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1
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See WZC, Naidu R, Tang KS. Paraquat and Parkinson's Disease: The Molecular Crosstalk of Upstream Signal Transduction Pathways Leading to Apoptosis. Curr Neuropharmacol 2024; 22:140-151. [PMID: 36703582 PMCID: PMC10716878 DOI: 10.2174/1570159x21666230126161524] [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: 10/04/2022] [Revised: 12/21/2022] [Accepted: 12/26/2022] [Indexed: 01/28/2023] Open
Abstract
Parkinson's disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/β-catenin signaling pathways.
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Affiliation(s)
- Wesley Zhi Chung See
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia
| | - Kim San Tang
- School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia
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2
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SRT1720 as an SIRT1 activator for alleviating paraquat-induced models of Parkinson's disease. Redox Biol 2022; 58:102534. [DOI: 10.1016/j.redox.2022.102534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/27/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022] Open
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3
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The Interplay between Gut Microbiota and Parkinson's Disease: Implications on Diagnosis and Treatment. Int J Mol Sci 2022; 23:ijms232012289. [PMID: 36293176 PMCID: PMC9603886 DOI: 10.3390/ijms232012289] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/05/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
The bidirectional interaction between the gut microbiota (GM) and the Central Nervous System, the so-called gut microbiota brain axis (GMBA), deeply affects brain function and has an important impact on the development of neurodegenerative diseases. In Parkinson’s disease (PD), gastrointestinal symptoms often precede the onset of motor and non-motor manifestations, and alterations in the GM composition accompany disease pathogenesis. Several studies have been conducted to unravel the role of dysbiosis and intestinal permeability in PD onset and progression, but the therapeutic and diagnostic applications of GM modifying approaches remain to be fully elucidated. After a brief introduction on the involvement of GMBA in the disease, we present evidence for GM alterations and leaky gut in PD patients. According to these data, we then review the potential of GM-based signatures to serve as disease biomarkers and we highlight the emerging role of probiotics, prebiotics, antibiotics, dietary interventions, and fecal microbiota transplantation as supportive therapeutic approaches in PD. Finally, we analyze the mutual influence between commonly prescribed PD medications and gut-microbiota, and we offer insights on the involvement also of nasal and oral microbiota in PD pathology, thus providing a comprehensive and up-to-date overview on the role of microbial features in disease diagnosis and treatment.
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4
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See WZC, Naidu R, Tang KS. Cellular and Molecular Events Leading to Paraquat-Induced Apoptosis: Mechanistic Insights into Parkinson’s Disease Pathophysiology. Mol Neurobiol 2022; 59:3353-3369. [PMID: 35306641 PMCID: PMC9148284 DOI: 10.1007/s12035-022-02799-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 03/09/2022] [Indexed: 12/17/2022]
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the cardinal features of tremor, bradykinesia, rigidity, and postural instability, in addition to other non-motor symptoms. Pathologically, PD is attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta, with the hallmark of the presence of intracellular protein aggregates of α-synuclein in the form of Lewy bodies. The pathogenesis of PD is still yet to be fully elucidated due to the multifactorial nature of the disease. However, a myriad of studies has indicated several intracellular events in triggering apoptotic neuronal cell death in PD. These include oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, alteration in dopamine catabolism, inactivation of tyrosine hydroxylase, and decreased levels of neurotrophic factors. Laboratory studies using the herbicide paraquat in different in vitro and in vivo models have demonstrated the induction of many PD pathological features. The selective neurotoxicity induced by paraquat has brought a new dawn in our perspectives about the pathophysiology of PD. Epidemiological data have suggested an increased risk of developing PD in the human population exposed to paraquat for a long term. This model has opened new frontiers in the quest for new therapeutic targets for PD. The purpose of this review is to synthesize the relationship between the exposure of paraquat and the pathogenesis of PD in in vitro and in vivo models.
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Affiliation(s)
- Wesley Zhi Chung See
- Jeffrey Cheah School of Medicine and Health Science, Monash University Malaysia, 47500, Bandar Sunway, Selangor, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Science, Monash University Malaysia, 47500, Bandar Sunway, Selangor, Malaysia
| | - Kim San Tang
- School of Pharmacy, Monash University Malaysia, 47500, Bandar Sunway, Selangor, Malaysia.
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5
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Bacopaside-I Alleviates the Detrimental Effects of Acute Paraquat Intoxication in the Adult Zebrafish Brain. Neurochem Res 2021; 46:3059-3074. [PMID: 34357519 DOI: 10.1007/s11064-021-03416-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023]
Abstract
Paraquat (PQ), an environmental neurotoxicant, causes acute fatal poisoning upon accidental or intentional ingestion (suicidal cases) worldwide. To date, an effective remedy for PQ toxicity is not available. In this study, we have evaluated the therapeutic efficacy of Bacopaside-I (BS-I), an active compound found in the plant extract of Bacopa monnieri (Brahmi), against acute PQ intoxication using zebrafish as a model organism. Adult zebrafish were injected with a dose of either 30 mg/kg or 50 mg/kg PQ. PQ-intoxicated zebrafish showed an increased rate of mortality and oxidative imbalance in their brain. Also, the proliferation of neural cells in the adult zebrafish brain was inhibited. However, when BS-I pretreated zebrafish were intoxicated with PQ, the toxic effects of PQ were ameliorated. PQ treatment also affected the expression of particular genes concerned with the apoptosis and dopamine signaling, which was not altered by BS-I administration. Our results highlight the efficiency of BS-I as a novel therapeutic agent for PQ intoxication. It further compels us to search and evaluate the molecular mechanisms targeted by BS-I to develop a potent therapy for acute PQ intoxication.
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6
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Lu Y, Bian J, Kan H, Ding W, Wang D, Wang X, Luo Q, Wu X, Zhu L. Intermittent hypoxia preconditioning protects WRL68 cells against oxidative injury: Involvement of the PINK1/Parkin-mediated mitophagy regulated by nuclear respiratory factor 1. Mitochondrion 2021; 59:113-122. [PMID: 33933661 DOI: 10.1016/j.mito.2021.04.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 04/04/2021] [Accepted: 04/26/2021] [Indexed: 01/22/2023]
Abstract
The protective effect of intermittent hypoxia (IH) preconditioning against oxidative injury in hepatic cells was investigated and the involvement of the PINK1/Parkin-mediated mitophagy regulated by nuclear respiratory factor 1 (NRF-1) was evaluated. The results showed that IH preconditioning protected HepG2 cells against oxygen and glucose deprivation/reperfusion (OGD/Rep)-induced injury and protected WRL68 cells against H2O2 or AMA-induced oxidative injury. IH preconditioning up-regulated the protein level of NRF-1, PINK1, Parkin, and LC3 II, promoted the recruitment of the cytosolic Parkin, indicating the initiation of the PINK1/Parkin-mediated mitophagy in WRL68 cells. When NRF-1 was down-regulated by NRF-1 specific shRNA, the protein level of PINK1 and Parkin as well as the mitophagy level were significantly decreased. After IH preconditioning, the protein level of PINK1 and the recruitment of Parkin in CCCP-treated group were significantly higher than that of the control group, indicating the increased mitophagy capacity. And the increased mitophagy capacity induced by IH preconditioning was also reduced by down-regulation of NRF-1. Furthermore, the protective effect of IH preconditioning against H2O2-induced oxidative injury in WRL68 cells was inhibited when NRF-1 or PINK1 was down-regulated by specific shRNA. Mitochondrial ROS generation may be responsible for the increased expression of NRF-1 induced by IH preconditioning. In conclusion, the PINK1/Parkin-mediated mitophagy regulated by NRF-1 was involved in IH preconditioning-induced protective effect against oxidative cellular injury in hepatic cells.
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Affiliation(s)
- Yapeng Lu
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China.
| | - Jiangpei Bian
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Huiwen Kan
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Wangwang Ding
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Dan Wang
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Xueting Wang
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Qianqian Luo
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Xiaomei Wu
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China
| | - Li Zhu
- Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China.
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7
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Taylor SKB, Minhas MH, Tong J, Selvaganapathy PR, Mishra RK, Gupta BP. C. elegans electrotaxis behavior is modulated by heat shock response and unfolded protein response signaling pathways. Sci Rep 2021; 11:3115. [PMID: 33542359 PMCID: PMC7862228 DOI: 10.1038/s41598-021-82466-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 01/18/2021] [Indexed: 01/30/2023] Open
Abstract
The nematode C. elegans is a leading model to investigate the mechanisms of stress-induced behavioral changes coupled with biochemical mechanisms. Our group has previously characterized C. elegans behavior using a microfluidic-based electrotaxis device, and showed that worms display directional motion in the presence of a mild electric field. In this study, we describe the effects of various forms of genetic and environmental stress on the electrotactic movement of animals. Using exposure to chemicals, such as paraquat and tunicamycin, as well as mitochondrial and endoplasmic reticulum (ER) unfolded protein response (UPR) mutants, we demonstrate that chronic stress causes abnormal movement. Additionally, we report that pqe-1 (human RNA exonuclease 1 homolog) is necessary for the maintenance of multiple stress response signaling and electrotaxis behavior of animals. Further, exposure of C. elegans to several environmental stress-inducing conditions revealed that while chronic heat and dietary restriction caused electrotaxis speed deficits due to prolonged stress, daily exercise had a beneficial effect on the animals, likely due to improved muscle health and transient activation of UPR. Overall, these data demonstrate that the electrotaxis behavior of worms is susceptible to cytosolic, mitochondrial, and ER stress, and that multiple stress response pathways contribute to its preservation in the face of stressful stimuli.
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Affiliation(s)
- Shane K. B. Taylor
- grid.25073.330000 0004 1936 8227Department of Biology, McMaster University, Hamilton, ON Canada
| | - Muhammad H. Minhas
- grid.25073.330000 0004 1936 8227Department of Biology, McMaster University, Hamilton, ON Canada
| | - Justin Tong
- grid.25073.330000 0004 1936 8227Department of Biology, McMaster University, Hamilton, ON Canada
| | - P. Ravi Selvaganapathy
- grid.25073.330000 0004 1936 8227Department of Mechanical Engineering, McMaster University, Hamilton, ON Canada
| | - Ram K. Mishra
- grid.25073.330000 0004 1936 8227Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON Canada
| | - Bhagwati P. Gupta
- grid.25073.330000 0004 1936 8227Department of Biology, McMaster University, Hamilton, ON Canada
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8
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Lee IJ, Chao CY, Yang YC, Cheng JJ, Huang CL, Chiou CT, Huang HT, Kuo YH, Huang NK. Huang Lian Jie Du Tang attenuates paraquat-induced mitophagy in human SH-SY5Y cells: A traditional decoction with a novel therapeutic potential in treating Parkinson's disease. Biomed Pharmacother 2020; 134:111170. [PMID: 33383311 DOI: 10.1016/j.biopha.2020.111170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/12/2020] [Accepted: 12/15/2020] [Indexed: 10/22/2022] Open
Abstract
Huang Lian Jie Du Tang (HLJDT) is a traditional Chinese medical decoction for heat-fire clearing and detoxication. Theoretically, the cause of Parkinson's disease (PD) has been attributed to the dysregulations of internal wind, phlegm, fire, and stasis. Thus, HLJDT has been used to treat PD. However, the molecular mechanism is unknown. Besides, paraquat (PQ) as an herbicide has been known to impair midbrain dopaminergic neurons, resemblance to the pathology of PD. Thus, the molecular mechanism of HLJDT in treating PD and PQ-induced in vitro PD model was investigated in this study. Primarily, the dose-response of PQ (0.1∼1 mM)-induced neurotoxicity for 24 h was performed in the human neuroblastoma SH-SY5Y cells. The LD50 of PQ is around 0.3 mM and was applied throughout the following experiments. The neutral red assay was used to estimate cell viability. Co-transfection of the mitochondrial marker and proapoptotic factor genes were applied to measure the release of mitochondrial proapoptotic factors during PQ intoxication and HLJDT protection. The fluorescent dyes were used to detect mitochondrial membrane potential and free radical formation. Western blot and dot-blot analysis and immunocytochemistry were used to estimate the level of proteins related to apoptosis and mitophagy. PINK1 gene silencing was used to determine the significance of mitophagy during PQ intoxication. In this study, HLJDT attenuated PQ-induced apoptosis in SH-SY5Y cells. HLJDT reversed PQ-induced decreased mitochondrial membrane potential and suppressed PQ-induced increased cytosolic and mitochondrial free radical formations and mitochondrial proapoptotic factor releases. Furthermore, HLJDT mitigated PQ-induced increases in full-length PINK1, phosphorylations of Parkin and ubiquitin, mitochondrial translocation of phosphorylated Parkin, and mitophagy. PINK1 gene silencing attenuated PQ-induced neurotoxicity. Therefore, HLJDT attenuated PQ-induced cell death by regulating mitophagy.
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Affiliation(s)
- I-Jung Lee
- Herbal Medicine Department, Yokohama University of Pharmacy, Yokohama, Japan
| | - Che-Yi Chao
- Department of Psychiatry, Cardinal Tien Hospital, New Taipei City 23148, Taiwan, ROC
| | - Ying-Chen Yang
- Department of Biotechnology and Animal Science, National Ilan University, Ilan 26047, Taiwan, ROC
| | - Jing-Jy Cheng
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11267, Taiwan, ROC
| | - Chuen-Lin Huang
- Medical Research Center, Cardinal Tien Hospital, Hsintien, New Taipei City 23148, Taiwan, ROC; Graduate Institute of Physiology & Department of Physiology and Biophysics, National Defense Medical Center, Taipei 11490, Taiwan, ROC
| | - Chun-Tang Chiou
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11267, Taiwan, ROC
| | - Hung-Tse Huang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11267, Taiwan, ROC
| | - Yao-Haur Kuo
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11267, Taiwan, ROC; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, ROC
| | - Nai-Kuei Huang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11267, Taiwan, ROC; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, ROC; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan, ROC.
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9
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Afshari K, Momeni Roudsari N, Lashgari NA, Haddadi NS, Haj-Mirzaian A, Hassan Nejad M, Shafaroodi H, Ghasemi M, Dehpour AR, Abdolghaffari AH. Antibiotics with therapeutic effects on spinal cord injury: a review. Fundam Clin Pharmacol 2020; 35:277-304. [PMID: 33464681 DOI: 10.1111/fcp.12605] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/06/2020] [Accepted: 09/08/2020] [Indexed: 12/17/2022]
Abstract
Accumulating evidence indicates that a considerable number of antibiotics exert anti-inflammatory and neuroprotective effects in different central and peripheral nervous system diseases including spinal cord injury (SCI). Both clinical and preclinical studies on SCI have found therapeutic effects of antibiotics from different families on SCI. These include macrolides, minocycline, β-lactams, and dapsone, all of which have been found to improve SCI sequels and complications. These antibiotics may target similar signaling pathways such as reducing inflammatory microglial activity, promoting autophagy, inhibiting neuronal apoptosis, and modulating the SCI-related mitochondrial dysfunction. In this review paper, we will discuss the mechanisms underlying therapeutic effects of these antibiotics on SCI, which not only could supply vital information for investigators but also guide clinicians to consider administering these antibiotics as part of a multimodal therapeutic approach for management of SCI and its complications.
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Affiliation(s)
- Khashayar Afshari
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, 1419733141, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Nazanin Momeni Roudsari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, P. O. Box: 19419-33111, Iran
| | - Naser-Aldin Lashgari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, P. O. Box: 19419-33111, Iran
| | - Nazgol-Sadat Haddadi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, 1419733141, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.,Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Arvin Haj-Mirzaian
- Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Malihe Hassan Nejad
- Department of Infectious Diseases, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, 1419733141, Iran
| | - Hamed Shafaroodi
- Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Mehdi Ghasemi
- Department of Neurology, University of Massachusetts School of Medicine, Worcester, MA, 01655, USA
| | - Ahmad Reza Dehpour
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, 1419733141, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, P. O. Box: 19419-33111, Iran.,Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, 31375-1369, Iran.,Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, 1419733151, Iran
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10
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A molecularly imprinted electrochemical sensor based on Au nanocross-chitosan composites for detection of paraquat. J Solid State Electrochem 2019. [DOI: 10.1007/s10008-018-04192-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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11
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Sun DZ, Song CQ, Xu YM, Wang R, Liu W, Liu Z, Dong XS. Involvement of PINK1/Parkin-mediated mitophagy in paraquat- induced apoptosis in human lung epithelial-like A549 cells. Toxicol In Vitro 2018; 53:148-159. [DOI: 10.1016/j.tiv.2018.08.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 08/19/2018] [Accepted: 08/19/2018] [Indexed: 12/31/2022]
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12
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Solis GM, Kardakaris R, Valentine ER, Bar-Peled L, Chen AL, Blewett MM, McCormick MA, Williamson JR, Kennedy B, Cravatt BF, Petrascheck M. Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms. eLife 2018; 7:40314. [PMID: 30479271 PMCID: PMC6257811 DOI: 10.7554/elife.40314] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022] Open
Abstract
Aging impairs the activation of stress signaling pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here, we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient Caenorhabditis elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease. Editorial note This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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Affiliation(s)
- Gregory M Solis
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.,Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
| | - Rozina Kardakaris
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
| | - Elizabeth R Valentine
- Department of Integrative Structural and Computational Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States.,Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
| | - Liron Bar-Peled
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
| | - Alice L Chen
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
| | - Megan M Blewett
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
| | | | - James R Williamson
- Department of Integrative Structural and Computational Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States.,Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
| | - Brian Kennedy
- The Buck Institute for Research on Aging, Novato, United States
| | - Benjamin F Cravatt
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States
| | - Michael Petrascheck
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.,Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
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13
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Yang JM, Huang HM, Cheng JJ, Huang CL, Lee YC, Chiou CT, Huang HT, Huang NK, Yang YC. LGK974, a PORCUPINE inhibitor, mitigates cytotoxicity in an in vitro model of Parkinson's disease by interfering with the WNT/β-CATENIN pathway. Toxicology 2018; 410:65-72. [PMID: 30205152 DOI: 10.1016/j.tox.2018.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/03/2018] [Accepted: 09/06/2018] [Indexed: 01/10/2023]
Abstract
Paraquat (PQ) as an herbicide has been demonstrated to impair dopaminergic (DAergic) neurons and highly correlate with the etiology of Parkinson's disease (PD). WNT/β-CATENIN signaling is known for the specification and neurogenesis of midbrain DAergic neurons and implicated as a therapeutic target in treating many diseases, such as cancer and degenerative diseases. LGK974, a WNT pathway inhibitor, is currently under clinical trial for patients with malignancies. Since the exact role of WNT/β-CATENIN signaling in mediating PD is undetermined, LGK974 was used to examine its effect on the PQ-induced cell model of PD. LGK974 attenuated PQ-induced apoptosis and released mitochondrial pro-poptotic molecules in human neuroblastoma SH-SY5Y cell. PQ increased the levels of β-CATENIN, non-phosphorylated (Ser33/37/Thr41) β-CATENIN, and phosphorylated glycogen synthase kinase (GSK)-3α/β. PQ also increased the nuclear translocation of β-CATENIN, which can be attenuated by LKG974. Furthermore, LGK974 attenuated the PQ-induced release of mitochondrial proapoptotic factors and WNT agonist 1-induced cell death. Taken together, we have shown for the first time that LGK974 mediated through the WNT/β-CATENIN pathway to prevent PQ-induced cell death.
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Affiliation(s)
- Jung-Mou Yang
- Department of Emergency, Cardinal Tien Hospital, Hsintien, New Taipei City, Taiwan, ROC
| | - Huei-Mei Huang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Jing-Jy Cheng
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
| | - Chuen-Lin Huang
- Medical Research Center, Cardinal Tien Hospital, Hsintien, New Taipei City, Taiwan, ROC; Graduate Institute of Physiology & Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Chao Lee
- Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC
| | - Chun-Tang Chiou
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
| | - Hung-Tse Huang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
| | - Nai-Kuei Huang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC; Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Ying-Chen Yang
- Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan, ROC.
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14
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Liu Jun Zi Tang-A Potential, Multi-Herbal Complementary Therapy for Chemotherapy-Induced Neurotoxicity. Int J Mol Sci 2018; 19:ijms19041258. [PMID: 29690597 PMCID: PMC5979528 DOI: 10.3390/ijms19041258] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 04/10/2018] [Accepted: 04/18/2018] [Indexed: 12/25/2022] Open
Abstract
Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity.
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15
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Del Pino J, Moyano P, Díaz GG, Anadon MJ, Diaz MJ, García JM, Lobo M, Pelayo A, Sola E, Frejo MT. Primary hippocampal neuronal cell death induction after acute and repeated paraquat exposures mediated by AChE variants alteration and cholinergic and glutamatergic transmission disruption. Toxicology 2017; 390:88-99. [PMID: 28916328 DOI: 10.1016/j.tox.2017.09.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/09/2017] [Accepted: 09/11/2017] [Indexed: 11/12/2022]
Abstract
Paraquat (PQ) is a widely used non-selective contact herbicide shown to produce memory and learning deficits after acute and repeated exposure similar to those induced in Alzheimer's disease (AD). However, the complete mechanisms through which it induces these effects are unknown. On the other hand, cholinergic and glutamatergic systems, mainly in the hippocampus, are involved on learning, memory and cell viability regulation. An alteration of hippocampal cholinergic or glutamatergic transmissions or neuronal cell loss may induce these effects. In this regard, it has been suggested that PQ may induce cell death and affect cholinergic and glutamatergic transmission, which alteration could produce neuronal loss. According to these data, we hypothesized that PQ could induce hippocampal neuronal loss through cholinergic and glutamatergic transmissions alteration. To prove this hypothesis, we evaluated in hippocampal primary cell culture, the PQ toxic effects after 24h and 14 consecutive days exposure on neuronal viability and the cholinergic and glutamatergic mechanisms related to it. This study shows that PQ impaired acetylcholine levels and induced AChE inhibition and increased CHT expression only after 14days exposure, which suggests that acetylcholine levels alteration could be mediated by these actions. PQ also disrupted glutamate levels through induction of glutaminase activity. In addition, PQ induced, after 24h and 14days exposure, cell death on hippocampal neurons that was partially mediated by AChE variants alteration and cholinergic and gultamatergic transmissions disruption. Our present results provide new view of the mechanisms contributing to PQ neurotoxicity and may explain cognitive dysfunctions observed after PQ exposure.
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Affiliation(s)
- Javier Del Pino
- Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
| | - Paula Moyano
- Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - Gloria Gómez Díaz
- Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - María José Anadon
- Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - Maria Jesus Diaz
- Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain; Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain; Department of Pathological Anatomy, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - José Manuel García
- Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - Margarita Lobo
- Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Adela Pelayo
- Department of Pathological Anatomy, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - Emma Sola
- Department of Pathological Anatomy, Medical School, Complutense University of Madrid, 28041 Madrid, Spain
| | - María Teresa Frejo
- Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
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16
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Novel tactics for neuroprotection in Parkinson's disease: Role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol 2017; 155:120-148. [DOI: 10.1016/j.pneurobio.2015.10.004] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Revised: 10/08/2015] [Accepted: 10/26/2015] [Indexed: 02/04/2023]
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17
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Zhao G, Cao K, Xu C, Sun A, Lu W, Zheng Y, Li H, Hong G, Wu B, Qiu Q, Lu Z. Crosstalk between Mitochondrial Fission and Oxidative Stress in Paraquat-Induced Apoptosis in Mouse Alveolar Type II Cells. Int J Biol Sci 2017; 13:888-900. [PMID: 28808421 PMCID: PMC5555106 DOI: 10.7150/ijbs.18468] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 03/10/2017] [Indexed: 01/04/2023] Open
Abstract
Paraquat (PQ), as a highly effective and nonselective herbicide, induces cell apoptosis through generation of superoxide anions which forms reactive oxygen species (ROS). Mitochondria, as regulators for cellular redox signaling, have been proved to play an important role in PQ-induced cell apoptosis. This study aimed to evaluate whether and how mitochondrial fission interacts with oxidative stress in PQ-induced apoptosis in mouse alveolar type II (AT-II) cells. Firstly, we demonstrated that PQ promoted apoptosis and release of cytochrome-c (Cyt-c). Furthermore, we showed that PQ broke down mitochondrial network, enhanced the expression of fission-related proteins, increased Drp1 mitochondrial translocation while decreased the expression of fusion-related proteins in AT-II cells. Besides, inhibiting mitochondrial fission using mdivi-1, a selective inhibitor of Drp1, markedly attenuated PQ-induced apoptosis, release of Cyt-c and the generation of ROS. These results indicate that mitochondrial fission involves in PQ-induced apoptosis. Further study demonstrated that antioxidant ascorbic acid inhibited Drp1 mitochondrial translocation, mitochondrial fission and attenuated PQ-induced apoptosis. Overall, our findings suggest that mitochondrial fission interplays with ROS in PQ-induced apoptosis in mouse AT-II cells and mitochondrial fission could serve as a potential therapeutic target in PQ poisoning.
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Affiliation(s)
- Guangju Zhao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Municipal Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Kaiqiang Cao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Municipal Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Changqin Xu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Municipal Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Aifang Sun
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Wang Lu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yi Zheng
- Department of Microbiology and immunology, School of Laboratory Medicine, Wenzhou Medical University, Wenzhou 325000, China.,Key Lab of Laboratory Medicine, Ministry of Education of China, Wenzhou 325000, China
| | - Haixiao Li
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Municipal Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Guangliang Hong
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Municipal Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Bing Wu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qiaomeng Qiu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhongqiu Lu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Municipal Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
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18
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De-qian K, Yue L, Li L, Guangying Z. Downregulation of Smac attenuates H2O2-induced apoptosis via endoplasmic reticulum stress in human lens epithelial cells. Medicine (Baltimore) 2017; 96:e7419. [PMID: 28682901 PMCID: PMC5502174 DOI: 10.1097/md.0000000000007419] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Second mitochondria-derived activator of caspases (Smac) is reported to promote apoptosis. Given the important role of apoptosis in cataract development, the aim of this study was to investigate whether Smac induces human lens epithelial cell (HLEC) apoptosis via endoplasmic reticulum stress (ERS). METHODS Smac expression was examined by immunohistochemistry in anterior lens capsules from 157 patients with age-related cataracts and 5 normal controls. The role of Smac in hydrogen peroxide (H2O2)-induced ERS and apoptosis was further evaluated using small interfering RNA knockdown in an HLEC line. RESULTS Notably, Smac expression was significantly higher in patients with cataracts than in controls, but showed no association with cataract severity. Cell survival was inversely correlated with H2O2 concentration, and was most significantly affected at 200 μmol/L. Moreover, flow cytometry revealed that Smac knockdown attenuated H2O2-induced apoptosis and enhanced apoptotic- and endoplasmic reticulum-related marker expression-including that of glucose-regulated protein 78, C/EBP homologous protein, caspase 3, B-cell chronic lymphocytic leukemia/lymphoma 2-associated X, and BCL2-at the gene and protein level. CONCLUSION Collectively, these results indicate that Smac plays an important role in ERS-induced apoptosis in HLECs, suggesting its close association with cataract development.
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Affiliation(s)
- Kong De-qian
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University
- The Key Discipline Open Laboratory of Clinical Medicine for Institutions of Higher Learning in Henan Province, Zhengzhou, China
| | - Liu Yue
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University
- The Key Discipline Open Laboratory of Clinical Medicine for Institutions of Higher Learning in Henan Province, Zhengzhou, China
| | - Li Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University
- The Key Discipline Open Laboratory of Clinical Medicine for Institutions of Higher Learning in Henan Province, Zhengzhou, China
| | - Zheng Guangying
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University
- The Key Discipline Open Laboratory of Clinical Medicine for Institutions of Higher Learning in Henan Province, Zhengzhou, China
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19
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Li K, Cheng X, Jiang J, Wang J, Xie J, Hu X, Huang Y, Song L, Liu M, Cai L, Chen L, Zhao S. The toxic influence of paraquat on hippocampal neurogenesis in adult mice. Food Chem Toxicol 2017; 106:356-366. [PMID: 28576469 DOI: 10.1016/j.fct.2017.05.067] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 05/26/2017] [Accepted: 05/29/2017] [Indexed: 01/09/2023]
Abstract
Paraquat, a fast-acting non-selective contact herbicide, is considered an etiological factor related to Parkinson's disease. This study investigated its effects on hippocampal neurogenesis and cognition in adult mice as well as possible mechanisms for the effects. We administered paraquat (1.25 mg/kg, intraperitoneal injection, i.p.) and an equal volume of normal saline for 3 weeks to adult male C57BL/6J mice. The results showed that hippocampus-dependent spatial learning and memory was significantly impaired in paraquat-treated mice. Moreover, paraquat administration inhibited the proliferation of neural progenitor cells, and impaired the survival and altered the fate decision of newly generated cells in the hippocampus. The expression levels of caspase-3 and glial fibrillary acidic protein were significantly higher in paraquat-treated mice than in control mice. Interestingly, paraquat reduced the phosphorylation of Akt, but did not affect the total amount of Akt. In conclusion, our findings suggest that paraquat negatively affected adult hippocampal neurogenesis and cognition function.
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Affiliation(s)
- Kaikai Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Xinran Cheng
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Jinhua Jiang
- Zhejiang Academy of Agricultural Science, Hangzhou, Zhejiang 310021, People's Republic of China.
| | - Jiutao Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450003, People's Republic of China.
| | - Jiongfang Xie
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Xinde Hu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Yingxue Huang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Lingzhen Song
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Mengmeng Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
| | - Leiming Cai
- Zhejiang Academy of Agricultural Science, Hangzhou, Zhejiang 310021, People's Republic of China.
| | - Liezhong Chen
- Zhejiang Academy of Agricultural Science, Hangzhou, Zhejiang 310021, People's Republic of China.
| | - Shanting Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.
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20
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Shultz RB, Zhong Y. Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural Regen Res 2017; 12:702-713. [PMID: 28616020 PMCID: PMC5461601 DOI: 10.4103/1673-5374.206633] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Minocycline hydrochloride (MH), a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways as well as inhibition of matrix metalloproteinases (MMPs). Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate (NMDA) receptors, mitochondrial calcium uptake, poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.
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Affiliation(s)
- Robert B Shultz
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
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21
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Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells. Sci Rep 2016; 6:39123. [PMID: 27982118 PMCID: PMC5159874 DOI: 10.1038/srep39123] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 11/17/2016] [Indexed: 12/17/2022] Open
Abstract
Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor that induces adaptive responses upon low oxygen conditions in human cancers and triggers off a poor prognostic outcome of conventional treatments. In this study, we discovered for the first time that brusatol (BRU), a quassinoid extracted from Brucea Esters, has the capability to inhibit HIF-1 signaling pathway. We found that BRU concentration-dependently down-regulated HIF-1α protein levels under hypoxia or CoCl2-induced mimic hypoxia in HCT116 cells without causing significant cytotoxicity. Besides, the transactivation activity of HIF-1 was suppressed by BRU under hypoxic conditions, as well as the expression of HIF-1 target genes, including VEGF, GLUT1, HK2 and LDHA. In addition, BRU can also decrease glucose consumption under hypoxia through inhibition of HIF-1 signaling pathway. Further studies revealed that the inhibitory effect of BRU on HIF-1 signaling pathway might be attributed to promoting degradation of HIF-1α. Interestingly, intracellular reactive oxygen species (ROS) levels and mitochondrial ROS level were both decreased by BRU treatment, indicating the involvment of mitochondrial ROS regulation in the action of BRU. Taken together, these results provided clear evidence for BRU-mediated HIF-1α regulation and suggested its therapeutic potential in colon tumors.
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22
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He Y, Zou L, Zhou Y, Hu H, Yao R, Jiang Y, Lau WB, Yuan T, Huang W, Zeng Z, Cao Y. Adiponectin ameliorates the apoptotic effects of paraquat on alveolar type Ⅱ cells via improvements in mitochondrial function. Mol Med Rep 2016; 14:746-52. [PMID: 27220901 PMCID: PMC4918546 DOI: 10.3892/mmr.2016.5328] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 04/19/2016] [Indexed: 02/05/2023] Open
Abstract
Previous studies have demonstrated that excessive reactive oxygen/nitrogen species (ROS/RNS)-induced apoptosis is an important feature of the injury to the lung epithelium in paraquat (PQ) poisoning. However the precise mechanisms of PQ-induced dysfunction of the mitochondria, where ROS/RNS are predominantly produced, remain to be fully elucidated. Whether globular adiponectin (gAd), a potent molecule protective to mitochondria, regulates the mitochondrial function of alveolar type II cells to reduce PQ-induced ROS/RNS production remains to be investigated. The current study aimed to investigate the precise mechanisms of PQ poisoning in the mitochondria of alveolar type II cells, and to elucidate the role of gAd in protecting against PQ-induced lung epithelium injury. Therefore, lung epithelial injury was induced by PQ co-culture of alveolar type II A549 cells for 24 h. gAd was administrated to and removed from the injured cells in after 24 h. PQ was observed to reduce cell viability and increase apoptosis by ~1.5 fold in A549 cells. The oxidative/nitrative stress, resulting from ROS/RNS and disordered mitochondrial function were evidenced by increased
O2−., NO production and reduced mitochondrial membrane potential (ΔΨ), adenosine 5′-triphosphate (ATP) content in PQ-poisoned A549 cells. gAd treatment significantly reversed the PQ-induced cell injury and mitochondrial dysfunction in A549 cells. The protective effects of gAd were partly abrogated by an adenosine 5′-monophosphate-activated protein kinase (AMPK) inhibitor, compound C. The results suggest that reduced ΔΨ and ATP content may result in PQ-induced mitochondrial dysfunction of the lung epithelium, which constitutes a novel mechanism for gAd exerting pulmonary protection against PQ poisoning via AMPK activation.
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Affiliation(s)
- Yarong He
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Liqun Zou
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yaxiong Zhou
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hai Hu
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Rong Yao
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yaowen Jiang
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Wayne Bond Lau
- Emergency Medicine Department, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Tun Yuan
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan 610064, P.R. China
| | - Wen Huang
- Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhi Zeng
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu Cao
- Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Hosamani R, Krishna G, Muralidhara. Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain. Nutr Neurosci 2016; 19:434-446. [PMID: 25153704 DOI: 10.1179/1476830514y.0000000149] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. METHODS To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). RESULTS Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. DISCUSSION Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.
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Affiliation(s)
- Ravikumar Hosamani
- a Biochemistry and Nutrition Department , CSIR-Central Food Technological Research Institute , Mysore , Karnataka , India.,b Space Bioscience Division , NASA Ames Research Center , Moffett Field , CA , USA
| | - Gokul Krishna
- a Biochemistry and Nutrition Department , CSIR-Central Food Technological Research Institute , Mysore , Karnataka , India
| | - Muralidhara
- a Biochemistry and Nutrition Department , CSIR-Central Food Technological Research Institute , Mysore , Karnataka , India
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24
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Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:8923860. [PMID: 26649146 PMCID: PMC4663008 DOI: 10.1155/2016/8923860] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 07/08/2015] [Indexed: 02/07/2023]
Abstract
Compelling evidences have shown that diverse environmental insults arising during early life can either directly lead to a reduction in the number of dopaminergic neurons or cause an increased susceptibility to neurons degeneration with subsequent environmental insults or with aging alone. Oxidative stress is considered the main effect of neurotoxins exposure. In this study, we investigated the oxidative stress effect of Paraquat (PQ) on immortalized human embryonic neural progenitor cells by treating them with various concentrations of PQ. We show that PQ can decrease the activity of SOD and CAT but increase MDA and LDH level. Furthermore, the activities of Cyc and caspase-9 were found increased significantly at 10 μM of PQ treatment. The cytoplasmic Nrf2 protein expressions were upregulated at 10 μM but fell back at 100 μM. The nuclear Nrf2 protein expressions were upregulated as well as the downstream mRNA expressions of HO-1 and NQO1 in a dose-dependent manner. In addition, the proteins expression of PKC and CKII was also increased significantly even at 1 μM. The results suggested that Nrf2/ARE pathway is involved in mild to moderate PQ-induced oxidative stress which is evident from dampened Nrf2 activity and low expression of antioxidant genes in PQ induced oxidative damage.
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25
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Shen W, Wang L, Pi R, Li Z, Rikang Wang. L-F001, a multifunctional ROCK inhibitor prevents paraquat-induced cell death through attenuating ER stress and mitochondrial dysfunction in PC12 cells. Biochem Biophys Res Commun 2015; 464:794-9. [DOI: 10.1016/j.bbrc.2015.07.035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/07/2015] [Indexed: 12/01/2022]
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26
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Huang CL, Chao CC, Lee YC, Lu MK, Cheng JJ, Yang YC, Wang VC, Chang WC, Huang NK. Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability. Mol Neurobiol 2015; 53:2169-88. [DOI: 10.1007/s12035-015-9198-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 04/22/2015] [Indexed: 12/20/2022]
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27
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Li HF, Zhao SX, Xing BP, Sun ML. Ulinastatin suppresses endoplasmic reticulum stress and apoptosis in the hippocampus of rats with acute paraquat poisoning. Neural Regen Res 2015; 10:467-72. [PMID: 25878598 PMCID: PMC4396112 DOI: 10.4103/1673-5374.153698] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2014] [Indexed: 01/13/2023] Open
Abstract
Lung injury is the main manifestation of paraquat poisoning. Few studies have addressed brain damage after paraquat poisoning. Ulinastatin is a protease inhibitor that can effectively stabilize lysosomal membranes, prevent cell damage, and reduce the production of free radicals. This study assumed that ulinastatin would exert these effects on brain tissues that had been poisoned with paraquat. Rat models of paraquat poisoning were intraperitoneally injected with ulinastatin. Simultaneously, rats in the control group were administered normal saline. Hematoxylin-eosin staining showed that most hippocampal cells were contracted and nucleoli had disappeared in the paraquat group. Fewer cells in the hippocampus were concentrated and nucleoli had disappeared in the ulinastatin group. Western blot assay showed that expressions of GRP78 and cleaved-caspase-3 were significantly lower in the ulinastatin group than in the paraquat group. Immunohistochemical findings showed that CHOP immunoreactivity was significantly lower in the ulinastatin group than in the paraquat group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining showed that the number of apoptotic cells was reduced in the paraquat and ulinastatin groups. These data confirmed that endoplasmic reticular stress can be induced by acute paraquat poisoning. Ulinastatin can effectively inhibit this stress as well as cell apoptosis, thereby exerting a neuroprotective effect.
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Affiliation(s)
- Hai-Feng Li
- Department of Emergency Medicine, the First Hospital of Jilin University-the Eastern Division, Changchun, Jilin Province, China
| | - Shi-Xing Zhao
- Department of Emergency Medicine, the First Hospital of Jilin University-the Eastern Division, Changchun, Jilin Province, China
| | - Bao-Peng Xing
- Department of Emergency Medicine, the First Hospital of Jilin University-the Eastern Division, Changchun, Jilin Province, China
| | - Ming-Li Sun
- Department of Emergency Medicine, the First Hospital of Jilin University-the Eastern Division, Changchun, Jilin Province, China
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Abdel-Salam OME. Drug therapy for Parkinson’s disease: An update. World J Pharmacol 2015; 4:117. [DOI: 10.5497/wjp.v4.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 01/26/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
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Abstract
Herbicides remain the most effective, efficient and economical way to control weeds; and its market continues to grow even with the plethora of generic products. With the development of herbicide-tolerant crops, use of herbicides is increasing around the world that has resulted in severe contamination of the environment. The strategies are now being developed to clean these substances in an economical and eco-friendly manner. In this review, an attempt has been made to pool all the available literature on the biodegradation of key herbicides, clodinafop propargyl, 2,4-dichlorophenoxyacetic acid, atrazine, metolachlor, diuron, glyphosate, imazapyr, pendimethalin and paraquat under the following objectives: (1) to highlight the general characteristic and mode of action, (2) to enlist toxicity in animals, (3) to pool microorganisms capable of degrading herbicides, (4) to discuss the assessment of herbicides degradation by efficient microbes, (5) to highlight biodegradation pathways, (6) to discuss the molecular basis of degradation, (7) to enlist the products of herbicides under degradation process, (8) to highlight the factors effecting biodegradation of herbicides and (9) to discuss the future aspects of herbicides degradation. This review may be useful in developing safer and economic microbiological methods for cleanup of soil and water contaminated with such compounds.
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Affiliation(s)
- Baljinder Singh
- a Department of Biotechnology , Panjab University , Chandigarh , Punjab , India
| | - Kashmir Singh
- a Department of Biotechnology , Panjab University , Chandigarh , Punjab , India
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Agrawal S, Singh A, Tripathi P, Mishra M, Singh PK, Singh MP. Cypermethrin-Induced Nigrostriatal Dopaminergic Neurodegeneration Alters the Mitochondrial Function:A Proteomics Study. Mol Neurobiol 2014; 51:448-65. [DOI: 10.1007/s12035-014-8696-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 03/24/2014] [Indexed: 12/29/2022]
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A high content screening approach to identify molecules neuroprotective for photoreceptor cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 801:773-81. [PMID: 24664770 DOI: 10.1007/978-1-4614-3209-8_97] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE Retinal degenerations are a heterogeneous group of diseases in which there is slow but progressive loss of photoreceptors (PR). There are currently no approved therapies for treating retinal degenerations. In an effort to identify novel small molecules that are (1) neuroprotective and (2) promote PR differentiation, we have developed microscale (1,536 well) cell culture assays using primary retinal neurons. METHODS Primary murine retinal cells are isolated, seeded, treated with a 1,280 compound chemical library in a 7 point titration and then cultured under conditions developed to assay protection against an introduced stress or enhance PR differentiation. In the protection assays a chemical insult is introduced and viability assessed after 72 h using CellTiterGlo, a single-step chemiluminescent reagent. In the differentiation assay, cells are isolated from the rhodopsin-GFP knock-in mouse and PR differentiation is assessed by fixing cells after 21 days in culture and imaging with the Acumen plate-based laser cytometer (TTP Labtech) to determine number and intensity of GFP-expressing cells. Positive wells are re-imaged at higher resolution with an INCell2000 automated microscope (GE). Concentration-response curves are generated to pharmacologically profile each compound and hits identified by xx. RESULTS We have developed PR differentiation and neuroprotection assays with a signal to background (S/B) ratios of 11 and 3, and a coefficient of variation (CV) of 20 and 9 %, suitable for chemical screening. Staurosporine has been shown in our differentiation assay to simultaneously increase the number of rhodopsin positive objects while decreasing the mean rhodopsin intensity and punctate rhodopsin fluorescent objects. CONCLUSIONS Using primary murine retinal cells, we developed high throughput assays to identify small molecules that influence PR development and survival. By screening multiple compound concentrations, dose-response curves can be generated, and the false negative rate minimized. It is hoped that this work will identify both potential preclinical candidates as well as molecular probes that will be useful for analysis of the molecular mechanisms that promote PR differentiation and survival.
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Wang Z, Ge Y, Bao H, Dworkin L, Peng A, Gong R. Redox-sensitive glycogen synthase kinase 3β-directed control of mitochondrial permeability transition: rheostatic regulation of acute kidney injury. Free Radic Biol Med 2013; 65:849-858. [PMID: 23973862 PMCID: PMC3859848 DOI: 10.1016/j.freeradbiomed.2013.08.169] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 07/31/2013] [Accepted: 08/16/2013] [Indexed: 01/29/2023]
Abstract
Mitochondrial dysfunction plays a pivotal role in necroapoptotic cell death and in the development of acute kidney injury (AKI). Evidence suggests that glycogen synthase kinase (GSK) 3β resides at the nexus of multiple signaling pathways implicated in the regulation of mitochondrial permeability transition (MPT). In cultured renal tubular epithelial cells, a discrete pool of GSK3β was detected in mitochondria. Coimmunoprecipitation assay confirmed that GSK3β physically interacts with cyclophilin F and voltage-dependent anion channel (VDAC), key MPT regulators that possess multiple GSK3β phosphorylation consensus motifs, suggesting that GSK3β has a direct control of MPT. Upon a strong burst of reactive oxygen species elicited by the pro-oxidant herbicide paraquat, the activity of the redox-sensitive GSK3β was drastically enhanced. This was accompanied by augmented phosphorylation of cyclophilin F and VDAC, associated with MPT and cell death. Inhibition of GSK3β by either the selective inhibitor 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) or forced expression of a kinase-dead mutant obliterated paraquat-induced phosphorylation of cyclophilin F and VDAC, prevented MPT, and improved cellular viability. Conversely, ectopic expression of a constitutively active GSK3β amplified the effect of paraquat on cyclophilin F and VDAC phosphorylation and sensitized cells to paraquat-induced MPT and death. In vivo, paraquat injection elicited marked oxidant stress in the kidney and resulted in acute kidney dysfunction and massive tubular apoptosis and necrosis. Consistent with in vitro findings, the activity of GSK3β was augmented in the kidney after paraquat injury, associated with increased phosphorylation of cyclophilin F and VDAC and sensitized MPT. TDZD-8 blocked GSK3β activity in the kidney, intercepted cyclophilin F and VDAC phosphorylation, prevented MPT, attenuated tubular cell death, and ameliorated paraquat-induced AKI. Our data suggest that the redox-sensitive GSK3β regulates renal tubular injury in AKI by controlling the activity of MPT regulators.
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Affiliation(s)
- Zhen Wang
- Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA
| | - Yan Ge
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA
| | - Hui Bao
- Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA
| | - Lance Dworkin
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA
| | - Ai Peng
- Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rujun Gong
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA.
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Li CH, Liao PL, Yang YT, Huang SH, Lin CH, Cheng YW, Kang JJ. Minocycline accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase, von Hippel-Lindau-dependent pathway. Arch Toxicol 2013; 88:659-71. [PMID: 24292262 DOI: 10.1007/s00204-013-1175-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 11/20/2013] [Indexed: 01/08/2023]
Abstract
Hypoxia-mediated stress responses are important in tumor progression, especially when tumor growth causes the tumor to become deprived of its blood supply. The oxygen-labile transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in regulating hypoxia stress-related gene expression and is considered a novel therapeutic target. Lung adenocarcinoma cell lines were exposed to minocycline, followed by incubation at hypoxic condition for 3-6 h. Here, we show that minocycline, a second-generation tetracycline, can induce HIF-1α proteasomal degradation under hypoxia by increasing the expression prolyl hydroxylase-2 and HIF-1α/von Hippel-Lindau protein interaction, thereby overcoming hypoxia-induced HIF-1α stabilization. Neither repression of hypoxia-induced phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway nor inhibition of Hsp90 was required for minocycline-induced HIF-1α degradation. The HIF-1α degradation-enhancing effect of minocycline was evident in both cancerous and primary cells. Minocycline-pretreated, hypoxia-conditioned cells showed a clear reduction in hypoxia response element reporter expression and amelioration of vascular endothelial growth factor C/D (VEGF-C/D), matrix metalloproteinase 2, and glucose transporter 1 expression. By decreasing VEGF secretion of cancerous cells, minocycline could suppress endothelial cell neovasculogenesis. These findings suggest a novel application of minocycline in the treatment of tumor angiogenesis as well as hypoxia-related diseases.
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Affiliation(s)
- Ching-Hao Li
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Dixit A, Srivastava G, Verma D, Mishra M, Singh PK, Prakash O, Singh MP. Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease. Biochim Biophys Acta Mol Basis Dis 2013; 1832:1227-40. [PMID: 23562983 DOI: 10.1016/j.bbadis.2013.03.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 03/25/2013] [Accepted: 03/26/2013] [Indexed: 12/31/2022]
Abstract
Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.
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Affiliation(s)
- Anubhuti Dixit
- CSIR-Indian Institute of Toxicology Research CSIR-IITR, M. G. Marg, Post Box-80, Lucknow-226 001, UP, India
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Fahim MA, Shehab S, Nemmar A, Adem A, Dhanasekaran S, Hasan MY. Daily subacute paraquat exposure decreases muscle function and substantia nigra dopamine level. Physiol Res 2013; 62:313-21. [PMID: 23489189 DOI: 10.33549/physiolres.932386] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The use of the herbicide paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride; PQ) which is widely used in agriculture is known to cause dopaminergic neurotoxicity. However, the mechanisms underlying this effect are not fully understood. This present study investigated the behavioral manifestations, motor coordination, and dopaminergic neurodegeneration following exposure to PQ. Male rats were injected with PQ (10 mg/kg i.p.) daily for three weeks. Rotarod systems were used for measuring locomotor activity and motor coordination. The effects of PQ on dorsiflexor, electrophysiologically-induced muscle contraction were studied. Dopamine concentrations in the ventral mesencephalon were measured by high performance liquid chromatography and the number of dopaminergic neurons in substantia nigra pars compacta was estimated by tyrosine hydroxylase immunohistochemistry. PQ induced difficulty in movement and significant reduction in motor activity and twitch tension at the dorsiflexor skeletal muscle. The number of tyrosine hydroxylase positive neurons was significantly less in the substantia nigra pars compacta and nigral dopamine level was significantly reduced in PQ treated animals (20.4+/-3.4 pg/mg) when compared with control animals (55.0+/-2.4 pg/mg wet tissue). Daily treatment of PQ for three weeks induces selective dopaminergic neuronal loss in the substantia nigra and significant behavioral and peripheral motor deficit effects.
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Affiliation(s)
- M A Fahim
- Faculty of Medicine, UAE University, Al Ain, United Arab Emirates.
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Wu B, Song B, Yang H, Huang B, Chi B, Guo Y, Liu H. Central nervous system damage due to acute paraquat poisoning: An experimental study with rat model. Neurotoxicology 2013; 35:62-70. [DOI: 10.1016/j.neuro.2012.12.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 12/08/2012] [Accepted: 12/08/2012] [Indexed: 12/17/2022]
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Chen X, Chen S, Jiang Y, Zhu C, Wu A, Ma X, Peng F, Ma L, Zhu D, Wang Q, Pi R. Minocycline reduces oxygen-glucose deprivation-induced PC12 cell cytotoxicity via matrix metalloproteinase-9, integrin β1 and phosphorylated Akt modulation. Neurol Sci 2012; 34:1391-6. [PMID: 23224583 DOI: 10.1007/s10072-012-1246-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 11/08/2012] [Indexed: 01/17/2023]
Abstract
Minocycline has shown anti-inflammatory, anti-apoptotic, and antioxidative activities in many models of cerebral ischemia and human acute ischemic stroke. However, the cellular and molecular bases for its neuroprotective effects have not been fully elucidated. In this study, we investigated whether pre-treatment with minocycline could attenuate oxygen-glucose deprivation-induced PC12 cytotoxicity. The activity of matrix metalloproteinase-9 was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. And the expressions of integrin β1, Akt and phosphorylated Akt were analyzed by Western blot. Our results showed that minocycline could ameliorate oxygen-glucose deprivation-induced PC12 cell cytotoxicity at concentrations of 20 nM-20 μM, down-regulate the production and activity of matrix metalloproteinase-9, inhibit the degradation of integrin β1, and up-regulate Akt phosphorylation at optimal concentration of 200 nM. The results may provide a new area for minocycline's therapeutic intervention for improving the outcomes of cerebral ischemia.
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Affiliation(s)
- Xiaohong Chen
- Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
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Yadav S, Dixit A, Agrawal S, Singh A, Srivastava G, Singh AK, Srivastava PK, Prakash O, Singh MP. Rodent models and contemporary molecular techniques: notable feats yet incomplete explanations of Parkinson's disease pathogenesis. Mol Neurobiol 2012; 46:495-512. [PMID: 22736079 DOI: 10.1007/s12035-012-8291-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 06/13/2012] [Indexed: 12/20/2022]
Abstract
Rodent models and molecular tools, mainly omics and RNA interference, have been rigorously used to decode the intangible etiology and pathogenesis of Parkinson's disease (PD). Although convention of contemporary molecular techniques and multiple rodent models paved imperative leads in deciphering the role of putative causative factors and sequential events leading to PD, complete and clear-cut mechanisms of pathogenesis are still hard to pin down. The current article reviews the implications and pros and cons of rodent models and molecular tools in understanding the molecular and cellular bases of PD pathogenesis based on the existing literature. Probable rationales for short of comprehensive leads and future possibilities in spite of the extensive applications of molecular tools and rodent models have also been discussed.
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Affiliation(s)
- Sharawan Yadav
- CSIR-Indian Institute of Toxicology Research, Lucknow-226 001, Uttar Pradesh, India
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