of Natural Sciences and Mathematics, University of Toledo, Toledo, OH 43606
| | - John Vergis
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Kari L. Neifer
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Zachary V. Johnson
- Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Morgan L. Gustison
- Department of Psychology, The University of Western Ontario, London, ON, Canada (current); Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA
| | - F. Scott Hall
- Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA
| | - James P. Burkett
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
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Liu SH, Weber ES, Manz KE, McCarthy KJ, Chen Y, Schüffler PJ, Zhu CW, Tracy M. Assessing the Impact and Cost-Effectiveness of Exposome Interventions on Alzheimer's Disease: A Review of Agent-Based Modeling and Other Data Science Methods for Causal Inference. Genes (Basel) 2024; 15:1457. [PMID: 39596657 PMCID: PMC11593565 DOI: 10.3390/genes15111457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
Background: The exposome (e.g., totality of environmental exposures) and its role in Alzheimer's Disease and Alzheimer's Disease and Related Dementias (AD/ADRD) are increasingly critical areas of study. However, little is known about how interventions on the exposome, including personal behavioral modification or policy-level interventions, may impact AD/ADRD disease burden at the population level in real-world settings and the cost-effectiveness of interventions. Methods: We performed a critical review to discuss the challenges in modeling exposome interventions on population-level AD/ADRD burden and the potential of using agent-based modeling (ABM) and other advanced data science methods for causal inference to achieve this. Results: We describe how ABM can be used for empirical causal inference modeling and provide a virtual laboratory for simulating the impacts of personal and policy-level interventions. These hypothetical experiments can provide insight into the optimal timing, targeting, and duration of interventions, identifying optimal combinations of interventions, and can be augmented with economic analyses to evaluate the cost-effectiveness of interventions. We also discuss other data science methods, including structural equation modeling and Mendelian randomization. Lastly, we discuss challenges in modeling the complex exposome, including high dimensional and sparse data, the need to account for dynamic changes over time and over the life course, and the role of exposome burden scores developed using item response theory models and artificial intelligence to address these challenges. Conclusions: This critical review highlights opportunities and challenges in modeling exposome interventions on population-level AD/ADRD disease burden while considering the cost-effectiveness of different interventions, which can be used to aid data-driven policy decisions.
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Affiliation(s)
- Shelley H. Liu
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ellerie S. Weber
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Katherine E. Manz
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Katharine J. McCarthy
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yitong Chen
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Peter J. Schüffler
- Institute of Pathology, Technical University of Munich, 81675 Munich, Germany
- Munich Data Science Institute, 85748 Garching, Germany
| | - Carolyn W. Zhu
- Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Melissa Tracy
- Department of Epidemiology and Biostatistics, State University of New York at Albany, Albany, NY 12222, USA;
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Khoo SC, Zhang N, Luang-In V, Goh MS, Sonne C, Ma NL. Exploring environmental exposomes and the gut-brain nexus: Unveiling the impact of pesticide exposure. ENVIRONMENTAL RESEARCH 2024; 250:118441. [PMID: 38350544 DOI: 10.1016/j.envres.2024.118441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 01/20/2024] [Accepted: 02/06/2024] [Indexed: 02/15/2024]
Abstract
This review delves into the escalating concern of environmental pollutants and their profound impact on human health in the context of the modern surge in global diseases. The utilisation of chemicals in food production, which results in residues in food, has emerged as a major concern nowadays. By exploring the intricate relationship between environmental pollutants and gut microbiota, the study reveals a dynamic bidirectional interplay, as modifying microbiota profile influences metabolic pathways and subsequent brain functions. This review will first provide an overview of potential exposomes and their effect to gut health. This paper is then emphasis the connection of gut brain function by analysing microbiome markers with neurotoxicity responses. We then take pesticide as example of exposome to elucidate their influence to biomarkers biosynthesis pathways and subsequent brain functions. The interconnection between neuroendocrine and neuromodulators elements and the gut-brain axis emerges as a pivotal factor in regulating mental health and brain development. Thus, manipulation of gut microbiota function at the onset of stress may offer a potential avenue for the prevention and treatment for mental disorder and other neurodegenerative illness.
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Affiliation(s)
- Shing Ching Khoo
- Biological Security and Sustainability (BioSES) Research Interest Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia
| | - Nan Zhang
- Synerk Biotech, BioBay, Suzhou, 215000, China; Neuroscience Program, Department of Neurology, Houston Methodist Research Institute, TX, 77030, USA; Department of Neurology, Weill Cornell Medicine, New York, 10065, USA
| | - Vijitra Luang-In
- Natural Antioxidant Innovation Research Unit, Department of Biotechnology, Faculty of Technology, Mahasarakham University, Khamriang, Kantharawichai, Mahasarakham, 44150, Thailand
| | - Meng Shien Goh
- Biological Security and Sustainability (BioSES) Research Interest Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia
| | - Christian Sonne
- Aarhus University, Faculty of Science and Technology, Department of Bioscience, Arctic Research Centre (ARC), Danish Centre for Environment and Energy (DCE), Frederiksborgvej 399, PO Box 358, DK-4000, Roskilde, Denmark
| | - Nyuk Ling Ma
- Biological Security and Sustainability (BioSES) Research Interest Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia; Center for Global Health Research (CGHR), Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India.
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6
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Arsuffi-Marcon R, Souza LG, Santos-Miranda A, Joviano-Santos JV. Neurotoxicity of Pyrethroids in neurodegenerative diseases: From animals' models to humans' studies. Chem Biol Interact 2024; 391:110911. [PMID: 38367681 DOI: 10.1016/j.cbi.2024.110911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/15/2024] [Accepted: 02/08/2024] [Indexed: 02/19/2024]
Abstract
Neurodegenerative diseases are associated with diverse symptoms, both motor and mental. Genetic and environmental factors can trigger neurodegenerative diseases. Chemicals as pesticides are constantly used in agriculture and also domestically. In this regard, pyrethroids (PY), are a class of insecticides in which its main mechanism of action is through disruption of voltage-dependent sodium channels function in insects. However, in mammals, they can also induce oxidative stress and enzyme dysfunction. This review investigates the association between PY and neurodegenerative diseases as Alzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis, and Autism in animal models and humans. Published works using specific and non-specific models for these diseases were selected. We showed a tendency toward the development and/or aggravating of these neurodegenerative diseases following exposure to PYs. In animal models, the biochemical mechanisms of the diseases and their interaction with the insecticides are more deeply investigated. Nonetheless, only a few studies considered the specific model for each type of disease to analyze the impacts of the exposure. The choice of a specific model during the research is an important step and our review highlights the knowledge gaps of PYs effects using these models reinforcing the importance of them during the design of the experiments.
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Affiliation(s)
- Rafael Arsuffi-Marcon
- Center for Mathematics, Computing, and Cognition (CMCC), Federal University of ABC (UFABC), São Bernardo Do Campo, São Paulo, Brazil
| | - Lizandra Gomes Souza
- Center for Mathematics, Computing, and Cognition (CMCC), Federal University of ABC (UFABC), São Bernardo Do Campo, São Paulo, Brazil
| | - Artur Santos-Miranda
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Julliane V Joviano-Santos
- Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil.
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7
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Mujtaba S, Patro IK, Patro N. Multiple Early Life Stressors as Risk Factors for Neurodevelopmental Abnormalities in the F1 Wistar Rats. Brain Sci 2023; 13:1360. [PMID: 37891729 PMCID: PMC10605318 DOI: 10.3390/brainsci13101360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/07/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
Cumulative exposure to multiple early life stressors is expected to affect behavioral development, causing increased susceptibility to neuropsychiatric disorders. The present study was designed to mimic such conditions in a rat model to study behavioral impairments during adolescence and adulthood. Female Wistar rats (n = 32; 140-150 gm) were switched to a low protein (LP; 8% protein) or control (20% protein) diet 15 days prior to conception, and then the diet regime was maintained throughout the experimental period. Pups born to control and LP dams were intraperitoneally injected with deltamethrin (DLT-pyrethroid insecticide; 0.7 mg/kg body weight; PND 1 to 7), lipopolysaccharide (LPS-bacterial endotoxin; 0.3 mg/kg body weight; PND 3 and 5), or DLT+LPS, on designated days forming eight experimental groups (Control, LP, Control+LPS, LP+LPS, Control+DLT, LP+DLT, Control+DLT+LPS and LP+DLT+LPS). Neurobehavioral assessments were performed in F1 rats (1, 3, 6 months) by open field, elevated plus maze, light and dark box, and rotarod tests. LP rats were found to be highly susceptible to either singular or cumulative exposure as compared to their age-matched control counterparts, showing significantly severe behavioral abnormalities, such as hyperactivity, attention deficits and low anxiety, the hallmark symptoms of neuropsychiatric disorders like schizophrenia and ADHD, suggesting thereby that early life multi-hit exposure may predispose individuals to developmental disorders.
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Affiliation(s)
- Syed Mujtaba
- School of Studies in Neuroscience, Jiwaji University, Gwalior 474011, India; (S.M.); (I.K.P.)
- School of Studies in Zoology, Jiwaji University, Gwalior 474011, India
| | - Ishan Kumar Patro
- School of Studies in Neuroscience, Jiwaji University, Gwalior 474011, India; (S.M.); (I.K.P.)
- School of Studies in Zoology, Jiwaji University, Gwalior 474011, India
| | - Nisha Patro
- School of Studies in Neuroscience, Jiwaji University, Gwalior 474011, India; (S.M.); (I.K.P.)
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8
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Torres-Sánchez ED, Ortiz GG, Reyes-Uribe E, Torres-Jasso JH, Salazar-Flores J. Effect of pesticides on phosphorylation of tau protein, and its influence on Alzheimer's disease. World J Clin Cases 2023; 11:5628-5642. [PMID: 37727721 PMCID: PMC10506003 DOI: 10.12998/wjcc.v11.i24.5628] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/17/2023] [Accepted: 08/08/2023] [Indexed: 08/24/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive and neurodegenerative illness which results in alterations in cognitive development. It is characterized by loss/dysfunction of cholinergic neurons, and formation of amyloid plaques, and formation of neurofibrillary tangles, among other changes, due to hyperphosphorylation of tau-protein. Exposure to pesticides in humans occurs frequently due to contact with contaminated food, water, or particles. Organochlorines, organophosphates, carbamates, pyrethroids and neonicotinoids are associated with the most diagnosed incidents of severe cognitive impairment. The aim of this study was to determine the effects of these pesticides on the phosphorylation of tau protein, and its cognitive implications in the development of AD. It was found that exposure to pesticides increased the phosphorylation of tau protein at sites Ser198, Ser199, Ser202, Thr205, Ser396 and Ser404. Contact with these chemicals altered the enzymatic activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta, and protein phosphatase-2A. Moreover, it altered the expression of the microtubule associated protein tau gene, and changed levels of intracellular calcium. These changes affected tau protein phosphorylation and neuroinflammation, and also increased oxidative stress. In addition, the exposed subjects had poor level of performance in tests that involved evaluation of novelty, as test on verbal, non-verbal, spatial memory, attention, and problem-solving skills.
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Affiliation(s)
- Erandis D Torres-Sánchez
- Department of Medical and Life Sciences, University Center of la Cienega, University of Guadalajara, Ocotlan 47820, Jalisco, Mexico
| | - Genaro G Ortiz
- Department of Philosophical and Methodological Disciplines and Service of Molecular Biology in Medicine Hospital Civil, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Emmanuel Reyes-Uribe
- Department of Medical and Life Sciences, University Center of la Cienega, University of Guadalajara, Ocotlan 47820, Jalisco, Mexico
| | - Juan H Torres-Jasso
- Department of Biological Sciences, CUCOSTA, University of Guadalajara, Puerto Vallarta 48280, Jalisco, Mexico
| | - Joel Salazar-Flores
- Department of Medical and Life Sciences, University Center of la Cienega, University of Guadalajara, Ocotlan 47820, Jalisco, Mexico
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9
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Intui K, Nuchniyom P, Laoung-on J, Jaikang C, Quiggins R, Sudwan P. Neuroprotective Effect of White Nelumbo nucifera Gaertn. Petal Tea in Rats Poisoned with Mancozeb. Foods 2023; 12:2175. [PMID: 37297420 PMCID: PMC10252518 DOI: 10.3390/foods12112175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Nelumbo nucifera Gaertn. (N. nucifera) tea is used as food and folk medicine to reduce toxicity in Southeast Asia. Mancozeb (Mz) is used for controlling fungi in agriculture and contains heavy metals. This study aimed to examine the effect of white N. nucifera petal tea on cognitive behavior, hippocampus histology, oxidative stress, and amino acid metabolism in rats poisoned with mancozeb. Seventy-two male Wistar rats were divided into nine groups (n = 8 in each). Y-maze spontaneous alternation test was used to assess cognitive behavior, and amino acid metabolism was investigated by nuclear magnetic resonance spectroscopy (1H-NMR) from blood. There was a significant increase in relative brain weight in the Mz co-administered with the highest dose (2.20 mg/kg bw) of white N. nucifera group. The levels of tryptophan, kynurenine, picolinic acid, and serotonin in blood showed a significant decrease in the Mz group and a significant increase in the Mz co-administered with low dose (0.55 mg/kg bw) of white N. nucifera group. However, there was no significant difference in cognitive behavior, hippocampus histology, oxidative stress, and corticosterone. This study demonstrated that a low dose of white N. nucifera petal tea has a neuroprotective effect against mancozeb.
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Affiliation(s)
- Ketsarin Intui
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (K.I.)
| | - Pimchanok Nuchniyom
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (K.I.)
| | - Jiraporn Laoung-on
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (K.I.)
| | - Churdsak Jaikang
- Toxicology Section, Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Ranida Quiggins
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (K.I.)
| | - Paiwan Sudwan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (K.I.)
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10
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Tsamou M, Roggen EL. Building a Network of Adverse Outcome Pathways (AOPs) Incorporating the Tau-Driven AOP Toward Memory Loss (AOP429). J Alzheimers Dis Rep 2022; 6:271-296. [PMID: 35891639 PMCID: PMC9277675 DOI: 10.3233/adr-220015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/15/2022] [Indexed: 11/15/2022] Open
Abstract
The adverse outcome pathway (AOP) concept was first proposed as a tool for chemical hazard assessment facilitating the regulatory decision-making in toxicology and was more recently recommended during the BioMed21 workshops as a tool for the characterization of crucial endpoints in the human disease development. This AOP framework represents mechanistically based approaches using existing data, more realistic and relevant to human biological systems. In principle, AOPs are described by molecular initiating events (MIEs) which induce key events (KEs) leading to adverse outcomes (AOs). In addition to the individual AOPs, the network of AOPs has been also suggested to beneficially support the understanding and prediction of adverse effects in risk assessment. The AOP-based networks can capture the complexity of biological systems described by different AOPs, in which multiple AOs diverge from a single MIE or multiple MIEs trigger a cascade of KEs that converge to a single AO. Here, an AOP network incorporating a recently proposed tau-driven AOP toward memory loss (AOP429) related to sporadic (late-onset) Alzheimer’s disease is constructed. This proposed AOP network is an attempt to extract useful information for better comprehending the interactions among existing mechanistic data linked to memory loss as an early phase of sporadic Alzheimer’s disease pathology.
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Affiliation(s)
- Maria Tsamou
- ToxGenSolutions (TGS), Maastricht, The Netherlands
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11
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Tsamou M, Carpi D, Pistollato F, Roggen EL. Sporadic Alzheimer's Disease- and Neurotoxicity-Related microRNAs Affecting Key Events of Tau-Driven Adverse Outcome Pathway Toward Memory Loss. J Alzheimers Dis 2022; 86:1427-1457. [PMID: 35213375 DOI: 10.3233/jad-215434] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer's disease (sAD). OBJECTIVE Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. METHODS Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to create miR-target interaction networks. RESULTS The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. CONCLUSION Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms.
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Affiliation(s)
- Maria Tsamou
- ToxGenSolutions (TGS), Maastricht, The Netherlands
| | - Donatella Carpi
- European Commission, Joint Research Centre (JRC), Ispra VA, Italy
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12
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Rajendran R, Ragavan RP, Al-Sehemi AG, Uddin MS, Aleya L, Mathew B. Current understandings and perspectives of petroleum hydrocarbons in Alzheimer's disease and Parkinson's disease: a global concern. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:10928-10949. [PMID: 35000177 DOI: 10.1007/s11356-021-17931-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 11/30/2021] [Indexed: 06/14/2023]
Abstract
Over the last few decades, the global prevalence of neurodevelopmental and neurodegenerative illnesses has risen rapidly. Although the aetiology remains unclear, evidence is mounting that exposure to persistent hydrocarbon pollutants is a substantial risk factor, predisposing a person to neurological diseases later in life. Epidemiological studies correlate environmental hydrocarbon exposure to brain disorders including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders like autism spectrum disorder (ASD); and neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD). Particulate matter, benzene, toluene, ethylbenzene, xylenes, polycyclic aromatic hydrocarbons and endocrine-disrupting chemicals have all been linked to neurodevelopmental problems in all class of people. There is mounting evidence that supports the prevalence of petroleum hydrocarbon becoming neurotoxic and being involved in the pathogenesis of AD and PD. More study is needed to fully comprehend the scope of these problems in the context of unconventional oil and natural gas. This review summarises in vitro, animal and epidemiological research on the genesis of neurodegenerative disorders, highlighting evidence that supports inexorable role of hazardous hydrocarbon exposure in the pathophysiology of AD and PD. In this review, we offer a summary of the existing evidence gathered through a Medline literature search of systematic reviews and meta-analyses of the most important epidemiological studies published so far.
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Affiliation(s)
- Rajalakshmi Rajendran
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, 682041, Kerala, India
| | - Roshni Pushpa Ragavan
- Research Center for Advanced Materials Science, King Khalid University, Abha, 61413, Saudi Arabia.
| | - Abdullah G Al-Sehemi
- Research Center for Advanced Materials Science, King Khalid University, Abha, 61413, Saudi Arabia
- Department of Chemistry, King Khalid University, Abha, 61413, Saudi Arabia
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Lotfi Aleya
- Laboratoire Chrono-Environment, CNRS6249, Universite de Bourgogne Franche-Comte, Besancon, France
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, India.
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13
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Nisa FY, Rahman MA, Hossen MA, Khan MF, Khan MAN, Majid M, Sultana F, Haque MA. Role of neurotoxicants in the pathogenesis of Alzheimer's disease: a mechanistic insight. Ann Med 2021; 53:1476-1501. [PMID: 34433343 PMCID: PMC8405119 DOI: 10.1080/07853890.2021.1966088] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/04/2021] [Indexed: 12/13/2022] Open
Abstract
Alzheimer's disease (AD) is the most conspicuous chronic neurodegenerative syndrome, which has become a significant challenge for the global healthcare system. Multiple studies have corroborated a clear association of neurotoxicants with AD pathogenicity, such as Amyloid beta (Aβ) proteins and neurofibrillary tangles (NFTs), signalling pathway modifications, cellular stress, cognitive dysfunctions, neuronal apoptosis, neuroinflammation, epigenetic modification, and so on. This review, therefore, aimed to address several essential mechanisms and signalling cascades, including Wnt (wingless and int.) signalling pathway, autophagy, mammalian target of rapamycin (mTOR), protein kinase C (PKC) signalling cascades, cellular redox status, energy metabolism, glutamatergic neurotransmissions, immune cell stimulations (e.g. microglia, astrocytes) as well as an amyloid precursor protein (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2) and other AD-related gene expressions that have been pretentious and modulated by the various neurotoxicants. This review concluded that neurotoxicants play a momentous role in developing AD through modulating various signalling cascades. Nevertheless, comprehension of this risk agent-induced neurotoxicity is far too little. More in-depth epidemiological and systematic investigations are needed to understand the potential mechanisms better to address these neurotoxicants and improve approaches to their risk exposure that aid in AD pathogenesis.Key messagesInevitable cascade mechanisms of how Alzheimer's Disease-related (AD-related) gene expressions are modulated by neurotoxicants have been discussed.Involvement of the neurotoxicants-induced pathways caused an extended risk of AD is explicited.Integration of cell culture, animals and population-based analysis on the clinical severity of AD is addressed.
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Affiliation(s)
- Fatema Yasmin Nisa
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Md. Atiar Rahman
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Md. Amjad Hossen
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
| | - Mohammad Forhad Khan
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
| | - Md. Asif Nadim Khan
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Mumtahina Majid
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Farjana Sultana
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Md. Areeful Haque
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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14
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Tsamou M, Pistollato F, Roggen EL. A Tau-Driven Adverse Outcome Pathway Blueprint Toward Memory Loss in Sporadic (Late-Onset) Alzheimer's Disease with Plausible Molecular Initiating Event Plug-Ins for Environmental Neurotoxicants. J Alzheimers Dis 2021; 81:459-485. [PMID: 33843671 DOI: 10.3233/jad-201418] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The worldwide prevalence of sporadic (late-onset) Alzheimer's disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.
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15
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Varma N, Singh A, Ravi VK, Thakur M, Kumar S. Deltamethrin modulates the native structure of Hen Egg White Lysozyme and induces its aggregation at physiological pH. Colloids Surf B Biointerfaces 2021; 201:111646. [PMID: 33652208 DOI: 10.1016/j.colsurfb.2021.111646] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/26/2021] [Accepted: 02/16/2021] [Indexed: 10/22/2022]
Abstract
Deltamethrin, a type II pyrethroid pesticide was initially considered as safe for human use. Recent studies have reported several pathophysiological effects of deltamethrin on human and non-human species. However, its effect on structure and function of protein leading to progressive neurodegeneration is poorly understood. In present study, we investigated the interaction of deltamethrin with Hen Egg White Lysozyme (HEWL) at physiological pH and tried to understand the effect of pesticide on structure and function of protein. Employing different biophysical techniques, we shown that deltamethrin induces in vitro aggregation of HEWL in concentration dependent manner. Interaction of pesticide with different amino acids, followed by exposure of hydrophobic regions was driving force of aggregation process. Apart from modulating the hydrophobic domain, deltamethrin is observed to reduce α-helical and promote β-sheet content of lysozyme, eventually converting the globular protein into ThT sensitive amyloid fibrils and amorphous aggregates. Our study also indicate that deltamethrin induced aggregation reduces the catalytic activity of lysozyme.
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Affiliation(s)
- Neelakant Varma
- Laboratory of Forensic Biology and Biotechnology, School of Forensic Science, National Forensic Sciences University, Gandhinagar, Gujarat, 382 007, India(1)
| | - Abhishek Singh
- Laboratory of Forensic Biology and Biotechnology, School of Forensic Science, National Forensic Sciences University, Gandhinagar, Gujarat, 382 007, India(1); Zoological Survey of India, New Alipore, Kolkata, West Bengal, 700 053, India
| | - Vijay K Ravi
- Centre for Nanoscience and Nanotechnology, Aryabhatta Knowledge University, Mithapur, Patna, Bihar, 800 001, India
| | - Mukesh Thakur
- Zoological Survey of India, New Alipore, Kolkata, West Bengal, 700 053, India
| | - Satish Kumar
- Laboratory of Forensic Biology and Biotechnology, School of Forensic Science, National Forensic Sciences University, Gandhinagar, Gujarat, 382 007, India(1).
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16
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Saquib Q, Siddiqui MA, Ansari SM, Alwathnani HA, Al-Khedhairy AA. Carbofuran cytotoxicity, DNA damage, oxidative stress, and cell death in human umbilical vein endothelial cells: Evidence of vascular toxicity. J Appl Toxicol 2021; 41:847-860. [PMID: 33629750 DOI: 10.1002/jat.4150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 02/01/2021] [Accepted: 02/04/2021] [Indexed: 12/17/2022]
Abstract
Carbofuran is a broad-spectrum carbamate insecticide, which principally inhibits the acetylcholinesterase (AChE) enzyme in the nervous system. Nonetheless, their selective action is not restricted to a single species and expanded to humans. No studies are available on the toxicological effects of carbofuran in the endothelial cells (ECs), which first confronts the toxicants in blood vessels. Hence, we have exposed the human umbilical vein ECs (HUVECs) with carbofuran for 24 h, which significantly reduced the cell survival to 25.16% and 33.48% at 500 and 1,000 μM analyzed by MTT assay. In the neutral red uptake (NRU) assay, 16.68%, 30.99%, and 58.11% survival decline was found at 250, 500, and 1,000 μM of carbofuran. HUVECs exposed to carbofuran showed significant increase in the intracellular reactive oxygen species (ROS), indicating oxidative stress at low concentrations. In parallel, HUVECs showed hyperpolarization effects in the mitochondrial membrane potential (ΔΨm) upon carbofuran exposure. Carbofuran induced DNA damage in HUVECs measured as 8.80, 11.82, 35.56, and 79.69 Olive tail moment (OTM) in 100-, 250-, 500-, and 1,000-μM exposure groups. Flow cytometric analysis showed apoptotic peak (SubG1) and G2M arrest in the HUVECs exposed to carbofuran. Overall, our novel data confirm that carbofuran is toxic for the EC cells, especially at the higher concentrations, which may affect the vascular functions and possibly angiogenesis. Hence, carbofuran should be applied judiciously, and detailed vascular studies are warranted to gain an in-depth information focusing the transcriptomic and translation changes employing suitable in vivo and in vitro test models.
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Affiliation(s)
- Quaiser Saquib
- Zoology Department, College of Sciences, King Saud University, Riyadh, Saudi Arabia.,Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Maqsood A Siddiqui
- Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sabiha M Ansari
- Botany & Microbiology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hend A Alwathnani
- Botany & Microbiology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
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17
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Khan A, Fahad TM, Akther T, Zaman T, Hasan MF, Islam Khan MR, Islam MS, Kishi S. Carbofuran accelerates the cellular senescence and declines the life span of spns1 mutant zebrafish. J Cell Mol Med 2020; 25:1048-1059. [PMID: 33277797 PMCID: PMC7812278 DOI: 10.1111/jcmm.16171] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 11/03/2020] [Accepted: 11/17/2020] [Indexed: 12/16/2022] Open
Abstract
Carbofuran is a carbamate pesticide, widely used in agricultural practices to increase crop productivity. In mammals, carbofuran is known to cause several untoward effects, such as apoptosis in the hippocampal neuron, oxidative stress, loss of memory and chromosomal anomalies. Most of these effects are implicated with cellular senescence. Therefore, the present study aimed to determine the effect of carbofuran on cellular senescence and biological ageing. Spinster homolog 1 (Spns1) is a transmembrane transporter, regulates autolysosomal biogenesis and plays a role in cellular senescence and survival. Using senescence‐associated β‐galactosidase staining, we found that carbofuran accelerates the cellular senescence in spns1 mutant zebrafish. The yolk opaqueness, a premature ageing phenotype in zebrafish embryos, was accelerated by carbofuran treatment. In the survival study, carbofuran shortened the life span of spns1 mutant zebrafish. Autophagy is the cellular lysosomal degradation, usually up‐regulated in the senescent cells. To know the impact of carbofuran exposure on autophagy progress, we established a double‐transgenic zebrafish line, harbouring EGFP‐tagged LC3‐II and mCherry‐tagged Lamp1 on spns1 mutant background, whereas we found, carbofuran exposure synergistically accelerates autolysosome formation with insufficient lysosome‐mediated degradation. Our data collectively suggest that carbofuran exposure synergistically accelerates the cellular senescence and affects biological ageing in spns1 defective animals.
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Affiliation(s)
- Alam Khan
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh.,Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA
| | | | - Tanjima Akther
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Tanjeena Zaman
- Department of Fisheries, University of Rajshahi, Rajshahi, Bangladesh.,Department of Biology, University of Hail, Hail, Saudi Arabia
| | - Md Faruk Hasan
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, Bangladesh
| | | | | | - Shuji Kishi
- S&J Kishi Research Corporation, Jupiter, FL, USA
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18
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Rahman MA, Rahman MS, Uddin MJ, Mamum-Or-Rashid ANM, Pang MG, Rhim H. Emerging risk of environmental factors: insight mechanisms of Alzheimer's diseases. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:44659-44672. [PMID: 32201908 DOI: 10.1007/s11356-020-08243-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/25/2020] [Indexed: 06/10/2023]
Abstract
Neurodegenerative disorders are typically sporadic in nature in addition to usually influenced through an extensive range of environmental factors, lifestyle, and genetic elements. Latest observations have hypothesized that exposure of environmental factors may increase the prospective risk of Alzheimer's diseases (AD). However, the role of environmental factors as a possible dangerous issue has extended importance concerned in AD pathology, although actual etiology of the disorder is still not yet clear. Thus, the aim of this review is to highlight the possible correlation between environmental factors and AD, based on the present literature view. Environmental risk factors might play an important role in decelerating or accelerating AD progression. Among well-known environmental risk factors, prolonged exposure to several heavy metals, for example, aluminum, arsenic, cadmium, lead, and mercury; particulate air, and some pesticides as well as metal-containing nanoparticles have been participated to cause AD. These heavy metals have the capacity to enhance amyloid β (Aβ) peptide along with tau phosphorylation, initiating amyloid/senile plaques, as well as neurofibrillary tangle formation; therefore, neuronal cell death has been observed. Furthermore, particulate air, pesticides, and heavy metal exposure have been recommended to lead AD susceptibility and phenotypic diversity though epigenetic mechanisms. Therefore, this review deliberates recent findings detailing the mechanisms for a better understanding the relationship between AD and environmental risk factors along with their mechanisms of action on the brain functions.
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Affiliation(s)
- Md Ataur Rahman
- Center for Neuroscience, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
- Department of Biotechnology and Genetic Engineering, Global Biotechnology & Biomedical Research Network (GBBRN), Faculty of Biological Sciences, Islamic University, Kushtia, 7003, Bangladesh.
| | - Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, 456-756, Republic of Korea
| | - Md Jamal Uddin
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Republic of Korea
- ABEx Bio-Research Center, East Azampur, Dhaka, 1230, Bangladesh
| | - A N M Mamum-Or-Rashid
- Anti-Aging Medical Research Center and Glycation Stress Research Center, Graduate School of Life and Medical Sciences, Doshisha University, Kyoto, Japan
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, 456-756, Republic of Korea
| | - Hyewhon Rhim
- Center for Neuroscience, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
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19
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Mir RH, Sawhney G, Pottoo FH, Mohi-Ud-Din R, Madishetti S, Jachak SM, Ahmed Z, Masoodi MH. Role of environmental pollutants in Alzheimer's disease: a review. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:44724-44742. [PMID: 32715424 DOI: 10.1007/s11356-020-09964-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 06/30/2020] [Indexed: 06/11/2023]
Abstract
Neurodegenerative disorders are commonly erratic influenced by various factors including lifestyle, environmental, and genetic factors. In recent observations, it has been hypothesized that exposure to various environmental factors enhances the risk of Alzheimer's disease (AD). The exact etiology of Alzheimer's disease is still unclear; however, the contribution of environmental factors in the pathology of AD is widely acknowledged. Based on the available literature, the review aims to culminate in the prospective correlation between the various environmental factors and AD. The prolonged exposure to the various well-known environmental factors including heavy metals, air pollutants (particulate matter), pesticides, nanoparticles containing metals, industrial chemicals results in accelerating the progression of AD. Common mechanisms have been documented in the field of environmental contaminants for enhancing amyloid-β (Aβ) peptide along with tau phosphorylation, resulting in the initiation of senile plaques and neurofibrillary tangles, which results in the death of neurons. This review offers a compilation of available data to support the long-suspected correlation between environmental risk factors and AD pathology. Graphical abstract .
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Affiliation(s)
- Reyaz Hassan Mir
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.
| | - Gifty Sawhney
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, Jammu, 180001, India
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam, 31441, Saudi Arabia
| | - Roohi Mohi-Ud-Din
- Pharmacognosy Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India
| | - Sreedhar Madishetti
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, Jammu, 180001, India
| | - Sanjay M Jachak
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab, 160062, India
| | - Zabeer Ahmed
- Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, Jammu, 180001, India
| | - Mubashir Hussain Masoodi
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.
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20
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Sharma S, Wakode S, Sharma A, Nair N, Dhobi M, Wani MA, Pottoo FH. Effect of environmental toxicants on neuronal functions. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:44906-44921. [PMID: 32996088 DOI: 10.1007/s11356-020-10950-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 09/20/2020] [Indexed: 05/22/2023]
Abstract
In the last few years, neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) have attracted attention due to their high prevalence worldwide. Environmental factors may be one of the biggest reasons for these diseases related to neuronal dysfunctions. Most of neuronal disorders are strongly associated with pre- and postnatal exposure to environmental toxins released from industries. Some of the neurotoxic metals such as lead, aluminum, mercury, manganese, cadmium, and arsenic as well as some pesticides and metal-based nanoparticles have been involved in AD and PD due to their ability to produce senile/amyloid plaques and NFTs which are the main feature of these neuronal dysfunctions. Exposure to solvents is also majorly responsible for neurodegenerative disorders. The present review highlights the impact of omnipresent heavy metals with some other neurotoxins on human health and how they give rise to neuronal dysfunctions which in turn causes socio-economic consequences due to increasing pollution worldwide. Graphical abstract.
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Affiliation(s)
- Supriya Sharma
- Department of Pharmacognosy, Delhi Pharmaceutical Sciences and Research University, Sector-3, MB road, Pushp Vihar, New Delhi, 110017, India
| | - Sharad Wakode
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Sector-3, MB road, Pushp Vihar, New Delhi, 110017, India
| | - Anjali Sharma
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Sector-3, MB road, Pushp Vihar, New Delhi, 110017, India
| | - Nisha Nair
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Sector-3, MB road, Pushp Vihar, New Delhi, 110017, India
| | - Mahaveer Dhobi
- Department of Pharmacognosy, Delhi Pharmaceutical Sciences and Research University, Sector-3, MB road, Pushp Vihar, New Delhi, 110017, India
| | - Mushtaq Ahmad Wani
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Kolkata, 163, Maniktala Main road, Kolkata, 700054, India
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Damman, 31441, Saudi Arabia.
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21
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Amine KM, Kahina C, Nawel H, Faiza Z, Jean G, Mohamed T, Saâdia M, Ahsene B. Protective Effects of Pelargonium graveolens Essential Oil on Methomyl-Induced Oxidative Stress and Spatial Working Memory Impairment in Association with Histopathological Changes in the Hippocampus of Male Wistar Rats. Basic Clin Neurosci 2020; 11:433-446. [PMID: 33613881 PMCID: PMC7878032 DOI: 10.32598/bcn.11.4.1402.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 06/25/2018] [Accepted: 12/15/2019] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Methomyl (MET) is a carbamate insecticide, used in agriculture and public health to eliminate harmful insects. Besides its advantages in agriculture, it causes neurotoxic effects. The aim of this study was to evaluate the effect of MET on Spatial Working Memory (SWM), oxidative stress parameters, and histopathological changes in the hippocampus, as well as the possible protective role of Pelargonium graveolens Essential Oil (EO). METHODS Male Wistar rats were randomized into four groups of six animals: group I as the control that received the vehicle; group II received EO (75 mg/kg b.w), group III received MET (2 mg/kg b.w); and group IV received both MET and EO. The rats were administered the respective doses orally by gavage for 28 days. SWM was assessed using Y-maze on the day before the first treatment and day 28 after the last dose. They were sacrificed by decapitation and their brains were taken for assessing oxidative stress parameters and histopathological analysis. RESULTS MET treatment caused SWM deficits. Furthermore, drastic changes were observed in aspartate transaminase, alanine aminotransferase, and alkaline phosphatase activities. The level of malondialdehyde significantly increased, whereas antioxidant (glutathioneS-transferase and catalase) enzyme activities significantly decreased. The CA1 region of the hippocampus of rats exposed to MET revealed severe histological alterations. However, supplementation with EO improved SWM and partially restored the activities of antioxidant systems and prevented neuronal cell damage. CONCLUSION P. graveolens EO has the potential in mitigating most of the adverse effects in the hippocampus and prevents SWM impairment induced by MET toxicity.
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Affiliation(s)
| | - Chabane Kahina
- Laboratory of Animal Physiology and Cell Signaling, ENS Kouba, Algiers, Algeria
| | - Habchi Nawel
- Laboratory of Animal Physiology and Cell Signaling, ENS Kouba, Algiers, Algeria
| | - Zaida Faiza
- Laboratory of Animal Physiology and Cell Signaling, ENS Kouba, Algiers, Algeria
| | - Giaimis Jean
- UMR Qualisud-Faculty of Pharmacy, University of Montpellier, Montpellier, France
| | - Toumi Mohamed
- Laboratory of Ethnobotany and Naturel Substances, ENS Kouba, Algiers, Algeria
| | - Mameri Saâdia
- Laboratory of Anatomopathology, Mustapha Bacha Hospital, Algiers, Algeria
| | - Baz Ahsene
- Laboratory of Animal Physiology and Cell Signaling, ENS Kouba, Algiers, Algeria
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Neuropathological Mechanisms Associated with Pesticides in Alzheimer's Disease. TOXICS 2020; 8:toxics8020021. [PMID: 32218337 PMCID: PMC7355712 DOI: 10.3390/toxics8020021] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/14/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022]
Abstract
Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.
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Wang D, Li B, Wu Y, Li B. The Effects of Maternal Atrazine Exposure and Swimming Training on Spatial Learning Memory and Hippocampal Morphology in Offspring Male Rats via PSD95/NR2B Signaling Pathway. Cell Mol Neurobiol 2019; 39:1003-1015. [PMID: 31187311 PMCID: PMC11457838 DOI: 10.1007/s10571-019-00695-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 06/01/2019] [Indexed: 12/22/2022]
Abstract
Atrazine (ATR), a widely used herbicide, has been previously shown to damage spatial memory capability and the hippocampus of male rats during the development. It has also been indicated that physical exercise can improve learning and memory in both humans and animals, as a neuroprotective method. Our aim here was to investigate the effect of maternal ATR exposure during gestation and lactation on spatial learning and memory function and hippocampal morphology in offspring and to further evaluate the neuroprotective effect of swimming training and identify possible related learning and memory signaling pathways. Using Sprague-Dawley rats, we examined behavioral and molecular biology effects associated with maternal ATR exposure, as well as the effects of 8 or 28 days swimming training. Maternal exposure to ATR was found to impair spatial learning and memory by behavioral test, damage the hippocampal morphology, and reduce related genes and proteins expression of learning and memory in the hippocampus. The extended, 28 days, period of swimming training produced a greater amelioration of the adverse effects of ATR exposure than the shorter, 8 days, training period. Our results suggest that maternal ATR exposure may damage the spatial learning and memory of offspring male rats via PSD95/NR2B signaling pathway. The negative effect of ATR could be at least partially reversed by swimming training, pointing to a potential neuroprotective role of physical exercise in nervous system diseases accompanying by learning and memory deficit.
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Affiliation(s)
- Dandan Wang
- Department of Toxicology, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Bai Li
- Department of Toxicology, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Yanping Wu
- Department of Toxicology, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Baixiang Li
- Department of Toxicology, School of Public Health, Harbin Medical University, Harbin, 150086, China.
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Mohammadzadeh L, Abnous K, Razavi BM, Hosseinzadeh H. Crocin-protected malathion-induced spatial memory deficits by inhibiting TAU protein hyperphosphorylation and antiapoptotic effects. Nutr Neurosci 2019; 23:221-236. [DOI: 10.1080/1028415x.2018.1492772] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Leila Mohammadzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khalil Abnous
- Pharmaceutical Research Center, Department of Medicinal Chemistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Proteasome inhibition by MG-132 protects against deltamethrin-induced apoptosis in rat hippocampus. Life Sci 2019; 220:76-83. [PMID: 30695709 DOI: 10.1016/j.lfs.2019.01.041] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/06/2019] [Accepted: 01/25/2019] [Indexed: 11/21/2022]
Abstract
AIMS Deltamethrin (DM), a type II synthetic pyrethroid insecticide, is widely used in agriculture and home pest control. The evaluation of their toxic effects is of major concern to public health. However, the molecular mechanism of DM-induced neurodegenerative disease is still far from clear. This study was designed to investigate the potential role of ubiquitin proteasome system (UPS) in DM-induced neurotoxicity where the proteasome inhibitor MG-132 could mitigate the neurotoxic effects. MAIN METHODS Male Sprague-Dawley rats were divided into two batches. The first batch of rats was administrated with a single dose of DM (12.5 mg/kg) by intraperitoneal injections (i.p.) and the animals were then euthanized at 5, 24, and 48 h post injection. The second batch was treated as follow: control group, DM (12.5 mg/kg) groups for 24 h, MG-132 (0.5 mg/kg, i.p.) 2 h plus DM 24 h group, and MG-132 alone group. Ubiqutinatied proteins, DNA damage and apoptosis were investigated. KEY FINDINGS DM treatment induced the ubiquitinated proteins expression with the peaks at 5 h. Moreover, DM increased DNA damage, early apoptotic rate, the expression level of Cleaved Caspase-3, caspase-3 activity and decreased the expression level of Bcl-2 at DM 24 h group. Compared to DM 24 h group, MG-132 pretreatment significantly down-regulated ubiquitinated proteins, lowered the DNA damage and apoptosis by decreasing Caspase-3 and increasing Bcl-2 expression. SIGNIFICANCE These results indicate that MG-132 effectively alleviates DM-induced DNA damage and apoptosis by inhibiting ubiquitinated proteins. UPS may play a role in DM-induced neurodegenerative disorders.
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Carbofuran hampers oligodendrocytes development leading to impaired myelination in the hippocampus of rat brain. Neurotoxicology 2019; 70:161-179. [DOI: 10.1016/j.neuro.2018.11.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 11/14/2018] [Accepted: 11/20/2018] [Indexed: 11/21/2022]
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Tsatsakis AM, Docea AO, Calina D, Buga AM, Zlatian O, Gutnikov S, Kostoff RN, Aschner M. Hormetic Neurobehavioral effects of low dose toxic chemical mixtures in real-life risk simulation (RLRS) in rats. Food Chem Toxicol 2018; 125:141-149. [PMID: 30594548 DOI: 10.1016/j.fct.2018.12.043] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 12/18/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022]
Abstract
The current study aims to assess the long-term effects of very low dose exposures to a complex chemical mixture on motor performance and behavioural changes in rats. For twelve months (equivalent to thirty years in human terms), four groups of Sprague Dawley rats (five males and five females per group) were exposed to a thirteen chemical mixture (in drinking water) in doses of 0, 0.25, 1 and 5xADI/TDI (acceptable daily intake/tolerable daily intake) (mg/kg body weight/day). After twelve month exposure, the rats' motor performances were assessed by rotarod test, and their behavioural changes were assessed by open field exploratory test and elevated plus maze test. Exposure to the chemical mixture resulted in a statistically significant increase in the locomotor activity quantified by the number of crossings over external squares and in the spatial orientation activity quantified as the number of rearings in the lower dose group (0.25xADI/TDI) compared with the control group (p < 0.05). No significant changes were observed in the two higher dose groups (1xADI/TDI, 5xADI/TDI) compared with the control group. The administration of a very low doses of a cocktail of 13 chemicals led to a dose-dependent stimulation of the nervous system, rather than its inhibition.
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Affiliation(s)
- Aristidis M Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, GR-71003, Heraklion, Crete, Greece.
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy, Faculty of Pharmacy, Craiova, 200349, Romania.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| | - Ana Maria Buga
- Department of Biochemistry, University of Medicine and Pharmacy Craiova, 200349, Craiova, Romania.
| | - Ovidiu Zlatian
- Department of Microbiology, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania.
| | - Sergei Gutnikov
- Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom.
| | - Ronald N Kostoff
- School of Public Policy, Georgia Institute of Technology, Gainesville, VA, 20155, USA.
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einsten College of Medicine, Bronx, NY, 10461, USA.
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Çomakli S, Köktürk M, Topal A, Özkaraca M, Ceyhun SB. Immunofluorescence/fluorescence assessment of brain-derived neurotrophic factor, c-Fos activation, and apoptosis in the brain of zebrafish (Danio rerio) larvae exposed to glufosinate. Neurotoxicology 2018; 69:60-67. [DOI: 10.1016/j.neuro.2018.09.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 09/13/2018] [Accepted: 09/13/2018] [Indexed: 12/19/2022]
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Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1483791. [PMID: 30112360 PMCID: PMC6077677 DOI: 10.1155/2018/1483791] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/19/2018] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
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Seth B, Yadav A, Agarwal S, Tiwari SK, Chaturvedi RK. Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran. J Biol Chem 2017; 292:19423-19440. [PMID: 28982980 DOI: 10.1074/jbc.m117.798074] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 09/29/2017] [Indexed: 12/22/2022] Open
Abstract
The widely used carbamate pesticide carbofuran causes neurophysiological and neurobehavioral deficits in rodents and humans and therefore poses serious health hazards around the world. Previously, we reported that gestational carbofuran exposure has detrimental effects on hippocampal neurogenesis, the generation of new neurons from neural stem cells (NSC), in offspring. However, the underlying cellular and molecular mechanisms for carbofuran-impaired neurogenesis remain unknown. Herein, we observed that chronic carbofuran exposure from gestational day 7 to postnatal day 21 altered expression of genes and transcription factors and levels of proteins involved in neurogenesis and the TGF-β pathway (i.e. TGF-β; SMAD-2, -3, and -7; and SMURF-2) in the rat hippocampus. We found that carbofuran increases TGF-β signaling (i.e. increased phosphorylated SMAD-2/3 and reduced SMAD-7 expression) in the hippocampus, which reduced NSC proliferation because of increased p21 levels and reduced cyclin D1 levels. Moreover, the carbofuran-altered TGF-β signaling impaired neuronal differentiation (BrdU/DCX+ and BrdU/NeuN+ cells) and increased apoptosis and neurodegeneration in the hippocampus. Blockade of the TGF-β pathway with the specific inhibitor SB431542 and via SMAD-3 siRNA prevented carbofuran-mediated inhibition of neurogenesis in both hippocampal NSC cultures and the hippocampus, suggesting the specific involvement of this pathway. Of note, both in vitro and in vivo studies indicated that TGF-β pathway attenuation reverses carbofuran's inhibitory effects on neurogenesis and associated learning and memory deficits. These results suggest that carbofuran inhibits NSC proliferation and neuronal differentiation by altering TGF-β signaling. Therefore, we conclude that TGF-β may represent a potential therapeutic target against carbofuran-mediated neurotoxicity and neurogenesis disruption.
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Affiliation(s)
- Brashket Seth
- From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.,the Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Lucknow Campus, Lucknow 226001, Uttar Pradesh, India
| | - Anuradha Yadav
- From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.,the Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Lucknow Campus, Lucknow 226001, Uttar Pradesh, India
| | - Swati Agarwal
- From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.,the Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and
| | - Shashi Kant Tiwari
- From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.,the Department of Pediatrics, University of California San Diego, La Jolla, California 92093
| | - Rajnish Kumar Chaturvedi
- From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India, .,the Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Lucknow Campus, Lucknow 226001, Uttar Pradesh, India
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Fournier K, Baumont E, Glorennec P, Bonvallot N. Relative toxicity for indoor semi volatile organic compounds based on neuronal death. Toxicol Lett 2017; 279:33-42. [PMID: 28709981 DOI: 10.1016/j.toxlet.2017.07.875] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 07/03/2017] [Accepted: 07/09/2017] [Indexed: 11/30/2022]
Abstract
BACKGROUND Semi Volatile Organic Compounds (SVOCs) are contaminants commonly found in dwellings as a result of their use as plasticizers, flame retardants, or pesticides in building materials and consumer products. Many SVOCs are suspected of being neurotoxic, based on mammal experimentation (impairment of locomotor activity, spatial learning/memory or behavioral changes), raising the question of cumulative risk assessment. The aim of this work is to estimate the relative toxicity of such SVOCs, based on neuronal death. METHOD SVOCs fulfilling the following conditions were included: detection frequency >10% in dwellings, availability of data on effects or mechanism of action for neurotoxicity, and availability of dose-response relationships based on cell viability assays as a proxy of neuronal death. Benchmark concentration values (BMC) were estimated using a Hill model, and compared to assess relative toxicity. RESULTS Of the 58 SVOCs selected, 28 were suspected of being neurotoxic in mammals, and 21 have been documented as inducing a decrease in cell viability in vitro. 13 have at least one dose-response relationship that can be used to derive a BMC based on a 10% fall in neuronal viability. Based on this in vitro endpoint, PCB-153 appeared to be the most toxic compound, having the lowest BMC10 (0.072μM) and diazinon the least toxic compound, having the highest BMC10 (94.35μM). We showed that experimental designs (in particular choice of cell lines) had a significant influence on BMC calculation. CONCLUSION For the first time, the relative in vitro toxicity of 13 indoor contaminants belonging to different chemical families has been assessed on the basis of neuronal cell viability. Lack of comparable toxicity datasets limits the number of SVOCs that can be included. More standardized protocols in terms of cell lines, species and exposure duration should be developed with a view to cumulative risk assessment.
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Affiliation(s)
- Kevin Fournier
- EHESP School of Public Health, Sorbonne Paris Cité, Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France; INSERM UMR1085 IRSET (Research Institute in Environmental and Occupational Health), Rennes, France.
| | - Emmanuel Baumont
- EHESP School of Public Health, Sorbonne Paris Cité, Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France; INSERM UMR1085 IRSET (Research Institute in Environmental and Occupational Health), Rennes, France.
| | - Philippe Glorennec
- EHESP School of Public Health, Sorbonne Paris Cité, Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France; INSERM UMR1085 IRSET (Research Institute in Environmental and Occupational Health), Rennes, France.
| | - Nathalie Bonvallot
- EHESP School of Public Health, Sorbonne Paris Cité, Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France; INSERM UMR1085 IRSET (Research Institute in Environmental and Occupational Health), Rennes, France.
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Ma RH, Zhang Y, Hong XY, Zhang JF, Wang JZ, Liu GP. Role of microtubule-associated protein tau phosphorylation in Alzheimer's disease. ACTA ACUST UNITED AC 2017; 37:307-312. [PMID: 28585125 DOI: 10.1007/s11596-017-1732-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 05/01/2017] [Indexed: 12/16/2022]
Abstract
As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer's disease (AD) and other tauopathies, the abnormally hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the form of neurofibrillary tangles. An imbalanced regulation in protein kinases and protein phosphatases is the direct cause of tau hyperphosphorylation. Among various kinases and phosphatases, glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) are the most implicated. Accumulation of the hyperphosphorylated tau induces synaptic toxicity and cognitive impairments. Here, we review the upstream factors or pathways that can regulate GSK-3β or PP2A activity mainly based on our recent findings. We will also discuss the mechanisms that may underlie tau-induced synaptic toxicity.
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Affiliation(s)
- Rong-Hong Ma
- Department of Laboratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yao Zhang
- Department of Endocrinology, Liyuan Hospital, Key Laboratory of Hubei Province for Neurological Disorders, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiao-Yue Hong
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Hubei Province and Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jun-Fei Zhang
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Hubei Province and Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jian-Zhi Wang
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Hubei Province and Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Gong-Ping Liu
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Hubei Province and Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Wang Q, Xia X, Deng X, Li N, Wu D, Zhang L, Yang C, Tao F, Zhou J. Lambda-cyhalothrin disrupts the up-regulation effect of 17β-estradiol on post-synaptic density 95 protein expression via estrogen receptor α-dependent Akt pathway. J Environ Sci (China) 2016; 41:252-260. [PMID: 26969072 DOI: 10.1016/j.jes.2015.04.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 03/30/2015] [Accepted: 04/02/2015] [Indexed: 06/05/2023]
Abstract
Lambda-cyhalothrin (LCT), one of the type II pyrethroids, has been widely used throughout the world. The estrogenic effect of LCT to increase cell proliferation has been well established. However, whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated. In addition, 17β-Estradiol (E2) plays a crucial role in neurodevelopment and induces an increase in synaptic proteins. The post-synaptic density 95 (PSD95) protein, which is involved in the development of the structure and function of new spines and localized with estrogen receptor α (ERα) at the post-synaptic density (PSD), was detected in our study by using hippocampal neuron cell line HT22. We found that LCT up-regulated PSD95 and ERα expression, estrogen receptor (ER) antagonist ICI182,780 and phosphatidylinositol-4; 5-bisphosphate 3-kinase (PI3K) inhibitor LY294,002 blocked this effect. In addition, LCT disrupted the promotion effect of E2 on PSD95. To investigate whether the observed changes are caused by ERα-dependent signaling activation, we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B (PKB/Akt)-eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) pathway. There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment. In addition, LCT could disrupt the activation effect of E2 on the Akt pathway. However, no changes in cAMP response element-binding protein (CREB) activation and PSD95 messenger ribonucleic acid (mRNA) were observed. Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway, and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.
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Affiliation(s)
- Qunan Wang
- Chinese Academy of Science Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China; Department of Toxicology, College of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Xin Xia
- Department of Toxicology, College of Public Health, Anhui Medical University, Hefei 230032, China
| | - Xiaomei Deng
- Department of Pharmacy, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
| | - Nian Li
- Department of Toxicology, College of Public Health, Anhui Medical University, Hefei 230032, China
| | - Daji Wu
- Department of Toxicology, College of Public Health, Anhui Medical University, Hefei 230032, China
| | - Long Zhang
- Department of Toxicology, College of Public Health, Anhui Medical University, Hefei 230032, China
| | - Chengwei Yang
- Department of Toxicology, College of Public Health, Anhui Medical University, Hefei 230032, China
| | - Fangbiao Tao
- Department of Maternal and Child health, College of Public Health, Anhui Medical University, Hefei 230032, China
| | - Jiangning Zhou
- Chinese Academy of Science Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China.
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Liu G, Liu C, Zhang XN. Comparison of the neuropsychological mechanisms of 2,6-diisopropylphenol and N-methyl-D-aspartate receptor antagonist against electroconvulsive therapy-induced learning and memory impairment in depressed rats. Mol Med Rep 2015; 12:3297-3308. [PMID: 25998151 PMCID: PMC4526078 DOI: 10.3892/mmr.2015.3803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Accepted: 04/14/2015] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to examine the neurophysiological mechanisms of the 2,6-diisopropylphenol and N-methyl-D-aspartate (NMDA) receptor antagonist against learning and memory impairment, induced by electroconvulsive therapy (ECT). A total of 48 adult depressed rats without olfactory bulbs were randomly divided into six experimental groups: i) saline; ii) 10 mg/kg MK‑801; iii) 10 mg/kg MK‑801 and a course of ECT; iv) 200 mg/kg 2,6‑diisopropylphenol; v) 200 mg/kg 2,6‑diisopropylphenol and a course of ECT; and vi) saline and a course of ECT. The learning and memory abilities of the rats were assessed using a Morris water maze 1 day after a course of ECT. The hippocampus was removed 1 day after assessment using the Morris water maze assessment. The content of glutamate in the hippocampus was detected using high‑performance liquid chromatography. The expression levels of p‑AT8Ser202 and GSK‑3β1H8 in the hippocampus were determined using immunohistochemical staining and western blot analysis. The results demonstrated that the 2,6‑diisopropylphenol NMDA receptor antagonist, MK‑801 and ECT induced learning and memory impairment in the depressed rats. The glutamate content was significantly upregulated by ECT, reduced by 2,6‑diisopropylphenol, and was unaffected by the NMDA receptor antagonist in the hippocampus of the depressed rats. Tau protein hyperphosphorylation in the hippocampus was upregulated by ECT, but was reduced by 2,6‑diisopropylphenol and the MK‑801 NMDA receptor antagonist. It was also demonstrated that 2,6‑diisopropylphenol prevented learning and memory impairment and reduced the hyperphosphorylation of the Tau protein, which was induced by eECT. GSK‑3β was found to be the key protein involved in this signaling pathway. The ECT reduced the learning and memory impairment, caused by hyperphosphorylation of the Tau protein, in the depressed rats by upregulating the glutamate content.
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Affiliation(s)
- Gang Liu
- Department of Anesthesiology, General Hospital of Beijing Military Area of PLA, Beijing 100700, P.R. China
| | - Chao Liu
- Department of Anesthesiology, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Xue-Ning Zhang
- Department of Radiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci 2015; 9:124. [PMID: 25914621 PMCID: PMC4392704 DOI: 10.3389/fncel.2015.00124] [Citation(s) in RCA: 393] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 03/17/2015] [Indexed: 12/21/2022] Open
Abstract
Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.
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Shiue I. Arsenic, heavy metals, phthalates, pesticides, hydrocarbons and polyfluorinated compounds but not parabens or phenols are associated with adult remembering condition: US NHANES, 2011-2012. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2015; 22:6381-6386. [PMID: 25744817 DOI: 10.1007/s11356-015-4261-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 02/19/2015] [Indexed: 06/04/2023]
Abstract
Links between environmental chemicals and human health have emerged, but the effects on cognition were less studied. Therefore, it was aimed to study the relationships of different sets of environmental chemicals and the remembering condition in a national and population-based study in recent years. Data was retrieved from the US National Health and Nutrition Examination Surveys, 2011-2012, including demographics, blood pressure readings, serum measurements, lifestyle factors, self-reported remembering condition and urinary environmental chemical concentrations. Analyses included Chi-square test, t test and survey-weighted logistic and multi-nominal regression models. Among the elderly aged 60-80 (n = 1791), 320 (17.9%) had difficulties in thinking or remembering. People who had difficulties in thinking or remembering had higher levels of urinary heavy metals, phthalates, pesticides and hydrocarbon concentrations but lower levels of urinary arsenic and polyfluorinated compound concentrations. During the recent past week, 146 people (8.2%) had trouble remembering for more than three times while 619 people (35.2%) had that for one to three times. These people had higher levels of urinary heavy metals, phthalates, pesticides and hydrocarbon concentrations but lower levels of urinary polyfluorinated compound concentrations. There were no associations with urinary bisphenols, parabens, perchlorate, nitrate or thiocyanate concentrations. This is the first time observing statistically significant risk associations of urinary heavy metals, phthalates, pesticides and hydrocarbon concentrations and the remembering condition specifically in the elderly, although the causality cannot be established. Elimination of such environmental chemicals in humans might need to be considered in future health policy and intervention programs.
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Affiliation(s)
- Ivy Shiue
- School of Energy, Geoscience, Infrastructure and Society, Heriot-Watt University, Riccarton, EH14 4AS, Edinburgh, Scotland, UK,
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Maurya SK, Mishra J, Abbas S, Bandyopadhyay S. Cypermethrin Stimulates GSK3β-Dependent Aβ and p-tau Proteins and Cognitive Loss in Young Rats: Reduced HB-EGF Signaling and Downstream Neuroinflammation as Critical Regulators. Mol Neurobiol 2015; 53:968-982. [PMID: 25575682 DOI: 10.1007/s12035-014-9061-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 12/09/2014] [Indexed: 10/24/2022]
Abstract
Pesticide exposure is recognized as a risk factor for Alzheimer's disease (AD). We investigated early signs of AD-like pathology upon exposure to a pyrethroid pesticide, cypermethrin, reported to impair neurodevelopment. We treated weanling rats with cypermethrin (10 and 25 mg/kg) and detected dose-dependent increase in the key proteins of AD, amyloid beta (Aβ), and phospho-tau, in frontal cortex and hippocampus as early as postnatal day 45. Upregulation of Aβ pathway involved an increase in amyloid precursor protein (APP) and its pro-amyloidogenic processing through beta-secretase (BACE) and gamma-secretase. Tau pathway entailed elevation in tau and glycogen-synthase kinase-3-beta (GSK3β)-dependent, phospho-tau. GSK3β emerged as a molecular link between the two pathways, evident from reduction in phospho-tau as well as BACE upon treating GSK3β inhibitor, lithium chloride. Exploring the mechanism revealed an attenuated heparin-binding epidermal growth factor (HB-EGF) signaling and downstream astrogliosis-mediated neuroinflammation to be responsible for inducing Aβ and phospho-tau. Cypermethrin caused a proximal reduction in HB-EGF, which promoted astrocytic nuclear factor kappa B signaling and astroglial activation close to Aβ and phospho-tau. Glial activation stimulated generation of interleukin-1 (IL-1), which upregulated GSK3β, and APP and tau as well, resulting in co-localization of Aβ and phospho-tau with IL-1 receptor. Intracerebral insertion of exogenous HB-EGF restored its own signaling and suppressed neuroinflammation and thereby Aβ and phospho-tau in cypermethrin-exposed rats, proving a central role of reduced HB-EGF signaling in cypermethrin-mediated neurodegeneration. Furthermore, cypermethrin stimulated cognitive impairments, which could be prevented by exogenous HB-EGF. Our data demonstrate that cypermethrin induces premature upregulation of GSK3β-dependent Aβ and tau pathways, where HB-EGF signaling and neuroinflammation serve as essential regulators.
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Affiliation(s)
- Shailendra Kumar Maurya
- Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India
| | - Juhi Mishra
- Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India
| | - Sabiya Abbas
- Food and Chemical Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India
| | - Sanghamitra Bandyopadhyay
- Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, India.
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Yegambaram M, Manivannan B, Beach TG, Halden RU. Role of environmental contaminants in the etiology of Alzheimer's disease: a review. Curr Alzheimer Res 2015; 12:116-46. [PMID: 25654508 PMCID: PMC4428475 DOI: 10.2174/1567205012666150204121719] [Citation(s) in RCA: 177] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 12/10/2014] [Accepted: 01/14/2015] [Indexed: 12/11/2022]
Abstract
Alzheimer's dis ease (AD) is a leading cause of mortality in the developed world with 70% risk attributable to genetics. The remaining 30% of AD risk is hypothesized to include environmental factors and human lifestyle patterns. Environmental factors possibly include inorganic and organic hazards, exposure to toxic metals (aluminium, copper), pesticides (organochlorine and organophosphate insecticides), industrial chemicals (flame retardants) and air pollutants (particulate matter). Long term exposures to these environmental contaminants together with bioaccumulation over an individual's life-time are speculated to induce neuroinflammation and neuropathology paving the way for developing AD. Epidemiologic associations between environmental contaminant exposures and AD are still limited. However, many in vitro and animal studies have identified toxic effects of environmental contaminants at the cellular level, revealing alterations of pathways and metabolisms associated with AD that warrant further investigations. This review provides an overview of in vitro, animal and epidemiological studies on the etiology of AD, highlighting available data supportive of the long hypothesized link between toxic environmental exposures and development of AD pathology.
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Affiliation(s)
| | | | | | - Rolf U Halden
- Center for Environmental Security, The Biodesign Institute, Arizona State University, PO Box 875904 Tempe, AZ 85287, USA.
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Hossain MM, DiCicco-Bloom E, Richardson JR. Hippocampal ER stress and learning deficits following repeated pyrethroid exposure. Toxicol Sci 2014; 143:220-8. [PMID: 25359175 DOI: 10.1093/toxsci/kfu226] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.
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Affiliation(s)
- Muhammad M Hossain
- *Department of Environmental and Occupational Medicine, Rutgers-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854; and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Emanuel DiCicco-Bloom
- *Department of Environmental and Occupational Medicine, Rutgers-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854; and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Jason R Richardson
- *Department of Environmental and Occupational Medicine, Rutgers-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854; and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
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