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Chen X, Liu L, Jiang W, Hu Y, Zou W, Zhang P, Wang B. Hydrogen Sulfide Inhibits Ferritinophagy-Mediated Ferroptosis in the Hippocampus of Rotenone-Exposed Rats. JOURNAL OF PHYSIOLOGICAL INVESTIGATION 2025; 68:91-99. [PMID: 40103451 DOI: 10.4103/ejpi.ejpi-d-24-00099] [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: 11/24/2024] [Accepted: 02/03/2025] [Indexed: 03/20/2025]
Abstract
ABSTRACT Our previous research has established that hydrogen sulfide (H 2 S) exerts an antagonistic effect against the hippocampal neurotoxicity induced by Rotenone (ROT). However, the underlying mechanisms are so far poorly understood. Substantial evidence corroborates the involvement of ferroptosis in ROT-induced neurotoxicity. To elucidate the protective mechanism of H 2 S against ROT-induced hippocampal neurotoxicity, this study explores its regulatory role in ferroptosis and its underlying mechanisms. We used Fluoro-Jade B staining to detect dead neurons. The levels of ferrous ions and glutathione (GSH) were measured by a kit. The ferroptosis-related proteins, including light-chain subunit (xCT), GSH peroxidase 4(GPX4), ferroptosis marker acyl-CoA synthetase long-chain family member 4(ACSL4), and ferritinophagy-related protein, including ferritin heavy chain 1 (FTH1), sequestosome 1 (p62), ferritinophagy markers autophagosome marker light-chain I/II (LC3I/II), and nuclear receptor coactivator 4 (NCOA4), were measured by Western blot. Our findings indicate that H 2 S reduces hippocampal neuron deaths in ROT-exposed rats. Meanwhile, H 2 S reverses the downregulations of xCT and GPX4, and the upregulations of ferrous ion and ACSL4 in the hippocampus induced by ROT. Furthermore, H 2 S reverses the upregulations of LC3I/II and NCOA4, and the downregulations of P62 and FTH1. Based on these findings, we concluded that the protective role of H 2 S against ROT-induced hippocampal neuronal death involves inhibiting ferroptosis triggered by ferritinophagy.
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Affiliation(s)
- Xi Chen
- Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Li Liu
- Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Wu Jiang
- Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yu Hu
- Institute of Clinical Laboratory, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Wei Zou
- Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ping Zhang
- Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Institute of Neuroscience, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bo Wang
- Department of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyan, Hunan, China
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Tryphena KP, Anuradha U, Kumar R, Rajan S, Srivastava S, Singh SB, Khatri DK. Understanding the Involvement of microRNAs in Mitochondrial Dysfunction and Their Role as Potential Biomarkers and Therapeutic Targets in Parkinson's Disease. J Alzheimers Dis 2023; 94:S187-S202. [PMID: 35848027 PMCID: PMC10473154 DOI: 10.3233/jad-220449] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2022] [Indexed: 11/15/2022]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting the elderly worldwide and causing significant movement impairments. The goal of PD treatment is to restore dopamine levels in the striatum and regulate movement symptoms. The lack of specific biomarkers for early diagnosis, as well as medication aimed at addressing the pathogenic mechanisms to decelerate the progression of dopaminergic neurodegeneration, are key roadblocks in the management of PD. Various pathogenic processes have been identified to be involved in the progression of PD, with mitochondrial dysfunction being a major contributor to the disease's pathogenesis. The regulation of mitochondrial functions is influenced by a variety of factors, including epigenetics. microRNAs (miRNAs) are epigenetic modulators involved in the regulation of gene expression and regulate a variety of proteins that essential for proper mitochondrial functioning. They are found to be dysregulated in PD, as evidenced by biological samples from PD patients and in vitro and in vivo research. In this article, we attempt to provide an overview of several miRNAs linked to mitochondrial dysfunction and their potential as diagnostic biomarkers and therapeutic targets in PD.
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Affiliation(s)
- Kamatham Pushpa Tryphena
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Urati Anuradha
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Rohith Kumar
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Shruti Rajan
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Shashi Bala Singh
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Dharmendra Kumar Khatri
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
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Shen LH, Luo QQ, Hu CB, Jiang H, Yang Y, Wang GH, Ji QH, Jia ZZ. DL-3-n-butylphthalide alleviates motor disturbance by suppressing ferroptosis in a rat model of Parkinson’s disease. Neural Regen Res 2023; 18:194-199. [PMID: 35799542 PMCID: PMC9241398 DOI: 10.4103/1673-5374.343892] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Schmitt F, Babylon L, Dieter F, Eckert GP. Effects of Pesticides on Longevity and Bioenergetics in Invertebrates-The Impact of Polyphenolic Metabolites. Int J Mol Sci 2021; 22:ijms222413478. [PMID: 34948274 PMCID: PMC8707434 DOI: 10.3390/ijms222413478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 02/07/2023] Open
Abstract
Environmentally hazardous substances such as pesticides are gaining increasing interest in agricultural and nutritional research. This study aims to investigate the impact of these compounds on the healthspan and mitochondrial functions in an invertebrate in vivo model and in vitro in SH-SY5Y neuroblastoma cells, and to investigate the potential of polyphenolic metabolites to compensate for potential impacts. Wild-type nematodes (Caenorhabditis elegans, N2) were treated with pesticides such as pyraclostrobin (Pyr), glyphosate (Gly), or fluopyram (Fluo). The lifespans of the nematodes under heat stress conditions (37 °C) were determined, and the chemotaxis was assayed. Energetic metabolites, including adenosine triphosphate (ATP), lactate, and pyruvate, were analyzed in lysates of nematodes and cells. Genetic expression patterns of several genes associated with lifespan determination and mitochondrial parameters were assessed via qRT-PCR. After incubation with environmentally hazardous substances, nematodes were incubated with a pre-fermented polyphenol mixture (Rechtsregulat®Bio, RR) or protocatechuic acid (PCA) to determine heat stress resistance. Treatment with Pyr, Glyph and Fluo leads to dose-dependently decreased heat stress resistance, which was significantly improved by RR and PCA. The chemotaxes of the nematodes were not affected by pesticides. ATP levels were not significantly altered by the pesticides, except for Pyr, which increased ATP levels after 48 h leads. The gene expression of healthspan and mitochondria-associated genes were diversely affected by the pesticides, while Pyr led to an overall decrease of mRNA levels. Over time, the treatment of nematodes leads to a recovery of the nematodes on the mitochondrial level but not on stress resistance on gene expression. Fermented extracts of fruits and vegetables and phenolic metabolites such as PCA seem to have the potential to recover the vitality of C. elegans after damage caused by pesticides.
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Queiroz Junior NF, Steffani JA, Machado L, Longhi PJH, Montano MAE, Martins M, Machado SA, Machado AK, Cadoná FC. Antioxidant and cytoprotective effects of avocado oil and extract ( Persea americana Mill) against rotenone using monkey kidney epithelial cells (Vero). JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2021; 84:875-890. [PMID: 34256683 DOI: 10.1080/15287394.2021.1945515] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Oxidative stress is known to be involved in development of numerous diseases including cardiovascular, respiratory, renal, kidney and cancer. Thus, investigations that mimic oxidative stress in vitro may play an important role to find new strategies to control oxidative stress and subsequent consequences are important. Rotenone, widely used as a pesticide has been used as a model to simulate oxidative stress. However, this chemical was found to produce several diseases. Therefore, the aim of this study was to investigate the antioxidant and cytoprotective effect of avocado (Persea americana Mill) extract and oil in monkey kidney epithelial cells (VERO) exposed to rotenone. VERO cells were exposed to IC50 of rotenone in conjunction with different concentrations of avocado extract and oil (ranging from 1 to 1000 µg/ml), for 24 hr. Subsequently, cell viability and oxidative metabolism were assessed. Data demonstrated that avocado extract and oil in the presence of rotenone increased cellular viability at all tested concentrations compared to cells exposed only to rotenone. In addition, extract and avocado oil exhibited antioxidant action as evidenced by decreased levels of reactive oxygen species (ROS), superoxide ion, and lipid peroxidation, generated by rotenone. Further, avocado extract and oil appeared to be safe, since these compounds did not affect cell viability and or generate oxidative stress. Therefore, avocado appears to display a promising antioxidant potential by decreasing oxidative stress.
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Affiliation(s)
| | - Jovani Antônio Steffani
- Postgraduate Program of Biosciences and Health, West University of Santa Catarina, Joaçaba, SC, Brazil
| | - Larissa Machado
- Biological Sciences Course, West University of Santa Catarina, Joaçaba, SC, Brazil
| | | | | | - Mathias Martins
- Postgraduate Program in Health and Animal Production, West University of Santa Catarina, Joaçaba, SC, Brazil
| | - Sérgio Abreu Machado
- Postgraduate Program in Health and Animal Production, West University of Santa Catarina, Joaçaba, SC, Brazil
| | | | - Francine Carla Cadoná
- Postgraduate Program in Sciences of Health and Life, Franciscan University, Santa Maria, RS, Brazil
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1,5-Anhydro-D-fructose Protects against Rotenone-Induced Neuronal Damage In Vitro through Mitochondrial Biogenesis. Int J Mol Sci 2021; 22:ijms22189941. [PMID: 34576111 PMCID: PMC8466044 DOI: 10.3390/ijms22189941] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 12/29/2022] Open
Abstract
Mitochondrial functional abnormalities or quantitative decreases are considered to be one of the most plausible pathogenic mechanisms of Parkinson’s disease (PD). Thus, mitochondrial complex inhibitors are often used for the development of experimental PD. In this study, we used rotenone to create in vitro cell models of PD, then used these models to investigate the effects of 1,5-anhydro-D-fructose (1,5-AF), a monosaccharide with protective effects against a range of cytotoxic substances. Subsequently, we investigated the possible mechanisms of these protective effects in PC12 cells. The protection of 1,5-AF against rotenone-induced cytotoxicity was confirmed by increased cell viability and longer dendritic lengths in PC12 and primary neuronal cells. Furthermore, in rotenone-treated PC12 cells, 1,5-AF upregulated peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) expression and enhanced its deacetylation, while increasing AMP-activated protein kinase (AMPK) phosphorylation. 1,5-AF treatment also increased mitochondrial activity in these cells. Moreover, PGC-1α silencing inhibited the cytoprotective and mitochondrial biogenic effects of 1,5-AF in PC12 cells. Therefore, 1,5-AF may activate PGC-1α through AMPK activation, thus leading to mitochondrial biogenic and cytoprotective effects. Together, our results suggest that 1,5-AF has therapeutic potential for development as a treatment for PD.
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Makino SI, Shirata N, Oliva Trejo JA, Yamamoto-Nonaka K, Yamada H, Miyake T, Mori K, Nakagawa T, Tashiro Y, Yamashita H, Yanagita M, Takahashi R, Asanuma K. Impairment of Proteasome Function in Podocytes Leads to CKD. J Am Soc Nephrol 2021; 32:597-613. [PMID: 33510039 PMCID: PMC7920174 DOI: 10.1681/asn.2019101025] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 11/20/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood. METHODS To investigate the role of the UPS in podocytes, mice were generated that had deletion of Rpt3 (Rpt3pdKO), which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function. RESULTS Rpt3pdKO mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of Rpt3pdKO mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an in vitro study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the Rpt3pdKO mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of Rpt3pdKO mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of Rpt3pdKO mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes. CONCLUSIONS Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.
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Affiliation(s)
- Shin-ichi Makino
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naritoshi Shirata
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharmaceutical Corporation, Saitama, Japan
| | - Juan Alejandro Oliva Trejo
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kanae Yamamoto-Nonaka
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Yamada
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takafumi Miyake
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kiyoshi Mori
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Molecular and Clinical Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
- Department of Nephrology, Shizuoka General Hospital, Shizuoka, Japan
| | - Takahiko Nakagawa
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Nephrology, Rakuwakai Otowa Hospital, Kyoto, Japan
| | - Yoshitaka Tashiro
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirofumi Yamashita
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Motoko Yanagita
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan
| | - Ryosuke Takahashi
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Katsuhiko Asanuma
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
- The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Li M, Hu J, Yuan X, Shen L, Zhu L, Luo Q. Hepcidin Decreases Rotenone-Induced α-Synuclein Accumulation via Autophagy in SH-SY5Y Cells. Front Mol Neurosci 2020; 13:560891. [PMID: 33177988 PMCID: PMC7596286 DOI: 10.3389/fnmol.2020.560891] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 09/11/2020] [Indexed: 12/11/2022] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder, and the hallmarks of this disease include iron deposition and α-synuclein (α-syn) aggregation. Hepcidin could reduce iron in the central and peripheral nervous systems. Here, we hypothesized that hepcidin could further decrease α-syn accumulation via reducing iron. Therefore, rotenone or α-syn was introduced into human neuroblastoma SH-SY5Y cells to imitate the pathological progress of PD in vitro. This study investigated the clearance effects of hepcidin on α-syn induced by a relatively low concentration of rotenone exposure or α-syn overexpression to elucidate the potential clearance pathway involved in this process. We demonstrated that SH-SY5Y cell viability was impaired after rotenone treatment in a dose-dependent manner. α-syn expression and iron content increased under a low concentration rotenone (25 nM for 3 days) treatment in SH-SY5Y cells. Pre-treatment with hepcidin peptide suppressed the abovementioned effects of rotenone. However, hepcidin did not affect treatment with rotenone under high iron conditions. Hepcidin also played a role in reducing α-syn accumulation in rotenone and α-syn overexpression conditions. We identified that the probable clearance effect of hepcidin on α-syn was mediated by the autophagy pathway using pretreatment with autophagy inhibitors (3-MA and CQ) and detection of autophagy protein markers (LC3II/I and p62). In conclusion, hepcidin eliminated α-syn expression via the autophagy pathway in rotenone-treated and α-syn overexpression SH-SY5Y cells. This study highlights that hepcidin may offer a potential therapeutic perspective in α-syn accumulation diseases.
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Affiliation(s)
- Meiqi Li
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jianan Hu
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xiaoyu Yuan
- Department of Emergency, Affiliated Hospital of Nantong University, Nantong, China
| | - Lihua Shen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| | - Li Zhu
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Qianqian Luo
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
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Indrieri A, Pizzarelli R, Franco B, De Leonibus E. Dopamine, Alpha-Synuclein, and Mitochondrial Dysfunctions in Parkinsonian Eyes. Front Neurosci 2020; 14:567129. [PMID: 33192254 PMCID: PMC7604532 DOI: 10.3389/fnins.2020.567129] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/22/2020] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is characterized by motor dysfunctions including bradykinesia, tremor at rest and motor instability. These symptoms are associated with the progressive degeneration of dopaminergic neurons originating in the substantia nigra pars compacta and projecting to the corpus striatum, and by accumulation of cytoplasmic inclusions mainly consisting of aggregated alpha-synuclein, called Lewy bodies. PD is a complex, multifactorial disorder and its pathogenesis involves multiple pathways and mechanisms such as α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation. Motor symptoms manifest when there is already an extensive dopamine denervation. There is therefore an urgent need for early biomarkers to apply disease-modifying therapeutic strategies. Visual defects and retinal abnormalities, including decreased visual acuity, abnormal spatial contrast sensitivity, color vision defects, or deficits in more complex visual tasks are present in the majority of PD patients. They are being considered for early diagnosis together with retinal imaging techniques are being considered as non-invasive biomarkers for PD. Dopaminergic cells can be found in the retina in a subpopulation of amacrine cells; however, the molecular mechanisms leading to visual deficits observed in PD patients are still largely unknown. This review provides a comprehensive analysis of the retinal abnormalities observed in PD patients and animal models and of the molecular mechanisms underlying neurodegeneration in parkinsonian eyes. We will review the role of α-synuclein aggregates in the retina pathology and/or in the onset of visual symptoms in PD suggesting that α-synuclein aggregates are harmful for the retina as well as for the brain. Moreover, we will summarize experimental evidence suggesting that the optic nerve pathology observed in PD resembles that seen in mitochondrial optic neuropathies highlighting the possible involvement of mitochondrial abnormalities in the development of PD visual defects. We finally propose that the eye may be considered as a complementary experimental model to identify possible novel disease’ pathways or to test novel therapeutic approaches for PD.
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Affiliation(s)
- Alessia Indrieri
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Institute for Genetic and Biomedical Research, National Research Council, Milan, Italy
| | - Rocco Pizzarelli
- Center for Life Nanoscience, Istituto Italiano di Tecnologia, Rome, Italy
| | - Brunella Franco
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Medical Genetics, Department of Translational Medical Science, University of Naples "Federico II", Naples, Italy
| | - Elvira De Leonibus
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Institute of Biochemistry and Cellular Biology, National Research Council, Rome, Italy
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Amaral de Brito AP, Galvão de Melo IMDS, El-Bachá RS, Guedes RCA. Valeriana officinalis Counteracts Rotenone Effects on Spreading Depression in the Rat Brain in vivo and Protects Against Rotenone Cytotoxicity Toward Rat Glioma C6 Cells in vitro. Front Neurosci 2020; 14:759. [PMID: 32792901 PMCID: PMC7390944 DOI: 10.3389/fnins.2020.00759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/29/2020] [Indexed: 12/21/2022] Open
Abstract
Astrocytes can protect neurons against oxidative stress and excitability-dependent disorders, such as epilepsy. Valeriana officinalis has been used as anticonvulsant and can exert an antioxidant effect, which may underlie its opposing action against the toxic effects of the pesticide rotenone. We investigated the V. officinalis/rotenone interaction in the cortical spreading depression (CSD), a phenomenon that depends upon brain excitability (in vivo model). In addition, we analyzed the protective action of V. officinalis against the cytotoxic effects of rotenone in cultures of rat C6 glioma cells (in vitro model). For the CSD study, Wistar rats received either V. officinalis (250 mg/kg/day via gavage for 15 days; n = 8) or 10 mg/kg/day rotenone via subcutaneous injections for 7 days (n = 7), or they received both substances (n = 5). Two control groups received either saline (vehicle for V. officinalis; n = 8) or 1% Tween-80 aqueous solution (vehicle for rotenone; n = 9). After treatment, CSD was recorded for 4 h. The rotenone- and V. officinalis-treated groups presented, respectively, with lower (2.96 ± 0.14 mm/min), and higher CSD propagation velocity (3.81 ± 0.10 mm/min) when compared with the controls (Tween-80, 3.37 ± 0.06 mm/min and saline, 3.35 ± 0.08 mm/min; p < 0.05). The rotenone plus V. officinalis-treated group displayed a CSD velocity (3.38 ± 0.07 mm/min) that was similar to controls. In line with these results, in vitro experiments on rat glioma C6 cells revealed a protective effect (MTT assay) of V. officinalis against rotenone-induced cytotoxicity. These results suggest the therapeutic potential of V. officinalis for treating neurological diseases involving redox imbalance and astrocyte dysfunction.
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Affiliation(s)
| | | | - Ramon Santos El-Bachá
- Department of Biochemistry and Biophysics, Universidade Federal da Bahia, Salvador, Brazil
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Oxidative Stress and Neuroinflammation Potentiate Each Other to Promote Progression of Dopamine Neurodegeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6137521. [PMID: 32714488 PMCID: PMC7354668 DOI: 10.1155/2020/6137521] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 01/07/2023]
Abstract
Parkinson's disease (PD) is a chronic and complex disease of the central nervous system (CNS). Progressive loss of dopamine (DA) neurons in midbrain substantia nigra is considered to be the main cause of PD. The hallmark of PD pathology is the formation of Lewy bodies and the deposition of α-synuclein (α-syn). The mechanisms responsible for the progressive feature of DA neurodegeneration are not fully illustrated. Recently, oxidative stress and neuroinflammation have received extensive attention as two important entry points in the pathogenesis of PD. The occurrence of oxidative stress and neuroinflammation is usually derived from external influences or changes in internal environment, such as the accumulation of reactive oxygen species, exposure to a toxic environment, and the transformation of systemic inflammation. However, PD never results from a single independent factor and the simultaneous participation of oxidative stress and neuroinflammation contributed to PD development. Oxidative stress and neuroinflammation could potentiate each other to promote progression of PD. In this review, we briefly summarized the conditions of oxidative stress and neuroinflammation and the crosstalk between oxidative stress and neuroinflammation on the development of PD.
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Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, Masliah E. The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease. Mol Neurobiol 2020; 57:2959-2980. [PMID: 32445085 DOI: 10.1007/s12035-020-01926-1] [Citation(s) in RCA: 226] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 04/22/2020] [Indexed: 12/15/2022]
Abstract
Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.
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Affiliation(s)
- Giacomo Monzio Compagnoni
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. .,Department of Neurology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. .,Department of Neurology, Khurana Laboratory, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Alessio Di Fonzo
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Corti
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Giacomo P Comi
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Nereo Bresolin
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Eliezer Masliah
- Division of Neuroscience and Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, MD, USA
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13
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McCarty MF, Lerner A. Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson's Disease. Int J Mol Sci 2020; 21:3624. [PMID: 32455532 PMCID: PMC7279222 DOI: 10.3390/ijms21103624] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/29/2020] [Accepted: 05/18/2020] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) is a chronic low-grade inflammatory process in which activated microglia generate cytotoxic factors-most prominently peroxynitrite-which induce the death and dysfunction of neighboring dopaminergic neurons. Dying neurons then release damage-associated molecular pattern proteins such as high mobility group box 1 which act on microglia via a range of receptors to amplify microglial activation. Since peroxynitrite is a key mediator in this process, it is proposed that nutraceutical measures which either suppress microglial production of peroxynitrite, or which promote the scavenging of peroxynitrite-derived oxidants, should have value for the prevention and control of PD. Peroxynitrite production can be quelled by suppressing activation of microglial NADPH oxidase-the source of its precursor superoxide-or by down-regulating the signaling pathways that promote microglial expression of inducible nitric oxide synthase (iNOS). Phycocyanobilin of spirulina, ferulic acid, long-chain omega-3 fatty acids, good vitamin D status, promotion of hydrogen sulfide production with taurine and N-acetylcysteine, caffeine, epigallocatechin-gallate, butyrogenic dietary fiber, and probiotics may have potential for blunting microglial iNOS induction. Scavenging of peroxynitrite-derived radicals may be amplified with supplemental zinc or inosine. Astaxanthin has potential for protecting the mitochondrial respiratory chain from peroxynitrite and environmental mitochondrial toxins. Healthful programs of nutraceutical supplementation may prove to be useful and feasible in the primary prevention or slow progression of pre-existing PD. Since damage to the mitochondria in dopaminergic neurons by environmental toxins is suspected to play a role in triggering the self-sustaining inflammation that drives PD pathogenesis, there is also reason to suspect that plant-based diets of modest protein content, and possibly a corn-rich diet high in spermidine, might provide protection from PD by boosting protective mitophagy and thereby aiding efficient mitochondrial function. Low-protein diets can also promote a more even response to levodopa therapy.
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Affiliation(s)
| | - Aaron Lerner
- B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel
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14
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He B, Wang X, Yang C, Zhu J, Jin Y, Fu Z. The regulation of autophagy in the pesticide-induced toxicity: Angel or demon? CHEMOSPHERE 2020; 242:125138. [PMID: 31670000 DOI: 10.1016/j.chemosphere.2019.125138] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 10/15/2019] [Accepted: 10/16/2019] [Indexed: 05/20/2023]
Abstract
Pesticides have become an essential tool for pest kill, weed control and microbiome inhibition for both agricultural and domestic use. However, with the massive use, pesticides can exist in soil, air and water, and sometimes even accumulate in the human or other mammals through food chains. Lots of researches have proven that pesticides possess toxicity to mammals on endocrine, neural and immune systems. Autophagy, as a conservative intracellular process, which is activated by stress-related signals, plays a pivotal role, either "angle" or "demon", in regulation of cell fate and function. Recent evidences in researches elucidated a strong link between the autophagy and the toxicity of pesticides. In this review, we summarized the previous researches which focus on the autophagy regulation in the pesticides-induced toxicity, and hope that this work can help us to discover a potential strategy for the treatment of the disease caused by pesticides.
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Affiliation(s)
- Bingnan He
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Xia Wang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Chunlei Yang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Jianbo Zhu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Yuanxiang Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China.
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15
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Alikatte K, Palle S, Rajendra Kumar J, Pathakala N. Fisetin Improved Rotenone-Induced Behavioral Deficits, Oxidative Changes, and Mitochondrial Dysfunctions in Rat Model of Parkinson's Disease. J Diet Suppl 2020; 18:57-71. [PMID: 31992104 DOI: 10.1080/19390211.2019.1710646] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD), particularly the inhibition of mitochondrial complex-I. This study aimed to evaluate the effect of fisetin in the rotenone-induced rat model of PD. Rotenone was administered (2 mg/kg s.c.) for 35 days to induce PD in animals. Fisetin was administered at two doses (10 mg/kg and 20 mg/kg p.o.) for 25 days to the animals that were given rotenone. Behavioral experiment, i.e. cylinder test, was performed to assess the motor asymmetry. Animals were euthanized, and mid brains were isolated for the estimation of tricarboxylic acid cycle enzymes, oxidative measures (lipid peroxidation (LPO), glutathione (GSH) and catalase) and complex-I activity. In addition, histopathological studies were conducted. Fisetin treatment improved motor function in the cylinder test and reversed the rotenone-induced changes in mitochondrial enzymes, striatal dopamine levels, antioxidant enzyme levels and histological changes. An important finding of this study was both the doses of fisetin significantly (p < 0.05) enhanced rotenone-induced behavioral and biochemical changes and the effects were found to be dose dependent. Based on the present results, we hypothesize that fisetin may improve the mitochondrial enzyme activity, thereby preventing the pathogenesis of PD.
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Affiliation(s)
- Kanakalatha Alikatte
- Department of Pharmacology, St. Peters Institute of Pharmaceutical Sciences, Warangal, Telangana, India
| | - Suresh Palle
- Department of Pharmacology, Vaagdevi Institute of Pharmaceutical Sciences, Warangal, Telangana, India
| | - Jadi Rajendra Kumar
- Department of Pharmaceutics, University College of Technology, Osmania University, Hyderabad, Telangana, India
| | - Naveen Pathakala
- Department of Pharmaceutics, University College of Technology, Osmania University, Hyderabad, Telangana, India
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16
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Comet assay genotoxicity evaluation of occupationally exposed tea-garden workers in northern West Bengal, India. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2019; 844:1-9. [DOI: 10.1016/j.mrgentox.2019.06.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 06/13/2019] [Accepted: 06/17/2019] [Indexed: 12/27/2022]
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17
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Tsai SF, Liu YW, Kuo YM. Acute and long-term treadmill running differentially induce c-Fos expression in region- and time-dependent manners in mouse brain. Brain Struct Funct 2019; 224:2677-2689. [PMID: 31352506 DOI: 10.1007/s00429-019-01926-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 07/22/2019] [Indexed: 11/25/2022]
Abstract
Acute and long-term exercise differentially affect brain functions. It has been suggested that neuronal activation is one of the mechanisms for exercise-induced enhancement of brain functions. However, the differential effects of acute and long-term exercise on the spatial and temporal profiles of neuronal activation in the brain have been scarcely explored. In this study, we profiled the expression of c-Fos, a marker of neuronal activation, in selected 26 brain regions of 2-month-old male C57/B6 mice that received either a single bout of treadmill running (acute exercise) or a 4-week treadmill training (long-term exercise) at the same duration (1 h/day) and intensity (10 m/min). The c-Fos expression was determined before, immediately after, and 2 h after the run. The results showed that acute exercise increased the densities of c-Fos+ cells in the ventral hippocampal CA1 region, followed by (in a high to low order) the primary somatosensory cortex, other hippocampal subregions, and striatum immediately after the run; significant changes remained evident in the hippocampal subregions after a 2-h rest. Long-term exercise increased the densities of c-Fos+ cells in the striatum, followed by the primary somatosensory, primary and secondary motor cortices, hippocampal subregions, hypothalamic nuclei, and lateral periaqueductal gray; significant changes remained evident in the striatum, hippocampal subregions, hypothalamic nuclei, and lateral periaqueductal gray after a 2-h rest. Interestingly, the densities of c-Fos+ cells in the substantia nigra and ventral tegmental area only increased after a 2-h rest after the run in the long-term exercise group. The densities of c-Fos+ cells were positively correlated with the expression of brain-derived neurotrophic factor in the selected brain regions. In conclusion, both acute and long-term treadmill running at mild intensity induce c-Fos expression in the limbic system and movement-associated cortical and subcortical regions, with long-term exercise involving more brain regions (i.e., hypothalamus and periaqueductal gray) and longer lasting effects.
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Affiliation(s)
- Sheng-Feng Tsai
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No.1 University Road, Tainan, 701, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Wen Liu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No.1 University Road, Tainan, 701, Taiwan
| | - Yu-Min Kuo
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No.1 University Road, Tainan, 701, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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18
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Wani AA, Dar AA, Jan I, Sofi KA, Sofi JA, Dar IH. Method validation and simultaneous quantification of eight organochlorines/organophosphates in apple by gas chromatography. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2019; 99:3687-3692. [PMID: 30666637 DOI: 10.1002/jsfa.9599] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 01/14/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND The increasing and extensive use of pesticides worldwide has resulted in a significant loss of non-target populations particularly humans by direct or indirect exposures. Also, various methods have been used for the estimation of pesticide residues in fruits and vegetables from recent past which are either tedious, time consuming or expensive. Therefore, the present study was performed to determine the pesticide residues from apple by simple and novel validated gas chromatography. RESULTS A novel, accurate, ecofriendly and cost-effective gas chromatography method was developed for simultaneous quantification of eight pesticides, namely chlorpyrifos-methyl (1), chlorpyrifos (2), quinolphos (3), profenofos (4), myclobutnil (5), ethion (6), fenpropathrin (7) and cypermethrin (8). The developed method was validated as per the SANTE guidelines. All calibration curves showed a good linear relationship (r > 0.99) within the test range. Precision was evaluated by intra- and inter-day tests with relative standard deviations (RSDs) < 2.0%, recovery in between 70% and 120% with RSDs < 2.00%. CONCLUSION The results demonstrate that the concentration of pesticides 1 to 8 were found below the detectable limit. Method validation parameters like linearity, precision, accuracy, specificity, robustness, detection and quantification limits were found within the acceptable range. The proposed method makes it possible to determine simultaneously pesticides 1-8 in one run which can be extended for residue-based standardization of pesticides from apple and other fruits and vegetables. © 2019 Society of Chemical Industry.
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Affiliation(s)
- Ashraf A Wani
- Research Centre for Residue & Quality Analysis, Division of Entomology, Sher-e-Kashmir University of Agricultural sciences & Technology of Kashmir, Shalimar, Srinagar, India
| | - Alamgir A Dar
- Research Centre for Residue & Quality Analysis, Division of Entomology, Sher-e-Kashmir University of Agricultural sciences & Technology of Kashmir, Shalimar, Srinagar, India
| | - Ishrat Jan
- Research Centre for Residue & Quality Analysis, Division of Entomology, Sher-e-Kashmir University of Agricultural sciences & Technology of Kashmir, Shalimar, Srinagar, India
| | - Khurshid A Sofi
- Research Centre for Residue & Quality Analysis, Division of Entomology, Sher-e-Kashmir University of Agricultural sciences & Technology of Kashmir, Shalimar, Srinagar, India
| | - Javid A Sofi
- Research Centre for Residue & Quality Analysis, Division of Entomology, Sher-e-Kashmir University of Agricultural sciences & Technology of Kashmir, Shalimar, Srinagar, India
| | - Irshad H Dar
- Research Centre for Residue & Quality Analysis, Division of Entomology, Sher-e-Kashmir University of Agricultural sciences & Technology of Kashmir, Shalimar, Srinagar, India
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Fernandez-Abascal J, Ripullone M, Valeri A, Leone C, Valoti M. β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP⁺ Toxicity in Human Neuroblastoma SH-SY5Y Cells. Int J Mol Sci 2018; 19:ijms19113369. [PMID: 30373287 PMCID: PMC6274691 DOI: 10.3390/ijms19113369] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/26/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022] Open
Abstract
Cytochrome P450 (CYP) isozymes vary their expression depending on the brain area, the cell type, and the presence of drugs. Some isoforms are involved in detoxification and/or toxic activation of xenobiotics in central nervous system. However, their role in brain metabolism and neurodegeneration is still a subject of debate. We have studied the inducibility of CYP isozymes in human neuroblastoma SH-SY5Y cells, treated with β-naphtoflavone (β-NF) or ethanol (EtOH) as inducers, by qRT-PCR, Western blot (WB), and metabolic activity assays. Immunohistochemistry was used to localize the isoforms in mitochondria and/or endoplasmic reticulum (ER). Tetrazolium (MTT) assay was performed to study the role of CYPs during methylphenyl pyridine (MPP+) exposure. EtOH increased mRNA and protein levels of CYP2D6 by 73% and 60% respectively. Both β-NF and EtOH increased CYP2E1 mRNA (4- and 1.4-fold, respectively) and protein levels (64% both). The 7-ethoxycoumarin O-deethylation and dextromethorphan O-demethylation was greater in treatment samples than in controls. Furthermore, both treatments increased by 22% and 18%, respectively, the cell viability in MPP+-treated cells. Finally, CYP2D6 localized at mitochondria and ER. These data indicate that CYP is inducible in SH-SY5Y cells and underline this in vitro system for studying the role of CYPs in neurodegeneration.
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Affiliation(s)
- Jesus Fernandez-Abascal
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
| | - Mariantonia Ripullone
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
| | - Aurora Valeri
- Molecular Horizon srl, Via Montelino 32, Bettona, 06084 Perugia, Italy.
| | - Cosima Leone
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
| | - Massimo Valoti
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
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20
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Peng K, Xiao J, Yang L, Ye F, Cao J, Sai Y. Mutual Antagonism of PINK1/Parkin and PGC-1α Contributes to Maintenance of Mitochondrial Homeostasis in Rotenone-Induced Neurotoxicity. Neurotox Res 2018; 35:331-343. [PMID: 30242625 DOI: 10.1007/s12640-018-9957-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) is a progressive, selective, and age-related neurodegenerative disease. The pathogenic focus of PD is mitochondrial dysfunction. When mitochondrial homeostasis was damaged, it can lead to reactive oxygen species formation to further accelerate the accumulation of dysfunctional mitochondria, resulting in a vicious cycle harmful to the neuron. PINK1 and Parkin, two proteins that are linked to PD, play vital roles in mitophagy, which was very important in maintaining mitochondrial homeostasis. Thus, at present, we explored mitochondrial biogenesis, mitophagy, and fission/fusion in rotenone-induced dopamine neurotoxicity. In particular, we focused on interactions between the PINK1/Parkin pathway and PGC-1α in the regulation of mitochondrial homeostasis impairment. The results indicated that both the autophagy and mitophagy levels increased significantly and were accompanied by altered levels of PINK1/Parkin proteins in rotenone-induced neurotoxicity. PINK1 influenced mitochondrial biogenesis by inhibiting PGC-1α and mtTFA protein expression as well as the mtDNA copy number. PGC-1α, in turn, inhibited PINK1/Parkin protein expression and the mitophagy levels. Furthermore, the results demonstrated that PINK1 influenced mitochondrial fission/fusion by regulating MFN2 and phosphorylating Drp1. In summary, mutual antagonism of the PINK1/Parkin pathway and PGC-1α formed a balance that regulated mitochondrial biogenesis, fission/fusion, and mitophagy. These effects contributed to the maintenance of mitochondrial homeostasis in rotenone-induced neurotoxicity.
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Affiliation(s)
- Kaige Peng
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Jingsong Xiao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Likui Yang
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Feng Ye
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Jia Cao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Yan Sai
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
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21
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Elmazoglu Z, Yar Saglam AS, Sonmez C, Karasu C. Luteolin protects microglia against rotenone-induced toxicity in a hormetic manner through targeting oxidative stress response, genes associated with Parkinson’s disease and inflammatory pathways. Drug Chem Toxicol 2018; 43:96-103. [PMID: 30207190 DOI: 10.1080/01480545.2018.1504961] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Zubeyir Elmazoglu
- Cellular Stress Response and Signal Transduction Research Laboratory, Department of Medical Pharmacology, Gazi University, Ankara, Turkey
| | | | - Can Sonmez
- Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Cimen Karasu
- Cellular Stress Response and Signal Transduction Research Laboratory, Department of Medical Pharmacology, Gazi University, Ankara, Turkey
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22
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Lowered iPLA2γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson's disease. Exp Neurol 2018; 300:74-86. [DOI: 10.1016/j.expneurol.2017.10.031] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/26/2017] [Accepted: 10/30/2017] [Indexed: 12/25/2022]
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23
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Afifi MA, Jiman-Fatani AA, Al-Rabia MW, Al-Hussainy NH, El Saadany S, Mayah W. More Than an Association: Latent Toxoplasmosis Might Provoke a Local Oxidative Stress That Triggers the Development of Bipolar Disorder. J Microsc Ultrastruct 2018; 6:139-144. [PMID: 30221140 PMCID: PMC6130242 DOI: 10.4103/jmau.jmau_22_18] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Introduction: Toxoplasma gondii, a common parasitic infection, has a special affinity to the brain. It has a lifelong existence without an apparent clinical disease. While the etiology of bipolar disorder (BD) remains unclear, epidemiological studies suggest a role for infections. Central nervous system is particularly susceptible to oxidative stress (OS) because of its high metabolic rate and its low levels of antioxidant defenses. OS is a contributor to the initiation and progression of many neurological illnesses. OS injury is a constantly and compelling finding associated with BD and toxoplasmosis. Aim: This cross-sectional study has investigated a possible role of toxoplasma-induced OS in the development of BD. Methods: Healthy controls and BD patients were examined for anti-Toxoplasma immunoglobulin-G (IgG) and two protein (3-nitrotyrosine) and DNA (8-hydroxy-2’ deoxyguanosine [8-OHdG]) OS markers. Results: Toxoplasma positivity was higher (40%) among BD patients compared to controls (12%). Significantly higher levels of anti-Toxoplasma IgG were detected in BD patients compared to controls. Nitrotyrosine (796.7 ± 106.28) and especially 8-OHdG (20.31 ± 8.38) were significantly higher among toxo-positive BD compared to toxo-negative BD (675.97 ± 144.19 and 7.44 ± 2.86) and healthy controls (464.02 ± 134.6 and 4.17 ± 1.43). Conclusion: These findings might indicate a role for Toxoplasma infection in the development of BD, possibly through creating a highly oxidative brain environment.
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Affiliation(s)
- Mohammed A Afifi
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Parasitology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Asif A Jiman-Fatani
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed W Al-Rabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nabeel H Al-Hussainy
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sherif El Saadany
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt.,Fakeeh College for Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Wael Mayah
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt.,Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
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24
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Riaz S, Manzoor F, Mahmood N, Shahid S. Molecular detection of M. tuberculosis and M. bovis and hematological and biochemical analyses in agricultural sprayers exposed to pesticides: A cross-sectional study in Punjab, Pakistan during 2014-2016. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2017; 27:434-443. [PMID: 28145400 DOI: 10.1038/jes.2016.88] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 12/19/2016] [Indexed: 06/06/2023]
Abstract
We determined the correlation between a pesticide exposure, physical health and susceptibility toward tuberculosis along with hematological indices and liver enzymes' alterations in sprayers exposed to pesticides. Molecular detection of Mycobacterium tuberculosis and Mycobacterium bovis was detected by targeting histone-like protein (hupB) gene. The WBC (white blood cells) and RBC (red blood cells) levels of male sprayers and non-sprayers were significantly different (P<0.05). In female spray workers, the WBC and neutrophils levels were significantly different as compared with non-sprayers. Overall, in both male and female pesticide-exposed sprayers, mean values of alanine amino transferase and aspartate amino transferase were higher as compared with unexposed workers. M. Tuberculosis were detected in 15% male sprayers and 36% female sprayers while, M. bovis was detected in 5% male sprayers and 10% female sprayers. A χ2-test indicated that there existed a significant different (P<0.05) between positive and negative M. tuberculosis and M. bovis in both male/female spray workers out of total. The susceptibility of pesticide-exposed sprayers to tuberculosis and alterations in hematology and liver enzymes is crucial for health. Toxic effects of pesticides may lead to a weak immune system and increased tuberculosis susceptibility.
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Affiliation(s)
- Saffora Riaz
- Department of Zoology, Lahore College for Women University, Lahore, Pakistan
| | - Farkhanda Manzoor
- Department of Zoology, Lahore College for Women University, Lahore, Pakistan
| | - Nasir Mahmood
- Department of Biochemistry, Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan
| | - Saman Shahid
- Department of Sciences and Humanities, National University of Computer and Emerging Sciences Foundation for Advancement of Science and Technology, Lahore, Pakistan
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Huang C, Zhu L, Li H, Shi FG, Wang GQ, Wei YZ, Liu J, Zhang F. Adulthood Exposure to Lipopolysaccharide Exacerbates the Neurotoxic and Inflammatory Effects of Rotenone in the Substantia Nigra. Front Mol Neurosci 2017; 10:131. [PMID: 28533741 PMCID: PMC5421296 DOI: 10.3389/fnmol.2017.00131] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 04/20/2017] [Indexed: 01/09/2023] Open
Abstract
Parkinson's disease (PD) is the second most neurodegenerative disorder with a regional decrease of dopamine (DA) neurons in the substantia nigra (SN). Despite intense exploration, the etiology of PD progressive process remains unclear. This study was to investigate the synergistic effects of systemic inflammation of lipopolysaccharide (LPS) and neurotoxicity of rotenone (ROT) on exacerbating DA neuron lesion. Male SD adulthood rats received a single intraperitoneal injection of LPS. Seven months later, rats were subcutaneously given ROT five times a week for consecutive 4 weeks. Rat behavior changes were assessed via rotarod and open-field tests. Brain SN was immunostained to evaluate DA neuronal loss and microglia activation. Striatum DA and its metabolites levels were determined by high performance liquid chromatography (HPLC) coupled with electrochemistry. The protein levels of α-synuclein (α-Syn), inflammatory factors and mitogen-activated protein kinase (MAPK) pathway activation were detected by western blotting analysis. Results indicated that no significant difference between the control and LPS alone groups was shown. Compared with ROT alone group, LPS combined with ROT significantly reduced motor activity and induced SN DA neurons loss accompanied by the decreased contents of striatum DA and its metabolites. Furthermore, LPS together with ROT enhanced microglia activation and the increased expressions of α-Syn and inflammatory factors and also MAPK signaling pathway activation. However, LPS alone had no significant effects on the above parameters. These findings suggest that adulthood exposure to LPS exacerbates the neurotoxic and inflammatory effects of ROT in the SN.
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Affiliation(s)
- Chun Huang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Li Zhu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Huan Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Fu-Guo Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Guo-Qing Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Yi-Zheng Wei
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Jie Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityZunyi, China
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More than an association: Latent toxoplasmosis might provoke a local oxidative stress that triggers the development of bipolar disorder. J Microsc Ultrastruct 2017. [DOI: 10.1016/j.jmau.2017.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Giannoccaro MP, La Morgia C, Rizzo G, Carelli V. Mitochondrial DNA and primary mitochondrial dysfunction in Parkinson's disease. Mov Disord 2017; 32:346-363. [PMID: 28251677 DOI: 10.1002/mds.26966] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/27/2017] [Accepted: 01/30/2017] [Indexed: 12/15/2022] Open
Abstract
In 1979, it was observed that parkinsonism could be induced by a toxin inhibiting mitochondrial respiratory complex I. This initiated the long-standing hypothesis that mitochondrial dysfunction may play a key role in the pathogenesis of Parkinson's disease (PD). This hypothesis evolved, with accumulating evidence pointing to complex I dysfunction, which could be caused by environmental or genetic factors. Attention was focused on the mitochondrial DNA, considering the occurrence of mutations, polymorphic haplogroup-specific variants, and defective mitochondrial DNA maintenance with the accumulation of multiple deletions and a reduction of copy number. Genetically determined diseases of mitochondrial DNA maintenance frequently manifest with parkinsonism, but the age-related accumulation of somatic mitochondrial DNA errors also represents a major driving mechanism for PD. Recently, the discovery of the genetic cause of rare inherited forms of PD highlighted an extremely complex homeostatic control over mitochondria, involving their dynamic fission/fusion cycle, the balancing of mitobiogenesis and mitophagy, and consequently the quality control surveillance that corrects faulty mitochondrial DNA maintenance. Many genes came into play, including the PINK1/parkin axis, but also OPA1, as pieces of the same puzzle, together with mitochondrial DNA damage, complex I deficiency and increased oxidative stress. The search for answers will drive future research to reach the understanding necessary to provide therapeutic options directed not only at limiting the clinical evolution of symptoms but also finally addressing the pathogenic mechanisms of neurodegeneration in PD. © 2017 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Maria Pia Giannoccaro
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Chiara La Morgia
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Rizzo
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Valerio Carelli
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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Dincel GC, Atmaca HT. Role of oxidative stress in the pathophysiology of Toxoplasma gondii infection. Int J Immunopathol Pharmacol 2016; 29:226-40. [PMID: 26966143 PMCID: PMC5806720 DOI: 10.1177/0394632016638668] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 02/19/2016] [Indexed: 11/17/2022] Open
Abstract
Oxidative stress (OS) plays an essential role in the pathogenesis of common neurodegenerative diseases. We have previously shown that Toxoplasma gondii (T. gondii) induces high nitric oxide (NO) production, glial activation, and apoptosis that altogether cause severe neuropathology in toxoplasma encephalitis (TE). The objective of this study was to investigate the cytotoxic effect of OS and to identify a correlation between the causes of T. gondii induced neuropathology. Expression levels of glutathione reductase (GR), Cu/Zn superoxide dismutase (SOD1), neuron specific enolase (NSE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were investigated. Results of the study revealed that the levels of GR (P <0.005) and NSE (P <0.001) expression in the brain tissue markedly increased while SOD1 activity decreased (P <0.001) in the infected group compared to the non-infected group. In addition, intense staining for 8-OHdG (P <0.05) was observed both in the nucleus and the cytoplasm of neurons and glial cells that underwent OS. These results were reasonable to suggest that T. gondii-mediated OS might play a pivotal role and a different type of role in the mechanism of neurodegeneration/neuropathology in the process of TE. The results also clearly indicated that increased levels of NO and apoptosis might contribute to OS-related pathogenesis of TE. As a result, OS and expression of NSE might give an idea of the disease progress and may have a critical diagnostic significance for patients with T. gondii infection.
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Affiliation(s)
- Gungor Cagdas Dincel
- Gumushane University, Siran Mustafa Beyaz Vocational High School, Siran, Gumushane, Turkey
| | - Hasan Tarik Atmaca
- Kirikkale University, Faculty of Veterinary Medicine, Department of Pathology, Yahsihan, Kirikkale, Turkey
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Vanillin Attenuated Behavioural Impairments, Neurochemical Deficts, Oxidative Stress and Apoptosis Against Rotenone Induced Rat Model of Parkinson's Disease. Neurochem Res 2016; 41:1899-910. [PMID: 27038927 DOI: 10.1007/s11064-016-1901-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 03/14/2016] [Accepted: 03/24/2016] [Indexed: 12/14/2022]
Abstract
Vanillin (4-hydroxy-3-methoxybenzaldehyde), a pleasant smelling organic aromatic compound, is widely used as a flavoring additive in food, beverage, cosmetic and drug industries. It is reported to cross the blood brain barrier and also displayed antioxidant and neuroprotective activities. We previously reported the neuroprotective effect of vanillin against rotenone induced in in vitro model of PD. The present experiment was aimed to analyze the neuroprotective effect of vanillin on the motor and non-motor deficits, neurochemical variables, oxidative, anti-oxidative indices and the expression of apoptotic markers against rotenone induced rat model of Parkinson's disease (PD). Rotenone treatment exhibited motor and non-motor impairments, neurochemical deficits, oxidative stress and apoptosis, whereas oral administration of vanillin attenuated the above-said indices. However further studies are needed to explore the mitochondrial protective and anti-inflammatory properties of vanillin, as these processes play a vital role in the cause and progression of PD.
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Ahmed HH, Salem AM, Atta HM, Eskandar EF, Farrag ARH, Ghazy MA, Salem NA, Aglan HA. Updates in the pathophysiological mechanisms of Parkinson’s disease: Emerging role of bone marrow mesenchymal stem cells. World J Stem Cells 2016; 8:106-117. [PMID: 27022441 PMCID: PMC4807309 DOI: 10.4252/wjsc.v8.i3.106] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 11/27/2015] [Accepted: 02/24/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson’s disease (PD) pathophysiology.
METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done.
RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs.
CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD pathophysiology via multi-mechanistic actions.
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Shen W, Wang L, Pi R, Li Z, Rikang Wang. L-F001, a multifunctional ROCK inhibitor prevents paraquat-induced cell death through attenuating ER stress and mitochondrial dysfunction in PC12 cells. Biochem Biophys Res Commun 2015; 464:794-9. [DOI: 10.1016/j.bbrc.2015.07.035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/07/2015] [Indexed: 12/01/2022]
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Tan Z, Xu H, Shen X, Jiang H. Nesfatin-1 antagonized rotenone-induced neurotoxicity in MES23.5 dopaminergic cells. Peptides 2015; 69:109-14. [PMID: 25937598 DOI: 10.1016/j.peptides.2015.04.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 04/15/2015] [Accepted: 04/23/2015] [Indexed: 12/21/2022]
Abstract
Nesfatin-1 is a recently identified brain-gut peptide involved in feeding and energy homeostasis. Recently, it has been proved that nesfatin-1 could exert its neuroprotective effect against subarachnoid hemorrhage-induced injury via its anti-apoptotic and anti-inflammatory properties. However, whether it has neuroprotective effect on dopamine neurons is largely unknown. In the present study, we investigated the neuroprotective effect of nesfatin-1 on rotenone-treated MES23.5 dopaminergic cells and illustrated the underlying mechanisms. Our results showed that nesfatin-1 pretreatment could significantly attenuate rotenone-induced cell loss. Further studies showed that the neuroprotective effect of nesfatin-1 against rotenone was mediated by reversing rotenone-induced mitochondrial dysfunction. Nesfatin-1 could rescue rotenone-induced mitochondrial transmembrane potential collapse and restore the function of mitochondrial respiratory chain complex I. In addition, rotenone-induced release of cytochrome C from mitochondria, ROS production and the subsequent caspase-3 activation were also attenuated by nesfatin-1 pretreatment. Our data suggested that nesfatin-1 exerted its neuroprotective effect on dopaminergic cells against rotenone by ameliorating mitochondrial dysfunction and its anti-apoptotic property. This suggested that nesfatin-1 had the potential to be considered as an aid for prevention of Parkinson's disease.
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Affiliation(s)
- Zhen Tan
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Medical College of Qingdao University, Qingdao, 266071, China
| | - Huamin Xu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Medical College of Qingdao University, Qingdao, 266071, China
| | - Xiaoli Shen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Medical College of Qingdao University, Qingdao, 266071, China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Medical College of Qingdao University, Qingdao, 266071, China.
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Stangenberg S, Nguyen LT, Chen H, Al-Odat I, Killingsworth MC, Gosnell ME, Anwer AG, Goldys EM, Pollock CA, Saad S. Oxidative stress, mitochondrial perturbations and fetal programming of renal disease induced by maternal smoking. Int J Biochem Cell Biol 2015; 64:81-90. [PMID: 25849459 DOI: 10.1016/j.biocel.2015.03.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 11/30/2022]
Abstract
An adverse in-utero environment is increasingly recognized to predispose to chronic disease in adulthood. Maternal smoking remains the most common modifiable adverse in-utero exposure leading to low birth weight, which is strongly associated with chronic kidney disease (CKD) in later life. In order to investigate underlying mechanisms for such susceptibility, female Balb/c mice were sham or cigarette smoke-exposed (SE) for 6 weeks before mating, throughout gestation and lactation. Offspring kidneys were examined for oxidative stress, expression of mitochondrial proteins, mitochondrial structure as well as renal functional parameters on postnatal day 1, day 20 (weaning) and week 13 (adult age). From birth throughout adulthood, SE offspring had increased renal levels of mitochondrial-derived reactive oxygen species (ROS), which left a footprint on DNA with increased 8-hydroxydeoxyguanosin (8-OHdG) in kidney tubular cells. Mitochondrial structural abnormalities were seen in SE kidneys at day 1 and week 13 along with a reduction in oxidative phosphorylation (OXPHOS) proteins and activity of mitochondrial antioxidant Manganese superoxide dismutase (MnSOD). Smoke exposure also resulted in increased mitochondrial DNA copy number (day 1-week 13) and lysosome density (day 1 and week 13). The appearance of mitochondrial defects preceded the onset of albuminuria at week 13. Thus, mitochondrial damage caused by maternal smoking may play an important role in development of CKD at adult life.
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Affiliation(s)
- Stefanie Stangenberg
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia
| | - Long T Nguyen
- School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, Australia
| | - Hui Chen
- School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, Australia
| | - Ibrahim Al-Odat
- School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, Australia
| | - Murray C Killingsworth
- Department of Anatomical Pathology, Sydney South West Pathology Service, Liverpool, Australia
| | - Martin E Gosnell
- MQ BioFocus Research Centre, Macquarie University, Sydney, NSW, Australia
| | - Ayad G Anwer
- MQ BioFocus Research Centre, Macquarie University, Sydney, NSW, Australia
| | - Ewa M Goldys
- MQ BioFocus Research Centre, Macquarie University, Sydney, NSW, Australia
| | - Carol A Pollock
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia
| | - Sonia Saad
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia.
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Chen Y, Zhang DQ, Liao Z, Wang B, Gong S, Wang C, Zhang MZ, Wang GH, Cai H, Liao FF, Xu JP. Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson's disease. Mol Neurodegener 2015; 10:4. [PMID: 26013581 PMCID: PMC4506434 DOI: 10.1186/1750-1326-10-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 12/27/2014] [Indexed: 12/21/2022] Open
Abstract
Background Compelling evidence suggests that inhibition of the complex I of the electron transport chain and elevated oxidative stress are the earliest events during the pathogenesis of Parkinson’s disease (PD). Therefore, anti-oxidants, especially those from natural sources, hold good promise in treating PD as demonstrated mostly by the studies in rodent models. Results Herein, we determined if polydatin (piceid), a natural polyphenol, could exert anti-oxidative activity and attenuate dopaminergic neurodegeneration in three commonly used rodent models of PD. Male Sprague Dawley rats given rotenone subcutaneously for 5 weeks developed all the essential features of PD, including a strong increase in catalepsy score and a decrease in motor coordination activity, starting at 4 weeks. Selective increase in oxidative damage was found in the striatal region as compared to the hippocampus and cortex, accompanied by massive degeneration of dopaminergic neurons in the substantia nigra (SNc). Co-administration of piceid orally was able to attenuate rotenone-induced motor defects in a dose dependent manner, with 80 mg/kg dosage showing even better effect than L-levodopa (L-dopa). Piceid treatment significantly prevented the rotenone-induced changes in the levels of glutathione, thioredoxin, ATP, malondialdehyde (MDA) and the manganese superoxide dismutases (SOD) in striatum. Furthermore, piceid treatment rescued rotenone-induced dopaminergic neurodegeneration in the SNc region. Similar protective effect of piceid was also observed in two additional models of PD, MPTP in mice and 6-OHDA in rats, showing corrected motor functions, SOD and MDA activities as well as p-Akt and activated caspase-3 levels. Conclusion In three rodent models of PD, piceid preserves and corrects several major anti-oxidant pathways/parameters selectively in the affected SNc region. This implies its potent anti-oxidant activity as one major underscoring mechanism for protecting the vulnerable SNc neurodegeneration in these models. Taken together, these findings strongly suggest a therapeutic potential of piceid in treating PD. Electronic supplementary material The online version of this article (doi:10.1186/1750-1326-10-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yupin Chen
- Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Dong-qi Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Zhong Liao
- Spinal Cord Surgery, Fuzhou Second Hospital Affiliated to Xiaman University, Fuzhou, 35007, China.
| | - Bin Wang
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, 38164, USA.
| | - Suzhen Gong
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, 38164, USA.
| | - Chuang Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Ming-zi Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Guo-hua Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Huaibin Cai
- Transgenics Section and Bioinformatics Core, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, 20892, USA.
| | - Francesca-Fang Liao
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, 38164, USA.
| | - Jiang-ping Xu
- Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
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Hou Y, Xin N, Chen S, Deng C, Xiang J. Controllable Release and High-Efficiency Collection of Hydrogen Peroxide: Application on the Quantitative Investigation of Biomolecule Oxidation Induced by Reactive Oxygen Species. ELECTROANAL 2014. [DOI: 10.1002/elan.201400012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Rivero-Ríos P, Gómez-Suaga P, Fdez E, Hilfiker S. Upstream deregulation of calcium signaling in Parkinson's disease. Front Mol Neurosci 2014; 7:53. [PMID: 24987329 PMCID: PMC4060956 DOI: 10.3389/fnmol.2014.00053] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 05/27/2014] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is a major health problem affecting millions of people worldwide. Recent studies provide compelling evidence that altered Ca2+ homeostasis may underlie disease pathomechanism and be an inherent feature of all vulnerable neurons. The downstream effects of altered Ca2+ handling in the distinct subcellular organelles for proper cellular function are beginning to be elucidated. Here, we summarize the evidence that vulnerable neurons may be exposed to homeostatic Ca2+ stress which may determine their selective vulnerability, and suggest how abnormal Ca2+ handling in the distinct intracellular compartments may compromise neuronal health in the context of aging, environmental, and genetic stress. Gaining a better understanding of the varied effects of Ca2+ dyshomeostasis may allow novel combinatorial therapeutic strategies to slow PD progression.
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Affiliation(s)
- Pilar Rivero-Ríos
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
| | - Patricia Gómez-Suaga
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
| | - Elena Fdez
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
| | - Sabine Hilfiker
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
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Zhou Y, Wang K, Yan C, Li WS, Li H, Zhang N, Zhang ZX. Effect of two formulations on the decline curves and residue levels of rotenone in cabbage and soil under field conditions. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2014; 104:23-27. [PMID: 24632119 DOI: 10.1016/j.ecoenv.2014.02.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 02/09/2014] [Accepted: 02/12/2014] [Indexed: 06/03/2023]
Abstract
The dissipation and residue levels of rotenone with suspension concentrate (SC) as well as water dispersible granule (WDG) formulations in cabbage and soil were investigated under field conditions. The decline curves of rotenone residues in cabbage and soil corresponded with first-order kinetics. The dissipation rate of rotenone in cabbage was faster than that in soil. The half-lives of the SC formulations in cabbage and soil were 1.14d to 1.85d and 2.26d to 3.98d, respectively. For the WDG formulation, the values were 1.33d to 1.96d and 2.41d to 3.38d. Less spraying, lower dosage, and longer pre-harvest intervals could reduce terminal residue levels. Terminal residues below the MRL (0.5mg kg(-1)) were achieved after pre-harvest intervals of 3d at either once (45g a.i. ha(-1)) or twice (90g a.i. ha(-1)) the recommended dosage. The different dissipation processes of rotenone in cabbage and soil under field conditions could be attributed to the different climate and soil properties, and the types of formulation had no apparent effect on half-life. Formulation type affected the initial concentrations and finally led to different terminal residues. Prolonged pre-harvest intervals are necessary to ensure that the products are sufficiently safe for consumption.
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Affiliation(s)
- You Zhou
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou, PR China
| | - Kun Wang
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou, PR China
| | - Chao Yan
- Environment and Plant Protection Research Institute, Chinese Academy of Tropical Agricultural Sciences, Danzhou, PR China
| | - Wei-Sheng Li
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou, PR China
| | - Hong Li
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou, PR China
| | - Ning Zhang
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou, PR China
| | - Zhi-Xiang Zhang
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou, PR China.
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Tamilselvam K, Braidy N, Manivasagam T, Essa MM, Prasad NR, Karthikeyan S, Thenmozhi AJ, Selvaraju S, Guillemin GJ. Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson's disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:102741. [PMID: 24205431 PMCID: PMC3800605 DOI: 10.1155/2013/102741] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 08/15/2013] [Indexed: 01/24/2023]
Abstract
Rotenone a widely used pesticide that inhibits mitochondrial complex I has been used to investigate the pathobiology of PD both in vitro and in vivo. Studies have shown that the neurotoxicity of rotenone may be related to its ability to generate reactive oxygen species (ROS), leading to neuronal apoptosis. The current study was carried out to investigate the neuroprotective effects of hesperidin, a citrus fruit flavanol, against rotenone-induced apoptosis in human neuroblastoma SK-N-SH cells. We assessed cell death, mitochondrial membrane potential, ROS generation, ATP levels, thiobarbituric acid reactive substances, reduced glutathione (GSH) levels, and the activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) using well established assays. Apoptosis was determined in normal, rotenone, and hesperidin treated cells, by measuring the protein expression of cytochrome c (cyt c), caspases 3 and 9, Bax, and Bcl-2 using the standard western blotting technique. The apoptosis in rotenone-induced SK-N-SH cells was accompanied by the loss of mitochondrial membrane potential, increased ROS generation, the depletion of GSH, enhanced activities of enzymatic antioxidants, upregulation of Bax, cyt c, and caspases 3 and 9, and downregulation of Bcl-2, which were attenuated in the presence of hesperidin. Our data suggests that hesperidin exerts its neuroprotective effect against rotenone due to its antioxidant, maintenance of mitochondrial function, and antiapoptotic properties in a neuroblastoma cell line.
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Affiliation(s)
- Kuppusamy Tamilselvam
- Department of Biochemistry and Biotechnology, Faculty of Science, College Rd, Annamalai Nagar, Chidambaram, Tamil Nadu 608002, India
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New SouthWales, Sydney 2031, Australia
| | - Thamilarasan Manivasagam
- Department of Biochemistry and Biotechnology, Faculty of Science, College Rd, Annamalai Nagar, Chidambaram, Tamil Nadu 608002, India
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, College of Agriculture and Marine Sciences, Sultan Qaboos University, P.O. Box 50, Muscat 123, Oman
| | - Nagarajan Rajendra Prasad
- Department of Biochemistry and Biotechnology, Faculty of Science, College Rd, Annamalai Nagar, Chidambaram, Tamil Nadu 608002, India
| | - Subburayan Karthikeyan
- Department of Biochemistry and Biotechnology, Faculty of Science, College Rd, Annamalai Nagar, Chidambaram, Tamil Nadu 608002, India
| | - Arokyasamy Justin Thenmozhi
- Department of Biochemistry and Biotechnology, Faculty of Science, College Rd, Annamalai Nagar, Chidambaram, Tamil Nadu 608002, India
| | - Subash Selvaraju
- Department of Food Science and Nutrition, College of Agriculture and Marine Sciences, Sultan Qaboos University, P.O. Box 50, Muscat 123, Oman
| | - Gilles J. Guillemin
- Neuropharmacology Group, MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine, Macquarie University, Balaclava Road, North Ryde, Sydney, NSW 2109, Australia
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Zhou Y, Zhang N, Wang K, Li W, Li H, Zhang Z. Dissipation and residue of rotenone in cabbage and soil under field conditions. BULLETIN OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2013; 91:251-255. [PMID: 23807683 DOI: 10.1007/s00128-013-1040-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 06/08/2013] [Indexed: 06/02/2023]
Abstract
Rotenone dissipation and terminal residue in cabbage and soil under field conditions were determined by high-performance liquid chromatography. The dissipation rates of rotenone were described using first-order kinetics. The half-lives ranged from 0.89 to 1.55 days in cabbage and 1.98 to 2.76 days in soil. Prolonged pre-harvest interval times ensure that the cabbage is safe for consumption. Temperature and the physico-chemical properties of the soil were identified as the key factors affecting rotenone degradation in cabbage and soil under field conditions.
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Affiliation(s)
- You Zhou
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China
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1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application. Neurotox Res 2013; 25:1-12. [PMID: 23719903 PMCID: PMC3889699 DOI: 10.1007/s12640-013-9402-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 05/06/2013] [Indexed: 12/21/2022]
Abstract
This review outlines the effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), endogenous substances imbued with high pharmacological potential and broad spectrum of action in brain. 1MeTIQ has gained special interest as a neuroprotectant, and its ability to antagonize the behavioral syndrome produced by well-known neurotoxins (e.g., MPTP; rotenone). This review is thus focused on mechanisms of action of 1MeTIQ in behavioral, neurochemical, and molecular studies in rodents; also, effects of TIQ and 1MeTIQ on dopamine metabolism; and neuroprotective properties of TIQ and 1MeTIQ in vitro and in vivo. Finally, antiaddictive properties of 1MeTIQ will be described in cocaine self-administered rats. Findings implicate TIQ and especially its methyl derivative 1MeTIQ in unique and complex mechanisms of neuroprotection in various neurodegenerative illnesses of the central nervous system. We believe that MAO inhibition, free radicals scavenging properties, and antagonism to the glutamatergic system may play an essential role in neuroprotection. In addition, the results strongly support the view that 1MeTIQ has a considerable potential as a drug for combating substance abuse, through the attenuation of craving.
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Lindgren HS, Dunnett SB. Cognitive dysfunction and depression in Parkinson's disease: what can be learned from rodent models? Eur J Neurosci 2012; 35:1894-907. [PMID: 22708601 DOI: 10.1111/j.1460-9568.2012.08162.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Parkinson's disease (PD) has for decades been considered a pure motor disorder and its cardinal motor symptoms have been attributed to the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and to nigral Lewy body pathology. However, there has more recently been a shift in the conceptualization of the disease, and its pathological features have now been recognized as involving several other areas of the brain and indeed even outside the central nervous system. There are a corresponding variety of intrinsic non-motor symptoms such as autonomic dysfunction, cognitive impairment, sleep disturbances and neuropsychiatric problems, which cannot be explained exclusively by nigral pathology. In this review, we will focus on cognitive impairment and affective symptoms in PD, and we will consider whether, and how, these deficits can best be modelled in rodent models of the disorder. As only a few of the non-motor symptoms respond to standard DA replacement therapies, the quest for a broader therapeutic approach remains a major research effort, and success in this area in particular will be strongly dependent on appropriate rodent models. In addition, better understanding of the different models, as well as the advantages and disadvantages of the available behavioural tasks, will result in better tools for evaluating new treatment strategies for PD patients suffering from these neuropsychological symptoms.
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Affiliation(s)
- Hanna S Lindgren
- Brain Repair Group, School of Biosciences, Cardiff University, Life Sciences Building, Museum Avenue, Cardiff, Wales, CF10 3AX, UK.
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Alexander GE. Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. DIALOGUES IN CLINICAL NEUROSCIENCE 2012. [PMID: 22033559 PMCID: PMC3181806 DOI: 10.31887/dcns.2004.6.3/galexander] [Citation(s) in RCA: 307] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.
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Affiliation(s)
- Garrett E Alexander
- Department of Neurology, Emory University School of Medicine, Atlanta, Ga, USA
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Joselin AP, Hewitt SJ, Callaghan SM, Kim RH, Chung YH, Mak TW, Shen J, Slack RS, Park DS. ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum Mol Genet 2012; 21:4888-903. [PMID: 22872702 DOI: 10.1093/hmg/dds325] [Citation(s) in RCA: 169] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Mutations in several genes, including Parkin, PTEN-induced kinase 1 (Pink1) and DJ-1, are associated with rare inherited forms of Parkinson's disease (PD). Despite recent attention on the function of these genes, the interplay between DJ-1, Pink1 and Parkin in PD pathogenesis remains unclear. In particular, whether these genes regulate mitochondrial control pathways in neurons is highly controversial. Here we report that Pink1-dependent Parkin translocation does occur in mouse cortical neurons in response to a variety of mitochondrial damaging agents. This translocation only occurs in the absence of antioxidants in the neuronal culturing medium, implicating a key role of reactive oxygen species (ROS) in this response. Consistent with these observations, ROS blockers also prevent Parkin recruitment in mouse embryonic fibroblasts. Loss of DJ-1, a gene linked to ROS management, results in increased stress-induced Parkin recruitment and increased mitophagy. Expression of wild-type DJ-1, but not a cysteine-106 mutant associated with defective ROS response, rescues this accelerated Parkin recruitment. Interestingly, DJ-1 levels increase at mitochondria following oxidative damage in both fibroblasts and neurons, and this process also depends on Parkin and possibly Pink1. These results not only highlight the presence of a Parkin/Pink1-mediated pathway of mitochondrial quality control (MQC) in neurons, they also delineate a complex reciprocal relationship between DJ-1 and the Pink1/Parkin pathway of MQC.
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Affiliation(s)
- Alvin P Joselin
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada
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Kimura R, Ma L, Wu C, Turner D, Shen J, Ellsworth K, Wakui M, Maalouf M, Wu J. Acute exposure to the mitochondrial complex I toxin rotenone impairs synaptic long-term potentiation in rat hippocampal slices. CNS Neurosci Ther 2012; 18:641-6. [PMID: 22613619 PMCID: PMC6493358 DOI: 10.1111/j.1755-5949.2012.00337.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AIMS To evaluate the acute effects of the mitochondrial complex I inhibitor rotenone on rat hippocampal synaptic plasticity. METHODS Electrophysiological field potential recordings were used to measure basal synaptic transmission and synaptic plasticity in rat coronal hippocampal slices. Synaptic long-term potentiation (LTP) was induced by high-frequency stimulation (100 Hz, 1 second × 3 at an interval of 20 seconds). In addition, mitochondrial complex I function was measured using MitoSOX imaging in mitochondrial preparations. RESULTS Acute exposure of hippocampal slices to 50 nM rotenone for 1 h did not alter basal CA3-CA1 synaptic transmission though 500 nM rotenone significantly reduced basal synaptic transmission. However, 50 nM rotenone significantly impaired LTP and this rotenone's effect was prevented by co-application of rotenone plus the ketones acetoacetate and β-hydroxybutyrate (1 mM each). Finally, we measured mitochondrial function using MitoSOX imaging in mitochondrial preparations and found that 50 nM rotenone partially reduced mitochondrial function whereas 500 nM rotenone completely eliminated mitochondrial function. CONCLUSIONS Our findings suggest that mitochondrial activity driven by complex I is a sensitive modulator of synaptic plasticity in the hippocampus. Acute exposure of the hippocampus to rotenone eliminates complex I function and in turn impairs LTP.
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Affiliation(s)
- Ryoichi Kimura
- Department of Physiology, Shantou University Medical College, Shantou, China
- Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Lu‐Yao Ma
- Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Chen Wu
- Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Dharshaun Turner
- Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Jian‐Xin Shen
- Department of Physiology, Shantou University Medical College, Shantou, China
| | - Kevin Ellsworth
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Makoto Wakui
- Clinical Research, Hirosaki National Hospital, Hirosaki, Japan
| | - Marwan Maalouf
- Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Jie Wu
- Department of Physiology, Shantou University Medical College, Shantou, China
- Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
- Department of Basic Medical Science, the University of Arizona College of Medicine‐Phoenix, AZ, USA
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Fluazinam targets mitochondrial complex I to induce reactive oxygen species-dependent cytotoxicity in SH-SY5Y cells. Neurochem Int 2012; 60:773-81. [DOI: 10.1016/j.neuint.2012.03.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 03/05/2012] [Accepted: 03/13/2012] [Indexed: 11/17/2022]
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Ki YW, Lee JE, Park JH, Shin IC, Koh HC. Reactive oxygen species and mitogen-activated protein kinase induce apoptotic death of SH-SY5Y cells in response to fipronil. Toxicol Lett 2012; 211:18-28. [DOI: 10.1016/j.toxlet.2012.02.022] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Revised: 02/24/2012] [Accepted: 02/27/2012] [Indexed: 12/21/2022]
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Zhou H, Zhang F, Chen SH, Zhang D, Wilson B, Hong JS, Gao HM. Rotenone activates phagocyte NADPH oxidase by binding to its membrane subunit gp91phox. Free Radic Biol Med 2012; 52:303-13. [PMID: 22094225 PMCID: PMC3253173 DOI: 10.1016/j.freeradbiomed.2011.10.488] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Revised: 10/18/2011] [Accepted: 10/22/2011] [Indexed: 12/21/2022]
Abstract
Rotenone, a widely used pesticide, reproduces parkinsonism in rodents and associates with increased risk for Parkinson disease. We previously reported that rotenone increased superoxide production by stimulating the microglial phagocyte NADPH oxidase (PHOX). This study identified a novel mechanism by which rotenone activates PHOX. Ligand-binding assay revealed that rotenone directly bound to membrane gp91(phox), the catalytic subunit of PHOX; such binding was inhibited by diphenyleneiodonium, a PHOX inhibitor with a binding site on gp91(phox). Functional studies showed that both membrane and cytosolic subunits were required for rotenone-induced superoxide production in cell-free systems, intact phagocytes, and COS7 cells transfected with membrane subunits (gp91(phox)/p22(phox)) and cytosolic subunits (p67(phox) and p47(phox)). Rotenone-elicited extracellular superoxide release in p47(phox)-deficient macrophages suggested that rotenone enabled activation of PHOX through a p47(phox)-independent mechanism. Increased membrane translocation of p67(phox), elevated binding of p67(phox) to rotenone-treated membrane fractions, and coimmunoprecipitation of p67(phox) and gp91(phox) in rotenone-treated wild-type and p47(phox)-deficient macrophages indicated that p67(phox) played a critical role in rotenone-induced PHOX activation via its direct interaction with gp91(phox). Rac1, a Rho-like small GTPase, enhanced p67(phox)-gp91(phox) interaction; Rac1 inhibition decreased rotenone-elicited superoxide release. In conclusion, rotenone directly interacted with gp91(phox); such an interaction triggered membrane translocation of p67(phox), leading to PHOX activation and superoxide production.
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Affiliation(s)
- Hui Zhou
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
| | - Feng Zhang
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
| | - Shih-heng Chen
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
| | - Dan Zhang
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
| | - Belinda Wilson
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
| | - Jau-shyong Hong
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
| | - Hui-Ming Gao
- Neuropharmacology Section, Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, 27709
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Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 2011; 30:2520-31. [PMID: 21587205 PMCID: PMC3155297 DOI: 10.1038/emboj.2011.162] [Citation(s) in RCA: 211] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Accepted: 05/02/2011] [Indexed: 12/14/2022] Open
Abstract
Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Here, we survey the molecular mechanisms that link ageing to main stress response pathways, and mediate age-related changes in the effectiveness of the response to stress. We also discuss how each pathway contributes to modulate the ageing process. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies.
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Singh S, Kumar V, Thakur S, Banerjee BD, Chandna S, Rautela RS, Grover SS, Rawat DS, Pasha ST, Jain SK, Ichhpujani RL, Rai A. DNA damage and cholinesterase activity in occupational workers exposed to pesticides. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2011; 31:278-285. [PMID: 21787695 DOI: 10.1016/j.etap.2010.11.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Revised: 11/17/2010] [Accepted: 11/18/2010] [Indexed: 05/31/2023]
Abstract
The present study was designed to evaluate genotoxicity, acetyl cholinesterase (AChE) activity, hepatic and renal toxicity in occupational workers exposed to mixture of pesticides (n=70) with same number of healthy subjects as controls. The mean comet tail DNA % (TD %) and tail moment (TM) were used to measure DNA damage, while AChE activity and other biochemical parameters such as markers of nephrotoxicity (urea and creatinine) and hepatotoxicity (AST, ALT and ALP) were measured as biomarkers for toxicity due to exposure of pesticides. The occupational workers were continuously exposed to mixture of pirimiphos methyl, chlorpyrifos, temephos and malathion on a regular interval as per usage and activity. The comet assay using lymphocytes of exposed workers showed significantly higher TD percentage value (60.43% vs. 31.86%, p<0.001) and TM value (14.48 μm vs. 6.42 μm, p<0.001) in occupational workers as compared to controls. AChE activity in erythrocytes was found to be decreased (3.45 KAU/L vs. 9.55 KAU/L in controls, p<0.001) and associated with the duration of exposure to pesticides used by the workers. Enzyme levels for hepatic and renal functions were also found significantly different in occupational workers than healthy controls (p<0.001). These results suggest that the exposure to mixture of pirimiphos methyl, chlorpyrifos, temephos and malathion may induce DNA damage, decrease in AChE activity, hepatotoxicity as well as nephrotoxicity. Periodic biomonitoring of these biomarkers along with imparting education and training to occupational workers for safe application of pesticides is recommended for its potential hazards.
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Affiliation(s)
- Satyender Singh
- Division of Biochemistry & Biotechnology, National Centre for Disease Control (Formerly NICD), 22, Sham Nath Marg, Delhi 110054, India
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Antkiewicz-Michaluk L, Wąsik A, Romańska I, Bojarski A, Michaluk J. Both stereoselective (R)- and (S)-1-Methyl-1,2,3,4-tetrahydroisoquinoline enantiomers protect striatal terminals against rotenone-induced suppression of dopamine release. Neurotox Res 2010; 20:134-49. [PMID: 21069490 PMCID: PMC3110269 DOI: 10.1007/s12640-010-9228-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Revised: 10/15/2010] [Accepted: 10/15/2010] [Indexed: 12/21/2022]
Abstract
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is present in the human and rodent brain as a mixture of stereospecific (R)- and (S)-1MeTIQ enantiomers. The racemate, (R,S)-1MeTIQ, exhibits neuroprotective activity as shown in the earlier study by the authors, and In addition, it was suggested to play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. In this article, we investigated the influence of stereospecific enantiomers of 1MeTIQ, (R)- and (S)-1MeTIQ (50 mg/kg i.p.) on rotenone-induced (3 mg/kg s.c.) behavioral and neurochemical changes in the rat. In behavioral study, in order to record dynamic motor function of rats, we measured locomotor activity using automated locomotor activity boxes. In biochemical studies, we analyzed in rat striatum the concentration of dopamine (DA) and its metabolites: intraneuronal DOPAC, extraneuronal 3-MT, and final HVA using HPLC with electrochemical detection. Otherwise, DA release was estimated by in vivo microdialysis study. The behavioral study has demonstrated that both acute and repeated (3 times) rotenone administration unimportantly depressed a basic locomotor activity in rat. (R)- and (S)-1MeTIQ stereoisomers (50 mg/kg i.p.) produced a modest behavioral activation both in naïve and rotenone-treated rats. The data from ex vivo neurochemical experiments have shown stereospecificity of 1MeTIQ enantiomers in respect of their effects on DA catabolism. (R)-1MeTIQ significantly increased both the level of the final DA metabolite, HVA (by about 70%), and the rate of DA metabolism (by 50%). In contrast to that, (S)-1MeTIQ significantly depressed DOPAC, HVA levels (by 60 and 40%, respectively), and attenuated the rate of DA metabolism (by about 60%). On the other hand, both the enantiomers increased the concentrations of DA and its extraneuronal metabolite, 3-MT in rat striatum. In vivo microdialysis study has shown that repeated but not acute administration of rotenone produced a deep and significant functional impairment of striatal DA release. Both (R)- and (S)- stereospecific enantiomers of 1MeTIQ antagonized rotenone-induced suppression of DA release; however, the effect of (R)-1MeTIQ was more strongly expressed in microdialysis study. In conclusion, we suggest that both chiral isomers of 1MeTIQ offer neuroprotection against rotenone-induced disturbances in the function of dopaminergic neurons and (R,S)-1MeTIQ will be useful as a drug with marked neuroprotective activity in the brain.
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Affiliation(s)
- Lucyna Antkiewicz-Michaluk
- Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Krakow, Poland.
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