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Fang X, Wang X, Hao M, Zhong G, Gao M, Ma Y, Pan Y, Yang H, Yin X, Shen J, Huang S, Wang Q. The role of copper homeostasis and cuproptosis in cerebrovascular diseases:A novel therapeutic target. Eur J Pharmacol 2025; 1001:177649. [PMID: 40320113 DOI: 10.1016/j.ejphar.2025.177649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 06/02/2025]
Abstract
Copper has a broad and important role in biological systems, where it acts as a cofactor at the active sites of a variety of enzymes and is involved in a wide range of physiological activities such as oxidative stress, lipid metabolism, and energy metabolism. Like other trace elements, copper levels maintain a balanced homeostasis in the body, and imbalances in copper homeostasis and cuproptosis it induces are involved in the progression of a range of diseases, such as cerebrovascular diseases (CVDs), including atherosclerosis (AS), hypertension, and stroke. Therefore, a deeper understanding of the relationship between copper and cerebrovascular pathologies may unearth more effective therapeutic strategies that can be effectively applied in the clinic. In this paper, we will briefly describe the process of copper metabolism and cuproptosis, and analyze how copper acts in CVDs from multiple perspectives, to further deepen the understanding of copper metabolism and provide new ideas for the treatment of CVDs.
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Affiliation(s)
- Xiaoling Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Xinyue Wang
- Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
| | - Mengmeng Hao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Guangcheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Minghuang Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yujie Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yaru Pan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Hongying Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Xuanying Yin
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Jiangang Shen
- School of Chinese Medicine, University of Hong Kong, Hong Kong, China.
| | - Shuiqing Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China.
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Kong Y, Tai Y, Chen B, Li C, Chen H, Shi L. Serum potassium level is associated with serum neurofilament light chain in American adult population: a cross-sectional analysis of the 2013-2014 National Health and Nutrition Examination Survey. Front Aging Neurosci 2025; 17:1511881. [PMID: 40171384 PMCID: PMC11959064 DOI: 10.3389/fnagi.2025.1511881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/05/2025] [Indexed: 04/03/2025] Open
Abstract
Objective Serum neurofilament light chain (sNfL) is one of the most sensitive diagnostic biomarkers for a variety of neurodegenerative pathologies. Potassium, an essential electrolyte, plays a critical role in maintaining neuronal health and the proper functioning of the central nervous system (CNS). The aim of our research was to investigate the association between serum potassium level and sNfL levels. Methods Based on the National Health and Nutrition Examination Survey (NHANES) database, we analyzed data from the 2013 to 2014 NHANES. Serum potassium concentrations were measured via ion-selective electrode (ISE) technology. The levels of sNfL were measured using a sensitive immunoassay developed by Siemens Healthineers. Our researcher analyzed the association between potassium level in serum and sNfL in American persons using multivariate logistic regression analysis and smoothed curve fitting. The consistency of these results was examined in various population subgroups. Results A total of 1,670 participants were involved in our research, including 872 women (50.5%) and 798 men (49.5%). The median serum potassium concentration was 4.0 mmol/L and the median sNfL was 12.3 pg/ml. After adjusting for potential confounders in the full model, individuals with higher serum potassium concentrations had higher sNfL levels (Q3 vs. Q1, β = 2.86, 95% CI: 0.33-5.39, P = 0.027). There was a non-linear positive dose-response association between higher serum potassium concentrations and sNfL levels (P for non-linearity = 0.028). Based on the results of stratified analysis, the relationship was stronger in the low- and middle-income group, non-drinking and non-physical activity participants, and participants with hypertension and diabetes. Interpretation In the cohort of American adults, a greater serum potassium concentration was linked to a higher sNfL. However, causality still needs to be further verified.
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Affiliation(s)
- Yingming Kong
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Basic Medical College, Shanxi Medical University, Taiyuan, China
| | - Yanghao Tai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Basic Medical College, Shanxi Medical University, Taiyuan, China
| | - Bin Chen
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Basic Medical College, Shanxi Medical University, Taiyuan, China
| | - Chunzheng Li
- Basic Medical College, Shanxi Medical University, Taiyuan, China
| | - Hao Chen
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Basic Medical College, Shanxi Medical University, Taiyuan, China
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Liang Shi
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Basic Medical College, Shanxi Medical University, Taiyuan, China
- Department of Neurology, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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Selvaraji S, Mosberger J, Fann DY, Lai MK, Hsian Chen CL, Arumugam TV. Unveiling the Therapeutic Promise of Epigenetics in Vascular Cognitive Impairment and Vascular Dementia. Aging Dis 2025:AD.2025.0010. [PMID: 39965251 DOI: 10.14336/ad.2025.0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 02/05/2025] [Indexed: 02/20/2025] Open
Abstract
Vascular dementia (VaD) is a progressive neurodegenerative disease characterized by cognitive decline and memory deficits. Despite its significant prevalence and impact, the pathophysiology of VaD remains poorly understood, and current treatments are limited to symptom management. Emerging evidence highlights the importance of lifestyle-associated risk factors in VaD, emphasizing the role of gene-environment interactions, particularly in the realm of epigenetics. While preclinical studies using animal models have provided valuable insights into epigenetic mechanisms, the translatability of these findings to human clinical settings remains limited, and research into VaD-specific epigenetics is still in its infancy. This review aims to elucidate the intricate interplay between epigenetics and VaD, shedding light on potential therapeutic interventions rooted in epigenetic mechanisms. By synthesizing insights from existing literature, we also discuss the challenges and opportunities in translating preclinical findings into clinically viable treatments, underscoring the need for further research to bridge the gap between animal models and human applications.
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Affiliation(s)
- Sharmelee Selvaraji
- Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore
- Research Laboratory of Electronics, Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America
| | - Jasmine Mosberger
- Research Laboratory of Electronics, Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America
| | - David Y Fann
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore
| | - Mitchell Kp Lai
- Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Christopher Li Hsian Chen
- Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Thiruma V Arumugam
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Australia
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
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Cao C, Li J, Cui W, Dai J, Guan Z, Wang D, Zhao X. Metalomics Revealed that Changes of Serum Elements were Associated with Oxidative Stress-Induced Inflammation of Cortex in a Mouse Model of Autism. Biol Trace Elem Res 2024:10.1007/s12011-024-04501-0. [PMID: 39733022 DOI: 10.1007/s12011-024-04501-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/23/2024] [Indexed: 12/30/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder emerging during early childhood. However, the mechanism underlying the pathogenesis of ASD remains unclear. This study investigated the alterations of elements in serum and prefrontal cortex of BTBR T + tf/J (BTBR) mice and potential mechanisms. The male BTBR mice were used for experimental group and C57BL/6 J (C57) mice were used for control group (n = 15). After behavioral tests were monitored, serum and prefrontal cortex of mice were analyzed by ICP-MS. The results demonstrated that the level of copper (Cu) was increased, and the levels of calcium (Ca), magnesium (Mg), selenium (Se), cobalt (Co), iron (Fe) and zinc (Zn) were decreased in BTBR mice compared to C57 mice (p < 0.01). The levels of above differential elements in serum demonstrated positive correlations with those in prefrontal cortex. Meanwhile, differential elements in prefrontal cortex had correlations with the total distance traveled (open field test) and the number of marbles buried (marble burying test) in BTBR mice (p < 0.05 or p < 0.01). The abnormally changed elements in serum might cross blood-brain-barrier into the brain and lead to oxidative stress, causing inflammation. Furtherly, the levels of inflammation-related indicators including tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were increased in prefrontal cortex of BTBR mice (p < 0.01), which were consistent with the aforementioned results. Our study suggested that the abnormal elements in the serum of BTBR mice may cause oxidative stress and inflammation in prefrontal cortex, which might contribute to increase the understanding of ASD pathogenesis.
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Affiliation(s)
- Can Cao
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Jian Li
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Wenqi Cui
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Jiaohua Dai
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Zhiyu Guan
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Dan Wang
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China.
| | - Xiujuan Zhao
- School of Public Health, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China.
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Aschner M, Skalny AV, Lu R, Martins AC, Tizabi Y, Nekhoroshev SV, Santamaria A, Sinitskiy AI, Tinkov AA. Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy. Front Mol Neurosci 2024; 17:1504802. [PMID: 39703721 PMCID: PMC11655512 DOI: 10.3389/fnmol.2024.1504802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/25/2024] [Indexed: 12/21/2024] Open
Abstract
Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.
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Affiliation(s)
- Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Anatoly V. Skalny
- Institute of Bioelementology, Orenburg State University, Orenburg, Russia
- Center of Bioelementology and Human Ecology, IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Department of Medical Elementology, Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia
| | - Rongzhu Lu
- Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Airton C. Martins
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Yousef Tizabi
- Department of Pharmacology, Howard University College of Medicine, Washington, DC, United States
| | - Sergey V. Nekhoroshev
- Problem Research Laboratory, Khanty-Mansiysk State Medical Academy, Khanty-Mansiysk, Russia
| | - Abel Santamaria
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Laboratorio de Nanotecnología y Nanomedicina, Departamento de Atención a la Salud, Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico
| | - Anton I. Sinitskiy
- Department of Biochemistry, South Ural State Medical University, Chelyabinsk, Russia
| | - Alexey A. Tinkov
- Institute of Bioelementology, Orenburg State University, Orenburg, Russia
- Center of Bioelementology and Human Ecology, IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Laboratory of Ecobiomonitoring and Quality Control and Department of Physical Education, Yaroslavl State University, Yaroslavl, Russia
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Kawahara M, Tanaka KI, Kato-Negishi M. Zinc, Copper, and Calcium: A Triangle in the Synapse for the Pathogenesis of Vascular-Type Senile Dementia. Biomolecules 2024; 14:773. [PMID: 39062487 PMCID: PMC11274390 DOI: 10.3390/biom14070773] [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: 06/05/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, in pathological conditions such as transient global ischemia, excess Zn is secreted to synaptic clefts, which causes neuronal death and can eventually trigger the pathogenesis of a vascular type of senile dementia. We have previously investigated the characteristics of Zn-induced neurotoxicity and have demonstrated that low concentrations of Cu can exacerbate Zn neurotoxicity. Furthermore, during our pharmacological approaches to clarify the molecular pathways of Cu-enhanced Zn-induced neurotoxicity, we have revealed the involvement of Ca homeostasis disruption. In the present review, we discuss the roles of Zn and Cu in the synapse, as well as the crosstalk between Zn, Cu, and Ca, which our study along with other recent studies suggest may underlie the pathogenesis of vascular-type senile dementia.
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Affiliation(s)
- Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi 202-8585, Tokyo, Japan
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Wang C, Zhao H, Liu Y, Qu M, Lv S, He G, Liang H, Chen K, Yang L, He Y, Ou C. Neurotoxicity of manganese via ferroptosis induced by redox imbalance and iron overload. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 278:116404. [PMID: 38705038 DOI: 10.1016/j.ecoenv.2024.116404] [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: 02/01/2024] [Revised: 04/03/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024]
Abstract
Manganese (Mn) is an essential trace element for maintaining bodily functions. Excessive exposure to Mn can pose serious health risks to humans and animals, particularly to the nervous system. While Mn has been implicated as a neurotoxin, the exact mechanism of its toxicity remains unclear. Ferroptosis is a form of programmed cell death that results from iron-dependent lipid peroxidation. It plays a role in various physiological and pathological cellular processes and may be closely related to Mn-induced neurotoxicity. However, the mechanism of ferroptosis in Mn-induced neurotoxicity has not been thoroughly investigated. Therefore, this study aims to investigate the role and mechanism of ferroptosis in Mn-induced neurotoxicity. Using bioinformatics, we identified significant changes in genes associated with ferroptosis in Mn-exposed animal and cellular models. We then evaluated the role of ferroptosis in Mn-induced neurotoxicity at both the animal and cellular levels. Our findings suggest that Mn exposure causes weight loss and nervous system damage in mice. In vitro and in vivo experiments have shown that exposure to Mn increases malondialdehyde, reactive oxygen species, and ferrous iron, while decreasing glutathione and adenosine triphosphate. These findings suggest that Mn exposure leads to a significant increase in lipid peroxidation and disrupts iron metabolism, resulting in oxidative stress injury and ferroptosis. Furthermore, we assessed the expression levels of proteins and mRNAs related to ferroptosis, confirming its significant involvement in Mn-induced neurotoxicity.
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Affiliation(s)
- Changyong Wang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Hongyan Zhao
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Yaoyang Liu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Minghai Qu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Shanyu Lv
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Guoguo He
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Hongshuo Liang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Kemiao Chen
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Lin Yang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China
| | - Yonghua He
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
| | - Chaoyan Ou
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi 541199, China; School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
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Mizuno D, Kawahara M, Konoha-Mizuno K, Hama R, Ogawara T. The Role of Zinc in the Development of Vascular Dementia and Parkinson's Disease and the Potential of Carnosine as Their Therapeutic Agent. Biomedicines 2024; 12:1296. [PMID: 38927502 PMCID: PMC11201809 DOI: 10.3390/biomedicines12061296] [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: 04/25/2024] [Revised: 05/10/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson's disease (PD). In this article, we reviewed the current comprehension of the Zn2+-induced neurotoxicity that leads to the pathogenesis of these neuronal diseases. Zn2+-induced neurotoxicity was investigated by using immortalised hypothalamic neurons (GT1-7 cells). This cell line is useful for the development of a rapid and convenient screening system for investigating Zn2+-induced neurotoxicity. GT1-7 cells were also used to search for substances that prevent Zn2+-induced neurotoxicity. Among the tested substances was a protective substance in the extract of Japanese eel (Anguilla japonica), and we determined its structure to be like carnosine (β-alanylhistidine). Carnosine may be a therapeutic drug for VD and PD. Furthermore, we reviewed the molecular mechanisms that involve the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cytotoxicity and discussed the prospects for the future therapeutic applications of this dipeptide for neurodegenerative diseases and dementia.
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Affiliation(s)
- Dai Mizuno
- Department of Forensic Medicine, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata-shi 990-9585, Yamagata, Japan; (K.K.-M.); (R.H.); (T.O.)
| | - Masahiro Kawahara
- Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishitokyo-shi 202-8585, Tokyo, Japan;
| | - Keiko Konoha-Mizuno
- Department of Forensic Medicine, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata-shi 990-9585, Yamagata, Japan; (K.K.-M.); (R.H.); (T.O.)
| | - Ryoji Hama
- Department of Forensic Medicine, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata-shi 990-9585, Yamagata, Japan; (K.K.-M.); (R.H.); (T.O.)
| | - Terumasa Ogawara
- Department of Forensic Medicine, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata-shi 990-9585, Yamagata, Japan; (K.K.-M.); (R.H.); (T.O.)
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Suthar JK, Vaidya A, Ravindran S. Size, Surface Properties, and Ion Release of Zinc Oxide Nanoparticles: Effects on Cytotoxicity, Dopaminergic Gene Expression, and Acetylcholinesterase Inhibition in Neuronal PC-12 Cells. Biol Trace Elem Res 2024; 202:2254-2271. [PMID: 37713055 DOI: 10.1007/s12011-023-03832-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 08/25/2023] [Indexed: 09/16/2023]
Abstract
The extensive applications of zinc oxide nanoparticles (ZnO NPs) have resulted in a substantial risk of human exposure. However, the knowledge of the toxicity of these NPs in the nervous system is still limited. A comparative analysis of ZnO NPs of various sizes and NPs of the same size, with and without surface coating, and the potential role of released zinc ions is yet to be thoroughly explored. As a result, we have studied the cellular toxicity of two different-sized ZnO NPs, ZnO-22 (22 nm) and ZnO-43 (43 nm), and NPs with similar size but with polyvinylpyrrolidone coating (ZnO-P, 45 nm). The findings from our study suggested a time-, size-, and surface coating-dependent cytotoxicity in PC-12 cells at a concentration ≥ 10 μg/ml. ZnO NP treatment significantly elevated reactive oxygen and reactive nitrogen species, thereby increasing oxidative stress. The exposure of ZnO-22 and ZnO-43 significantly upregulated the expression of monoamine oxidase-A and downregulated the α-synuclein gene expression associated with the dopaminergic system. The interaction of NPs enzymes in the nervous system is also hazardous. Therefore, the inhibition activity of acetylcholinesterase enzyme was also studied for its interaction with these NPs, and the results indicated a dose-dependent inhibition of enzyme activity. Particle size, coating, and cellular interactions modulate ZnO NP's cytotoxicity; smaller sizes enhance cellular uptake and reactivity, while coating reduces cytotoxicity by limiting direct cell contact and potentially mitigating oxidative stress. Furthermore, the study of released zinc ions from the NPs suggested no significant contribution to the observed cytotoxicity compared to the NPs.
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Affiliation(s)
- Jitendra Kumar Suthar
- Symbiosis School of Biological Sciences, Faculty of Medical and Health Sciences, Symbiosis International (Deemed) University, Pune, India
| | - Anuradha Vaidya
- Symbiosis Centre for Stem Cell Research, Symbiosis School of Biological Sciences, Symbiosis International (Deemed) University, Pune, India
| | - Selvan Ravindran
- Symbiosis School of Biological Sciences, Faculty of Medical and Health Sciences, Symbiosis International (Deemed) University, Pune, India.
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de Jesus JR, Linhares LA, Aragão AZB, Arruda MAZ, Ramos CHI. The stability and function of human cochaperone Hsp40/DNAJA1 are affected by zinc removal and partially restored by copper. Biochimie 2023; 213:123-129. [PMID: 37244380 DOI: 10.1016/j.biochi.2023.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 05/11/2023] [Accepted: 05/16/2023] [Indexed: 05/29/2023]
Abstract
The imbalance in metal homeostasis can be associated with several human diseases, and exposure to increasing concentrations of metals promotes cell stress and toxicity. Therefore, understanding the cytotoxic effect of metal imbalance is important to unravel the biochemical mechanism of homeostasis and the action of potential protective proteins against metal toxicity. Several studies, including gene deletion in yeast, provide evidence indicating the possible indirect involvement of cochaperones from the Hsp40/DNAJA family in metal homeostasis, possibly through modulating the activity of Hsp 70.This work first investigated the effect of zinc and copper on the conformation and function of the human Hsp40 cochaperone DNAJA1, a zinc-binding protein. DNAJA1 was capable to complement the phenotype of a yeast strain deleted of the ydj1 gene, which was more sensitive to the presence of zinc and copper than the wild-type strain. To gain further insight about the role of the DNAJA family in metal binding, the recombinant human DNAJA1 protein was studied. Zinc removal from DNAJA1 affected both its stability and ability to act as a chaperone, i.e., to protect other proteins from aggregation. The reintroduction of zinc restored the native properties of DNAJA1 and, surprisingly, the addition of copper partially restored the native properties.
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Affiliation(s)
| | | | | | - Marco A Z Arruda
- Institute of Chemistry, University of Campinas UNICAMP, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, University of Campinas UNICAMP, Campinas, Brazil
| | - Carlos H I Ramos
- Institute of Chemistry, University of Campinas UNICAMP, Campinas, Brazil; National Institute of Science and Technology for Bioimage and Structural Biology INBEB, Brazil.
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11
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Rajeev V, Chai YL, Poh L, Selvaraji S, Fann DY, Jo DG, De Silva TM, Drummond GR, Sobey CG, Arumugam TV, Chen CP, Lai MKP. Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment. Acta Neuropathol Commun 2023; 11:93. [PMID: 37309012 PMCID: PMC10259064 DOI: 10.1186/s40478-023-01590-1] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/14/2023] Open
Abstract
Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.
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Affiliation(s)
- Vismitha Rajeev
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
| | - Yuek Ling Chai
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
| | - Luting Poh
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
| | - Sharmelee Selvaraji
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - David Y Fann
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - T Michael De Silva
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher G Sobey
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Thiruma V Arumugam
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher P Chen
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mitchell K P Lai
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore.
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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12
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Kawahara M, Kato-Negishi M, Tanaka KI. Dietary Trace Elements and the Pathogenesis of Neurodegenerative Diseases. Nutrients 2023; 15:2067. [PMID: 37432185 PMCID: PMC10180548 DOI: 10.3390/nu15092067] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 07/12/2023] Open
Abstract
Trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are absorbed from food via the gastrointestinal tract, transported into the brain, and play central roles in normal brain functions. An excess of these trace elements often produces reactive oxygen species and damages the brain. Moreover, increasing evidence suggests that the dyshomeostasis of these metals is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, prion diseases, and Lewy body diseases. The disease-related amyloidogenic proteins can regulate metal homeostasis at the synapses, and thus loss of the protective functions of these amyloidogenic proteins causes neurodegeneration. Meanwhile, metal-induced conformational changes of the amyloidogenic proteins contribute to enhancing their neurotoxicity. Moreover, excess Zn and Cu play central roles in the pathogenesis of vascular-type senile dementia. Here, we present an overview of the intake, absorption, and transport of four essential elements (Fe, Zn, Cu, Mn) and one non-essential element (aluminum: Al) in food and their connections with the pathogenesis of neurodegenerative diseases based on metal-protein, and metal-metal cross-talk.
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Affiliation(s)
- Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan
| | - Midori Kato-Negishi
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan
| | - Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan
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13
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Zhang YY, Ren KD, Luo XJ, Peng J. COVID-19-induced neurological symptoms: focus on the role of metal ions. Inflammopharmacology 2023; 31:611-631. [PMID: 36892679 PMCID: PMC9996599 DOI: 10.1007/s10787-023-01176-2] [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: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 03/10/2023]
Abstract
Neurological symptoms are prevalent in both the acute and post-acute phases of coronavirus disease 2019 (COVID-19), and they are becoming a major concern for the prognosis of COVID-19 patients. Accumulation evidence has suggested that metal ion disorders occur in the central nervous system (CNS) of COVID-19 patients. Metal ions participate in the development, metabolism, redox and neurotransmitter transmission in the CNS and are tightly regulated by metal ion channels. COVID-19 infection causes neurological metal disorders and metal ion channels abnormal switching, subsequently resulting in neuroinflammation, oxidative stress, excitotoxicity, neuronal cell death, and eventually eliciting a series of COVID-19-induced neurological symptoms. Therefore, metal homeostasis-related signaling pathways are emerging as promising therapeutic targets for mitigating COVID-19-induced neurological symptoms. This review provides a summary for the latest advances in research related to the physiological and pathophysiological functions of metal ions and metal ion channels, as well as their role in COVID-19-induced neurological symptoms. In addition, currently available modulators of metal ions and their channels are also discussed. Collectively, the current work offers a few recommendations according to published reports and in-depth reflections to ameliorate COVID-19-induced neurological symptoms. Further studies need to focus on the crosstalk and interactions between different metal ions and their channels. Simultaneous pharmacological intervention of two or more metal signaling pathway disorders may provide clinical advantages in treating COVID-19-induced neurological symptoms.
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Affiliation(s)
- Yi-Yue Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Kai-Di Ren
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiu-Ju Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
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14
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Zinc in Cognitive Impairment and Aging. Biomolecules 2022; 12:biom12071000. [PMID: 35883555 PMCID: PMC9312494 DOI: 10.3390/biom12071000] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023] Open
Abstract
Zinc, an essential micronutrient for life, was first discovered in 1869 and later found to be indispensable for the normal development of plants and for the normal growth of rats and birds. Zinc plays an important role in many physiological and pathological processes in normal mammalian brain development, especially in the development of the central nervous system. Zinc deficiency can lead to neurodegenerative diseases, mental abnormalities, sleep disorders, tumors, vascular diseases, and other pathological conditions, which can cause cognitive impairment and premature aging. This study aimed to review the important effects of zinc and zinc-associated proteins in cognitive impairment and aging, to reveal its molecular mechanism, and to highlight potential interventions for zinc-associated aging and cognitive impairments.
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15
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Philbert SA, Xu J, Church SJ, Unwin RD, Roncaroli F, Cooper GJS. Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis. Front Aging Neurosci 2022; 14:926463. [PMID: 35923550 PMCID: PMC9340791 DOI: 10.3389/fnagi.2022.926463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/28/2022] [Indexed: 01/31/2023] Open
Abstract
Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in post-mortem VaD brain tissue (n = 10) and age-/sex-matched controls (n = 10) from seven brain regions. We found novel evidence for elevated wet-weight cerebral sodium levels in VaD brain tissue in six out of the seven regions analyzed. Decreased cerebral-potassium levels as well as increased Na/K ratios (consistent with high tissue sodium and low potassium levels) were also observed in several brain regions. These data suggest that reduced Na+/K+-exchanging ATPase (EC 7.2.2.13) activity could contribute to the contrasting changes in sodium and potassium measured here.
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Affiliation(s)
- Sasha A. Philbert
- Division of Cardiovascular Sciences, Centre for Advanced Discovery and Experimental Therapeutics, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- *Correspondence: Sasha A. Philbert,
| | - Jingshu Xu
- Division of Cardiovascular Sciences, Centre for Advanced Discovery and Experimental Therapeutics, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Stephanie J. Church
- Division of Cardiovascular Sciences, Centre for Advanced Discovery and Experimental Therapeutics, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Richard D. Unwin
- Division of Cardiovascular Sciences, Centre for Advanced Discovery and Experimental Therapeutics, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Division of Cancer Sciences, Stoller Biomarker Discovery Centre, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester, United Kingdom
| | - Federico Roncaroli
- Division of Neuroscience and Experimental Psychology, Geoffrey Jefferson Brain Research Centre, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom
| | - Garth J. S. Cooper
- Division of Cardiovascular Sciences, Centre for Advanced Discovery and Experimental Therapeutics, Faculty of Biology, Medicine and Health, School of Medical Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Faculty of Science, School of Biological Sciences, The University of Auckland, Auckland, New Zealand
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16
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Kawahara M, Tanaka KI, Kato-Negishi M. Crosstalk of copper and zinc in the pathogenesis of vascular dementia. J Clin Biochem Nutr 2022; 71:7-15. [PMID: 35903609 PMCID: PMC9309079 DOI: 10.3164/jcbn.22-40] [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: 04/01/2022] [Accepted: 05/12/2022] [Indexed: 11/23/2022] Open
Abstract
Copper and zinc are essential for normal brain functions. Both are localized in presynaptic vesicles and are secreted into synaptic clefts during neuronal excitation. Despite their significance, excesses of copper and zinc are neurotoxic. In particular, excess zinc after transient global ischemia plays a central role in the ischemia-induced neurodegeneration and pathogenesis of vascular type senile dementia. We previously found that sub-lethal concentrations of copper remarkably exacerbated zinc-induced neurotoxicity, and we investigated the molecular pathways of copper-enhanced zinc-induced neurotoxicity. The endoplasmic reticulum stress pathway, the stress-activated protein kinases/c-Jun amino-terminal kinases pathway, and mitochondrial energy production failure were revealed to be involved in the neurodegenerative processes. Regarding the upstream factors of these pathways, we focused on copper-derived reactive oxygen species and the disruption of calcium homeostasis. Because excess copper and zinc may be present in the synaptic clefts during ischemia, it is possible that secreted copper and copper-induced reactive oxygen species may enhance zinc neurotoxicity and eventually contribute to the pathogenesis of vascular type senile dementia.
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Affiliation(s)
- Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
| | - Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
| | - Midori Kato-Negishi
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
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17
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Mitra S, Chakraborty AJ, Tareq AM, Emran TB, Nainu F, Khusro A, Idris AM, Khandaker MU, Osman H, Alhumaydhi FA, Simal-Gandara J. Impact of heavy metals on the environment and human health: Novel therapeutic insights to counter the toxicity. JOURNAL OF KING SAUD UNIVERSITY - SCIENCE 2022; 34:101865. [DOI: 10.1016/j.jksus.2022.101865] [Citation(s) in RCA: 405] [Impact Index Per Article: 135.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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18
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Zhao Y, Ding M, Yang N, Huang Y, Sun C, Shi W. Zinc Accumulation Aggravates Cerebral Ischemia/Reperfusion Injury Through Inducing Endoplasmic Reticulum Stress. Neurochem Res 2022; 47:1419-1428. [PMID: 35129772 DOI: 10.1007/s11064-022-03536-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 10/19/2022]
Abstract
Zinc is highly enriched in the central nervous system. Numerous evidences suggest that high concentration of zinc acts as a critical mediator of neuronal death in the ischemic brain, however, the possible mechanisms of neurotoxicity of zinc during cerebral ischemia/reperfusion (I/R) remain elusive. Endoplasmic reticulum (ER) is a storage location of intracellular zinc. ER stress related genes were up-regulated during zinc-induced neuronal death in vascular-type senile dementia. In the present study, we investigated whether intracellular accumulated zinc aggravates I/R injury through ER stress and ER stress-associated apoptosis. Male Sprague-Dawley rats were subjected to 90 min middle cerebral artery occlusion (MCAO) and received either vehicle or zinc chelator TPEN 15 mg/kg. The expression of ER stress related factors glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α), ER stress related apoptotic proteins CCAAT-enhancer-binding protein homologous protein (CHOP) and caspase-12, as well as anti-apoptotic factor B-cell lymphoma-2 (Bcl-2) were assessed 24 h after reperfusion. Our results showed that the levels of GRP78 and p-eIF2α, as well as CHOP and caspase-12, were increased in ischemic brain, indicating that cerebral I/R triggers ER stress. Furthermore, GRP78, CHOP and caspase-12 were all colocalized with the zinc-specific dyes NG, suggesting that there is certain relationship between cytosolic labile zinc and ER stress following cerebral ischemia. Chelating zinc with TPEN reversed the expression of GRP78, p-eIF2α in ischemic rats. Moreover, CHOP and NeuN double staining positive cells, as well as caspase-12 and TUNEL double staining positive cells were also decreased after TPEN treatment, indicating that chelating zinc might inhibit ER stress and decreased ER stress associated neuronal apoptosis. In addition, TPEN treatment reversed the downregulated level of Bcl-2, which localized in the ER membrane and involved in the dysfunction of ER, confirming that the anti-apoptosis effects of chelating zinc following I/R are exerted via inhibition of the ER stress. Taken together, this study demonstrated that excessive zinc activates ER stress and zinc induced neuronal cell death is at least partially due to ER stress specific neuronal apoptosis in ischemic penumbra, which may provide an important mechanism of cerebral I/R injury.
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Affiliation(s)
- Yongmei Zhao
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China. .,Beijing Geriatric Medical Research Center, Beijing, 100053, China.
| | - Mao Ding
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China.,Beijing Geriatric Medical Research Center, Beijing, 100053, China
| | - Nan Yang
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China.,Beijing Geriatric Medical Research Center, Beijing, 100053, China
| | - Yuyou Huang
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China
| | - Chengjiao Sun
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China
| | - Wenjuan Shi
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China.,Beijing Geriatric Medical Research Center, Beijing, 100053, China
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19
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Tanaka KI, Shimoda M, Kawahara M. Effects of selenium-containing compounds on Cu 2+/Zn 2+-induced neuronal cell death and potential application as therapeutic agents for neurological diseases. Neural Regen Res 2022; 17:311-312. [PMID: 34269196 PMCID: PMC8463969 DOI: 10.4103/1673-5374.317968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Shinmachi, Nishitokyo, Tokyo, Japan
| | - Mikako Shimoda
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Shinmachi, Nishitokyo, Tokyo, Japan
| | - Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Shinmachi, Nishitokyo, Tokyo, Japan
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20
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Isaev NK, Stelmashook EV, Genrikhs EE. Role of zinc and copper ions in the pathogenetic mechanisms of traumatic brain injury and Alzheimer's disease. Rev Neurosci 2021; 31:233-243. [PMID: 31747384 DOI: 10.1515/revneuro-2019-0052] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/24/2019] [Indexed: 12/24/2022]
Abstract
The disruption of homeostasis of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Wilson's, Creutzfeldt-Jakob, Parkinson's, and Alzheimer's diseases (AD), and traumatic brain injury (TBI). The last two pathological conditions of the brain are the most common; moreover, it is possible that TBI is a risk factor for the development of AD. Disruptions of Zn2+ and Cu2+ homeostasis play an important role in the mechanisms of pathogenesis of both TBI and AD. This review attempts to summarize and systematize the currently available research data on this issue. The neurocytotoxicity of Cu2+ and Zn2+, the synergism of the toxic effect of calcium and Zn2+ ions on the mitochondria of neurons, and the interaction of Zn2+ and Cu2+ with β-amyloid (Abeta) and tau protein are considered.
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Affiliation(s)
- Nickolay K Isaev
- M.V. Lomonosov Moscow State University, N.A. Belozersky Institute of Physico-Chemical Biology, Biological Faculty, Moscow 119991, Russia.,Research Center of Neurology, Moscow 125367, Russia
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21
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Kawahara M, Tanaka KI, Kato-Negishi M. Copper as a Collaborative Partner of Zinc-Induced Neurotoxicity in the Pathogenesis of Vascular Dementia. Int J Mol Sci 2021; 22:ijms22147242. [PMID: 34298862 PMCID: PMC8305384 DOI: 10.3390/ijms22147242] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/17/2021] [Accepted: 06/29/2021] [Indexed: 12/18/2022] Open
Abstract
Copper is an essential trace element and possesses critical roles in various brain functions. A considerable amount of copper accumulates in the synapse and is secreted in neuronal firings in a manner similar to zinc. Synaptic copper and zinc modulate neuronal transmission and contribute to information processing. It has been established that excess zinc secreted during transient global ischemia plays central roles in ischemia-induced neuronal death and the pathogenesis of vascular dementia. We found that a low concentration of copper exacerbates zinc-induced neurotoxicity, and we have demonstrated the involvement of the endoplasmic reticulum (ER) stress pathway, the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) signaling pathway, and copper-induced reactive oxygen species (ROS) production. On the basis of our results and other studies, we discuss the collaborative roles of copper in zinc-induced neurotoxicity in the synapse and the contribution of copper to the pathogenesis of vascular dementia.
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22
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Joshi A, Farber K, Scheiber IF. Neurotoxicity of copper and copper nanoparticles. ADVANCES IN NEUROTOXICOLOGY 2021:115-157. [DOI: 10.1016/bs.ant.2020.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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23
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Carnosine suppresses neuronal cell death and inflammation induced by 6-hydroxydopamine in an in vitro model of Parkinson's disease. PLoS One 2020; 15:e0240448. [PMID: 33052927 PMCID: PMC7556511 DOI: 10.1371/journal.pone.0240448] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/25/2020] [Indexed: 12/22/2022] Open
Abstract
Parkinson's disease is a progressive neurodegenerative disease for which prevention and effective treatments are lacking. The pathogenesis of Parkinson's disease is not clearly understood. It is thought to be caused by oxidative stress-dependent loss of dopamine neurons in the substantia nigra and the promotion of inflammatory responses by microglia at the lesion site. In addition, cell loss occurs in the hypothalamus of Parkinson's disease patients. Carnosine is an endogenous dipeptide that can exert many beneficial effects, including an antioxidant action, metal ion chelation, proton buffering capacity, and inhibition of protein carbonylation and glycolysis. Previously, we found that carnosine inhibits trace metal-induced death of immortalized hypothalamic neuronal GT1-7 cells. In this study, we analyzed the efficacy of carnosine on 6-hydroxydopamine (6-OHDA)-dependent GT1-7 cell death and inflammatory responses. We found that carnosine significantly prevented 6-OHDA-dependent GT1-7 cell death in a dose-dependent manner. Moreover, carnosine significantly suppressed the expression of 6-OHDA-induced integrated stress response (ISR)-related factors and pro-inflammatory cytokines. Carnosine also significantly inhibited 6-OHDA-dependent reactive oxygen species (ROS) production and c-Jun amino-terminal kinase (JNK) pathway activation in GT1-7 cells. These results indicate that carnosine inhibits hypothalamic neuronal cell death and inflammatory responses by inhibiting the ROS-JNK pathway. We therefore suggest that carnosine may be effective in preventing the onset or the exacerbation of Parkinson's disease.
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24
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Nakano Y, Shimoda M, Okudomi S, Kawaraya S, Kawahara M, Tanaka KI. Seleno-l-methionine suppresses copper-enhanced zinc-induced neuronal cell death via induction of glutathione peroxidase. Metallomics 2020; 12:1693-1701. [PMID: 32926024 DOI: 10.1039/d0mt00136h] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Excessive zinc ion (Zn2+) release is induced in pathological situations and causes neuronal cell death. Previously, we have reported that copper ions (Cu2+) markedly exacerbated Zn2+-induced neuronal cell death by potentiating oxidative stress, the endoplasmic reticulum (ER) stress response, and the activation of the c-Jun amino-terminal kinase (JNK) signaling pathway. In contrast, selenium (Se), an essential trace element, and amino acids containing selenium (such as seleno-l-methionine) have been reported to inhibit stress-induced neuronal cell death and oxidative stress. Thus, we investigated the effect of seleno-l-methionine on Cu2+/Zn2+-induced neuronal cell death in GT1-7 cells. Seleno-l-methionine treatment clearly restored the Cu2+/Zn2+-induced decrease in the viable cell number and attenuated the Cu2+/Zn2+-induced cytotoxicity. Accordingly, the levels of ER stress-related factors (especially, CHOP and GADD34) and of phosphorylated JNK increased upon CuCl2 and ZnCl2 co-treatment, whereas pre-treatment with seleno-l-methionine significantly suppressed these upregulations. Analysis of reactive oxygen species (ROS) as upstream factors of these pathways revealed that Cu2+/Zn2+-induced ROS production was clearly suppressed by seleno-l-methionine treatment. Finally, we found that seleno-l-methionine induced the antioxidative protein, glutathione peroxidase. Taken together, our findings suggest that seleno-l-methionine suppresses Cu2+/Zn2+-induced neuronal cell death and oxidative stress via induction of glutathione peroxidase. Thus, we think that seleno-l-methionine may help prevent refractory neurological diseases.
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Affiliation(s)
- Yukari Nakano
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
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25
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Esteves AR, Cardoso SM. Differential protein expression in diverse brain areas of Parkinson's and Alzheimer's disease patients. Sci Rep 2020; 10:13149. [PMID: 32753661 PMCID: PMC7403590 DOI: 10.1038/s41598-020-70174-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 07/10/2020] [Indexed: 11/09/2022] Open
Abstract
Many hypotheses have been postulated to define the etiology of sporadic Parkinson's and Alzheimer's disorders (PD and AD) but there is no consensus on what causes these devastating age-related diseases. Braak staging of both pathologies helped researchers to better understand the progression and to identify their prodromal and symptomatic phases. Indeed, it is well accepted that Lewy body pathology and neurofibrillary tangles appearance correlates with disease progression and severity of symptoms in PD and AD, respectively. Additionally, several studies in PD and AD models try to disclose which cellular mechanisms are defaulted and trigger the neurodegenerative process that culminates with neuronal death causing PD and AD classical symptomatology. Herein, we determined expression levels of proteins involved in microtubule assembly, autophagic-lysosomal pathway and unfolded protein response in the cortex, hippocampus and SNpc of PD and AD patients, vascular dementia patients and aged-match controls. The differential expression allowed us to determine which pathways are determinant to synaptic dysfunction and to establish a time line for disease progression. Our results allow us to challenge the hypothesis that both PD and AD pathologies are caused by α-synuclein or Aβ pathology propagation throughout the brain in a prion-like manner.
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Affiliation(s)
- A R Esteves
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal.,CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - S M Cardoso
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal. .,CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal. .,Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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26
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Kimura K, Nakano Y, Sugizaki T, Shimoda M, Kobayashi N, Kawahara M, Tanaka KI. Protective effect of polaprezinc on cadmium-induced injury of lung epithelium. Metallomics 2020; 11:1310-1320. [PMID: 31236550 DOI: 10.1039/c9mt00060g] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cadmium is a toxic metal contained in food, water and the atmosphere, and exposure to cadmium can cause respiratory diseases in humans. Various health problems caused by cadmium result from oxidative stress-dependent cellular injury. Metallothioneins are intracellular, cysteine-rich, metal-binding proteins that have a detoxifying action on heavy metals such as cadmium in various organs. In addition, expression of metallothioneins is induced by metals with low biological toxicity, such as zinc. Therefore, in this study we examined whether polaprezinc, a chelate compound consisting of carnosine and zinc, can suppress cadmium-induced lung epithelial cell death. We found that cell viability markers (intracellular ATP levels and mitochondrial activity) and cytotoxicity (lactate dehydrogenase release) were decreased and increased, respectively by cadmium treatment; however, polaprezinc significantly reversed these changes. Moreover, cadmium-dependent endoplasmic reticulum stress responses were suppressed by polaprezinc treatment. We then examined the protective mechanisms of polaprezinc, focusing on oxidative stress. Cadmium induced the production of reactive oxygen species (ROS) in A549 cells in a dose-dependent manner and polaprezinc significantly suppressed this cadmium-induced ROS production. Finally, we examined whether polaprezinc exerts an antioxidative action by inducing metallothioneins. We found that polaprezinc dose-dependently induced metallothioneins using real-time RT-PCR, ELISA, and western blotting analyses. These results indicate that polaprezinc can suppress cadmium-induced lung epithelial cell death and oxidative stress by inducing metallothioneins. We therefore suggest that polaprezinc may have therapeutic effects against respiratory diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.
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Affiliation(s)
- Kazuma Kimura
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Yukari Nakano
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Toshifumi Sugizaki
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Mikako Shimoda
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Nahoko Kobayashi
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
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Tanaka KI, Shimoda M, Kasai M, Ikeda M, Ishima Y, Kawahara M. Involvement of SAPK/JNK Signaling Pathway in Copper Enhanced Zinc-Induced Neuronal Cell Death. Toxicol Sci 2020; 169:293-302. [PMID: 30768131 DOI: 10.1093/toxsci/kfz043] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Zinc (Zn) plays an important role in many organisms in various physiological functions such as cell division, immune mechanisms and protein synthesis. However, excessive Zn release is induced in pathological situations and causes neuronal cell death. Previously, we reported that Cu ions (Cu2+) markedly exacerbates Zn2+-induced neuronal cell death by potentiating oxidative stress and the endoplasmic reticulum stress response. In contrast, the stress-activated protein kinase/c-Jun amino-terminal kinase (SAPK/JNK) signaling pathway is important in neuronal cell death. Thus, in this study, we focused on the SAPK/JNK signaling pathway and examined its involvement in Cu2+/Zn2+-induced neurotoxicity. Initially, we examined expression of factors involved in the SAPK/JNK signaling pathway. Accordingly, we found that phosphorylated (ie, active) forms of SAPK/JNK (p46 and p54) are increased by CuCl2 and ZnCl2 co-treatment in hypothalamic neuronal mouse cells (GT1-7 cells). Downstream factors of SAPK/JNK, phospho-c-Jun, and phospho-activating transcription factor 2 are also induced by CuCl2 and ZnCl2 co-treatment. Moreover, an inhibitor of the SAPK/JNK signaling pathway, SP600125, significantly suppressed neuronal cell death and activation of the SAPK/JNK signaling pathway induced by CuCl2 and ZnCl2 cotreatment. Finally, we examined involvement of oxidative stress in activation of the SAPK/JNK signaling pathway, and found that human serum albumin-thioredoxin fusion protein, an antioxidative protein, suppresses activation of the SAPK/JNK signaling pathway. On the basis of these results, our findings suggest that activation of ZnCl2-dependent SAPK/JNK signaling pathway is important in neuronal cell death, and CuCl2-induced oxidative stress triggers the activation of this pathway.
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Affiliation(s)
- Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Nishitokyo-shi, Tokyo, Japan
| | - Mikako Shimoda
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Nishitokyo-shi, Tokyo, Japan
| | - Misato Kasai
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Nishitokyo-shi, Tokyo, Japan
| | - Mayumi Ikeda
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yu Ishima
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Nishitokyo-shi, Tokyo, Japan
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Kawahara M, Sadakane Y, Mizuno K, Kato-Negishi M, Tanaka KI. Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia. Int J Mol Sci 2020; 21:ijms21072570. [PMID: 32272780 PMCID: PMC7177235 DOI: 10.3390/ijms21072570] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022] Open
Abstract
Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (β-alanyl histidine) as a possible therapeutic agent for vascular dementia.
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Affiliation(s)
- Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan; (M.K.-N.); (K.T.)
- Correspondence: ; Tel.: +81–42–468–8299
| | - Yutaka Sadakane
- Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Japan;
| | - Keiko Mizuno
- Department of Forensic Medicine, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan;
| | - Midori Kato-Negishi
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan; (M.K.-N.); (K.T.)
| | - Ken-ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan; (M.K.-N.); (K.T.)
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de Jesus JR, Aragão AZB, Arruda MAZ, Ramos CHI. Optimization of a Methodology for Quantification and Removal of Zinc Gives Insights Into the Effect of This Metal on the Stability and Function of the Zinc-Binding Co-chaperone Ydj1. Front Chem 2019; 7:416. [PMID: 31263692 PMCID: PMC6584821 DOI: 10.3389/fchem.2019.00416] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/21/2019] [Indexed: 01/13/2023] Open
Abstract
Ydj1, a class B J-protein (Hsp40) in yeast, has two zinc finger domains in each monomer and belongs to an important co-chaperone family that plays crucial roles in cells, such as recognizing and binding partially folded proteins and assisting the Hsp70 chaperone family in protein folding. Yeast cells with ydj1 deletion were less efficient at coping with zinc stress than wild-type cells, and site-directed mutagenesis studies that impair or delete the zinc finger region have confirmed the importance of this region to the function of Ydj1; however, little is known about whether the presence of zinc is critical for the function of the protein. To gain insights into the effect of zinc on the structure and function of Ydj1 without having to modify its primary structure, a method was developed and optimized to quantify and remove the zinc from the protein. Recombinant Ydj1 was produced and purified, and its zinc content was determined by ICP-MS. The result showed that two zinc atoms were bound per monomer of protein, a good indicator that all sites were saturated. To optimize the removal of the bound zinc, variations on chelating agent (EDTA, EGTA, 1,10-phenanthroline), chelator concentration, reaction time, pH, and temperature were tested. These procedures had no effect on the overall secondary structure of the protein, since no significant changes in the circular dichroism spectrum were observed. The most significant removal (91 ± 2%, n = 3) of zinc was achieved using 1,10-phenanthroline (1 × 10−3 mol L−1) at 37°C with a pH 8.5 for 24 h. Zinc removal affected the stability of the protein, as observed by a thermal-induced unfolding assay showing that the temperature at the middle of the transition (Tm) decreased from 63 ± 1°C to 60 ± 1°C after Zn extraction. In addition, the effect on the ability of Ydj1 to protect a model protein (luciferase) against aggregation was completely abolished after the Zn removal procedure. The main conclusion is that zinc plays an important role in the stability and activity of Ydj1. Additionally, the results highlight the medical importance of chaperones, as altered zinc homeostasis is implicated in many diseases, such as neurodegenerative disorders.
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Affiliation(s)
- Jemmyson Romário de Jesus
- Department of Organic Chemistry, Institute of Chemistry, University of Campinas - UNICAMP, Campinas, Brazil
| | | | - Marco Aurélio Zezzi Arruda
- National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, University of Campinas - UNICAMP, Campinas, Brazil.,Spectrometry, Sample Preparation and Mechanization Group - GEPAM, Institute of Chemistry, University of Campinas - UNICAMP, Campinas, Brazil
| | - Carlos H I Ramos
- Department of Organic Chemistry, Institute of Chemistry, University of Campinas - UNICAMP, Campinas, Brazil.,National Institute of Science and Technology for Bioimage and Structural Biology (INBEB), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
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Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9693726. [PMID: 31316722 PMCID: PMC6604344 DOI: 10.1155/2019/9693726] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/16/2019] [Accepted: 05/29/2019] [Indexed: 12/11/2022]
Abstract
Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.
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31
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Emodin inhibits zinc-induced neurotoxicity in neuroblastoma SH-SY5Y cells. Biosci Rep 2019; 39:BSR20182378. [PMID: 31023967 PMCID: PMC6522748 DOI: 10.1042/bsr20182378] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 02/06/2023] Open
Abstract
Emodin is a natural anthraquinone derivative with numerous beneficial effects, including antioxidant properties, anti-tumor activities, and protecting the nerves. Zinc-induced neurotoxicity plays a crucial role in the pathogenesis of vascular dementia (VD) and Parkinson’s disease (PD). Here, the protective activity of emodin inhibiting zinc-induced neurotoxicity and its molecular mechanisms such as cellular Zn2+ influx and zinc-induced gene expression were examined using human neuroblastoma cells (SH-SY5Y cells). Our findings showed that emodin obviously enhanced cell viability and reduced cell apoptosis and lactate dehydrogenase release. Bedsides, we detected a decrease of intracellular Zn2+ concentration after SH-SY5Y cells were pretreated with emodin. Simultaneously, the expression of zinc transporter-1, metallothionein-1, and metallothionein-2 were weakened in emodin-pretreated SH-SY5Y cells. In addition, emodin prevented the depletion of NAD+ and ATP induced by zinc. Emodin also reduced intracellular reactive oxygen species and endoplasmic reticulum-stress levels. Strikingly, emodin elevated SH-SY5Y cell viability and inhibited cell apoptosis caused by AMP-activated protein kinase signaling pathway activation. Thus, emodin could protect against neurotoxicity induced by Zn2+ in neuroblastoma SH-SY5Y cells. It is expected to have future therapeutic potential for VD or PD and other neurodegenerative diseases.
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Physiological role of Prion Protein in Copper homeostasis and angiogenic mechanisms of endothelial cells. THE EUROBIOTECH JOURNAL 2019. [DOI: 10.2478/ebtj-2019-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
The Prion Protein (PrP) is mostly known for its role in prion diseases, where its misfolding and aggregation can cause fatal neurodegenerative conditions such as the bovine spongiform encephalopathy and human Creutzfeldt–Jakob disease. Physiologically, PrP is involved in several processes including adhesion, proliferation, differentiation and angiogenesis, but the molecular mechanisms behind its role remain unclear. PrP, due to its well-described structure, is known to be able to regulate copper homeostasis; however, copper dyshomeostasis can lead to developmental defects. We investigated PrP-dependent regulation of copper homeostasis in human endothelial cells (HUVEC) using an RNA-interference protocol. PrP knockdown did not influence cell viability in silenced HUVEC (PrPKD) compared to control cells, but significantly increased PrPKD HUVEC cells sensitivity to cytotoxic copper concentrations. A reduction of PrPKD cells reductase activity and copper ions transport capacity was observed. Furthermore, PrPKD-derived spheroids exhibited altered morphogenesis and their derived cells showed a decreased vitality 24 and 48 hours after seeding. PrPKD spheroid-derived cells also showed disrupted tubulogenesis in terms of decreased coverage area, tubule length and total nodes number on matrigel, preserving unaltered VEGF receptors expression levels. Our results highlight PrP physiological role in cellular copper homeostasis and in the angiogenesis of endothelial cells.
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Aivazidis S, Anderson CC, Roede JR. Toxicant-mediated redox control of proteostasis in neurodegeneration. CURRENT OPINION IN TOXICOLOGY 2019; 13:22-34. [PMID: 31602419 PMCID: PMC6785977 DOI: 10.1016/j.cotox.2018.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Disruption in redox signaling and control of cellular processes has emerged as a key player in many pathologies including neurodegeneration. As protein aggregations are a common hallmark of several neuronal pathologies, a firm understanding of the interplay between redox signaling, oxidative and free radical stress, and proteinopathies is required to sort out the complex mechanisms in these diseases. Fortunately, models of toxicant-induced neurodegeneration can be utilized to evaluate and report mechanistic alterations in the proteostasis network (PN). The epidemiological links between environmental toxicants and neurological disease gives further credence into characterizing the toxicant-mediated PN disruptions observed in these conditions. Reviewed here are examples of mechanistic interaction between oxidative or free radical stress and PN alterations. Additionally, investigations into toxicant-mediated PN disruptions, specifically focusing on environmental metals and pesticides, are discussed. Finally, we emphasize the need to distinguish whether the presence of protein aggregations are contributory to phenotypes related to neurodegeneration, or if they are a byproduct of PN deficiencies.
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Affiliation(s)
- Stefanos Aivazidis
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Colin C Anderson
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - James R Roede
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
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Sarasamma S, Audira G, Juniardi S, Sampurna BP, Liang ST, Hao E, Lai YH, Hsiao CD. Zinc Chloride Exposure Inhibits Brain Acetylcholine Levels, Produces Neurotoxic Signatures, and Diminishes Memory and Motor Activities in Adult Zebrafish. Int J Mol Sci 2018; 19:ijms19103195. [PMID: 30332818 PMCID: PMC6213992 DOI: 10.3390/ijms19103195] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/08/2018] [Accepted: 10/09/2018] [Indexed: 12/16/2022] Open
Abstract
In this study, we evaluated the acute (24, 48, 72, and 96 h) and chronic (21 days) adverse effects induced by low doses (0.1, 0.5, 1, and 1.5 mg/L) of zinc chloride (ZnCl2) exposure in adult zebrafish by using behavioral endpoints like three-dimensional (3D) locomotion, passive avoidance, aggression, circadian rhythm, and predator avoidance tests. Also, brain tissues were dissected and subjected to analysis of multiple parameters related to oxidative stress, antioxidant responses, superoxide dismutase (SOD), neurotoxicity, and neurotransmitters. The results showed that ZnCl2-exposed fishes displayed decreased locomotor behavior and impaired short-term memory, which caused an Alzheimer’s Disease (AD)-like syndrome. In addition, low concentrations of ZnCl2 induced amyloid beta (amyloid β) and phosphorylated Tau (p-Tau) protein levels in brains. In addition, significant induction in oxidative stress indices (reactive oxygen species (ROS) and malondialdehyde (MDA)), reduction in antioxidant defense system (glutathione (GSH), GSH peroxidase (GSH-Px) and SOD) and changes in neurotransmitters were observed at low concentrations of ZnCl2. Neurotoxic effects of ZnCl2 were observed with significant inhibition of acetylcholine (ACh) activity when the exposure dose was higher than 1 ppm. Furthermore, we found that zinc, metallothionein (MT), and cortisol levels in brain were elevated compared to the control group. A significantly negative correlation was observed between memory and acetylcholinesterase (AChE) activity. In summary, these findings revealed that exposure to ZnCl2 affected the behavior profile of zebrafish, and induced neurotoxicity which may be associated with damaged brain areas related to memory. Moreover, our ZnCl2-induced zebrafish model may have potential for AD-associated research in the future.
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Affiliation(s)
- Sreeja Sarasamma
- Department of Chemistry, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, No. 200, Chung-Pei Rd., Chung-Li 32023, Taiwan.
| | - Gilbert Audira
- Department of Chemistry, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, No. 200, Chung-Pei Rd., Chung-Li 32023, Taiwan.
| | - Stevhen Juniardi
- Department of Bioscience Technology, Chung Yuan Christian University, No. 200, Chung-Pei Rd., Chung-Li 32023, Taiwan.
| | - Bonifasius Putera Sampurna
- Department of Bioscience Technology, Chung Yuan Christian University, No. 200, Chung-Pei Rd., Chung-Li 32023, Taiwan.
| | - Sung-Tzu Liang
- Department of Bioscience Technology, Chung Yuan Christian University, No. 200, Chung-Pei Rd., Chung-Li 32023, Taiwan.
| | - Erwei Hao
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi, China.
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi, China.
| | - Yu-Heng Lai
- Department of Chemistry, Chinese Culture University, No. 55 Hwa-Kang Rd, Taipei 11114, Taiwan.
| | - Chung-Der Hsiao
- Department of Chemistry, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, No. 200, Chung-Pei Rd., Chung-Li 32023, Taiwan.
- Center for Biomedical Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Center for Nanotechnology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
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Kawahara M, Kato-Negishi M, Tanaka K. Cross talk between neurometals and amyloidogenic proteins at the synapse and the pathogenesis of neurodegenerative diseases. Metallomics 2018; 9:619-633. [PMID: 28516990 DOI: 10.1039/c7mt00046d] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Increasing evidence suggests that disruption of metal homeostasis contributes to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, prion diseases, Lewy body diseases, and vascular dementia. Conformational changes of disease-related proteins (amyloidogenic proteins), such as β-amyloid protein, prion proteins, and α-synuclein, are well-established contributors to neurotoxicity and to the pathogenesis of these diseases. Recent studies have demonstrated that these amyloidogenic proteins are metalloproteins that bind trace elements, including zinc, iron, copper, and manganese, and play significant roles in the maintenance of metal homeostasis. We present a current review of the role of trace elements in the functions and toxicity of amyloidogenic proteins, and propose a hypothesis integrating metal homeostasis and the pathogenesis of neurodegenerative diseases that is focused on the interactions among metals and between metals and amyloidogenic proteins at the synapse, considering that these amyloidogenic proteins and metals are co-localized at the synapse.
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Affiliation(s)
- M Kawahara
- Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
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Oh-Hashi K, Soga A, Naruse Y, Takahashi K, Kiuchi K, Hirata Y. Elucidating post-translational regulation of mouse CREB3 in Neuro2a cells. Mol Cell Biochem 2018; 448:287-297. [PMID: 29455434 DOI: 10.1007/s11010-018-3333-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/09/2018] [Indexed: 12/30/2022]
Abstract
CREB3 is an ER membrane-bound transcription factor; however, post-translational regulation of CREB3, including expression, processing, and activation, is not fully characterized. We therefore constructed several types of mouse CREB3 expression genes and elucidated their expression in Neuro2a cells by treatment with stimuli and co-transfection with genes associated with ER-Golgi homeostasis, such as mutant Sar1 [H79G], GRP78, and KDEL receptor 1 (KDELR1). Interestingly, treatment of Neuro2a cells expressing Flag-tagged full-length CREB3 with monensin and nigericin induced the expression of the approximately 50 kDa N-terminal fragment; however, its cleavage was not parallel to the levels of GADD153 and LC3-II. Co-transfection of full-length CREB3 together with Sar1 [H79G], GRP78, or KDELR1 showed that only Sar1 [H79G] induced expression of the cleaved form, and KDELR1 dramatically decreased the expression of the full-length form. Accordingly, Sar1 [H79G]- and KDELR1-overexpression influenced GAL4-CREB3-dependent luciferase activities. To understand the activation of CREB3 under more pathophysiological conditions, we focused on the effect of metal ions on CREB3 cleavage in Neuro2a cells. Among the six metal ions we tested, only copper ion stabilized full-length CREB3 expression. Copper ion also increased its N-terminal form and GAL4-CREB3-dependent luciferase activity, which was accompanied by the increase in the ubiquitinated proteins in Neuro2a cells. Taken together, CREB3 expression is regulated by multiple ER-Golgi resident factors in a post-translational manner, but its processing is not directly associated with ER stress and autophagic dysfunction. This finding is especially true for the unique action of the copper ion on CREB3 stabilization and processing in parallel to aberration of ubiquitin-proteasome system, which might provide new insights into understanding the mechanisms of intractable disorders.
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Affiliation(s)
- Kentaro Oh-Hashi
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. .,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
| | - Ayano Soga
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yoshihisa Naruse
- Department of Natural Science, Medical Education and Research Center, Meiji University of Integrative Medicine, Hiyoshi-cho, Nantan-shi, Kyoto, 629-0392, Japan
| | - Kanto Takahashi
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Kazutoshi Kiuchi
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yoko Hirata
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
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Kawahara M, Tanaka KI, Kato-Negishi M. Zinc, Carnosine, and Neurodegenerative Diseases. Nutrients 2018; 10:E147. [PMID: 29382141 PMCID: PMC5852723 DOI: 10.3390/nu10020147] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 01/02/2023] Open
Abstract
Zinc (Zn) is abundantly present in the brain, and accumulates in the synaptic vesicles. Synaptic Zn is released with neuronal excitation, and plays essential roles in learning and memory. Increasing evidence suggests that the disruption of Zn homeostasis is involved in various neurodegenerative diseases including Alzheimer's disease, a vascular type of dementia, and prion diseases. Our and other numerous studies suggest that carnosine (β-alanyl histidine) is protective against these neurodegenerative diseases. Carnosine is an endogenous dipeptide abundantly present in the skeletal muscles and in the brain, and has numerous beneficial effects such as antioxidant, metal chelating, anti-crosslinking, and anti-glycation activities. The complex of carnosine and Zn, termed polaprezinc, is widely used for Zn supplementation therapy and for the treatment of ulcers. Here, we review the link between Zn and these neurodegenerative diseases, and focus on the neuroprotective effects of carnosine. We also discuss the carnosine level in various foodstuffs and beneficial effects of dietary supplementation of carnosine.
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Affiliation(s)
- Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Midori Kato-Negishi
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
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Tanaka KI, Shimoda M, Kawahara M. Pyruvic acid prevents Cu 2+/Zn 2+-induced neurotoxicity by suppressing mitochondrial injury. Biochem Biophys Res Commun 2017; 495:1335-1341. [PMID: 29180015 DOI: 10.1016/j.bbrc.2017.11.152] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/22/2017] [Indexed: 12/23/2022]
Abstract
Zinc (Zn) is known as a co-factor for over 300 metalloproteins or enzymes, and has essential roles in many physiological functions. However, excessively high Zn concentrations are induced in pathological conditions such as interruption of blood flow in stroke or transient global ischemia-induced neuronal cell death. Furthermore, we recently found that copper (Cu2+) significantly exacerbates Zn2+ neurotoxicity in mouse hypothalamic neuronal cells, suggesting that Zn2+ interaction with Cu2+ is important for the development of neurological disease. Meanwhile, organic acids such as pyruvic acid and citric acid are reported to prevent neuronal cell death induced by various stresses. Thus, in this study, we focused on organic acids and searched for compounds that inhibit Cu2+/Zn2+-induced neurotoxicity. Initially, we examined the protective effect of various organic acids on Cu2+/Zn2+-induced neurotoxicity, and found that pyruvic acid clearly suppresses Cu2+/Zn2+-induced neurotoxicity in GT1-7 cells. Next, we examined the protective mechanisms of pyruvic acid against Cu2+/Zn2+-induced neurotoxicity. Specifically, we examined the possibilities that pyruvic acid chelates Cu2+ and Zn2+ or suppresses the ER stress response, but found that neither was suppressed by pyruvic acid treatment. In contrast, pyruvic acid significantly suppressed cytochrome c release into cytoplasm, an index of mitochondrial injury, in a dose-dependent manner. These results suggest that pyruvic acid prevents Cu2+/Zn2+-induced neuronal cell death by suppressing mitochondrial injury. Based on our results, we assume that pyruvic acid may be therapeutically beneficial for neurological diseases involving neuronal cell death such as vascular dementia.
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Affiliation(s)
- Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | - Mikako Shimoda
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
| | - Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
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Tanaka KI, Shimoda M, Chuang VTG, Nishida K, Kawahara M, Ishida T, Otagiri M, Maruyama T, Ishima Y. Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity. Int J Pharm 2017; 535:140-147. [PMID: 29122608 DOI: 10.1016/j.ijpharm.2017.11.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 10/20/2017] [Accepted: 11/05/2017] [Indexed: 11/29/2022]
Abstract
Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu2+/Zn2+-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu2+/Zn2+-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu2+/Zn2+-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu2+ and Zn2+ after Cu2+/Zn2+ treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu2+/Zn2+ treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu2+/Zn2+-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases.
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Affiliation(s)
- Ken-Ichiro Tanaka
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
| | - Mikako Shimoda
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
| | - Victor T G Chuang
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Bandar Sunway, Selangor, Malaysia
| | - Kento Nishida
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
| | - Masahiro Kawahara
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
| | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
| | - Yu Ishima
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
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