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Gospodaryov DV. Alternative NADH dehydrogenase: A complex I backup, a drug target, and a tool for mitochondrial gene therapy. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2025; 1866:149529. [PMID: 39615731 DOI: 10.1016/j.bbabio.2024.149529] [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: 03/28/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 12/06/2024]
Abstract
Alternative NADH dehydrogenase, also known as type II NADH dehydrogenase (NDH-2), catalyzes the same redox reaction as mitochondrial respiratory chain complex I. Specifically, it oxidizes reduced nicotinamide adenine dinucleotide (NADH) while simultaneously reducing ubiquinone to ubiquinol. However, unlike complex I, this enzyme is non-proton pumping, comprises of a single subunit, and is resistant to rotenone. Initially identified in bacteria, fungi and plants, NDH-2 was subsequently discovered in protists and certain animal taxa including sea squirts. The gene coding for NDH-2 is also present in the genomes of some annelids, tardigrades, and crustaceans. For over two decades, NDH-2 has been investigated as a potential substitute for defective complex I. In model organisms, NDH-2 has been shown to ameliorate a broad spectrum of conditions associated with complex I malfunction, including symptoms of Parkinson's disease. Recently, lifespan extension has been observed in animals expressing NDH-2 in a heterologous manner. A variety of mechanisms have been put forward by which NDH-2 may extend lifespan. Such mechanisms include the activation of pro-longevity pathways through modulation of the NAD+/NADH ratio, decreasing production of reactive oxygen species (ROS) in mitochondria, or then through moderate increases in ROS production followed by activation of defense pathways (mitohormesis). This review gives an overview of the latest research on NDH-2, including the structural peculiarities of NDH-2, its inhibitors, its role in the pathogenicity of mycobacteria and apicomplexan parasites, and its function in bacteria, fungi, and animals.
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Affiliation(s)
- Dmytro V Gospodaryov
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenka, 76018, Ivano-Frankivsk, Ukraine.
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Subhan I, Siddique YH. Effect of Rotenone on the Neurodegeneration among Different Models. Curr Drug Targets 2024; 25:530-542. [PMID: 38698744 DOI: 10.2174/0113894501281496231226070459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/31/2023] [Accepted: 11/08/2023] [Indexed: 05/05/2024]
Abstract
Rotenone is a naturally occurring plant product used as an insecticide, pesticide and piscicide. It is lipophilic in nature and can cross the blood-brain barrier and induce the degeneration of neurons. It inhibits the mitochondrial respiratory chain complex I and stops the transfer of electrons. It induces ROS generation, which impairs mitochondrial activity. Rotenone is a toxic agent which causes the death of neurons. The present review describes the effect of rotenone on neurodegeneration with an emphasis on behavioral, pathological and neuropathological components carried out on various experimental models such as cell lines, Drosophila melanogaster, mice and rats.
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Affiliation(s)
- Iqra Subhan
- Laboratory of Alternative Animal Models, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India
| | - Yasir Hasan Siddique
- Laboratory of Alternative Animal Models, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India
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Vibrio cholerae Porin OmpU Activates Dendritic Cells via TLR2 and the NLRP3 Inflammasome. Infect Immun 2023; 91:e0033222. [PMID: 36794951 PMCID: PMC9933687 DOI: 10.1128/iai.00332-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
OmpU is one of the major porins of Vibrio cholerae, a Gram-negative human pathogen. Previously, we showed that OmpU stimulates host monocytes and macrophages and induces the production of proinflammatory mediators via activation of the Toll-like receptor 1/2 (TLR1/2)-MyD88-dependent pathways. In the present study, we show that OmpU activates murine dendritic cells (DCs) via activation of the TLR2-mediated pathway and the NLRP3 inflammasome, leading to the production of proinflammatory cytokines and DC maturation. Our data reveal that although TLR2 plays an important role in providing both priming and the activation signal for the NLRP3 inflammasome in OmpU-activated DCs, OmpU is capable of activating the NLRP3 inflammasome, even in the absence of TLR2, if a priming signal is given. Furthermore, we show that the OmpU-mediated interleukin-1β (IL-1β) production in DCs depends on calcium flux and mitochondrial reactive oxygen species (mitoROS) generation. Interestingly, both OmpU translocation to the mitochondria of DCs as well as calcium signaling contribute to mitoROS production and prompt NLRP3 inflammasome activation. We also demonstrate that OmpU induces downstream signaling via activation of phosphoinositide-3-kinase (PI3K)-AKT, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and transcription factor NF-κB. Furthermore, our data reveal that OmpU-mediated activation of TLR2 induces signaling via PKC, MAPKs p38 and extracellular signal-regulated kinase (ERK), and transcription factor NF-κB; however, PI3K and MAPK Jun N-terminal protein kinase (JNK) are activated in TLR2 independent manner.
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Jain J, Hasan W, Biswas P, Yadav RS, Jat D. Neuroprotective effect of quercetin against rotenone-induced neuroinflammation and alterations in mice behavior. J Biochem Mol Toxicol 2022; 36:e23165. [PMID: 35822592 DOI: 10.1002/jbt.23165] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 04/07/2022] [Accepted: 07/01/2022] [Indexed: 11/08/2022]
Abstract
Various studies suggested that neuroinflammation leads to the development of several neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Rotenone is an organic pesticide and potent inhibitor of complex I of electron transport chain widely used to develop the PD model. Numerous studies reported rotenone toxicity in the dopaminergic system but very few studies are available on rotenone-induced glial cell activation and subsequent neurodegeneration and alterations in various types of behavior. Therefore, the present study was designed to explore the effect of rotenone on neuroinflammation and its deleterious effect on the behavior of mice, and also how these effects can be protected through quercetin. Quercetin, a natural flavonoid having strong antioxidant and anti-inflammatory properties, is found in vegetables and fruits. The finding of the study indicated that rotenone 5 mg/kg body weight for 60 days through oral gavage leads to the release of inflammatory markers in blood serum, astrocytes activation in substantia nigra and hippocampus, and subsequently decreased density of dopaminergic fibers in the striatum. Rotenone also altered the memory of the mice as indicated by decreased spontaneous alteration in Y-maze and T-maze tests and reduction in exploration time in novel object recognition, increased immobility time in the forced swim test and reduced muscular strength. Co-treatment of quercetin 30 mg/kg/day through oral gavage for 60 days along with rotenone significantly reversed all these adverse effects, suggesting that quercetin could reduce neuroinflammation, and improve memory, and cognitive function.
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Affiliation(s)
- Juli Jain
- Neuroscience Research Lab, Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India
| | - Whidul Hasan
- Neuroscience Research Lab, Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India
| | - Pronit Biswas
- Department of Criminology and Forensic Science, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India
| | - Rajesh S Yadav
- Department of Criminology and Forensic Science, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India
| | - Deepali Jat
- Neuroscience Research Lab, Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India
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Amara I, Ontario ML, Scuto M, Lo Dico GM, Sciuto S, Greco V, Abid-Essefi S, Signorile A, Salinaro AT, Calabrese V. Moringa oleifera Protects SH-SY5YCells from DEHP-Induced Endoplasmic Reticulum Stress and Apoptosis. Antioxidants (Basel) 2021; 10:532. [PMID: 33805396 PMCID: PMC8065568 DOI: 10.3390/antiox10040532] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/23/2021] [Accepted: 03/19/2021] [Indexed: 12/29/2022] Open
Abstract
Moringa oleifera (MO) is a medicinal plant that has been shown to possess antioxidant, anticarcinogenic and antibiotic activities. In a rat model, MO extract (MOe) has been shown to have a protective effect against brain damage and memory decline. As an extending study, here, we have examined the protective effect of MOe against oxidative stress and apoptosis caused in human neuroblastome (SH-SY5Y) cells by di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to induce neurotoxicity. Our data show that MOe prevents oxidative damage by lowering reactive oxygen species (ROS) formation, restoring mitochondrial respiratory chain complex activities, and, in addition, by modulating the expression of vitagenes, i.e., antioxidant proteins Nrf2 and HO-1. Moreover, MOe prevented neuronal damage by partly inhibiting endoplasmic reticulum (ER) stress response, as indicated by decreased expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and Glucose-regulated protein 78 (GRP78) proteins. MOe also protected SH-SY5Y cells from DEHP-induced apoptosis, preserving mitochondrial membrane permeability and caspase-3 activation. Our findings provide insight into understanding of molecular mechanisms involved in neuroprotective effects by MOe against DEHP damage.
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Affiliation(s)
- Ines Amara
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
- Laboratory for Research on Biologically Compatible Compounds, Faculty of Dental Medicine, University of Monastir, Rue Avicenne, Monastir 5019, Tunisia;
| | - Maria Laura Ontario
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
| | - Maria Scuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Gianluigi Maria Lo Dico
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
| | - Sebastiano Sciuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
| | - Valentina Greco
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
| | - Salwa Abid-Essefi
- Laboratory for Research on Biologically Compatible Compounds, Faculty of Dental Medicine, University of Monastir, Rue Avicenne, Monastir 5019, Tunisia;
| | - Anna Signorile
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Angela Trovato Salinaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy; (I.A.); (M.L.O.); (M.S.); (G.M.L.D.); (S.S.); (V.G.); (V.C.)
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Folbergrová J, Ješina P, Otáhal J. Treatment With Resveratrol Ameliorates Mitochondrial Dysfunction During the Acute Phase of Status Epilepticus in Immature Rats. Front Neurosci 2021; 15:634378. [PMID: 33746702 PMCID: PMC7973046 DOI: 10.3389/fnins.2021.634378] [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: 12/01/2020] [Accepted: 02/11/2021] [Indexed: 12/29/2022] Open
Abstract
The aim of the present study was to elucidate the effect of resveratrol (natural polyphenol) on seizure activity, production of ROS, brain damage and mitochondrial function in the early phase of status epilepticus (SE), induced in immature 12 day-old rats by substances of a different mechanism of action (Li-pilocarpine, DL-homocysteic acid, 4-amino pyridine, and kainate). Seizure activity, production of superoxide anion, brain damage and mitochondrial function were assessed by EEG recordings, hydroethidium method, FluoroJadeB staining and Complex I activity measurement. A marked decrease of complex I activity associated with the acute phase of SE in immature brain was significantly attenuated by resveratrol, given i.p. in two or three doses (25 mg/kg each), 30 min before, 30 or 30 and 60 min after the induction of SE. Increased O2.– production was completely normalized, brain damage partially attenuated. Since resveratrol did not influence seizure activity itself (latency, intensity, frequency), the mechanism of protection is likely due to its antioxidative properties. The findings have a clinical relevance, suggesting that clinically available substances with antioxidant properties might provide a high benefit as an add-on therapy during the acute phase of SE, influencing also mechanisms involved in the development of epilepsy.
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Affiliation(s)
| | - Pavel Ješina
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Jakub Otáhal
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
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Flampouri E. Agrochemicals inhibiting mitochondrial respiration: Their effects on oxidative stress. Toxicology 2021. [DOI: 10.1016/b978-0-12-819092-0.00001-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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J B, Das A, Sakthivel KM. Anthraquinone from Edible Fungi Pleurotus ostreatus Protects Human SH-SY5Y Neuroblastoma Cells Against 6-Hydroxydopamine-Induced Cell Death-Preclinical Validation of Gene Knockout Possibilities of PARK7, PINK1, and SNCA1 Using CRISPR SpCas9. Appl Biochem Biotechnol 2019; 191:555-566. [PMID: 31820379 DOI: 10.1007/s12010-019-03188-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 11/11/2019] [Indexed: 10/25/2022]
Abstract
Parkinson's disease (PD) results from the degeneration of the nervous tissue brought about by ecological and hereditary components which affects nerve cells in the brain. It is the world's second most normal neurodegenerative issue, which can essentially weaken the personal satisfaction, make reliance, and trigger untimely mortality of affected people. The commonness pace of PD is 0.5-1% among individuals in the age group of 65-69 years and 1-3% among those 80 or more. Clinical appearances incorporate bradykinesia, tremors, unbending nature, and postural unsteadiness; spectrums of non-motor symptoms include psychological hindrance and passionate and behavioral brokenness. In this study, 6-OHDA-induced neurotoxicity was analyzed for various cytotoxicity analyses. The genes identified were PINK1 (PTEN-induced kinase 1), PARK7 (Parkinsonism-associated deglycase) and SNCA 1 (alpha synuclein1) validated using CRISPR spcas9 genome editing tool. In this study, Anthraquinone isolated from Pleurotus ostreatus was treated against a dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA), which induced neurotoxicity in SH-SY5Y cells. Experimental groups in SH-SY5Y neuroblastoma cells were treated with anthraquinone (50 nM) and 6-OHDA (100 nM). MTT and ROS assays were performed to assess the cell viability and oxidative stress within the cells, followed by mixed-member proportional (Mitochondrial membrane potential), dual staining, and immunoblotting. 6-OHDA-induced cell death in SH-SY5Y cells was dose-dependently attenuated by treatment with anthraquinone. The genes responsible for mutation were studied and the mutated RNAs knockout possibilities was studied using CRISPR spcas9 genome editing tool. Treatment with anthraquinone attenuated the level of oxidative stress and reduced the mitochondrial dysfunction associated with 6-OHDA treatment. Immunoblot analysis carried out with apoptotic markers showed that cytochrome C and caspase-3 expression increased significantly in anthraquinone-treated cells, whereas 6-OHDA-treated group showed a significant decrease when compared with an experimental control group. The mutated genes PARK7, PINK1, and SNCA1 were analyzed and found to exhibit four gene knock possibilities to treat PD. Reports demonstrate that other than following up on the biosynthesis of dopamine and its metabolites, these mixes counteract D2 receptors' extreme touchiness. It is proposed that further examinations need be directed to better understand the activity of the bioactive mixes circulated in these edible fungi Pleurotus ostreatus. The gene knockout possibilities identified by CRISPR SpCas9 will pave a way for better research for PD treatment.
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Affiliation(s)
- Bindhu J
- Molecular Diagnostics and Bacterial Pathogenomics Research Laboratory, Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, 638401, India
| | - Arunava Das
- Molecular Diagnostics and Bacterial Pathogenomics Research Laboratory, Department of Biotechnology, Bannari Amman Institute of Technology, Sathyamangalam, 638401, India.
| | - K M Sakthivel
- Department of Biochemistry, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore, 641014, India
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Kim SH, Park JW. Morin hydrate attenuates CSE-induced lipid accumulation, ER stress, and oxidative stress in RPE cells: implications for age-related macular degeneration. Free Radic Res 2019; 53:865-874. [PMID: 31257945 DOI: 10.1080/10715762.2019.1637862] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 06/13/2019] [Accepted: 06/17/2019] [Indexed: 01/19/2023]
Abstract
Oxidative stress has a key role in the pathogenesis of age-related macular degeneration (AMD). Cigarette smoking is known to the one of the main risk factors of AMD through oxidative stress-mediated endoplasmic reticulum (ER) stress and lipid accumulation in human retinal pigment epithelium (RPE) cells. A number of studies have investigated the benefits of antioxidants in the AMD. However, previous studies have not shown that efficacy of antioxidant in the treatment of AMD. Recent studies demonstrated that morin hydrate (MH) has antioxidant properties, anti-inflammatory, and antiapoptosis effects, however, the protective effects of MH against cigarette smoke extract (CSE)-induced AMD have not been studied in detail. We tested the potential effect of MH against the CSE-induced lipid accumulation in RPE cells and mice RPE layer. Herein, we observed that expose of RPE cells to CSE reduced cell viability, increased the lipid accumulation, ER stress, and oxidative stress. Concomitantly, CSE treatment to mice induced AMD associated histopathological changes, lipid accumulation, ER stress and oxidative stress in RPE layer. MH significantly attenuated cytotoxicity, lipid accumulation, ER stress, and oxidative stress via activated AMPK-Nrf2 signaling pathway in RPE cells and mice RPE layer. In addition, AMPK inhibition reversed MH-induced RPE cell protection against CSE. Thus, we conclude that MH protects RPE cells from CSE through reduced oxidative stress, ER stress, and lipid accumulation via activated AMPK-Nrf2-HO-1 signaling pathway. These findings suggest that MH treatment may be exploited in effective strategy against CSE-induced AMD.
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Affiliation(s)
- Sung Hwan Kim
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University , Daegu , Korea
| | - Jeen-Woo Park
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University , Daegu , Korea
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Hatamipour M, Ramezani M, Tabassi SAS, Johnston TP, Sahebkar A. Demethoxycurcumin: A naturally occurring curcumin analogue for treating non-cancerous diseases. J Cell Physiol 2019; 234:19320-19330. [PMID: 31344992 DOI: 10.1002/jcp.28626] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/17/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023]
Abstract
Turmeric extracts contain three primary compounds, which are commonly referred to as curcuminoids. They are curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin. While curcumin has been the most extensively studied of the curcuminoids, it suffers from low overall oral bioavailability due to extremely low absorption as a result of low water solubility and instability at acidic pH, as well as rapid metabolism and clearance from the body. However, DMC, which lacks the methoxy group on the benzene ring of the parent structure, has much greater chemical stability at physiological pH and has been recently reported to exhibit antitumor properties. However, the treatment of noncancerous diseases with DMC has not been comprehensively reviewed. Therefore, here we evaluate published scientific literature on the therapeutic properties of DMC. The beneficial pharmacological actions of DMC include anti-inflammatory, neuroprotective, antihypertensive, antimalarial, antimicrobial, antifungal, and vasodilatory properties. In addition, DMC's ability to ameliorate the effects of free radicals and an environment characterized by oxidative stress caused by the accumulation of advanced glycation end-products associated with diabetic nephropathy, as well as DMC's capacity to inhibit the migration and proliferation of vascular smooth muscle cells following balloon angioplasty are also addressed. This review collates the available literature regarding the therapeutic possibilities of DMC in noncancerous conditions.
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Affiliation(s)
- Mahdi Hatamipour
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahin Ramezani
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, Missouri
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Differential Effects of Yeast NADH Dehydrogenase (Ndi1) Expression on Mitochondrial Function and Inclusion Formation in a Cell Culture Model of Sporadic Parkinson's Disease. Biomolecules 2019; 9:biom9040119. [PMID: 30934776 PMCID: PMC6523508 DOI: 10.3390/biom9040119] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/14/2019] [Accepted: 03/16/2019] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that exhibits aberrant protein aggregation and mitochondrial dysfunction. Ndi1, the yeast mitochondrial NADH dehydrogenase (complex I) enzyme, is a single subunit, internal matrix-facing protein. Previous studies have shown that Ndi1 expression leads to improved mitochondrial function in models of complex I-mediated mitochondrial dysfunction. The trans-mitochondrial cybrid cell model of PD was created by fusing mitochondrial DNA-depleted SH-SY5Y cells with platelets from a sporadic PD patient. PD cybrid cells reproduce the mitochondrial dysfunction observed in a patient's brain and periphery and form intracellular, cybrid Lewy bodies comparable to Lewy bodies in PD brain. To improve mitochondrial function and alter the formation of protein aggregates, Ndi1 was expressed in PD cybrid cells and parent SH-SY5Y cells. We observed a dramatic increase in mitochondrial respiration, increased mitochondrial gene expression, and increased PGC-1α gene expression in PD cybrid cells expressing Ndi1. Total cellular aggregated protein content was decreased but Ndi1 expression was insufficient to prevent cybrid Lewy body formation. Ndi1 expression leads to improved mitochondrial function and biogenesis signaling, both processes that could improve neuron survival during disease. However, other aspects of PD pathology such as cybrid Lewy body formation were not reduced. Consequently, resolution of mitochondrial dysfunction alone may not be sufficient to overcome other aspects of PD-related cellular pathology.
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Prasad GVRK, Dhar V, Mukhopadhaya A. Vibrio cholerae OmpU Mediates CD36-Dependent Reactive Oxygen Species Generation Triggering an Additional Pathway of MAPK Activation in Macrophages. THE JOURNAL OF IMMUNOLOGY 2019; 202:2431-2450. [PMID: 30867241 DOI: 10.4049/jimmunol.1800389] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 02/06/2019] [Indexed: 01/18/2023]
Abstract
OmpU, one of the porins of Gram-negative bacteria Vibrio cholerae, induces TLR1/2-MyD88-NF-κB-dependent proinflammatory cytokine production by monocytes and macrophages of human and mouse origin. In this study, we report that in both the cell types, OmpU-induced proinflammatory responses involve activation of MAPKs (p38 and JNK). Interestingly, we observed that in OmpU-treated macrophages, p38 activation is TLR2 dependent, but JNK activation happens through a separate pathway involving reactive oxygen species (ROS) generation by NADPH oxidase complex and mitochondrial ROS. Further, we observed that OmpU-mediated mitochondrial ROS generation probably depends on OmpU translocation to mitochondria and NADPH oxidase-mediated ROS production is due to activation of scavenger receptor CD36. For the first time, to our knowledge, we are reporting that a Gram-negative bacterial protein can activate CD36 as a pattern recognition receptor. Additionally, we found that in OmpU-treated monocytes, both JNK and p38 activation is linked to the TLR2 activation only. Therefore, the ability of macrophages to employ multiple receptors such as TLR2 and CD36 to recognize a single ligand, as in this case OmpU, probably explains the very basic nature of macrophages being more proinflammatory than monocytes.
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Affiliation(s)
- G V R Krishna Prasad
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, 140306 Punjab, India
| | - Vinica Dhar
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, 140306 Punjab, India
| | - Arunika Mukhopadhaya
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, 140306 Punjab, India
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Alternative NAD(P)H dehydrogenase and alternative oxidase: Proposed physiological roles in animals. Mitochondrion 2019; 45:7-17. [DOI: 10.1016/j.mito.2018.01.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 11/01/2017] [Accepted: 01/26/2018] [Indexed: 12/12/2022]
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Antos-Krzeminska N, Jarmuszkiewicz W. Alternative Type II NAD(P)H Dehydrogenases in the Mitochondria of Protists and Fungi. Protist 2018; 170:21-37. [PMID: 30553126 DOI: 10.1016/j.protis.2018.11.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/12/2018] [Accepted: 11/04/2018] [Indexed: 01/11/2023]
Abstract
Plants, fungi, and some protists possess a more branched electron transport chain in their mitochondria compared to canonical one. In these organisms, the electron transport chain contains several rotenone-insensitive NAD(P)H dehydrogenases. Some are located on the outer surface, and others are located on the inner surface of the inner mitochondrial membrane. The putative role of these enzymes still remains elusive, but they may prevent the overreduction of the electron transport chain components and decrease the production of reaction oxygen species as a consequence. The last two decades resulted in the discovery of alternative rotenone-insensitive NAD(P)H dehydrogenases present in representatives of fungi and protozoa. The aim of this review is to gather and focus on current information concerning molecular and functional properties, regulation, and the physiological role of fungal and protozoan alternative NAD(P)H dehydrogenases.
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Affiliation(s)
- Nina Antos-Krzeminska
- Department of Bioenergetics, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, Poland.
| | - Wieslawa Jarmuszkiewicz
- Department of Bioenergetics, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, Poland
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Baptiste BA, Katchur SR, Fivenson EM, Croteau DL, Rumsey WL, Bohr VA. Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention. Free Radic Biol Med 2018; 124:149-162. [PMID: 29879444 PMCID: PMC6098717 DOI: 10.1016/j.freeradbiomed.2018.05.094] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/30/2018] [Accepted: 05/31/2018] [Indexed: 12/22/2022]
Abstract
The common oxidatively generated lesion, 8-oxo-7,8-dihydroguanine (8-oxoGua), is removed from DNA by base excision repair. The glycosylase primarily charged with recognition and removal of this lesion is 8-oxoGuaDNA glycosylase 1 (OGG1). When left unrepaired, 8-oxodG alters transcription and is mutagenic. Individuals homozygous for the less active OGG1 allele, Ser326Cys, have increased risk of several cancers. Here, small molecule enhancers of OGG1 were identified and tested for their ability to stimulate DNA repair and protect cells from the environmental hazard paraquat (PQ). PQ-induced mtDNA damage was inversely proportional to the levels of OGG1 expression whereas stimulation of OGG1, in some cases, entirely abolished its cellular effects. The PQ-mediated decline of mitochondrial membrane potential or nuclear condensation were prevented by the OGG1 activators. In addition, in Ogg1-/- mouse embryonic fibroblasts complemented with hOGG1S326C, there was increased cellular and mitochondrial reactive oxygen species compared to their wild type counterparts. Mitochondrial extracts from cells expressing hOGG1S326C were deficient in mitochondrial 8-oxodG incision activity, which was rescued by the OGG1 activators. These data demonstrate that small molecules can stimulate OGG1 activity with consequent cellular protection. Thus, OGG1-activating compounds may be useful in select humans to mitigate the deleterious effects of environmental oxidants and mutagens.
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Affiliation(s)
- Beverly A Baptiste
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Steven R Katchur
- Respiratory Therapy Area, GSK R&D, Collegeville, PA, United States
| | - Elayne M Fivenson
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Deborah L Croteau
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - William L Rumsey
- Respiratory Therapy Area, GSK R&D, Collegeville, PA, United States
| | - Vilhelm A Bohr
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.
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Folbergrová J, Ješina P, Kubová H, Otáhal J. Effect of Resveratrol on Oxidative Stress and Mitochondrial Dysfunction in Immature Brain during Epileptogenesis. Mol Neurobiol 2018; 55:7512-7522. [PMID: 29427088 DOI: 10.1007/s12035-018-0924-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 01/22/2018] [Indexed: 01/04/2023]
Abstract
The presence of oxidative stress in immature brain has been demonstrated during the acute phase of status epilepticus (SE). The knowledge regarding the long periods of survival after SE is not unequivocal, lacking direct evidence. To examine the presence and time profile of oxidative stress, its functional effect on mitochondria and the influence of an antioxidant treatment in immature rats during epileptogenesis, status epilepticus (SE) was induced in immature 12-day-old rats by Li-pilocarpine and at selected periods of the epileptogenesis; rat pups were subjected to examinations. Hydroethidine method was employed for detection of superoxide anion (O2.-), 3-nitrotyrosine (3-NT), and 4-hydroxynonenal (4-HNE) for oxidative damage of mitochondrial proteins and complex I activity for mitochondrial function. Natural polyphenolic antioxidant resveratrol was given in two schemes: "acute treatment," i.p. administration 30 min before, 30 and 60 min after induction of SE and "full treatment" when applications continued once daily for seven consecutive days (25 mg/kg each dose). The obtained results clearly document that the period of epileptogenesis studied (up to 4 weeks) in immature brain is associated with the significant enhanced production of O2.-, the increased levels of 3-NT and 4-HNE and the persisting deficiency of complex I activity. Application of resveratrol either completely prevented or significantly reduced markers both of oxidative stress and mitochondrial dysfunction. The findings suggest that targeting oxidative stress in combination with current antiepileptic therapies may provide a benefit in the treatment of epilepsy.
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Affiliation(s)
- Jaroslava Folbergrová
- Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic.
| | - Pavel Ješina
- Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic
| | - Hana Kubová
- Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic
| | - Jakub Otáhal
- Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic
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Katoh M, Wu B, Nguyen HB, Thai TQ, Yamasaki R, Lu H, Rietsch AM, Zorlu MM, Shinozaki Y, Saitoh Y, Saitoh S, Sakoh T, Ikenaka K, Koizumi S, Ransohoff RM, Ohno N. Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation. Sci Rep 2017; 7:4942. [PMID: 28694451 PMCID: PMC5503944 DOI: 10.1038/s41598-017-05232-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 05/25/2017] [Indexed: 12/18/2022] Open
Abstract
Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models. Mouse cerebral microglia in vitro demonstrated that stimulation of TLR4 with lipopolysaccharide, widely used to examine microglial reactions, caused the activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) and enhanced production of reactive oxygen species (ROS). The increase in the ROS level activated 5' adenosine monophosphate-activated protein kinase (AMPK), and facilitated elongation of mitochondria along the microtubule tracks. These results suggest that the polymorphic regulation of mitochondrial fission and fusion in reactive microglia is mediated by distinct signaling under inflammatory conditions, and modulates microglial phenotypes through the production of ROS.
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Affiliation(s)
- Mitsuhiko Katoh
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Bao Wu
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.,Department of Histology and Embryology, Medical College of Chifeng University, Inner Mongolia, 024000, China
| | - Huy Bang Nguyen
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Truc Quynh Thai
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Ryo Yamasaki
- Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Haiyan Lu
- Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Anna M Rietsch
- Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Musab M Zorlu
- Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Youichi Shinozaki
- Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Yurika Saitoh
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Sei Saitoh
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Takashi Sakoh
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Kazuhiro Ikenaka
- Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8787, Japan
| | - Schuichi Koizumi
- Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Richard M Ransohoff
- Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Nobuhiko Ohno
- Departments of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan. .,Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8787, Japan.
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Ramkumar M, Rajasankar S, Gobi VV, Dhanalakshmi C, Manivasagam T, Justin Thenmozhi A, Essa MM, Kalandar A, Chidambaram R. Neuroprotective effect of Demethoxycurcumin, a natural derivative of Curcumin on rotenone induced neurotoxicity in SH-SY 5Y Neuroblastoma cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:217. [PMID: 28420370 PMCID: PMC5395846 DOI: 10.1186/s12906-017-1720-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 04/04/2017] [Indexed: 12/17/2022]
Abstract
Background Mitochondrial dysfunction and oxidative stress are the main toxic events leading to dopaminergic neuronal death in Parkinson’s disease (PD) and identified as vital objective for therapeutic intercession. This study investigated the neuro-protective effects of the demethoxycurcumin (DMC), a derivative of curcumin against rotenone induced neurotoxicity. Methods SH-SY5Y neuroblastoma cells are divided into four experimental groups: untreated cells, cells incubated with rotenone (100 nM), cells treated with DMC (50 nM) + rotenone (100 nM) and DMC alone treated. 24 h after treatment with rotenone and 28 h after treatment with DMC, cell viability was assessed using the MTT assay, and levels of ROS and MMP, plus expression of apoptotic protein were analysed. Results Rotenone induced cell death in SH-SY5Y cells was significantly reduced by DMC pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of DMC. Rotenone treatment significantly increases the levels of ROS, loss of MMP, release of Cyt-c and expression of pro-apoptotic markers and decreases the expression of anti-apoptotic markers. Conclusions Even though the results of the present study indicated that the DMC may serve as a potent therapeutic agent particularly for the treatment of neurodegenerative diseases like PD, further pre-clinical and clinical studies are required. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1720-5) contains supplementary material, which is available to authorized users.
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Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2017; 29:92-97. [DOI: 10.1016/j.arteri.2016.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 03/30/2016] [Accepted: 04/05/2016] [Indexed: 12/26/2022]
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Le Borgne F, Ravaut G, Bernard A, Demarquoy J. L-carnitine protects C2C12 cells against mitochondrial superoxide overproduction and cell death. World J Biol Chem 2017; 8:86-94. [PMID: 28289521 PMCID: PMC5329717 DOI: 10.4331/wjbc.v8.i1.86] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/04/2016] [Accepted: 12/13/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To identify and characterize the protective effect that L-carnitine exerted against an oxidative stress in C2C12 cells. METHODS Myoblastic C2C12 cells were treated with menadione, a vitamin K analog that engenders oxidative stress, and the protective effect of L-carnitine (a nutrient involved in fatty acid metabolism and the control of the oxidative process), was assessed by monitoring various parameters related to the oxidative stress, autophagy and cell death. RESULTS Associated with its physiological function, a muscle cell metabolism is highly dependent on oxygen and may produce reactive oxygen species (ROS), especially under pathological conditions. High levels of ROS are known to induce injuries in cell structure as they interact at many levels in cell function. In C2C12 cells, a treatment with menadione induced a loss of transmembrane mitochondrial potential, an increase in mitochondrial production of ROS; it also induces autophagy and was able to provoke cell death. Pre-treatment of the cells with L-carnitine reduced ROS production, diminished autophagy and protected C2C12 cells against menadione-induced deleterious effects. CONCLUSION In conclusion, L-carnitine limits the oxidative stress in these cells and prevents cell death.
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Zhou MC, Zhu L, Cui X, Feng L, Zhao X, He S, Ping F, Li W, Li Y. Reduced peripheral blood mtDNA content is associated with impaired glucose-stimulated islet β cell function in a Chinese population with different degrees of glucose tolerance. Diabetes Metab Res Rev 2016; 32:768-774. [PMID: 27103506 PMCID: PMC5108437 DOI: 10.1002/dmrr.2814] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 02/17/2016] [Accepted: 04/13/2016] [Indexed: 12/15/2022]
Abstract
AIMS Our aim is to explore the associations between mitochondrial DNA (mtDNA) content and basal plasma glucose, plasma glucose after oral glucose administration and oxidative stress in a Chinese population with different levels of glucose tolerance. We also aimed to investigate the effect of mtDNA content on basal and oral glucose-stimulated insulin secretion. METHODS Five hundred and fifty-six Chinese subjects underwent a 75-g, 2-h oral glucose tolerance test. Subjects with diabetes (n = 159), pre-diabetes (n = 197) and normal glucose tolerance (n = 200) were screened. Blood lipid profile was assessed, and levels of the oxidative stress indicators superoxide dismutase, glutathione reductase (GR) and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Levels of HbA1c , plasma glucose, insulin and C-peptide were also determined. Measurements were taken at 0, 30, 60 and 120 min after 75 g oral glucose tolerance test. Peripheral blood mtDNA content was assessed using a real-time polymerase chain reaction assay. Insulin sensitivity was evaluated by homeostatic model assessment of insulin resistance and Matsuda index (ISIM ). Basal insulin secretion index (HOMA-β), early phase disposition index (DI30 ) and total phase disposition index (DI120 ) indicate insulin levels at different phases of insulin secretion. RESULTS Peripheral blood mtDNA content was positively associated with DI30 and DI120 and was negatively associated with plasma glucose measured 30, 60 and 120 min after oral glucose administration. However, there was no correlation between mtDNA content and basal insulin secretion (HOMA-β), serum lipid or oxidative stress indicators (8-oxo-dG, superoxide dismutase, GR). HbA1c was negatively associated with GR (r = -0.136, p = 0.001). Multiple linear regression analysis showed that reduced peripheral blood mtDNA content increased the risk of impaired glucose-stimulated β cell function (DI30 : β = 0.104, p = 0.019; DI120 : β = 0.116, p = 0.009). CONCLUSIONS Decreased peripheral blood mtDNA content was more closely associated with glucose-stimulated insulin secretion than with basal secretion. Reduction in glucose-stimulated insulin secretion causes postprandial hyperglycaemia. The oxidative stress was probably largely influenced by hyperglycaemia; it was probably that the decreased mt DNA content led to hyperglycaemia, which caused elevated oxidative stress. © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.
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Affiliation(s)
- Mei-Cen Zhou
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China
| | - Lixin Zhu
- Nankou Community Health Service Centers, Beijing, China
| | - Xiangli Cui
- Nankou Community Health Service Centers, Beijing, China
| | | | | | - Shuli He
- Department of Nutrition, Peking Union Medical College Hospital, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China.
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Folbergrová J, Ješina P, Kubová H, Druga R, Otáhal J. Status Epilepticus in Immature Rats Is Associated with Oxidative Stress and Mitochondrial Dysfunction. Front Cell Neurosci 2016; 10:136. [PMID: 27303267 PMCID: PMC4881382 DOI: 10.3389/fncel.2016.00136] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 05/10/2016] [Indexed: 01/01/2023] Open
Abstract
Epilepsy is a neurologic disorder, particularly frequent in infants and children where it can lead to serious consequences later in life. Oxidative stress and mitochondrial dysfunction are implicated in the pathogenesis of many neurological disorders including epilepsy in adults. However, their role in immature epileptic brain is unclear since there have been two contrary opinions: oxidative stress is age-dependent and does not occur in immature brain during status epilepticus (SE) and, on the other hand, evidence of oxidative stress in immature brain during a specific model of SE. To solve this dilemma, we have decided to investigate oxidative stress following SE induced in immature 12-day-old rats by three substances with a different mechanism of action, namely 4-aminopyridine, LiCl-pilocarpine or kainic acid. Fluoro-Jade-B staining revealed mild brain damage especially in hippocampus and thalamus in each of the tested models. Decrease of glucose and glycogen with parallel rises of lactate clearly indicate high rate of glycolysis, which was apparently not sufficient in 4-AP and Li-Pilo status, as evident from the decreases of PCr levels. Hydroethidium method revealed significantly higher levels of superoxide anion (by ∼60%) in the hippocampus, cerebral cortex and thalamus of immature rats during status. SE lead to mitochondrial dysfunction with a specific pronounced decrease of complex I activity that persisted for a long period of survival. Complexes II and IV activities remained in the control range. Antioxidant treatment with SOD mimetic MnTMPYP or peroxynitrite scavenger FeTPPS significantly attenuated oxidative stress and inhibition of complex I activity. These findings bring evidence that oxidative stress and mitochondrial dysfunction are age and model independent, and may thus be considered a general phenomenon. They can have a clinical relevance for a novel approach to the treatment of epilepsy, allowing to target the mechanisms which play a crucial or additive role in the pathogenesis of epilepsies in infants and children.
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Van Laar VS, Berman SB, Hastings TG. Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone. Neurobiol Dis 2016; 91:247-61. [PMID: 27001148 DOI: 10.1016/j.nbd.2016.03.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 03/04/2016] [Accepted: 03/16/2016] [Indexed: 12/15/2022] Open
Abstract
Mitochondrial dysfunction has been implicated in Parkinson's disease (PD) neuropathology. Mic60, also known as mitofilin, is a protein of the inner mitochondrial membrane and a key component of the mitochondrial contact site and cristae junction organizing system (MICOS). Mic60 is critical for maintaining mitochondrial membrane structure and function. We previously demonstrated that mitochondrial Mic60 protein is susceptible to both covalent modification and loss in abundance following exposure to dopamine quinone. In this study, we utilized neuronally-differentiated SH-SY5Y and PC12 dopaminergic cell lines to examine the effects of altered Mic60 levels on mitochondrial function and cellular vulnerability in response to PD-relevant stressors. Short hairpin RNA (shRNA)-mediated knockdown of endogenous Mic60 protein in neuronal SH-SY5Y cells significantly potentiated dopamine-induced cell death, which was rescued by co-expressing shRNA-insensitive Mic60. Conversely, in PC12 and SH-SY5Y cells, Mic60 overexpression significantly attenuated both dopamine- and rotenone-induced cell death as compared to controls. Mic60 overexpression in SH-SY5Y cells was also associated with increased mitochondrial respiration, and, following rotenone exposure, increased spare respiratory capacity. Mic60 knockdown cells exhibited suppressed respiration and, following rotenone treatment, decreased spare respiratory capacity. Mic60 overexpression also affected mitochondrial fission/fusion dynamics. PC12 cells overexpressing Mic60 exhibited increased mitochondrial interconnectivity. Further, both PC12 cells and primary rat cortical neurons overexpressing Mic60 displayed suppressed mitochondrial fission and increased mitochondrial length in neurites. These results suggest that altering levels of Mic60 in dopaminergic neuronal cells significantly affects both mitochondrial homeostasis and cellular vulnerability to the PD-relevant stressors dopamine and rotenone, carrying implications for PD pathogenesis.
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Affiliation(s)
- Victor S Van Laar
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sarah B Berman
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA
| | - Teresa G Hastings
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA.
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Protective Effect of Tempol on Buthionine Sulfoximine-Induced Mitochondrial Impairment in Hippocampal Derived HT22 Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:5059043. [PMID: 27069531 PMCID: PMC4812466 DOI: 10.1155/2016/5059043] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/05/2016] [Accepted: 02/14/2016] [Indexed: 11/21/2022]
Abstract
Using a simulated oxidative stress model of hippocampus-derived immortalized cell line (HT22), we report that prooxidant buthionine sulfoximine (BSO, 1 mM, 14 h), without adversely affecting cell viability or morphology, induced oxidative stress by inhibiting glutathione synthesis. BSO treatment also significantly reduced superoxide dismutase (SOD) activity (p < 0.05) and significantly lowered total antioxidant capacity (p < 0.001) in HT22 cells when compared to vehicle treated control cells. Antioxidant tempol, a piperidine nitroxide considered a SOD mimetic, reversed BSO-induced decline in SOD activity (p < 0.01) and also increased BSO-induced decline in total antioxidant capacity (p < 0.05). Interestingly, BSO treatment significantly reduced mitochondrial oxygen consumption (p < 0.05), decreased mitochondrial membrane potential (p < 0.05), and lowered ATP production (p < 0.05) when compared to vehicle treated control cells, collectively indicative of mitochondrial impairment. Antioxidant tempol treatment mitigated all three indicators of mitochondrial impairment. We postulate that BSO-induced oxidative stress in HT22 cells caused mitochondrial impairment, and tempol by increasing SOD activity and improving antioxidant capacity presumably protected the cells from BSO-induced mitochondrial impairment. In conclusion, present study provides an interesting simulation of oxidative stress in hippocampal cells, which will serve as an excellent model to study mitochondrial functions.
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Matus-Ortega MG, Cárdenas-Monroy CA, Flores-Herrera O, Mendoza-Hernández G, Miranda M, González-Pedrajo B, Vázquez-Meza H, Pardo JP. New complexes containing the internal alternative NADH dehydrogenase (Ndi1) in mitochondria of Saccharomyces cerevisiae. Yeast 2015; 32:629-41. [PMID: 26173916 DOI: 10.1002/yea.3086] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 06/27/2015] [Accepted: 06/27/2015] [Indexed: 11/07/2022] Open
Abstract
Mitochondria of Saccharomyces cerevisiae lack the respiratory complex I, but contain three rotenone-insensitive NADH dehydrogenases distributed on both the external (Nde1 and Nde2) and internal (Ndi1) surfaces of the inner mitochondrial membrane. These enzymes catalyse the transfer of electrons from NADH to ubiquinone without the translocation of protons across the membrane. Due to the high resolution of the Blue Native PAGE (BN-PAGE) technique combined with digitonin solubilization, several bands with NADH dehydrogenase activity were observed on the gel. The use of specific S. cerevisiae single and double mutants of the external alternative elements (ΔNDE1, ΔNDE2, ΔNDE1/ΔNDE2) showed that the high and low molecular weight complexes contained the Ndi1. Some of the Ndi1 associations took place with complexes III and IV, suggesting the formation of respirasome-like structures. Complex II interacted with other proteins to form a high molecular weight supercomplex with a molecular mass around 600 kDa. We also found that the majority of the Ndi1 was in a dimeric form, which is in agreement with the recently reported three-dimensional structure of the protein.
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Affiliation(s)
- M G Matus-Ortega
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
| | - C A Cárdenas-Monroy
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
| | - O Flores-Herrera
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
| | - G Mendoza-Hernández
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
| | - M Miranda
- Department of Biological Sciences, University of Texas, El Paso, TX, USA
| | - B González-Pedrajo
- Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
| | - H Vázquez-Meza
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
| | - J P Pardo
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán 04510, México, D. F., México
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Gonçalves AP, Videira A. Mitochondrial type II NAD(P)H dehydrogenases in fungal cell death. MICROBIAL CELL 2015; 2:68-73. [PMID: 28357279 PMCID: PMC5349180 DOI: 10.15698/mic2015.03.192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
During aerobic respiration, cells produce energy through oxidative phosphorylation, which includes a specialized group of multi-subunit complexes in the inner mitochondrial membrane known as the electron transport chain. However, this canonical pathway is branched into single polypeptide alternative routes in some fungi, plants, protists and bacteria. They confer metabolic plasticity, allowing cells to adapt to different environmental conditions and stresses. Type II NAD(P)H dehydrogenases (also called alternative NAD(P)H dehydrogenases) are non-proton pumping enzymes that bypass complex I. Recent evidence points to the involvement of fungal alternative NAD(P)H dehydrogenases in the process of programmed cell death, in addition to their action as overflow systems upon oxidative stress. Consistent with this, alternative NAD(P)H dehydrogenases are phylogenetically related to cell death - promoting proteins of the apoptosis-inducing factor (AIF)-family.
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Affiliation(s)
- A Pedro Gonçalves
- ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. ; IBMC-Instituto de Biologia Molecular e Celular - Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. ; Current address: Plant and Microbial Biology Department, The University of California, Berkeley, CA 94720, USA
| | - Arnaldo Videira
- ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. ; IBMC-Instituto de Biologia Molecular e Celular - Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. ; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
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Hong Y, Nie H, Wei X, Fu S, Ying W. NAD+ treatment can prevent rotenone-induced increases in DNA damage, Bax levels and nuclear translocation of apoptosis-inducing factor in differentiated PC12 cells. Neurochem Res 2015; 40:837-42. [PMID: 25813492 DOI: 10.1007/s11064-015-1534-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Revised: 01/27/2015] [Accepted: 01/30/2015] [Indexed: 12/16/2022]
Abstract
Nicotinamide adenine dinucleotide (NAD(+)) plays critical roles in energy metabolism, mitochondrial functions, calcium homeostasis and immunological functions. Our previous studies have found that NAD(+) administration can profoundly decrease ischemic brain injury and traumatic brain injury. Our recent study has also provided first direct evidence indicating that NAD(+) treatment can decrease cellular apoptosis, while the mechanisms underlying this protective effect remain unclear. In our current study, we determined the effects of NAD(+) treatment on several major factors in apoptosis and necrosis, including levels of Bax and nuclear translocation of apoptosis-inducing factor (AIF), as well as levels of DNA double-strand breaks (DSBs) and intracellular ATP in rotenone-treated differentiated PC12 cells. We found that NAD(+) treatment can markedly attenuate the rotenone-induced increases in the levels of Bax and nuclear translocation of AIF in the cells. We further found that NAD(+) treatment can significantly attenuate the rotenone-induced increase in the levels of DSBs and decrease in the intracellular ATP levels. Collectively, our study has suggested mechanisms underlying the preventive effects of NAD(+) on apoptosis, which has highlighted the therapeutic potential of NAD(+) for decreasing apoptotic changes in multiple major diseases.
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Affiliation(s)
- Yunyi Hong
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, People's Republic of China
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Gospodaryov DV, Lushchak OV, Rovenko BM, Perkhulyn NV, Gerards M, Tuomela T, Jacobs HT. Ciona intestinalis NADH dehydrogenase NDX confers stress-resistance and extended lifespan on Drosophila. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2014; 1837:1861-1869. [DOI: 10.1016/j.bbabio.2014.08.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Revised: 08/04/2014] [Accepted: 08/05/2014] [Indexed: 11/16/2022]
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Response to rotenone is glucose-sensitive in a model of human acute lymphoblastic leukemia: involvement of oxidative stress mechanism, DJ-1, Parkin, and PINK-1 proteins. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:457154. [PMID: 24949116 PMCID: PMC4037627 DOI: 10.1155/2014/457154] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 03/27/2014] [Indexed: 01/24/2023]
Abstract
To establish the effect of low (11 mM) and high (55 mM) glucose concentrations (G11, G55) on Jurkat cells exposed to rotenone (ROT, a class 5 mitocan). We demonstrated that ROT induces apoptosis in Jurkat cells cultured in G11 by oxidative stress (OS) mechanism involving the generation of anion superoxide radical (O2∙−, 68%)/hydrogen peroxide (H2O2, 54%), activation of NF-κB (32%), p53 (25%), c-Jun (17%) transcription factors, and caspase-3 (28%), apoptosis-inducing factor (AIF, 36%) nuclei translocation, c-Jun N-terminal kinase (JNK) activation, and loss of mitochondria transmembrane potential (ΔΨm, 62%) leading to nuclei fragmentation (~10% and ~40% stage I-II fragmented nuclei, resp.). ROT induces massive cytoplasmic aggregates of DJ-1 (93%), and upregulation of Parkin compared to untreated cells, but no effect on PINK-1 protein was observed. Cell death marker detection and DJ-1 and Parkin expression were significantly reduced when cells were cultured in G55 plus ROT. Remarkably, metformin sensitized Jurkat cells against ROT in G55. Our results indicate that a high-glucose milieu promotes resistance against ROT/H2O2-induced apoptosis in Jurkat cells. Our data suggest that combined therapy by using mitochondria-targeted damaging compounds and regulation of glucose (e.g., metformin) can efficiently terminate leukemia cells via apoptosis in hyperglycemic conditions.
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30
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Zou T, Tang X, Huang Z, Xu N, Hu Z. The Pael-R gene does not mediate the changes in rotenone-induced Parkinson's disease model cells. Neural Regen Res 2014; 9:402-6. [PMID: 25206827 PMCID: PMC4146201 DOI: 10.4103/1673-5374.128245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2014] [Indexed: 11/04/2022] Open
Abstract
In this study, we established cell models for Parkinson's disease using rotenone. An RNA interference vector targeting Parkin-associated endothelin receptor-like receptor (Pael-R) was transfected into the model cells. The results of reverse-transcription polymerase chain reaction and western blot analysis showed that Pael-R expression was decreased after RNA interference compared with the control group (no treatment) and the model group (rotenone treatment), while the rate of apoptosis and survival of dopaminergic cells did not differ significantly between groups, as detected by flow cytometry and an MTT assay. These experimental findings indicate that the Pael-R gene has no role in the changes in rotenone-induced Parkinson's disease model cells.
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Affiliation(s)
- Ting Zou
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Xiangqi Tang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Zhiling Huang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Niangui Xu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Zhiping Hu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
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31
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Mentzer RM, Wider J, Perry CN, Gottlieb RA. Reduction of infarct size by the therapeutic protein TAT-Ndi1 in vivo. J Cardiovasc Pharmacol Ther 2013; 19:315-20. [PMID: 24367006 DOI: 10.1177/1074248413515750] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Lethal myocardial ischemia-reperfusion (I/R) injury has been attributed in part to mitochondrial respiratory dysfunction (including damage to complex I) and the resultant excessive production of reactive oxygen species. Recent evidence has shown that reduced nicotinamide adenine dinucleotide-quinone internal oxidoreductase (Ndi1; the single-subunit protein that in yeast serves the analogous function as complex I), transduced by addition of the TAT-conjugated protein to culture media and perfusion buffer, can preserve mitochondrial function and attenuate I/R injury in neonatal rat cardiomyocytes and Langendorff-perfused rat hearts. However, this novel metabolic strategy to salvage ischemic-reperfused myocardium has not been tested in vivo. In this study, TAT-conjugated Ndi1 and placebo-control protein were synthesized using a cell-free system. Mitochondrial uptake and functionality of TAT-Ndi1 were demonstrated in mitochondrial preparations from rat hearts after intraperitoneal administration of the protein. Rats were randomized to receive either TAT-Ndi1 or placebo protein, and 2 hours later all animals underwent 45-minute coronary artery occlusion followed by 2 hours of reperfusion. Infarct size was delineated by tetrazolium staining and normalized to the volume of at-risk myocardium, with all analysis conducted in a blinded manner. Risk region was comparable in the 2 cohorts. Preischemic administration of TAT-Ndi1 was profoundly cardioprotective. These results demonstrate that it is possible to target therapeutic proteins to the mitochondrial matrix and that yeast Ndi1 can substitute for complex I to ameliorate I/R injury in the heart. Moreover, these data suggest that cell-permeable delivery of mitochondrial proteins may provide a novel molecular strategy to treat mitochondrial dysfunction in patients.
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Affiliation(s)
- Robert M Mentzer
- 1Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA
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Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis. PLoS One 2013; 8:e83283. [PMID: 24349480 PMCID: PMC3859650 DOI: 10.1371/journal.pone.0083283] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 11/11/2013] [Indexed: 12/19/2022] Open
Abstract
Cardiovascular diseases represent the main cause of mortality in the industrialized world and the identification of effective preventive strategies is of fundamental importance. Sulforaphane, an isothiocyanate from cruciferous vegetables, has been shown to up-regulate phase II enzymes in cardiomyocytes and counteract oxidative stress-induced apoptosis. Aim of the present study was the identification and characterization of novel sulforaphane targets in cardiomyocytes applying a proteomic approach. Two-dimensional gel electrophoresis and mass spectrometry were used to generate protein profiles of primary neonatal rat cardiomyocytes treated and untreated with 5 µM sulforaphane for 1-48 h. According to image analysis, 64 protein spots were found as differentially expressed and their functional correlations were investigated using the MetaCore program. We mainly focused on 3 proteins: macrophage migration inhibitory factor (MIF), CLP36 or Elfin, and glyoxalase 1, due to their possible involvement in cardioprotection. Validation of the time-dependent differential expression of these proteins was performed by western blotting. In particular, to gain insight into the cardioprotective role of the modulation of glyoxalase 1 by sulforaphane, further experiments were performed using methylglyoxal to mimic glycative stress. Sulforaphane was able to counteract methylglyoxal-induced apoptosis, ROS production, and glycative stress, likely through glyoxalase 1 up-regulation. In this study, we reported for the first time new molecular targets of sulforaphane, such as MIF, CLP36 and glyoxalase 1. In particular, we gave new insights into the anti-glycative role of sulforaphane in cardiomyocytes, confirming its pleiotropic behavior in counteracting cardiovascular diseases.
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Hong Y, Nie H, Wu D, Wei X, Ding X, Ying W. NAD(+) treatment prevents rotenone-induced apoptosis and necrosis of differentiated PC12 cells. Neurosci Lett 2013; 560:46-50. [PMID: 24304867 DOI: 10.1016/j.neulet.2013.11.039] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 11/18/2013] [Accepted: 11/20/2013] [Indexed: 12/27/2022]
Abstract
Nicotinamide adenine dinucleotide (NAD(+)) plays critical roles in not only energy metabolism and mitochondrial functions, but also calcium homeostasis and immunological functions. It has been reported that NAD(+) administration can reduce ischemic brain damage. However, the mechanisms underlying the protective effects remain unclear. Because mitochondrial impairments play a key role in the cell death in cerebral ischemia, in this study we tested our hypothesis that NAD(+) can decrease mitochondrial damage-induced cell death using differentiated PC12 cells as a cellular model. We found that NAD(+) can decrease both early-stage and late-stage apoptosis, as well as necrosis of rotenone-treated PC12 cells, as assessed by FACS-based Annexin V/AAD assay. We also found that NAD(+) treatment can restore the intracellular NAD(+) levels of the rotenone-treated cells. Moreover, NAD(+) treatment can prevent rotenone-induced mitochondria depolarization. In summary, our study has provided first direct evidence that NAD(+) treatment can prevent rotenone-induced apoptosis and necrosis. Our study has also indicated that NAD(+) treatment can prevent mitochondrial damage-induced cell death, which may at least partially result from its protective effects on rotenone-induced mitochondrial depolarization. Because both mitochondrial damage and apoptosis play key roles in multiple neurological disorders, our study has highlighted the therapeutic potential of NAD(+) for brain ischemia and other neurological diseases.
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Affiliation(s)
- Yunyi Hong
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | - Hui Nie
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | - Danhong Wu
- Department of Neurology, Third People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 201999, PR China
| | - Xunbin Wei
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | - Xianting Ding
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | - Weihai Ying
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, PR China; Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, PR China.
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34
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Marella M, Patki G, Matsuno-Yagi A, Yagi T. Complex I inhibition in the visual pathway induces disorganization of the node of Ranvier. Neurobiol Dis 2013; 58:281-8. [PMID: 23816754 PMCID: PMC3767286 DOI: 10.1016/j.nbd.2013.06.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 06/10/2013] [Accepted: 06/15/2013] [Indexed: 01/02/2023] Open
Abstract
Mitochondrial defects can have significant consequences on many aspects of neuronal physiology. In particular, deficiencies in the first enzyme complex of the mitochondrial respiratory chain (complex I) are considered to be involved in a number of human neurodegenerative diseases. The current work highlights a tight correlation between the inhibition of complex I and the state of axonal myelination of the optic nerve. Exposing the visual pathway of rats to rotenone, a complex I inhibitor, resulted in disorganization of the node of Ranvier. The structure and function of the node depend on specific cell adhesion molecules, among others, CASPR (contactin associated protein) and contactin. CASPR and contactin are both on the axonal surfaces and need to be associated to be able to anchor their myelin counterpart. Here we show that inhibition of mitochondrial complex I by rotenone in rats induces reactive oxygen species, disrupts the interaction of CASPR and contactin couple, and thus damages the organization and function of the node of Ranvier. Demyelination of the optic nerve occurs as a consequence which is accompanied by a loss of vision. The physiological impairment could be reversed by introducing an alternative NADH dehydrogenase to the mitochondria of the visual system. The restoration of the nodal structure was specifically correlated with visual recovery in the treated animal.
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Affiliation(s)
- Mathieu Marella
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
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35
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Branco AF, Sampaio SF, Wieckowski MR, Sardão VA, Oliveira PJ. Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: differential activation of stress and survival pathways. Int J Biochem Cell Biol 2013; 45:2379-91. [PMID: 23958426 DOI: 10.1016/j.biocel.2013.08.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 07/19/2013] [Accepted: 08/07/2013] [Indexed: 12/11/2022]
Abstract
β-Adrenergic receptor stimulation plays an important role in cardiomyocyte stress responses, which may result in apoptosis and cardiovascular degeneration. We previously demonstrated that toxicity of the β-adrenergic agonist isoproterenol on H9c2 cardiomyoblasts depends on the stage of cell differentiation. We now investigate β-adrenergic receptor downstream signaling pathways and stress responses that explain the impact of muscle cell differentiation on hyper-β-adrenergic stimulation-induced cytotoxicity. When incubated with isoproterenol, differentiated H9c2 muscle cells have increased cytosolic calcium, cyclic-adenosine monophosphate content and oxidative stress, as well as mitochondrial depolarization, increased superoxide anion, loss of subunits from the mitochondrial respiratory chain, decreased Bcl-xL content, increased p53 and phosphorylated-p66Shc as well as activated caspase-3. Undifferentiated H9c2 cells incubated with isoproterenol showed increased Bcl-xL protein and increased superoxide dismutase 2 which may act as protective mechanisms. We conclude that the differentiation of H9c2 is associated with differential regulation of stress responses, which impact the toxicity of several agents, namely those acting through β-adrenergic receptors and resulting in mitochondrial disruption in differentiated cells only.
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Affiliation(s)
- Ana F Branco
- CNC - Center for Neuroscience and Cell Biology, Largo Marques de Pombal, University of Coimbra, Portugal; Department of Life Sciences, Largo Marques de Pombal, University of Coimbra, Portugal
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36
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Lanju X, Jing X, Shichang L, Zhuo Y. Induction of apoptosis by antimycin A in differentiated PC12 cell line. J Appl Toxicol 2013; 34:651-7. [PMID: 23868660 DOI: 10.1002/jat.2890] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2013] [Revised: 03/26/2013] [Accepted: 03/26/2013] [Indexed: 11/10/2022]
Affiliation(s)
- Xu Lanju
- College of Medicine; Tianjin 300060 China
- CSPC The Institute of Pharmaceutical Research Shijiazhuang; Hebei 050051 China
| | - Xu Jing
- College of Medicine; Tianjin 300060 China
| | - Liu Shichang
- College of Medicine; Tianjin 300060 China
- Tianjin Medical University Cancer Institute and Hospital; Tianjin 300070 China
| | - Yang Zhuo
- College of Medicine; Tianjin 300060 China
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37
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Ferris CF, Marella M, Smerkers B, Barchet TM, Gershman B, Matsuno-Yagi A, Yagi T. A phenotypic model recapitulating the neuropathology of Parkinson's disease. Brain Behav 2013; 3:351-66. [PMID: 24381808 PMCID: PMC3869678 DOI: 10.1002/brb3.138] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 03/08/2013] [Accepted: 03/18/2013] [Indexed: 12/21/2022] Open
Abstract
This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8-9 month old, ovariectomized Long-Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11-12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5-6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2'-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the identification of biomarkers to identify patients in early stage, PD.
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Affiliation(s)
- Craig F Ferris
- Center for Translational NeuroImaging, Northeastern University Boston, Massachusetts
| | - Mathieu Marella
- Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, California
| | - Brian Smerkers
- State University of New York Upstate Medical University Syracuse, New York
| | - Thomas M Barchet
- Center for Translational NeuroImaging, Northeastern University Boston, Massachusetts
| | | | - Akemi Matsuno-Yagi
- Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, California
| | - Takao Yagi
- Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, California
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38
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Polster BM. AIF, reactive oxygen species, and neurodegeneration: a "complex" problem. Neurochem Int 2012; 62:695-702. [PMID: 23246553 DOI: 10.1016/j.neuint.2012.12.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 11/26/2012] [Accepted: 12/05/2012] [Indexed: 12/21/2022]
Abstract
Apoptosis-inducing factor (AIF) is a flavin-binding mitochondrial intermembrane space protein that is implicated in diverse but intertwined processes that include maintenance of electron transport chain function, reactive oxygen species regulation, cell death, and neurodegeneration. In acute brain injury, AIF acquires a pro-death role upon translocation from the mitochondria to the nucleus, where it initiates chromatin condensation and large-scale DNA fragmentation. Although harlequin mice exhibiting an 80-90% global reduction in AIF protein are resistant to numerous forms of acute brain injury, they paradoxically undergo slow, progressive neurodegeneration beginning at three months of age. Brain deterioration, accompanied by markers of oxidative stress, is most pronounced in the cerebellum and retina, although it also occurs in the cortex, striatum, and thalamus. Loss of an AIF pro-survival function linked to assembly or stabilization of electron transport chain complex I underlies chronic neurodegeneration. To date, most studies of neurodegeneration have failed to adequately separate the relative importance of the mitochondrial and nuclear functions of AIF in determining the extent of injury, or whether oxidative stress plays a causative role. This review explores the complicated relationship among AIF, complex I, and the regulation of mitochondrial reactive oxygen species levels. It also discusses the controversial role of complex I deficiency in Parkinson's disease, and what can be learned from the AIF- and complex I-depleted harlequin mouse.
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Affiliation(s)
- Brian M Polster
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, 685 W. Baltimore St., MSTF 5-34, Baltimore, MD 21201, USA.
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39
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Xie QR, Liu Y, Shao J, Yang J, Liu T, Zhang T, Wang B, Mruk DD, Silvestrini B, Cheng CY, Xia W. Male contraceptive Adjudin is a potential anti-cancer drug. Biochem Pharmacol 2012. [PMID: 23178657 DOI: 10.1016/j.bcp.2012.11.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Adjudin, also known as AF-2364 and an analog of lonidamine (LND), is a male contraceptive acting through the induction of premature sperm depletion from the seminiferous epithelium when orally administered to adult rats, rabbits or dogs. It is also known that LND can target mitochondria and block energy metabolism in tumor cells. However, whether Adjudin exhibits any anti-cancer activity remains to be elucidated. Herein we described the anti-proliferative activity of Adjudin on cancer cells in vitro and on lung and prostate tumors inoculated in nude mice. We found that Adjudin induced apoptosis in cancer cells through a Caspase-3-dependent pathway. Further experiments revealed that Adjudin could trigger mitochondrial dysfunction in cancer cells, apparently affecting the mitochondrial mass, inducing the loss of mitochondrial membrane potential and reducing cellular ATP levels. Intraperitoneal administration of Adjudin to tumor-bearing athymic nude mice also significantly suppressed the lung and prostate tumor growth. When used in combination with cisplatin, Adjudin enhances the sensitivity to cisplatin-induced cancer cell cytotoxicity. Taken together, these findings have demonstrated that Adjudin may be a potential drug for cancer therapy.
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Affiliation(s)
- Qian Reuben Xie
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
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Rotenone-induced neurotoxicity in rat brain areas: a study on neuronal and neuronal supportive cells. Neuroscience 2012; 230:172-83. [PMID: 23098804 DOI: 10.1016/j.neuroscience.2012.10.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 10/10/2012] [Accepted: 10/14/2012] [Indexed: 12/31/2022]
Abstract
The present study was conducted to correlate rotenone-induced neurotoxicity with cellular and molecular modifications in neuronal and neuronal supportive cells in rat brain regions. Rotenone was administered (3, 6 and 12 μg/μl) intranigrally in adult male Sprague-Dawley rats. After the 7th day of rotenone treatment, specific protein markers for neuronal cells - tyrosine hydroxylase (TH), astroglial cells - glial fibrillary acidic protein (GFAP), microglial cells - CD11b/c, and Iba-1 were evaluated by immunoblotting and immunofluorescence in the striatum (STR) and mid brain (MB). Apoptotic cell death was assessed by caspase-3 gene expression. Higher doses of rotenone significantly lowered TH protein levels and elevated Iba-1 levels in MB. All the doses of rotenone significantly increased GFAP and CD11b/c protein in the MB. In STR, rotenone elevated GFAP levels but did not affect TH, CD11b/c and Iba-1 protein levels. Caspase-3 expression was increased significantly by all the doses of rotenone in MB but in STR only by higher doses (6 and 12 μg). It may be suggested that astroglial activation and apoptosis play an important role in rotenone-induced neurotoxicity. MB appeared as more sensitive than STR toward rotenone-induced cell toxicity. The astroglial cells emerged as more susceptible than neuronal and microglial cells to rotenone in STR.
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Giordano S, Lee J, Darley-Usmar VM, Zhang J. Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death. PLoS One 2012; 7:e44610. [PMID: 22970265 PMCID: PMC3435291 DOI: 10.1371/journal.pone.0044610] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 08/03/2012] [Indexed: 12/21/2022] Open
Abstract
Parkinson's disease is characterized by dopaminergic neurodegeneration and is associated with mitochondrial dysfunction. The bioenergetic susceptibility of dopaminergic neurons to toxins which induce Parkinson's like syndromes in animal models is then of particular interest. For example, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+)), and 6-hydroxydopamine (6-OHDA), have been shown to induce dopaminergic cell death in vivo and in vitro. Exposure of animals to these compounds induce a range of responses characteristics of Parkinson's disease, including dopaminergic cell death, and Reactive Oxygen Species (ROS) production. Here we test the hypothesis that cellular bioenergetic dysfunction caused by these compounds correlates with induction of cell death in differentiated dopaminergic neuroblastoma SH-SY5Y cells. At increasing doses, rotenone induced significant cell death accompanied with caspase 3 activation. At these concentrations, rotenone had an immediate inhibition of mitochondrial basal oxygen consumption rate (OCR) concomitant with a decrease of ATP-linked OCR and reserve capacity, as well as a stimulation of glycolysis. MPP(+) exhibited a different behavior with less pronounced cell death at doses that nearly eliminated basal and ATP-linked OCR. Interestingly, MPP(+), unlike rotenone, stimulated bioenergetic reserve capacity. The effects of 6-OHDA on bioenergetic function was markedly less than the effects of rotenone or MPP(+) at cytotoxic doses, suggesting a mechanism largely independent of bioenergetic dysfunction. These studies suggest that these dopaminergic neurotoxins induce cell death through distinct mechanisms and differential effects on cellular bioenergetics.
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Affiliation(s)
- Samantha Giordano
- Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jisun Lee
- Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Victor M. Darley-Usmar
- Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jianhua Zhang
- Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, Alabama, United States of America
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Baxter KK, Uittenbogaard M, Chiaramello A. The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12-NeuroD6 cells to the mitochondrial stressor rotenone. Exp Cell Res 2012; 318:2200-14. [PMID: 22814253 DOI: 10.1016/j.yexcr.2012.07.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 06/16/2012] [Accepted: 07/08/2012] [Indexed: 11/18/2022]
Abstract
The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial biogenesis and bioenergetics to the need of developing neuronal cells has remained largely unexplored. In this study, we report that the neurogenic basic helix-loop-helix transcription factor NeuroD6 possesses mitochondrial biogenic properties by amplifying the mitochondrial DNA content and TFAM expression levels, a key regulator for mitochondrial biogenesis. NeuroD6-mediated increase in mitochondrial biogenesis in the neuronal progenitor-like PC12-NEUROD6 cells is concomitant with enhanced mitochondrial bioenergetic functions, including increased expression levels of specific subunits of respiratory complexes of the electron transport chain, elevated mitochondrial membrane potential and ATP levels produced by oxidative phosphorylation. Thus, NeuroD6 augments the bioenergetic capacity of PC12-NEUROD6 cells to generate an energetic reserve, which confers tolerance to the mitochondrial stressor, rotenone. We found that NeuroD6 induces an adaptive bioenergetic response throughout rotenone treatment involving maintenance of the mitochondrial membrane potential and ATP levels in conjunction with preservation of the actin network. In conclusion, our results support the concept that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronal differentiation with acquisition of adequate mitochondrial mass and energetic capacity to ensure energy demanding events, such as cytoskeletal remodeling, plasmalemmal expansion, and growth cone formation.
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Affiliation(s)
- Kristin Kathleen Baxter
- Department of Anatomy and Regenerative Biology, George Washington University Medical Center, Washington, DC 20037, United States
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Kluyveromyces lactis: a suitable yeast model to study cellular defense mechanisms against hypoxia-induced oxidative stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:634674. [PMID: 22928082 PMCID: PMC3425888 DOI: 10.1155/2012/634674] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Accepted: 06/22/2012] [Indexed: 11/17/2022]
Abstract
Studies about hypoxia-induced oxidative stress in human health disorders take advantage from the use of unicellular eukaryote models. A widely extended model is the fermentative yeast Saccharomyces cerevisiae. In this paper, we describe an overview of the molecular mechanisms induced by a decrease in oxygen availability and their interrelationship with the oxidative stress response in yeast. We focus on the differential characteristics between S. cerevisiae and the respiratory yeast Kluyveromyces lactis, a complementary emerging model, in reference to multicellular eukaryotes.
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Belyaeva EA, Sokolova TV, Emelyanova LV, Zakharova IO. Mitochondrial electron transport chain in heavy metal-induced neurotoxicity: effects of cadmium, mercury, and copper. ScientificWorldJournal 2012; 2012:136063. [PMID: 22619586 PMCID: PMC3349094 DOI: 10.1100/2012/136063] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 12/15/2011] [Indexed: 02/05/2023] Open
Abstract
To clarify the role of mitochondrial electron transport chain (mtETC) in heavy-metal-induced neurotoxicity, we studied action of Cd(2+), Hg(2+), and Cu(2+) on cell viability, intracellular reactive oxygen species formation, respiratory function, and mitochondrial membrane potential of rat cell line PC12. As found, the metals produced, although in a different way, dose- and time-dependent changes of all these parameters. Importantly, Cd(2+) beginning from 10 [mu]M and already at short incubation time (3 h) significantly inhibited the FCCP-uncoupled cell respiration; besides, practically the complete inhibition of the respiration was reached after 3 h incubation with 50 [mu]M Hg(2+) or 500 [mu]M Cd(2+), whereas even after 48 h exposure with 500 [mu]M Cu(2+), only a 50% inhibition of the respiration occurred. Against the Cd(2+)-induced cell injury, not only different antioxidants and mitochondrial permeability transition pore inhibitors were protective but also such mtETC effectors as FCCP and stigmatellin (complex III inhibitor). However, all mtETC effectors used did not protect against the Hg(2+)- or Cu(2+)-induced cell damage. Notably, stigmatellin was shown to be one of the strongest protectors against the Cd(2+)-induced cell damage, producing a 15-20% increase in the cell viability. The mechanisms of the mtETC involvement in the heavy-metal-induced mitochondrial membrane permeabilization and cell death are discussed.
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Affiliation(s)
- Elena A Belyaeva
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences, Thorez pr. 44, 194223 Saint-Petersburg, Russia.
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Sinha PK, Nakamaru-Ogiso E, Torres-Bacete J, Sato M, Castro-Guerrero N, Ohnishi T, Matsuno-Yagi A, Yagi T. Electron transfer in subunit NuoI (TYKY) of Escherichia coli NADH:quinone oxidoreductase (NDH-1). J Biol Chem 2012; 287:17363-17373. [PMID: 22474289 DOI: 10.1074/jbc.m111.329649] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Bacterial proton-translocating NADH:quinone oxidoreductase (NDH-1) consists of a peripheral and a membrane domain. The peripheral domain catalyzes the electron transfer from NADH to quinone through a chain of seven iron-sulfur (Fe/S) clusters. Subunit NuoI in the peripheral domain contains two [4Fe-4S] clusters (N6a and N6b) and plays a role in bridging the electron transfer from cluster N5 to the terminal cluster N2. We constructed mutants for eight individual Cys-coordinating Fe/S clusters. With the exception of C63S, all mutants had damaged architecture of NDH-1, suggesting that Cys-coordinating Fe/S clusters help maintain the NDH-1 structure. Studies of three mutants (C63S-coordinating N6a, P110A located near N6a, and P71A in the vicinity of N6b) were carried out using EPR measurement. These three mutations did not affect the EPR signals from [2Fe-2S] clusters and retained electron transfer activities. Signals at g(z) = 2.09 disappeared in C63S and P110A but not in P71A. Considering our data together with the available information, g(z,x) = 2.09, 1.88 signals are assigned to cluster N6a. It is of interest that, in terms of g(z,x) values, cluster N6a is similar to cluster N4. In addition, we investigated the residues (Ile-94 and Ile-100) that are predicted to serve as electron wires between N6a and N6b and between N6b and N2, respectively. Replacement of Ile-100 and Ile-94 with Ala/Gly did not affect the electron transfer activity significantly. It is concluded that conserved Ile-100 and Ile-94 are not essential for the electron transfer.
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Affiliation(s)
- Prem Kumar Sinha
- Department of Molecular and Experimental Medicine, MEM-256, The Scripps Research Institute, La Jolla, California 92037
| | - Eiko Nakamaru-Ogiso
- Johnson Research Foundation, Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Jesus Torres-Bacete
- Department of Molecular and Experimental Medicine, MEM-256, The Scripps Research Institute, La Jolla, California 92037
| | - Motoaki Sato
- Department of Molecular and Experimental Medicine, MEM-256, The Scripps Research Institute, La Jolla, California 92037
| | - Norma Castro-Guerrero
- Department of Molecular and Experimental Medicine, MEM-256, The Scripps Research Institute, La Jolla, California 92037
| | - Tomoko Ohnishi
- Johnson Research Foundation, Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Akemi Matsuno-Yagi
- Department of Molecular and Experimental Medicine, MEM-256, The Scripps Research Institute, La Jolla, California 92037
| | - Takao Yagi
- Department of Molecular and Experimental Medicine, MEM-256, The Scripps Research Institute, La Jolla, California 92037.
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Kamalden TA, Ji D, Osborne NN. Rotenone-Induced Death of RGC-5 Cells is Caspase Independent, Involves the JNK and p38 Pathways and is Attenuated by Specific Green Tea Flavonoids. Neurochem Res 2012; 37:1091-101. [DOI: 10.1007/s11064-012-0713-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Revised: 01/16/2012] [Accepted: 01/19/2012] [Indexed: 12/21/2022]
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Yang Y, Yamashita T, Nakamaru-Ogiso E, Hashimoto T, Murai M, Igarashi J, Miyoshi H, Mori N, Matsuno-Yagi A, Yagi T, Kosaka H. Reaction mechanism of single subunit NADH-ubiquinone oxidoreductase (Ndi1) from Saccharomyces cerevisiae: evidence for a ternary complex mechanism. J Biol Chem 2011; 286:9287-97. [PMID: 21220430 PMCID: PMC3059053 DOI: 10.1074/jbc.m110.175547] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 12/27/2010] [Indexed: 11/06/2022] Open
Abstract
The flavoprotein rotenone-insensitive internal NADH-ubiquinone (UQ) oxidoreductase (Ndi1) is a member of the respiratory chain in Saccharomyces cerevisiae. We reported previously that bound UQ in Ndi1 plays a key role in preventing the generation of reactive oxygen species. Here, to elucidate this mechanism, we investigated biochemical properties of Ndi1 and its mutants in which highly conserved amino acid residues (presumably involved in NADH and/or UQ binding sites) were replaced. We found that wild-type Ndi1 formed a stable charge transfer (CT) complex (around 740 nm) with NADH, but not with NADPH, under anaerobic conditions. The intensity of the CT absorption band was significantly increased by the presence of bound UQ or externally added n-decylbenzoquinone. Interestingly, however, when Ndi1 was exposed to air, the CT band transiently reached the same maximum level regardless of the presence of UQ. This suggests that Ndi1 forms a ternary complex with NADH and UQ, but the role of UQ in withdrawing an electron can be substitutable with oxygen. Proteinase K digestion analysis showed that NADH (but not NADPH) binding induces conformational changes in Ndi1. The kinetic study of wild-type and mutant Ndi1 indicated that there is no overlap between NADH and UQ binding sites. Moreover, we found that the bound UQ can reversibly dissociate from Ndi1 and is thus replaceable with other quinones in the membrane. Taken together, unlike other NAD(P)H-UQ oxidoreductases, the Ndi1 reaction proceeds through a ternary complex (not a ping-pong) mechanism. The bound UQ keeps oxygen away from the reduced flavin.
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Affiliation(s)
- Yu Yang
- From the Departments of Cardiovascular Physiology and
| | | | - Eiko Nakamaru-Ogiso
- Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6059
| | | | - Masatoshi Murai
- Division of Applied Life Science, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan, and
| | | | - Hideto Miyoshi
- Division of Applied Life Science, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan, and
| | - Nozomu Mori
- Otolaryngology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan
| | - Akemi Matsuno-Yagi
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
| | - Takao Yagi
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
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Perry CN, Huang C, Liu W, Magee N, Sousa Carreira R, Gottlieb RA. Xenotransplantation of mitochondrial electron transfer enzyme, Ndi1, in myocardial reperfusion injury. PLoS One 2011; 6:e16288. [PMID: 21339825 PMCID: PMC3038860 DOI: 10.1371/journal.pone.0016288] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Accepted: 12/10/2010] [Indexed: 12/03/2022] Open
Abstract
A significant consequence of ischemia/reperfusion (I/R) is mitochondrial
respiratory dysfunction, leading to energetic deficits and cellular toxicity
from reactive oxygen species (ROS). Mammalian complex I, a NADH-quinone
oxidoreductase enzyme, is a multiple subunit enzyme that oxidizes NADH and pumps
protons across the inner membrane. Damage to complex I leads to superoxide
production which further damages complex I as well as other proteins, lipids and
mtDNA. The yeast, S. cerevisiae, expresses internal rotenone
insensitive NADH-quinone oxidoreductase (Ndi1); a single 56kDa polypeptide
which, like the multi-subunit mammalian complex I, serves as the entry site of
electrons to the respiratory chain, but without proton pumping. Heterologous
expression of Ndi1 in mammalian cells results in protein localization to the
inner mitochondrial membrane which can function in parallel with endogenous
complex I to oxidize NADH and pass electrons to ubiquinone. Expression of Ndi1
in HL-1 cardiomyocytes and in neonatal rat ventricular myocytes protected the
cells from simulated ischemia/reperfusion (sI/R), accompanied by lower ROS
production, and preservation of ATP levels and NAD+/NADH ratios. We next
generated a fusion protein of Ndi1 and the 11aa protein transduction domain from
HIV TAT. TAT-Ndi1 entered cardiomyocytes and localized to mitochondrial
membranes. Furthermore, TAT-Ndi1 introduced into Langendorff-perfused rat hearts
also localized to mitochondria. Perfusion of TAT-Ndi1 before 30 min no-flow
ischemia and up to 2 hr reperfusion suppressed ROS production and preserved ATP
stores. Importantly, TAT-Ndi1 infused before ischemia reduced infarct size by
62%; TAT-Ndi1 infused at the onset of reperfusion was equally
cardioprotective. These results indicate that restoring NADH oxidation and
electron flow at reperfusion can profoundly ameliorate reperfusion injury.
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MESH Headings
- Animals
- Animals, Newborn
- Cell Death/genetics
- Cells, Cultured
- Electron Transport/genetics
- Electron Transport Complex I/genetics
- Electron Transport Complex I/metabolism
- Gene Transfer Techniques
- Genetic Therapy/methods
- Mitochondria, Heart/genetics
- Mitochondria, Heart/metabolism
- Myocardial Reperfusion Injury/genetics
- Myocardial Reperfusion Injury/metabolism
- Myocardial Reperfusion Injury/therapy
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Peptide Fragments/chemistry
- Peptide Fragments/genetics
- Peptide Fragments/metabolism
- Rats
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Saccharomyces cerevisiae/genetics
- Saccharomyces cerevisiae Proteins/genetics
- Saccharomyces cerevisiae Proteins/metabolism
- Tissue Distribution/genetics
- Transplantation, Heterologous
- tat Gene Products, Human Immunodeficiency Virus/chemistry
- tat Gene Products, Human Immunodeficiency Virus/genetics
- tat Gene Products, Human Immunodeficiency Virus/metabolism
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Affiliation(s)
- Cynthia N. Perry
- Department of Pathology, University of
California San Diego School of Medicine, La Jolla, California, United States of
America
- SDSU Bioscience Center, San Diego, California,
United States of America
| | - Chengqun Huang
- SDSU Bioscience Center, San Diego, California,
United States of America
| | - Wayne Liu
- SDSU Bioscience Center, San Diego, California,
United States of America
| | - Najib Magee
- SDSU Bioscience Center, San Diego, California,
United States of America
| | | | - Roberta A. Gottlieb
- SDSU Bioscience Center, San Diego, California,
United States of America
- * E-mail:
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Barber-Singh J, Seo BB, Matsuno-Yagi A, Yagi T. Protective Role of rAAV-NDI1, Serotype 5, in an Acute MPTP Mouse Parkinson's Model. PARKINSONS DISEASE 2010; 2011:438370. [PMID: 21188192 PMCID: PMC3005838 DOI: 10.4061/2011/438370] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 10/22/2010] [Indexed: 01/19/2023]
Abstract
Defects in mitochondrial proton-translocating NADH-quinone oxidoreductase (complex I) have been implicated in a number of acquired and hereditary diseases including Leigh's syndrome and more recently Parkinson's disease. A limited number of strategies have been attempted to repair the damaged complex I with little or no success. We have recently shown that the non-proton-pumping, internal NADH-ubiquinone oxidoreductase (Ndi1) from Saccharomyces cerevisiae (baker's yeast) can be successfully inserted into the mitochondria of mice and rats, and the enzyme was found to be fully active. Using recombinant adenoassociated virus vectors (serotype 5) carrying our NDI1 gene, we were able to express the Ndi1 protein in the substantia nigra (SN) of C57BL/6 mice with an expression period of two months. The results show that the AAV serotype 5 was highly efficient in expressing Ndi1 in the SN, when compared to a previous model using serotype 2, which led to nearly 100% protection when using an acute MPTP model. It is conceivable that the AAV-serotype5 carrying the NDI1 gene is a powerful tool for proof-of-concept study to demonstrate complex I defects as the causable factor in diseases of the brain.
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Affiliation(s)
- Jennifer Barber-Singh
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM256, La Jolla, CA 92037, USA
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Zhang ZT, Cao XB, Xiong N, Wang HC, Huang JS, Sun SG, Wang T. Morin exerts neuroprotective actions in Parkinson disease models in vitro and in vivo. Acta Pharmacol Sin 2010; 31:900-6. [PMID: 20644549 DOI: 10.1038/aps.2010.77] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
AIM To investigate the neuroprotective effects of morin on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced apoptosis in neuronal differentiated PC12 cells as well as in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease (PD). METHODS PC12 cells were challenged with MPP(+) in the presence or absence of morin. Cell viability was determined using MTT assay. Cell apoptosis was measured using flow cytometry. Generation of reactive oxygen species (ROS) was assayed using fluorescence assay. In an MPTP mouse model of PD, behavioral deficits, striatal dopamine content, and number of dopaminergic neurons were measured. RESULTS MPP(+) induced apoptosis and ROS formation in PC12 cells. Concomitant treatment with morin (5-50 mumol/L) significantly attenuated the loss of cell viability and apoptosis when compared with MPP(+) treatment alone. Morin also attenuated ROS formation induced by MPP(+). MPTP induced permanent behavioral deficits and nigrostriatal lesions in mice. When administered prior to MPTP, morin (20 to 100 mg/kg) attenuated behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model. CONCLUSION The findings suggest that morin has neuroprotective actions both in vitro and in vivo, and may provide a novel therapeutic agent for the treatment of PD and other neurodegenerative diseases.
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