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Min Y, Suminda GGD, Heo Y, Kim M, Ghosh M, Son YO. Metal-Based Nanoparticles and Their Relevant Consequences on Cytotoxicity Cascade and Induced Oxidative Stress. Antioxidants (Basel) 2023; 12:antiox12030703. [PMID: 36978951 PMCID: PMC10044810 DOI: 10.3390/antiox12030703] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/06/2023] [Accepted: 03/10/2023] [Indexed: 03/16/2023] Open
Abstract
Emerging nanoscience allows us to take advantage of the improved evolutionary components and apply today’s advanced characterization and fabrication techniques to solve environmental and biological problems. Despite the promise that nanotechnology will improve our lives, the potential risks of technology remain largely uncertain. The lack of information on bio-impacts and the absence of consistent standards are the limitations of using metal-based nanoparticles (mNPs) for existing applications. To analyze the role played by the mNPs physicochemical characteristics and tactics to protect live beings, the field of nanotoxicology nowadays is focused on collecting and analyzing data from in vitro and in vivo investigations. The degree of reactive oxygen species (ROS) and oxidative stress caused by material nanoparticles (NPs) depends on many factors, such as size, shape, chemical composition, etc. These characteristics enable NPs to enter cells and interact with biological macromolecules and cell organelles, resulting in oxidative damage, an inflammatory response, the development of mitochondrial dysfunction, damage to genetic material, or cytotoxic effects. This report explored the mechanisms and cellular signaling cascades of mNPs-induced oxidative stress and the relevant health consequences.
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Affiliation(s)
- Yunhui Min
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju-si 63243, Republic of Korea
| | | | - Yunji Heo
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju-si 63243, Republic of Korea
| | - Mangeun Kim
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju-si 63243, Republic of Korea
| | - Mrinmoy Ghosh
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju-si 63243, Republic of Korea
- Department of Biotechnology, School of Bio, Chemical and Processing Engineering (SBCE), Kalasalingam Academy of Research and Educational, Krishnankoil 626126, India
- Correspondence: (M.G.); (Y.-O.S.); Tel.: +82-10-6752-9677 (M.G.); +82-64-754-3331 (Y.-O.S.)
| | - Young-Ok Son
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju-si 63243, Republic of Korea
- Department of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju-si 63243, Republic of Korea
- Bio-Health Materials Core-Facility Center, Jeju National University, Jeju-si 63243, Republic of Korea
- Practical Translational Research Center, Jeju National University, Jeju-si 63243, Republic of Korea
- Correspondence: (M.G.); (Y.-O.S.); Tel.: +82-10-6752-9677 (M.G.); +82-64-754-3331 (Y.-O.S.)
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Huai Y, Hossen MN, Wilhelm S, Bhattacharya R, Mukherjee P. Nanoparticle Interactions with the Tumor Microenvironment. Bioconjug Chem 2019; 30:2247-2263. [PMID: 31408324 PMCID: PMC6892461 DOI: 10.1021/acs.bioconjchem.9b00448] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Compared to normal tissues, the tumor microenvironment (TME) has a number of aberrant characteristics including hypoxia, acidosis, and vascular abnormalities. Many researchers have sought to exploit these anomalous features of the TME to develop anticancer therapies, and several nanoparticle-based cancer therapeutics have resulted. In this Review, we discuss the composition and pathophysiology of the TME, introduce nanoparticles (NPs) used in cancer therapy, and address the interaction between the TME and NPs. Finally, we outline both the potential problems that affect TME-based nanotherapy and potential strategies to overcome these challenges.
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Affiliation(s)
- Yanyan Huai
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
| | - Md Nazir Hossen
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
| | - Stefan Wilhelm
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, Oklahoma 73072, United States
| | - Resham Bhattacharya
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
| | - Priyabrata Mukherjee
- peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
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Bulboacă AE, Bolboacă SD, Bulboacă AC, Porfire AS, Tefas LR, Suciu ŞM, Dogaru G, Stănescu IC. Liposomal Curcumin Enhances the Effect of Naproxen in a Rat Model of Migraine. Med Sci Monit 2019; 25:5087-5097. [PMID: 31287810 PMCID: PMC6636407 DOI: 10.12659/msm.915607] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Curcumin is an antioxidant that reduces inflammation and pain. This study aimed to assess the effect of pretreatment with naproxen and liposomal curcumin compared with naproxen and curcumin solution on oxidative stress parameters and pain in a rat model of migraine. MATERIAL AND METHODS Sixty-three male Wistar rats included a control group (n=9) and a rat model of migraine (n=54) induced by intraperitoneal injection of nitroglycerin (1 mg/0.1 kg). The rat model group was divided into an untreated control group (n=9), a group pretreated with naproxen alone (2.8 mg/kg) (n=9), a group pretreated with naproxen (2.8 mg/kg) combined with curcumin solution (1 mg/0.1 kg) (n=9), a group pretreated with naproxen (2.8 mg/kg) combined with curcumin solution (2 mg/0.1 kg) (n=9), a group pretreated with naproxen (2.8 mg/kg) combined with liposomal curcumin solution (1 mg/0.1 kg) (n=9) a group pretreated with naproxen (2.8 mg/kg) combined with liposomal curcumin solution (2 mg/0.1 kg) (n=9). Spectroscopy measured biomarkers of total oxidative status and nociception was tested using an injection of 1% of formalin into the rat paw. RESULTS Expression of biomarkers of oxidative stress and enhanced nociception were significantly increased following pretreatment with combined naproxen and liposomal curcumin compared with curcumin solution or naproxen alone (P<0.001). Combined curcumin solution and naproxen were more effective at a concentration of 2 mg/0.1kg for the first nociceptive phase (P<0.005). CONCLUSIONS In a rat model of migraine, combined therapy with liposomal curcumin and naproxen showed an improved antioxidant effect and anti-nociceptive effect.
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Affiliation(s)
- Adriana E. Bulboacă
- Department of Pathophysiology, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Sorana D. Bolboacă
- Department of Medical Informatics and Biostatistics, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Angelo C. Bulboacă
- Department of Neurology and Pediatric Neurology, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Alina S. Porfire
- Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Lucia R. Tefas
- Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Şoimiţa M. Suciu
- Department of Physiology, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Gabriela Dogaru
- Department of Physical Medicine and Rehabilitation, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Ioana C. Stănescu
- Department of Neurology and Pediatric Neurology, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
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Lagarde M, Guichardant M, Bernoud-Hubac N, Calzada C, Véricel E. Oxygenation of polyunsaturated fatty acids and oxidative stress within blood platelets. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:651-656. [PMID: 29555597 DOI: 10.1016/j.bbalip.2018.03.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 02/19/2018] [Accepted: 03/14/2018] [Indexed: 12/15/2022]
Abstract
The oxygenation metabolism of arachidonic acid (ArA) has been early described in blood platelets, in particular with its conversion into the potent labile thromboxane A2 that induces platelet aggregation and vascular smooth muscle cells contraction. In addition, the primary prostaglandins D2 and E2 have been mainly reported as inhibitors of platelet function. The platelet 12-lipoxygenase (12-LOX) product, i.e. the hydroperoxide 12-HpETE, appears to stimulate platelet ArA metabolism at the level of its release from membrane phospholipids through phospholipase A2 (cPLA2) and cyclooxygenase (COX-1) activities, the first enzymes in prostanoid production cascade. Also, 12-HpETE may regulate the oxygenation of other polyunsaturated fatty acids (PUFA) by platelets, especially that of eicosapentaenoic acid (EPA). On the other hand, the reduced product of 12-HpETE, 12-HETE, is able to antagonize TxA2 action. This is even more obvious for the 12-LOX end-products from docosahexaenoic acid (DHA), 11- and 14-HDoHE. In addition, 12-HpETE plays a key role in platelet oxidative stress as observed in pathophysiological conditions, but may be regulated by DHA with a bimodal way according to its concentration. Other oxygenated products of PUFA, especially omega-3 PUFA, produced outside platelets may affect platelet functions as well.
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Affiliation(s)
- Michel Lagarde
- Univ Lyon, INSA-Lyon, UMR 1060 Inserm, UMR 1397 Inra, CarMeN Lab, IMBL, F-69621 Villeurbanne, France.
| | - Michel Guichardant
- Univ Lyon, INSA-Lyon, UMR 1060 Inserm, UMR 1397 Inra, CarMeN Lab, IMBL, F-69621 Villeurbanne, France
| | - Nathalie Bernoud-Hubac
- Univ Lyon, INSA-Lyon, UMR 1060 Inserm, UMR 1397 Inra, CarMeN Lab, IMBL, F-69621 Villeurbanne, France
| | - Catherine Calzada
- Univ Lyon, INSA-Lyon, UMR 1060 Inserm, UMR 1397 Inra, CarMeN Lab, IMBL, F-69621 Villeurbanne, France
| | - Evelyne Véricel
- Univ Lyon, INSA-Lyon, UMR 1060 Inserm, UMR 1397 Inra, CarMeN Lab, IMBL, F-69621 Villeurbanne, France
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Phull AR, Nasir B, Haq IU, Kim SJ. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem Biol Interact 2018; 281:121-136. [PMID: 29258867 DOI: 10.1016/j.cbi.2017.12.024] [Citation(s) in RCA: 279] [Impact Index Per Article: 39.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 12/05/2017] [Accepted: 12/15/2017] [Indexed: 12/11/2022]
Abstract
There are numerous extra- and intra-cellular processes involved in the production of reactive oxygen species (ROS). Augmented ROS generation can cause the damage of biomolecules such as proteins, nucleic acid and lipids. ROS act as an intracellular signaling component and is associated with various inflammatory responses, chronic arthropathies, including rheumatoid arthritis (RA). It is well documented that ROS can activate different signaling pathways having a vital importance in the patho-physiology of RA. Hence, understanding of the molecular pathways and their interaction might be advantageous in the development of novel therapeutic approaches for RA.
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Affiliation(s)
- Abdul-Rehman Phull
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongju Daehak-Ro, Gongju-Si, Chungnam, 32588, Republic of Korea
| | - Bakht Nasir
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Ihsan Ul Haq
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Song Ja Kim
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongju Daehak-Ro, Gongju-Si, Chungnam, 32588, Republic of Korea.
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Messina S, Di Zazzo E, Moncharmont B. Early and Late Induction of KRAS and HRAS Proto-Oncogenes by Reactive Oxygen Species in Primary Astrocytes. Antioxidants (Basel) 2017; 6:antiox6030048. [PMID: 28661467 PMCID: PMC5618076 DOI: 10.3390/antiox6030048] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 06/17/2017] [Accepted: 06/19/2017] [Indexed: 12/13/2022] Open
Abstract
Astrocytes, one of the predominant types of glial cells, function as both supportive and metabolic cells for the brain. Among mammalian tissues, the highest levels of p21Ras protein are detected in the brain. Here, we investigated the expression of KRAS and HRAS proto-oncogenes in primary astrocytes following acute oxidative stimulation. Reactive oxygen species (ROS) changed the expression of proto-oncogenes at both transcriptional and translational levels. De novo protein synthesis analysis measured approximate values of proteins half-life, ranging from 1–4 h, of the different H- and K- isoforms by western blot analysis. Quantitative gene expression analysis of KRAS and HRAS revealed an unexpected short-term induction of KRAS mRNA in primary astrocytes in response to acute stimulation. Indeed, cultured astrocytes responded to proteasomal inhibition by preventing the reduction of c-K-Ras. A fraction of K-Ras protein accumulated in the presence of ROS and cycloheximide, while a substantial proportion was continuously synthesized. These data indicate that ROS regulate in a complementary fashion p21Ras isoforms in primary astrocytes: K-Ras is rapidly and transiently induced by post-translational and post-transcriptional mechanisms, while H-Ras is stably induced by mRNA accumulation. We suggest that K-Ras and H-Ras are ROS sensors that adapt cells to metabolic needs and oxidative stress.
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Affiliation(s)
- Samantha Messina
- Department of Human Sciences, Society and Health, University of Cassino and Southern Lazio, Cassino 03043, Italy.
| | - Erika Di Zazzo
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso 86100, Italy.
| | - Bruno Moncharmont
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso 86100, Italy.
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Elmann A, Telerman A, Erlank H, Ofir R, Kashman Y, Beit-Yannai E. Achillolide A Protects Astrocytes against Oxidative Stress by Reducing Intracellular Reactive Oxygen Species and Interfering with Cell Signaling. Molecules 2016; 21:301. [PMID: 26950103 PMCID: PMC6274406 DOI: 10.3390/molecules21030301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 02/23/2016] [Accepted: 02/25/2016] [Indexed: 11/17/2022] Open
Abstract
Achillolide A is a natural sesquiterpene lactone that we have previously shown can inhibit microglial activation. In this study we present evidence for its beneficial effects on astrocytes under oxidative stress, a situation relevant to neurodegenerative diseases and brain injuries. Viability of brain astrocytes (primary cultures) was determined by lactate dehydrogenase (LDH) activity, intracellular ROS levels were detected using 2',7'-dichlorofluorescein diacetate, in vitro antioxidant activity was measured by differential pulse voltammetry, and protein phosphorylation was determined using specific ELISA kits. We have found that achillolide A prevented the H₂O₂-induced death of astrocytes, and attenuated the induced intracellular accumulation of reactive oxygen species (ROS). These activities could be attributed to the inhibition of the H₂O₂-induced phosphorylation of MAP/ERK kinase 1 (MEK1) and p44/42 mitogen-activated protein kinases (MAPK), and to the antioxidant activity of achillolide A, but not to H₂O₂ scavenging. This is the first study that demonstrates its protective effects on brain astrocytes, and its ability to interfere with MAPK activation. We propose that achillolide A deserves further evaluation for its potential to be developed as a drug for the prevention/treatment of neurodegenerative diseases and brain injuries where oxidative stress is part of the pathophysiology.
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Affiliation(s)
- Anat Elmann
- Department of Food Quality and Safety, The Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel.
| | - Alona Telerman
- Department of Food Quality and Safety, The Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel.
| | - Hilla Erlank
- Department of Food Quality and Safety, The Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel.
| | - Rivka Ofir
- Dead Sea & Arava Science Center and Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheba 84105, Israel.
| | - Yoel Kashman
- Raymond and Beverly Sackler Faculty of Exact Sciences, School of chemistry, Tel Aviv University, Ramat Aviv 69978, Israel.
| | - Elie Beit-Yannai
- Clinical Biochemistry and Pharmacology Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheba 84105, Israel.
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Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, Trushina E, Brinton RD. White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease. EBioMedicine 2015; 2:1888-904. [PMID: 26844268 PMCID: PMC4703712 DOI: 10.1016/j.ebiom.2015.11.002] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 10/24/2015] [Accepted: 11/02/2015] [Indexed: 01/28/2023] Open
Abstract
White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.
Mitochondrial dysfunction activates mechanisms for catabolism of myelin lipids to generate ketone bodies for ATP production. Mechanisms leading to ketone body driven energy production in brain coincide with stages of reproductive aging in females. Sequential activation of myelin catabolism pathway during aging provides multiple therapeutic targets and windows of efficacy. The mechanisms underlying white matter degeneration, a hallmark of multiple neurodegenerative diseases including Alzheimer's, remain unclear. Herein we provide a mechanistic pathway, spanning multiple transitions of aging, that links mitochondrial dysfunction early in aging with later age white matter degeneration. Catabolism of myelin lipids to generate ketone bodies can be viewed as an adaptive survival response to address brain fuel and energy demand. Women are at greatest risk of late-onset-AD, thus, our analyses in female brain address mechanisms of AD pathology and therapeutic targets to prevent, delay and treat AD in the sex most affected with potential relevance to men.
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Key Words
- ABAD, Aβ-binding alcohol dehydrogenase
- ABAD, Aβ-binding-alcohol-dehydrogenase
- ACER3, alkaline ceramidase
- AD, Alzheimer's disease
- APO-ε4, apolipoprotein ε4
- APP, amyloid precursor protein
- Aging oxidative stress
- Alzheimer's disease
- BACE1, beta-secretase 1
- BBB, blood brain barrier
- CC, corpus callosum
- CMRglu, cerebral glucose metabolic rate
- COX, complex IV cytochrome c oxidase
- CPT1, carnitine palmitoyltransferase 1
- Cldn11, claudin 11
- Cyp2j6, arachidonic acid epoxygenase
- Cytosolic phospholipase A2
- DHA, docosahexaesnoic acid
- Erbb3, Erb-B2 receptor tyrosine kinase 3
- FDG-PET, 2-[18F]fluoro-2-deoxy-d-glucose
- GFAP, glial fibrillary acidic protein
- H2O2, hydrogen peroxide
- HADHA, hydroxyacyl-CoA dehydrogenase
- HK, hexokinase
- Ketone bodies
- LC MS, liquid chromatography mass spectrometer
- MAG, myelin associated glycoprotein
- MBP, myelin basic protein
- MCT1, monocarboxylate transporter 1
- MIB, mitochondrial isolation buffer
- MOG, myelin oligodendrocyte glycoprotein
- MTL, medial temporal lobe
- Mitochondria
- NEFA, nonesterified fatty acids
- Neurodegeneration
- OCR, oxygen consumption rate
- Olig2, oligodendrocyte transcription factor
- PB, phosphate buffer
- PCC, posterior cingulate
- PCR, polymerase chain reaction
- PDH, pyruvate dehydrogenase
- PEI, polyethyleneimine
- RCR, respiratory control ratio
- ROS, reactive oxygen species
- S1P, sphingosine
- TLDA, TaqMan low density array
- WM, white matter
- WT, wild type
- White matter
- cPLA2, cytosolic phospholipase A2
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Affiliation(s)
- Lauren P Klosinski
- Department of Neuroscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA
| | - Jia Yao
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Fei Yin
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | | | | | | | - Eugenia Trushina
- Department of Neurology, Mayo Clinic Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Roberta Diaz Brinton
- Department of Neuroscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Falnikar A, Hala TJ, Poulsen DJ, Lepore AC. GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury. Glia 2015; 64:396-406. [PMID: 26496514 DOI: 10.1002/glia.22936] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 10/06/2015] [Indexed: 01/23/2023]
Abstract
Development of neuropathic pain occurs in a major portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. Following SCI, chronic dysregulation of extracellular glutamate homeostasis has been shown to play a key role in persistent central hyperexcitability of superficial dorsal horn neurons that mediate pain neurotransmission, leading to various forms of neuropathic pain. Astrocytes express the major CNS glutamate transporter, GLT1, which is responsible for the vast majority of functional glutamate uptake, particularly in the spinal cord. In our unilateral cervical contusion model of mouse SCI that is associated with ipsilateral forepaw heat hypersensitivity (a form of chronic at-level neuropathic pain-related behavior), we previously reported significant and long-lasting reductions in GLT1 expression and functional GLT1-mediated glutamate uptake in cervical spinal cord dorsal horn. To therapeutically address GLT1 dysfunction following cervical contusion SCI, we injected an adeno-associated virus type 8 (AAV8)-Gfa2 vector into the superficial dorsal horn to increase GLT1 expression selectively in astrocytes. Compared to both contusion-only animals and injured mice that received AAV8-eGFP control injection, AAV8-GLT1 delivery increased GLT1 protein expression in astrocytes of the injured cervical spinal cord dorsal horn, resulting in a significant and persistent reversal of already-established heat hypersensitivity. Furthermore, AAV8-GLT1 injection significantly reduced expression of the transcription factor and marker of persistently increased neuronal activation, ΔFosB, in superficial dorsal horn neurons. These results demonstrate that focal restoration of GLT1 expression in the superficial dorsal horn is a promising target for treating chronic neuropathic pain following SCI.
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Affiliation(s)
- Aditi Falnikar
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, Pennsylvania
| | - Tamara J Hala
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, Pennsylvania
| | - David J Poulsen
- Department of Neurosurgery, University at Buffalo, SUNY-School of Medicine and Biomedical Sciences, Buffalo, New York
| | - Angelo C Lepore
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, Pennsylvania
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Liu LZ, Ding M, Zheng JZ, Zhu Y, Fenderson BA, Li B, Yu JJ, Jiang BH. Tungsten Carbide-Cobalt Nanoparticles Induce Reactive Oxygen Species, AKT, ERK, AP-1, NF-κB, VEGF, and Angiogenesis. Biol Trace Elem Res 2015; 166:57-65. [PMID: 25893364 DOI: 10.1007/s12011-015-0331-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 04/06/2015] [Indexed: 01/28/2023]
Abstract
Powder mixtures of tungsten carbide and metallic cobalt (WC-Co) are widely used in various products. Nanoparticles are engineered structures with at least one dimension of 100 nm or smaller. WC-Co is known to be associated with lung injury and diseases. Angiogenesis is a key process during vasculature, carcinogenesis, recovery of injury, and inflammatory diseases. However, the cellular effects of WC-Co nanoparticles on angiogenesis remain to be elucidated. In this study, we investigated angiogenic response and relative mechanisms after exposure to WC-Co nanoparticles. Our results showed that WC-Co nanoparticles at 5 μg/cm(2) induced ROS production which activated AKT and ERK1/2 signaling pathways in lung epithelial cells by reactive oxygen species (ROS) staining and immunoblotting; WC-Co treatment also increased transcriptional activation of AP-1, NF-κB, and VEGF by reporter assay. Further studies demonstrated that ROS are upstream molecules of AKT and ERK signaling pathways; the activation of AP-1, NF-κB, and VEGF was through ROS generation, AKT and ERK1/2 activation. In addition, WC-Co nanoparticles affected the cells to induce angiogenesis by chicken chorioallantoic membrane (CAM) assay. These results illustrate that exposure to WC-Co nanoparticles induces angiogenic response by activating ROS, AKT, and ERK1/2 signaling pathways and the downstream molecules and elucidate the potential molecular mechanisms during this process. This information may be useful for preventing potential damage from nanoparticle exposure in the future.
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Affiliation(s)
- Ling-Zhi Liu
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA,
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Rice KM, Nalabotu SK, Manne NDPK, Kolli MB, Nandyala G, Arvapalli R, Ma JY, Blough ER. Exposure to Cerium Oxide Nanoparticles Is Associated With Activation of Mitogen-activated Protein Kinases Signaling and Apoptosis in Rat Lungs. J Prev Med Public Health 2015; 48:132-41. [PMID: 26081650 PMCID: PMC4484279 DOI: 10.3961/jpmph.15.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 04/22/2015] [Indexed: 12/03/2022] Open
Abstract
Objectives: With recent advances in nanoparticle manufacturing and applications, potential exposure to nanoparticles in various settings is becoming increasing likely. No investigation has yet been performed to assess whether respiratory tract exposure to cerium oxide (CeO2) nanoparticles is associated with alterations in protein signaling, inflammation, and apoptosis in rat lungs. Methods: Specific-pathogen-free male Sprague-Dawley rats were instilled with either vehicle (saline) or CeO2 nanoparticles at a dosage of 7.0 mg/kg and euthanized 1, 3, 14, 28, 56, or 90 days after exposure. Lung tissues were collected and evaluated for the expression of proteins associated with inflammation and cellular apoptosis. Results: No change in lung weight was detected over the course of the study; however, cerium accumulation in the lungs, gross histological changes, an increased Bax to Bcl-2 ratio, elevated cleaved caspase-3 protein levels, increased phosphorylation of p38 MAPK, and diminished phosphorylation of ERK-1/2-MAPK were detected after CeO2 instillation (p<0.05). Conclusions: Taken together, these data suggest that high-dose respiratory exposure to CeO2 nanoparticles is associated with lung inflammation, the activation of signaling protein kinases, and cellular apoptosis, which may be indicative of a long-term localized inflammatory response.
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Affiliation(s)
- Kevin M Rice
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA ; School of Kinesiology, College of Health Professions, Marshall University, Huntington, WV, USA ; Biotechnology Department, West Virginia State University, Institute, WV, USA ; Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Siva K Nalabotu
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA ; Department of Pharmacology, Physiology and Toxicology, Marshall University, Joan C. Edwards School of Medicine, Huntington, WV, USA
| | | | - Madhukar B Kolli
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA ; Department of Pharmacology, Physiology and Toxicology, Marshall University, Joan C. Edwards School of Medicine, Huntington, WV, USA
| | - Geeta Nandyala
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA
| | | | - Jane Y Ma
- Health Effects Laboratory Division, NIOSH, Morgantown, WV, USA
| | - Eric R Blough
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA ; School of Kinesiology, College of Health Professions, Marshall University, Huntington, WV, USA ; Biotechnology Department, West Virginia State University, Institute, WV, USA ; Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA ; Department of Pharmacology, Physiology and Toxicology, Marshall University, Joan C. Edwards School of Medicine, Huntington, WV, USA ; Health Effects Laboratory Division, NIOSH, Morgantown, WV, USA ; Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, USA
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12
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Enriched inorganic compounds in diesel exhaust particles induce mitogen-activated protein kinase activation, cytoskeleton instability, and cytotoxicity in human bronchial epithelial cells. ACTA ACUST UNITED AC 2015; 67:323-9. [PMID: 25769681 DOI: 10.1016/j.etp.2015.02.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 02/20/2015] [Indexed: 11/23/2022]
Abstract
This study assessed the effects of the diesel exhaust particles on ERK and JNK MAPKs activation, cell rheology (viscoelasticity), and cytotoxicity in bronchial epithelial airway cells (BEAS-2B). Crude DEP and DEP after extraction with hexane (DEP/HEX) were utilized. The partial reduction of some DEP/HEX organics increased the biodisponibility of many metallic elements. JNK and ERK were activated simultaneously by crude DEP with no alterations in viscoelasticity of the cells. Mitochondrial activity, however, revealed a decrease through the MTT assay. DEP/HEX treatment increased viscoelasticity and cytotoxicity (membrane damage), and also activated JNK. Our data suggest that the greater bioavailability of metals could be involved in JNK activation and, consequently, in the reduction of fiber coherence and increase in the viscoelasticity and cytotoxicity of BEAS cells. The adverse findings detected after exposure to crude DEP and to DEP/HEX reflect the toxic potential of diesel compounds. Considering the fact that the cells of the respiratory epithelium are the first line of defense between the body and the environment, our data contribute to a better understanding of the pathways leading to respiratory cell injury and provide evidence for the onset of or worsening of respiratory diseases caused by inorganic compounds present in DEP.
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13
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Zhang T, Tang M, Kong L, Li H, Zhang T, Xue Y, Pu Y. Surface modification of multiwall carbon nanotubes determines the pro-inflammatory outcome in macrophage. JOURNAL OF HAZARDOUS MATERIALS 2015; 284:73-82. [PMID: 25463220 DOI: 10.1016/j.jhazmat.2014.11.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/06/2014] [Accepted: 11/14/2014] [Indexed: 06/04/2023]
Abstract
Carbon nanotubes (CNTs) are widely used in industry and biomedicine. While several studies have focused on biological matters, attempts to systematically elucidate the toxicity mechanisms of CNTs are limited. The aim of the present study was to evaluate and compare the cytotoxicity of raw multi-walled carbon nanotubes (MWCNTs) and MWCNTs functionalized with carboxylation (MWCNTs-COOH) or polyethylene glycol (MWCNTs-PEG) in murine macrophages. Our results show that only MWCNTs-COOH and raw MWCNTs alter the oxidative potential of macrophages by increasing reactive oxygen species and the expression of pro-inflammatory factors in both a concentration- and surface coating-dependent manner. The data suggest that compare with raw MWCNTs and MWCNTs-PEG, the MWCNTs-COOH produces a significant increase in ROS generation, interruption of ATP synthesis, and activation of the MAPK and NF-κB signaling pathways, which in turn upregulates IL-1β, IL-6, TNF-α, and iNOS to trigger cell death. These findings suggest that contributory cellar uptake caused by physicochemical factors rather than residual metal catalysts plays a role in ROS-mediated pro-inflammatory responses in vitro.
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Affiliation(s)
- Ting Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; Jiangsu key Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, China.
| | - Meng Tang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; Jiangsu key Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, China.
| | - Lu Kong
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; Jiangsu key Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, China.
| | - Han Li
- Department of Material Science and Engineering, National Key Laboratory of Solid State Microstructures, Nanjing University, Nanjing 210032, China.
| | - Tao Zhang
- Department of Material Science and Engineering, National Key Laboratory of Solid State Microstructures, Nanjing University, Nanjing 210032, China.
| | - Yuying Xue
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; Jiangsu key Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, China.
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; Jiangsu key Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, China.
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14
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Elmann A, Telerman A, Mordechay S, Erlank H, Rindner M, Ofir R, Kashman Y. 3,5,4'-Trihydroxy-6,7,3'-trimethoxyflavone protects astrocytes against oxidative stress via interference with cell signaling and by reducing the levels of intracellular reactive oxygen species. Neurochem Int 2014; 78:67-75. [PMID: 25217804 DOI: 10.1016/j.neuint.2014.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 08/31/2014] [Accepted: 09/02/2014] [Indexed: 12/11/2022]
Abstract
Oxidative stress is tightly involved in various neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, and conditions such as ischemia. Astrocytes, the most abundant glial cells in the brain, protect neurons from reactive oxygen species (ROS) and provide them with trophic support. Therefore, any damage to astrocytes will affect neuronal survival. In a previous study we have demonstrated that an extract prepared from the plant Achillea fragrantissima (Af) prevented the oxidative stress-induced death of astrocytes and attenuated the intracellular accumulation of ROS in astrocytes under oxidative stress. In the present study, using activity guided fractionation, we have purified from this plant the active compound, determined to be a flavonoid named 3,5,4'-trihydroxy-6,7,3'-trimethoxyflavone (TTF). The effects of TTF in any biological system have not been studied previously, and this is the first study to characterize the anti-oxidant and protective effects of this compound in the context of neurodegenerative diseases. Using primary cultures of astrocytes we have found that TTF prevented the hydrogen peroxide (H2O2)-induced death of astrocytes, and attenuated the intracellular accumulation of ROS following treatment of these cells with H2O2 or the peroxyl radicals generating molecule 2,2'-Azobis(amidinopropane) (ABAP). TTF also interfered with cell signaling events and inhibited the phosphorylation of the signaling proteins stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), extracellular signal regulated kinase (ERK 1/2) and mitogen activated protein kinase kinase (MEK1) and the phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB). The mechanism of the protective effect of TTF against H2O2-cytotoxicity could not be attributed to a direct H2O2 scavenging but rather to the scavenging of free radicals as was shown in cell free systems. Thus, TTF might be a therapeutic candidate for the prevention/treatment of neurodegenerative diseases where oxidative stress is part of the pathophysiology.
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Affiliation(s)
- Anat Elmann
- Department of Food Quality and Safety, Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel.
| | - Alona Telerman
- Department of Food Quality and Safety, Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel
| | - Sharon Mordechay
- Department of Food Quality and Safety, Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel
| | - Hilla Erlank
- Department of Food Quality and Safety, Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel
| | - Miriam Rindner
- Department of Food Quality and Safety, Volcani Center, Agricultural Research Organization, Bet Dagan 50250, Israel
| | - Rivka Ofir
- The Dead Sea & Arava Science Center and Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheba, 84105, Israel
| | - Yoel Kashman
- School of Chemistry, Tel Aviv University, Ramat Aviv 69978, Israel
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15
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Collins LM, Downer EJ, Toulouse A, Nolan YM. Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 in Nervous System Development and Disease. Mol Neurobiol 2014; 51:1158-67. [PMID: 24957007 DOI: 10.1007/s12035-014-8786-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 06/09/2014] [Indexed: 12/24/2022]
Abstract
Mitogen-activated protein kinase phosphatase (MKP)-1 provides a negative feedback mechanism for regulating mitogen-activated protein kinase (MAPK) activity and thus a variety of cellular processes such as proliferation, differentiation, growth and apoptosis. MKP-1 is established as a central regulator of a variety of functions in the immune, metabolic and cardiovascular systems, and it is now increasingly acknowledged as having a role to play in the nervous system. It has been implicated in regulating processes of neuronal cell development and death as well as in glial cell function. Reduced MKP-1 levels have been observed in models of neurological conditions including Huntington's disease, multiple sclerosis, ischemia and cerebral hypoxia. It has also been suggested to have a role to play in psychiatric disorders such as major depressive disorder. Here, we discuss the role of MKP-1 in nervous system development and disease and examine current evidence providing insight into MKP-1 as a potential therapeutic target for various diseases of the central nervous system.
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Affiliation(s)
- Louise M Collins
- Department of Anatomy and Neuroscience, University College Cork, Western Gate Building, Cork, Ireland
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16
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Yasuda D, Takahashi K, Ohe T, Nakamura S, Mashino T. Antioxidant activities of 5-hydroxyoxindole and its 3-hydroxy-3-phenacyl derivatives: The suppression of lipid peroxidation and intracellular oxidative stress. Bioorg Med Chem 2013; 21:7709-14. [DOI: 10.1016/j.bmc.2013.10.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/15/2013] [Accepted: 10/17/2013] [Indexed: 10/26/2022]
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17
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Mechanisms of nanoparticle-induced oxidative stress and toxicity. BIOMED RESEARCH INTERNATIONAL 2013; 2013:942916. [PMID: 24027766 PMCID: PMC3762079 DOI: 10.1155/2013/942916] [Citation(s) in RCA: 876] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 07/16/2013] [Indexed: 12/14/2022]
Abstract
The rapidly emerging field of nanotechnology has offered innovative discoveries in the medical, industrial, and consumer sectors. The unique physicochemical and electrical properties of engineered nanoparticles (NP) make them highly desirable in a variety of applications. However, these novel properties of NP are fraught with concerns for environmental and occupational exposure. Changes in structural and physicochemical properties of NP can lead to changes in biological activities including ROS generation, one of the most frequently reported NP-associated toxicities. Oxidative stress induced by engineered NP is due to acellular factors such as particle surface, size, composition, and presence of metals, while cellular responses such as mitochondrial respiration, NP-cell interaction, and immune cell activation are responsible for ROS-mediated damage. NP-induced oxidative stress responses are torch bearers for further pathophysiological effects including genotoxicity, inflammation, and fibrosis as demonstrated by activation of associated cell signaling pathways. Since oxidative stress is a key determinant of NP-induced injury, it is necessary to characterize the ROS response resulting from NP. Through physicochemical characterization and understanding of the multiple signaling cascades activated by NP-induced ROS, a systemic toxicity screen with oxidative stress as a predictive model for NP-induced injury can be developed.
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Oxidative stress posttranslationally regulates the expression of Ha-Ras and Ki-Ras in cultured astrocytes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:792705. [PMID: 23213349 PMCID: PMC3504475 DOI: 10.1155/2012/792705] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 09/20/2012] [Accepted: 09/20/2012] [Indexed: 01/15/2023]
Abstract
Addition of hydrogen peroxide to cultured astrocytes induced a rapid and transient increase in the expression of Ha-Ras and Ki-Ras. Pull-down experiments with the GTP-Ras-binding domain of Raf-1 showed that oxidative stress substantially increased the activation of Ha-Ras, whereas a putative farnesylated activated form of Ki-Ras was only slightly increased. The increase in both Ha-Ras and Ki-Ras was insensitive to the protein synthesis inhibitor, cycloheximide, and was occluded by the proteasomal inhibitor, MG-132. In addition, exposure to hydrogen peroxide reduced the levels of ubiquitinated Ras protein, indicating that oxidative stress leads to a reduced degradation of both isoforms through the ubiquitin/proteasome pathway. Indeed, the late reduction in Ha-Ras and Ki-Ras was due to a recovery of proteasomal degradation because it was sensitive to MG-132. The late reduction of Ha-Ras levels was abrogated by compound PD98059, which inhibits the MAP kinase pathway, whereas the late reduction of Ki-Ras was unaffected by PD98059. We conclude that oxidative stress differentially regulates the expression of Ha-Ras and Ki-Ras in cultured astrocytes, and that activation of the MAP kinase pathway by oxidative stress itself or by additional factors may act as a fail-safe mechanism limiting a sustained expression of the potentially detrimental Ha-Ras.
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19
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Liu M, Zhou L, Wei L, Villarreal R, Yang X, Hu D, Riojas RA, Holmes BM, Langlais PR, Lee H, Dong LQ. Phosphorylation of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif 1 (APPL1) at Ser430 mediates endoplasmic reticulum (ER) stress-induced insulin resistance in hepatocytes. J Biol Chem 2012; 287:26087-93. [PMID: 22685300 DOI: 10.1074/jbc.m112.372292] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
APPL1 is an adaptor protein that plays a critical role in regulating adiponectin and insulin signaling. However, how APPL1 is regulated under normal and pathological conditions remains largely unknown. In this study, we show that APPL1 undergoes phosphorylation at Ser(430) and that this phosphorylation is enhanced in the liver of obese mice displaying insulin resistance. In cultured mouse hepatocytes, APPL1 phosphorylation at Ser(430) is stimulated by phorbol 12-myristate 13-acetate, an activator of classic PKC isoforms, and by the endoplasmic reticulum (ER) stress inducer, thapsigargin. Overexpression of wild-type but not dominant negative PKCα increases APPL1 phosphorylation at Ser(430) in mouse hepatocytes. In addition, suppressing PKCα expression by shRNA in hepatocytes reduces ER stress-induced APPL1 phosphorylation at Ser(430) as well as the inhibitory effect of ER stress on insulin-stimulated Akt phosphorylation. Consistent with a negative regulatory role of APPL1 phosphorylation at Ser(430) in insulin signaling, overexpression of APPL1(S430D) but not APPL1(S430A) impairs the potentiating effect of APPL1 on insulin-stimulated Akt phosphorylation at Thr(308). Taken together, our results identify APPL1 as a novel target in ER stress-induced insulin resistance and PKCα as the kinase mediating ER stress-induced phosphorylation of APPL1 at Ser(430).
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Affiliation(s)
- Meilian Liu
- Department of Pharmacology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas 78229, USA.
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20
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Gwak YS, Hulsebosch CE. Neuronal hyperexcitability: a substrate for central neuropathic pain after spinal cord injury. Curr Pain Headache Rep 2012; 15:215-22. [PMID: 21387163 DOI: 10.1007/s11916-011-0186-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neuronal hyperexcitability produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (SCI). Spontaneous and evoked neuronal excitability normally are well controlled by neural circuits. However, SCI produces maladaptive synaptic circuits in the spinal dorsal horn that result in neuronal hyperexcitability. After SCI, activated primary afferent neurons produce enhanced release of glutamate, neuropeptides, adenosine triphosphate, and proinflammatory cytokines, which are known to be major components for pain transmission in the spinal dorsal horn. Enhanced neurochemical events contribute to neuronal hyperexcitability, and neuroanatomical changes also contribute to maladaptive synaptic circuits and neuronal hyperexcitability. These neurochemical and neuroanatomical changes produce enhanced cellular signaling cascades that ensure persistently enhanced pain transmission. This review describes altered neurochemical and neuroanatomical contributions on neuronal hyperexcitability in the spinal dorsal horn, which serve as substrates for central neuropathic pain after SCI.
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Affiliation(s)
- Young Seob Gwak
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1043, USA
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21
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Heo J. Redox control of GTPases: from molecular mechanisms to functional significance in health and disease. Antioxid Redox Signal 2011; 14:689-724. [PMID: 20649471 DOI: 10.1089/ars.2009.2984] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Small GTPases, including the proto-oncoprotein Ras and Rho GTPases, are involved in various cellular signaling events. Some of these small GTPases are redox sensitive, including Ras, Rho, Ran, Dexras1, and Rhes GTPases. Thus, the redox-mediated regulation of these GTPases often determines the course of their cellular signaling cascades. This article takes into consideration the application of Marcus theory to potential redox-based molecular mechanisms in the regulation of these redox-sensitive GTPases and the relevance of such mechanisms to a specific redox-sensitive motif. The discussion also takes into account various diseases, including cancers, heart, and neuronal disorders, that are often linked with the dysregulation of the redox signaling cascades associated with these redox-sensitive GTPases.
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Affiliation(s)
- Jongyun Heo
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas 76019, USA.
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22
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Schaeffer EL, da Silva ER, Novaes BDA, Skaf HD, Gattaz WF. Differential roles of phospholipases A2 in neuronal death and neurogenesis: implications for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1381-9. [PMID: 20804810 DOI: 10.1016/j.pnpbp.2010.08.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Revised: 08/04/2010] [Accepted: 08/21/2010] [Indexed: 01/06/2023]
Abstract
The involvement of phospholipase A(2) (PLA(2)) in Alzheimer disease (AD) was first investigated nearly 15 years ago. Over the years, several PLA(2) isoforms have been detected in brain tissue: calcium-dependent secreted PLA(2) or sPLA(2) (IIA, IIC, IIE, V, X, and XII), calcium-dependent cytosolic PLA(2) or cPLA(2) (IVA, IVB, and IVC), and calcium-independent PLA(2) or iPLA(2) (VIA and VIB). Additionally, numerous in vivo and in vitro studies have suggested the role of different brain PLA(2) in both physiological and pathological events. This review aimed to summarize the findings in the literature relating the different brain PLA(2) isoforms with alterations found in AD, such as neuronal cell death and impaired neurogenesis process. The review showed that sPLA(2)-IIA, sPLA(2)-V and cPLA(2)-IVA are involved in neuronal death, whereas sPLA(2)-III and sPLA(2)-X are related to the process of neurogenesis, and that the cPLA(2) and iPLA(2) groups can be involved in both neuronal death and neurogenesis. In AD, there are reports of reduced activity of the cPLA(2) and iPLA(2) groups and increased expression of sPLA(2)-IIA and cPLA(2)-IVA. The findings suggest that the inhibition of cPLA(2) and iPLA(2) isoforms (yet to be determined) might contribute to impaired neurogenesis, whereas stimulation of sPLA(2)-IIA and cPLA(2)-IVA might contribute to neurodegeneration in AD.
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Affiliation(s)
- Evelin L Schaeffer
- Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos 785, 05403-010, Sao Paulo, SP, Brazil.
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Dubinina EE, Dadali VA. Role of 4-hydroxy-trans-2-nonenal in cell functions. BIOCHEMISTRY (MOSCOW) 2010; 75:1069-87. [DOI: 10.1134/s0006297910090014] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Cañadillas S, Canalejo R, Rodriguez-Ortiz ME, Martinez-Moreno JM, Estepa JC, Zafra R, Perez J, Muñoz-Castañeda JR, Canalejo A, Rodriguez M, Almaden Y. Upregulation of parathyroid VDR expression by extracellular calcium is mediated by ERK1/2-MAPK signaling pathway. Am J Physiol Renal Physiol 2010; 298:F1197-204. [DOI: 10.1152/ajprenal.00529.2009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We have previously demonstrated that the activation of rat parathyroid calcium-sensing receptor (CaSR) upregulates VDR expression in vivo (Garfia B, Cañadillas S, Luque F, Siendones E, Quesada M, Almadén Y, Aguilera-Tejero E, Rodríguez M. J Am Soc Nephrol 13: 2945–2952, 2002; Rodriguez ME, Almaden Y, Cañadillas S, Canalejo A, Siendones E, Lopez I, Aguilera-Tejero E, Martin D, Rodriguez M. Am J Physiol Renal Physiol 292: F1390–F1395, 2007). The present study was designed to characterize the signaling system that mediates the stimulation of parathyroid VDR gene expression by extracellular calcium. Experiments were performed in vitro by the incubation of rat parathyroid glands and in vivo with normal and uremic (Nx) rats receiving injections of CaCl2or EDTA to obtain hypercalcemic or hypocalcemic clamps. A high calcium concentration increased VDR expression. The addition of arachidonic acid (AA) to the low-calcium medium produced an increase in VDR mRNA of the same magnitude as that observed with high calcium. The addition of ionophore to the low-calcium medium also increased VDR mRNA expression. High calcium or the addition of AA to the low-calcium medium induced the activation (phosphorylation) of ERK1/2-MAPK. The specific inhibition of the ERK1/2-MAPK activity prevented the stimulation of VDR expression by high calcium or AA. These results suggest that AA regulates parathyroid VDR gene expression through the activation of the ERK1/2-MAPK. CaSR activation induced the activation of transcription factor Sp1, but not of NF-κB p50 or p65 or activator protein-1. The addition of AA to the low-calcium medium increased specific DNA-binding activity of Sp1 to almost the same level as high calcium, which was prevented by the inhibition of ERK1/2. Furthermore, mithramycin A (a Sp1 inhibitor) prevented the upregulation of VDR mRNA by high calcium. Finally, both sham and Nx hypercalcemic rats showed similar increased levels of VDR mRNA compared with sham and Nx hypocalcemic rats. Our results demonstrate that extracellular calcium stimulates VDR expression in parathyroid glands through the elevation of the cytosolic calcium level and the stimulation of the PLA2-AA-dependent ERK1/2-pathway. Furthermore, the transcription factor Sp1 mediates this effect.
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Affiliation(s)
- Sagrario Cañadillas
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
| | - Rocio Canalejo
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
| | - Maria Encarnacion Rodriguez-Ortiz
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
| | - Julio Manuel Martinez-Moreno
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
| | | | - Rafael Zafra
- Departmento Anatomía Patológica, and Universidad de Cordoba, Cordoba; and
| | - Jose Perez
- Departmento Anatomía Patológica, and Universidad de Cordoba, Cordoba; and
| | - Juan Rafael Muñoz-Castañeda
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
| | - Antonio Canalejo
- Departmento Biología Ambiental y Salud Publica, Universidad de Huelva, Huelva, Spain
| | - Mariano Rodriguez
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
| | - Yolanda Almaden
- Unidad de Investigacion, Servicio de Nefrologia, Red in ren, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia,
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Titsworth WL, Cheng X, Ke Y, Deng L, Burckardt KA, Pendleton C, Liu NK, Shao H, Cao QL, Xu XM. Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia 2009; 57:1521-37. [PMID: 19306380 DOI: 10.1002/glia.20867] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
After the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipase activity and cytosolic PLA(2)-IV alpha protein expression increased. However, the expression of secreted isoforms of PLA(2) (sPLA(2)) and their possible roles in oligodendrocyte death following SCI remained unclear. Here we report that mRNAs extracted 15 min, 4 h, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA(2)-IIA and IIE at 4 h after injury. In contrast, SCI induced down regulation of sPLA(2)-X, and no change in sPLA(2)-IB, IIC, V, and XIIA expression. At the lesion site, sPLA(2)-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA(2)-IIA (0.01, 0.1, or 2 microM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA(2)-IIA inhibitor, before a 30 min H(2)O(2) injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 h. Similarly, pretreatment with S3319 before injury with IL-1 beta and TNFalpha prevented cell death and loss of oligodendrocyte processes at 72 h. Collectively, these findings suggest that sPLA(2)-IIA and IIE are increased following SCI, that increased sPLA(2)-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA(2) can create sparing of oligodendrocytes in two distinct injury models. Therefore, sPLA(2)-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI.
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Affiliation(s)
- W Lee Titsworth
- Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA
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p38MAPK and ERK promote nitric oxide production in cultured human retinal pigmented epithelial cells induced by high concentration glucose. Nitric Oxide 2008; 20:9-15. [PMID: 18854222 DOI: 10.1016/j.niox.2008.09.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2008] [Revised: 09/17/2008] [Accepted: 09/18/2008] [Indexed: 11/24/2022]
Abstract
Increased nitric oxide (NO) has been correlated with diabetic retinopathy. In this study we investigated the cell injury, production of NO in retinal pigment epithelial (RPE) cells exposed to increased glucose concentration, and its molecular mechanism involved. Cultured human RPE cells (ARPE-19) were exposed for 4 days with normal blood glucose concentration (5.5mM D-glucose), followed by exposure to either normal (5.5mM) or high (33 mM) concentrations of D-glucose for 48 h. To determine the cytotoxicity of high glucose, cell viability, ROS production and SOD activity were measured, respectively. The end product of NO (nitrite and nitrate) was determined by a colorimetric assay and nitrotyrosine levels were quantified by a competitive ELISA. The expression of iNOS and the activation of p38MAPK, ERK and JNK were analyzed by Western blot. Treatment of RPE cells with high glucose-induced a significant increased of iNOS, accompanied by an increase in cell damage, NO and nitrotyrosine levels. High glucose caused activation of p38MAPK and ERK, inhibition for p38MAPK and ERK abrogated the high glucose-induced increase in iNOS, cell injury and levels of NO and nitrotyrosine. High glucose causes increased cell damage and NO generation in RPE cells by a process of iNOS expression that requires the activation of p38MAPK and ERK.
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Coma M, Guix FX, Ill-Raga G, Uribesalgo I, Alameda F, Valverde MA, Muñoz FJ. Oxidative stress triggers the amyloidogenic pathway in human vascular smooth muscle cells. Neurobiol Aging 2008; 29:969-80. [PMID: 17306421 DOI: 10.1016/j.neurobiolaging.2007.01.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Revised: 12/01/2006] [Accepted: 01/13/2007] [Indexed: 10/23/2022]
Abstract
Cerebral amyloid angiopathy, associated to most cases of Alzheimer's disease (AD), is characterized by the deposition of amyloid ss-peptide (Ass) in brain vessels, although the origin of the vascular amyloid deposits is still controversial: neuronal versus vascular. In the present work, we demonstrate that primary cultures of human cerebral vascular smooth muscle cells (HC-VSMCs) have all the secretases involved in amyloid ss-protein precursor (APP) cleavage and produce Ass(1-40) and Ass(1-42). Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates ss-site APP cleaving enzyme 1 (BACE1) expression, as well as Ass(1-40) and Ass(1-42) secretion in HC-VSMCs. This process is mediated by c-Jun N-terminal Kinase and p38 MAPK signaling and appears restricted to BACE1 regulation as no changes in the other secretases were observed. In conclusion, oxidative stress-mediated up-regulation of the amyloidogenic pathway in human cerebral vascular smooth muscle cells may contribute to the overall cerebrovascular amyloid angiopathy observed in AD patients.
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Affiliation(s)
- Mireia Coma
- Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
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Lamirand A, Pallud-Mothré S, Ramaugé M, Pierre M, Courtin F. Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat astrocytes. Endocrinology 2008; 149:3713-21. [PMID: 18420745 DOI: 10.1210/en.2007-1462] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Type 2 deiodinase (D2) and type 3 deiodinase (D3) locally achieve the determination of the concentration of T3, which binds to the thyroid hormone receptor with high affinity. D2 converts T4 into T3, and D3 degrades T4 and T3. Neurons take up T3 released by astrocytes, the main cerebral site for the D2 expression. Because oxidative stress is believed to be involved in several neurological disorders, we explored the effects of oxidative stress on D3 and D2 in primary culture of rat astrocytes. H2O2 (250 microm) increased D3 activity with maximal effects around 8 h. Stimulation of D3 activity by H2O2 was synergistic with T4, phorbol ester, and also cAMP. H2O2 (250 microm) did not affect basal D2 activity but inhibited the stimulation of D2 activity by cAMP and factors implicating cAMP-independent pathways in astrocytes, TSH, and phorbol ester. N-Acetyl cysteine and selenium repletion, which respectively increase intracellular glutathione and glutathione peroxidase, inhibited D2 and D3 regulation by H2O2, whereas L-buthionine sulfoximine, which decreases intracellular glutathione, mimicked H2O2 effects. Oxidative stress up-regulated D3 and inhibited cAMP-stimulated D2 by transcriptional mechanisms. A decrease in cAMP by oxidative stress could contribute to the inhibition of cAMP-stimulated D2. Using specific inhibitors of signaling pathways, we show that the ERK pathway was required in D2 and D3 regulation by oxidative stress and that the p38 MAPK pathway was implicated in H2O2-induced D3. We suggest that the expected decrease in T3 might modulate the cellular injury of oxidative stress in some pathological brain conditions.
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Affiliation(s)
- Audrey Lamirand
- Institut National de la Santé et de la Recherche Médicale, UMR 854, 80 rue du Général Leclerc, Le Kremlin-Bicêtre, France
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Cholinergic and glutamatergic alterations beginning at the early stages of Alzheimer disease: participation of the phospholipase A2 enzyme. Psychopharmacology (Berl) 2008; 198:1-27. [PMID: 18392810 DOI: 10.1007/s00213-008-1092-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2007] [Accepted: 01/28/2008] [Indexed: 12/14/2022]
Abstract
RATIONALE Alzheimer disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of AD, and thus, treatment strategies should address impairments in both systems. Evidence suggests the involvement of phospholipase A(2) (PLA(2)) enzyme in memory impairment and neurodegeneration in AD via actions on both cholinergic and glutamatergic systems. OBJECTIVES To review cholinergic and glutamatergic alterations underlying cognitive impairment and neuropathology in AD and attempt to link PLA(2) with such alterations. METHODS Medline databases were searched (no date restrictions) for published articles with links among the terms Alzheimer disease (mild, moderate, severe), mild cognitive impairment, choline acetyltransferase, acetylcholinesterase, NGF, NGF receptor, muscarinic receptor, nicotinic receptor, NMDA, AMPA, metabotropic glutamate receptor, atrophy, glucose metabolism, phospholipid metabolism, sphingolipid, membrane fluidity, phospholipase A(2), arachidonic acid, attention, memory, long-term potentiation, beta-amyloid, tau, inflammation, and reactive species. Reference lists of the identified articles were checked to identify additional studies of interest. RESULTS Overall, results suggest the hypothesis that persistent inhibition of cPLA(2) and iPLA(2) isoforms at early stages of AD may play a central role in memory deficits and beta-amyloid production through down-regulation of cholinergic and glutamate receptors. As the disease progresses, beta-amyloid induced up-regulation of cPLA(2) and sPLA(2) isoforms may play critical roles in inflammation and oxidative stress, thus participating in the neurodegenerative process. CONCLUSION Activation and inhibition of specific PLA(2) isoforms at different stages of AD could be of therapeutic importance and delay cognitive dysfunction and neurodegeneration.
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Messina S, Molinaro G, Bruno V, Battaglia G, Spinsanti P, Di Pardo A, Nicoletti F, Frati L, Porcellini A. Enhanced expression of Harvey ras induced by serum deprivation in cultured astrocytes. J Neurochem 2008; 106:551-9. [PMID: 18410509 DOI: 10.1111/j.1471-4159.2008.05420.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Trophic deprivation contributes to astrocyte damage that occurs in acute and chronic neurodegenerative disorders. Unraveling the underlying mechanisms may pave way to novel cytoprotective strategies. Cultured mouse astrocytes responded to trophic deprivation with a large and transient increase in the expression of p21(ras), which was secondary to an enhanced formation of reactive oxygen species (ROS) detected by cytofluorimetric analysis after preloading with 2',7'-dichlorofluorescein diacetate. The increase in p21(ras) levels was largely attenuated by the reducing agent, N-acetylcysteine, which was proven to reduce ROS formation in astrocytes subjected to serum deprivation. We extended the analysis to the Ha-Ras isoform, which has been implicated in mechanisms of cytotoxicity. We found that serum deprivation enhanced the expression and activity of Ha-Ras without changing Ha-Ras mRNA levels. The increase in Ha-Ras levels was sensitive to the protein synthesis inhibitor, cycloheximide, suggesting that serum deprivation increases translation of preformed Ha-Ras mRNA. The late decline in Ha-Ras levels observed after 60 min was prevented by the proteasome inhibitor, MG132, as well as by the selective mitogen-activated protein kinase (MAPK) inhibitor, PD98059. Serum deprivation led to the activation of the MAPK pathway in cultured astrocytes, as shown by an increase in phosphorylated extracellular signal-regulated kinase 1/2 levels after 5 and 30 min. Finally, using the siRNA technology, we found that an acute knock-down of Ha-Ras was protective against astrocyte damage induced by serum deprivation. We conclude that cultured astrocytes respond to trophic deprivation with an increased expression in Ha-Ras, which is limited by the concomitant activation of the MAPK pathway, but is nevertheless involved in the pathophysiology of cell damage.
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Affiliation(s)
- Samantha Messina
- Department of Experimental Medicine and Pathology, University of Rome 'La Sapienza', Rome, Italy.
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Yoshida T, Sugiura H, Mitobe M, Tsuchiya K, Shirota S, Nishimura S, Shiohira S, Ito H, Nobori K, Gullans SR, Akiba T, Nitta K. ATF3 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 2008; 19:217-24. [PMID: 18235102 DOI: 10.1681/asn.2005111155] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.
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Affiliation(s)
- Takumi Yoshida
- Department of Internal Medicine IV, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-city, Tokyo, Japan 162-8666.
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Crivello NA, Rosenberg IH, Shukitt-Hale B, Bielinski D, Dallal GE, Joseph JA. Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide. AGE (DORDRECHT, NETHERLANDS) 2007; 29:191-203. [PMID: 19424838 PMCID: PMC2267029 DOI: 10.1007/s11357-007-9039-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Accepted: 08/24/2007] [Indexed: 05/27/2023]
Abstract
Our previous studies demonstrated a significant decline in brain function and behavior in Fischer 344 (F344) rats with age. The present study was designed to test the hypothesis that dysregulation in calcium homeostasis (as assessed through (45)Ca flux) may contribute to the increase in age-related vulnerability to oxidative stress in brain regions, and result in a deficit in behavior-mediated signaling. Crude membrane (P-2) and more purified synaptosomal fractions were isolated from the striatum, hippocampus, and frontal cortex of young (6 months) and old (22 months) F344 rats and were assessed for calcium flux and extracellular-regulated kinase activity 1 (ERK) under control and oxidative stress conditions induced by low dose hydrogen peroxide (final concentration 5 microM). The level of oxidative stress responses was monitored by measuring reactive oxygen species (ROS) and glutathione (GSH). The results showed a significant difference in oxidative stress responses between young and old rats in evaluated brain regions. Old rats showed higher sensitivity to oxidative stress than young rats. The present findings show the differential effects of oxidative stress on calcium flux in brain regions with age that are dependent upon the brain areas examined and the fraction assessed. The accumulation of ROS and the decrease in GSH in the frontal cortex were sufficient to decrease ERK activity in old rats. This is the first study, to our knowledge, that demonstrates age-related differential sensitivity to oxidative stress expressed as a function of behavior-mediated signaling and stress levels among different fractions isolated from brain regions controlling behavior.
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Affiliation(s)
- Natalia A Crivello
- Nutrition and Neurocognition Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
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Tephly LA, Carter AB. Constitutive NADPH oxidase and increased mitochondrial respiratory chain activity regulate chemokine gene expression. Am J Physiol Lung Cell Mol Physiol 2007; 293:L1143-55. [PMID: 17704189 DOI: 10.1152/ajplung.00114.2007] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Alveolar macrophages, which generate high levels of reactive oxygen species, especially O(2)(*-), are involved in the recruitment of neutrophils to sites of inflammation and injury in the lung, and the generation of chemotactic proteins triggers this cellular recruitment. In this study, we asked whether O(2)(*-) generation in alveolar macrophages had a role in the expression of chemokines. Specifically, we hypothesized that O(2)(*-) generation is necessary for chemokine expression in alveolar macrophages after TNF-alpha stimulation. We found that alveolar macrophages have high constitutive NADPH oxidase activity that was not increased by TNF-alpha, but TNF-alpha increased the activity of the mitochondrial respiratory chain. In addition, the mitochondrial respiratory chain increased O(2)(*-) generation if the NADPH oxidase was inhibited. O(2)(*-) generation was necessary for macrophage inflammatory protein-2 (MIP-2) gene expression, because inhibition of NADPH oxidase or the mitochondrial respiratory chain or overexpression of Cu,Zn-superoxide dismutase significantly inhibited expression of MIP-2. TNF-alpha activated the ERK MAP kinase, and ERK activity was essential for chemokine gene expression. In addition, overexpression of the MEK1-->ERK pathway significantly increased IL-8 expression, and a small interfering RNA to the NADPH oxidase inhibited ERK- and TNF-alpha-induced chemokine expression. Collectively, these results suggest that in alveolar macrophages, O(2)(*-) generation mediates chemokine expression after TNF-alpha stimulation in an ERK-dependent manner.
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Affiliation(s)
- Linda A Tephly
- Division of Pulmonary, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
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McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. BIOCHIMICA ET BIOPHYSICA ACTA 2007; 1773:1263-84. [PMID: 17126425 PMCID: PMC2696318 DOI: 10.1016/j.bbamcr.2006.10.001] [Citation(s) in RCA: 1752] [Impact Index Per Article: 97.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/05/2006] [Revised: 10/02/2006] [Accepted: 10/03/2006] [Indexed: 02/07/2023]
Abstract
Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Leo Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
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McCubrey JA, Steelman LS, Franklin RA, Abrams SL, Chappell WH, Wong EWT, Lehmann BD, Terrian DM, Basecke J, Stivala F, Libra M, Evangelisti C, Martelli AM. Targeting the RAF/MEK/ERK, PI3K/AKT and p53 pathways in hematopoietic drug resistance. ADVANCES IN ENZYME REGULATION 2007; 47:64-103. [PMID: 17382374 PMCID: PMC2696319 DOI: 10.1016/j.advenzreg.2006.12.013] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- James A McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
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Nasser Y, Fernandez E, Keenan CM, Ho W, Oland LD, Tibbles LA, Schemann M, MacNaughton WK, Rühl A, Sharkey KA. Role of enteric glia in intestinal physiology: effects of the gliotoxin fluorocitrate on motor and secretory function. Am J Physiol Gastrointest Liver Physiol 2006; 291:G912-27. [PMID: 16798727 DOI: 10.1152/ajpgi.00067.2006] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The role of enteric glia in gastrointestinal physiology remains largely unexplored. We examined the actions of the gliotoxin fluorocitrate (FC) on intestinal motility, secretion, and inflammation after assessing its efficacy and specificity in vitro. FC (100 microM) caused a significant decrease in the phosphorylation of the glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diaz-4-yl)amino]-2-deoxyglucose in enteric glial cultures and a reduction in glial uptake of the fluorescent dipeptide Ala-Lys-7-amino-4-methylcoumarin-3-acetic acid in both the ileum and colon. Dipeptide uptake by resident murine macrophages or guinea pig myenteric neurons was unaffected by FC. Incubation of isolated guinea pig ileal segments with FC caused a specific and significant increase in glial expression of the phosphorylated form of ERK-1/2. Disruption of enteric glial function with FC in mice reduced small intestinal motility in vitro, including a significant decrease in basal tone and the amplitude of contractility in response to electrical field stimulation. Mice treated with 10 or 20 micromol/kg FC twice daily for 7 days demonstrated a concentration-dependent decrease in small intestinal transit. In contrast, no changes in colonic transit or ion transport in vitro were observed. There were no changes in glial or neuronal morphology, any signs of inflammation in the FC-treated mice, or any change in the number of myenteric nitric oxide synthase-expressing neurons. We conclude that FC treatment causes enteric glial dysfunction, without causing intestinal inflammation. Our data suggest that enteric glia are involved in the modulation of enteric neural circuits underlying the regulation of intestinal motility.
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Affiliation(s)
- Yasmin Nasser
- Institute for Infection, Immunity and Inflammation, University of Calgary, Alberta, Canada
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Ringel F, Bieringer F, Baethmann A, Plesnila N. Effect of Oxidative Stress on Glial Cell Volume. J Neurotrauma 2006; 23:1693-704. [PMID: 17115914 DOI: 10.1089/neu.2006.23.1693] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Cytotoxic brain edema is a major contributor of tissue damage following cerebral ischemia and traumatic brain injury. The pathophysiology of cytotoxic edema formation is still not well understood. Although it is widely believed that oxidative stress causes cytotoxic brain edema, experimental proof is lacking. The aim of the present study was therefore to examine the effect of oxidative stress on cell volume of glial cells. C6 glial cells were exposed to hydrogen peroxide and the superoxide forming complex hypoxanthine/xanthine oxidase (HX/XO). Exposure to hydrogen peroxide (0.5-5 mM) resulted in initial cell shrinkage by 5.7 +/- 1.5% (mean +/- SEM; p < 0.05) and was followed by a dose-dependent recovery to baseline. Exposure to superoxide anions generated by HX/XO provoked a delayed, but sustained decrease of cell volume by 11.8 +/- 0.9% (p < 0.05). Cell volume showed no tendency to recover upon sustained exposure to superoxide. Neither hydrogen peroxide nor HX/XO exposure was associated with a decrease of cell viability. Thereby, the present study demonstrates that oxidative stress by hydrogen peroxide and superoxide anions does not induce cytotoxic cell swelling and suggests that free radicals are not directly involved in the formation of cytotoxic brain edema.
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Affiliation(s)
- Florian Ringel
- Laboratory of Experimental Neurosurgery, Institute for Surgical Research, Ludwig-Maximilians University, Munich, Germany
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Tanaka KI, Sato T, Ohnishi Y, Nishikawa T. Hydrogen peroxide-induced thymidine incorporation into cultured rat astrocytes. J Pharmacol Sci 2006; 102:296-304. [PMID: 17072101 DOI: 10.1254/jphs.fpj06012x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
We characterized [methyl-(3)H]thymidine ([(3)H]thymidine) and [5-(3)H]uridine ([(3)H]uridine) incorporation into cultured astrocytes and neurons in the presence and absence of hydrogen peroxide (H2O2) in order to define the response to oxidative stress in the central nervous system. [(3)H]Thymidine incorporation into cultured astrocytes was remarkably decreased by N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP), a permeable analogue of cAMP, which induced a morphological change from the polygonal form (undifferentiated astrocytes) to the process-bearing one (differentiated astrocytes). H2O2 induced [(3)H]thymidine, but not [(3)H]uridine, incorporation into cultured astrocytes at only an early time from 24 h after DBcAMP treatment, although the absolute quantities of [(3)H]thymidine incorporation into astrocytes pretreated with DBcAMP were less than those into astrocytes pretreated without DBcAMP. Hydroxyurea, a replicative DNA synthesis inhibitor, suppressed dose-dependently and completely [(3)H]thymidine incorporation into astrocytes pretreated without DBcAMP, but not astrocytes pretreated with DBcAMP. H2O2 did not stimulate [(3)H]thymidine or [(3)H]uridine incorporation into astrocytes pretreated without DBcAMP and neurons. These findings indicate that only astrocytes pretreated with DBcAMP are able to increase thymidine incorporation specifically in the presence of H2O2 for a purpose other than proliferation, including the repair of H2O2-induced DNA injury, for example.
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Affiliation(s)
- Koh-ichi Tanaka
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City, Kagoshima, Japan.
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McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal 2006; 8:1775-89. [PMID: 16987031 DOI: 10.1089/ars.2006.8.1775] [Citation(s) in RCA: 637] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
An abundance of scientific literature exists demonstrating that oxidative stress influences the MAPK signaling pathways. This review summarizes these findings for the ERK, JNK, p38, and BMK1 pathways. For each of these different MAPK signaling pathways, the following is reviewed: the proteins involved in the signaling pathways, how oxidative stress can activate cellular signaling via these pathways, the types of oxidative stress that are known to induce activation of the different pathways, and the specific cell types in which oxidants induce MAPK responses. In addition, the functional outcome of oxidative stress-induced activation of these pathways is discussed. The purpose of this review is to provide the reader with an overall understanding and appreciation of oxidative stress-induced MAPK signaling.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, and the Leo W. Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834, USA
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Tosti N, Pasqualini S, Borgogni A, Ederli L, Falistocco E, Crispi S, Paolocci F. Gene expression profiles of O3-treated Arabidopsis plants. PLANT, CELL & ENVIRONMENT 2006; 29:1686-702. [PMID: 16913859 DOI: 10.1111/j.1365-3040.2006.01542.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
To analyse cellular response to O(3), the tolerant Arabidopsis thaliana genotype Col-0 was exposed to O(3) fumigation (300 ppb) for 6 h and the modulation of gene expression during the treatment (3 h after the beginning of the treatment, T3 h) and the recovery phase (6 h from the end of the treatment, T12 h) assessed by gene chip microarray and real-time reverse transcriptase (RT)-PCR analyses. The Arabidopsis transcriptional profile is complex, as new genes (i.e. reticuline oxidase) and pathways, other than those already reported as O(3)-responsive, appear to be involved in the O(3) response. The steady-state transcript levels of several WRKY genes were increased in O(3)-treated plants and the W-box was the cis-element over-represented in the promoter region of T3 h up-regulated genes. The fact that the W-box element was also over-represented in almost all T3 h-induced receptor-like kinases (RLKs) suggests a WRKY-mediated control of RLKs under O(3) stress and a mechanicistic similarity with the pathogen-induced transcriptional responses. We investigated the molecular and physiological implications of our findings in relation to O(3)-induced plant stress response.
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Affiliation(s)
- Nicola Tosti
- Università degli Studi di Perugia, Dipartimento di Biologia Vegetale e Biotecnologie Agroambientali e Zootecniche, Borgo XX Giugno, 74, I-06121 Perugia, Italy
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Hong JH, Moon SJ, Byun HM, Kim MS, Jo H, Bae YS, Lee SI, Bootman MD, Roderick HL, Shin DM, Seo JT. Critical role of phospholipase Cgamma1 in the generation of H2O2-evoked [Ca2+]i oscillations in cultured rat cortical astrocytes. J Biol Chem 2006; 281:13057-13067. [PMID: 16543237 DOI: 10.1074/jbc.m601726200] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Reactive oxygen species, such as the superoxide anion, H2O2, and the hydroxyl radical, have been considered as cytotoxic by-products of cellular metabolism. However, recent studies have provided evidence that H2O2 serves as a signaling molecule modulating various physiological functions. Here we investigated the effect of H2O2 on the regulation of intracellular Ca2+ signaling in rat cortical astrocytes. H2O2 triggered the generation of oscillations of intracellular Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner over the range 10-100 microM. The H2O2-induced [Ca2+]i oscillations persisted in the absence of extracellular Ca2+ and were prevented by depletion of intracellular Ca2+ stores with thapsigargin. The H2O2-induced [Ca2+]i oscillations were not inhibited by pretreatment with ryanodine but were prevented by 2-aminoethoxydiphenyl borate and caffeine, known antagonists of inositol 1,4,5-trisphosphate receptors. H2O2 activated phospholipase C (PLC) gamma1 in a dose-dependent manner, and U73122, an inhibitor of PLC, completely abolished the H2O2-induced [Ca2+]i oscillations. In addition, RNA interference against PLCgamma1 and the expression of the inositol 1,4,5-trisphosphate-sequestering "sponge" prevented the generation of [Ca2+]i oscillations. H2O2-induced [Ca2+]i oscillations and PLC1 phosphorylation were inhibited by pretreatment with dithiothreitol, a sulfhydryl-reducing agent. Finally, epidermal growth factor induced H2O2 production, PLCgamma1 activation, and [Ca2+]i increases, which were attenuated by N-acetylcysteine and diphenyleneiodonium and by the overexpression of peroxiredoxin type II. Therefore, we conclude that low concentrations of exogenously applied H2O2 generate [Ca2+]i oscillations by activating PLCgamma1 through sulfhydryl oxidation-dependent mechanisms. Furthermore, we show that this mechanism underlies the modulatory effect of endogenously produced H2O2 on epidermal growth factor-induced Ca2+ signaling in rat cortical astrocytes.
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Affiliation(s)
- Jeong Hee Hong
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea
| | - Seok Jun Moon
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea
| | - Hae Mi Byun
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea
| | - Min Seuk Kim
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea
| | - Hae Jo
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea
| | - Yun Soo Bae
- Division of Molecular Life Science, Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea
| | - Syng-Ill Lee
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea
| | - Martin D Bootman
- Laboratory of Molecular Signalling, The Babraham Institute, Babraham, CB2 4AT Cambridge, United Kingdom
| | - H Llewelyn Roderick
- Laboratory of Molecular Signalling, The Babraham Institute, Babraham, CB2 4AT Cambridge, United Kingdom; Department of Pharmacology, University of Cambridge, CB2 1PD Cambridge, United Kingdom
| | - Dong Min Shin
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea.
| | - Jeong Taeg Seo
- Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea.
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Gwinn MR, Vallyathan V. Respiratory burst: role in signal transduction in alveolar macrophages. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2006; 9:27-39. [PMID: 16393868 DOI: 10.1080/15287390500196081] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Alveolar macrophages play an important role in defense against airborne pathogens and particles. These macrophages respond through both the adaptive and acquired immune responses, and through the activation of a multitude of signaling pathways. One major macrophage defense mechanism is respiratory burst, the production of reactive oxygen species (ROS). While the ROS produced may act directly in pathogen killing, they may also be involved as secondary signaling messengers. This review focuses on the activation of four main signaling pathways following the production of reactive oxygen species. These pathways include the nuclear factor kappa beta (NFkB), activating protein-1 (AP-1), mitogen-activating protein kinase (MAPK), and phosphotidyl inositol-3 kinase (PI3K) pathways. This review also briefly examines the role of ROS in DNA damage, in particular looking at the base excision repair pathway (BER), the main pathway involved in repair of oxidative DNA damage. This review highlights many of the studies in the field of ROS, signal transduction, and DNA damage; however, work still remains to further elucidate the role of ROS in disease.
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Affiliation(s)
- Maureen R Gwinn
- Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA
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Strokin M, Chechneva O, Reymann KG, Reiser G. Neuroprotection of rat hippocampal slices exposed to oxygen–glucose deprivation by enrichment with docosahexaenoic acid and by inhibition of hydrolysis of docosahexaenoic acid-containing phospholipids by calcium independent phospholipase A2. Neuroscience 2006; 140:547-53. [PMID: 16563639 DOI: 10.1016/j.neuroscience.2006.02.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Revised: 02/10/2006] [Accepted: 02/10/2006] [Indexed: 11/25/2022]
Abstract
Polyunsaturated fatty acids play an important role in the development of pathological states in brain after hypoxia/ischemia. Here, we investigated the role of docosahexaenoic acid (22:6n-3) in brain phospholipids for neuronal survival. We used organotypic cultures of rat brain hippocampal slices exposed to 40 min of oxygen-glucose deprivation, to study the consequences of experimental ischemia. In [14C]docosahexaenoic acid-labeled cultures, oxygen-glucose deprivation induced significant release of radioactive docosahexaenoic acid. This release could be blocked by the selective inhibitor of the Ca2+-independent phospholipase A2, 4-bromoenol lactone (10 microM), when it was added 30 min prior to oxygen-glucose deprivation. Addition of 4-bromoenol lactone at 30 min prior to oxygen-glucose deprivation markedly decreased the neuronal damage induced by oxygen-glucose deprivation. The protective effect was substantially higher in dentate gyrus than in CA1 and CA3 areas. Enrichment of the hippocampal tissue with docosahexaenoic acid by incubation with 10 microM docosahexaenoic acid for 24 h exerted the same neuroprotective effect, which was observed after treatment with 4-bromoenol lactone. In contrast to the 24 h-preincubation, simultaneous addition of docosahexaenoic acid with the onset of oxygen-glucose deprivation had no protective effect. This suggests that incorporation of docosahexaenoic acid into phospholipids is required for the protective effect observed. Then the possible involvement of arachidonic acid metabolism in docosahexaenoic acid-induced neuroprotection was tested. Inhibition of prostaglandin production by ibuprofen produced no change in neuroprotection after 24-h incubation of the hippocampal slices with docosahexaenoic acid. Simultaneous inhibition of Ca2+-independent and Ca2+-dependent phospholipases A2 by treatment with the general phospholipase A2 inhibitor methyl arachidonyl fluorophosphonate (3 microM, 30 min prior to oxygen-glucose deprivation) resulted in significant enhancement of the neuroprotective effect in the dentate gyrus, but not in the CA1 and CA3 areas. In summary, the results reported here indicate that docosahexaenoic acid and docosahexaenoic acid-containing phospholipids provide potent protection against neurodegeneration after hypoxia/hypoglycemia. Furthermore, our data suggest that Ca2+-independent phospholipase A2, the isoform, which has been largely ignored so far, is a possible target for treatment of ischemia-related pathologies in brain.
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Affiliation(s)
- M Strokin
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Strasse 44, D-39120, Magdeburg, Germany
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Leonarduzzi G, Chiarpotto E, Biasi F, Poli G. 4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. Mol Nutr Food Res 2005; 49:1044-9. [PMID: 16270277 DOI: 10.1002/mnfr.200500090] [Citation(s) in RCA: 301] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
4-Hydroxynonenal (HNE) is by far the most investigated aldehydic end-product of oxidative breakdown of membrane n-6 polyunsaturated fatty acids. Its potential involvement in the pathogenesis of atherosclerosis has been corroborated by its consistent detection in both oxidized LDL and fibrotic plaque in humans. HNE has been shown to activate both macrophage and smooth muscle cells, i.e. the two key cell types in chronic inflammatory processes characterized by excessive fibrogenesis. By signalling to the nucleus, the aldehyde may up-regulate in these cells both expression and synthesis of monocyte chemotactic protein 1 (MCP-1) and transforming growth factor beta1 (TGFbeta1). Oxysterols, namely 27 carbon atoms oxidation products of cholesterol, are found in relatively high amount in LDL from hypercholesterolemic individuals and are consistently detectable in foam cells and necrotic core of human atherosclerotic lesion. As for HNE, the challenge of cells of the macrophage lineage with a mixture of oxysterols like that detectable in hypercholesterolemic individuals led to a marked overexpression of TGFbeta1 and MCP-1. Both HNE and oxysterols then appear to be candidates for a primary role in the progression of the atherosclerotic process.
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Noble M, Mayer-Pröschel M, Pröschel C. Redox regulation of precursor cell function: insights and paradoxes. Antioxid Redox Signal 2005; 7:1456-67. [PMID: 16356108 DOI: 10.1089/ars.2005.7.1456] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Studies on oligodendrocytes, the myelin-forming cells of the central nervous system, and on the progenitor cells from which they are derived, have provided several novel insights into the role of intracellular redox state in cell function. This review discusses our findings indicating that intracellular redox state is utilized by the organism as a means of regulating the balance between progenitor cell division and differentiation. This regulation is achieved in part through cell-intrinsic differences that modify the response of cells to extracellular signaling molecules, such that cells that are slightly more reduced are more responsive to inducers of cell survival and division and less responsive to inducers of differentiation or cell death. Cells that are slightly more oxidized, in contrast, show a greater response to inducers of differentiation or cell death, but less response to inducers of proliferation or survival. Regulation is also achieved by the ability of exogenous signaling molecules to modify intracellular redox state in a highly predictable manner, such that signaling molecules that promote self-renewal make progenitor cells more reduced and those that promote differentiation make cells more oxidized. In both cases, the redox changes induced by exposure to exogenous signaling molecules are a necessary component of their mode of action. Paradoxically, the results obtained through studies on the oligodendrocyte lineage are precisely the opposite of what might be predicted from a large number of studies demonstrating the ability of reactive oxidative species to enhance the effects of signaling through receptor tyrosine kinase receptors and to promote cell proliferation. Taken in sum, available data demonstrate clearly the existence of two distinct programs of cellular responses to changes in oxidative status. In one of these, becoming even slightly more oxidized is sufficient to inhibit proliferation and induce differentiation. In the second program, similar changes enhance proliferation. It is not yet clear how cells can interpret putatively identical signals in such opposite manners, but it does already seem clear that resolving this paradox will provide insights of considerable relevance to the understanding of normal development, tissue repair, and tumorigenesis.
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Affiliation(s)
- Mark Noble
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
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Huang C, Liu LY, Song TS, Ni L, Yang L, Hu XY, Hu JS, Song LP, Luo Y, Si LS. Apoptosis of pancreatic cancer BXPC-3 cells induced by indole-3-acetic acid in combination with horseradish peroxidase. World J Gastroenterol 2005; 11:4519-23. [PMID: 16052681 PMCID: PMC4398701 DOI: 10.3748/wjg.v11.i29.4519] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the mechanisms underlying the apoptosis of human pancreatic cancer BXPC-3 cells induced by indole-3-acetic acid (IAA) in combination with horseradish peroxidase (HRP).
METHODS: BXPC-3 cells derived from human pancreatic cancer were exposed to 40 or 80 µmol/L IAA and 1.2 µg/mL HRP at different times. Then, MTT assay was used to detect the cell proliferation. Flow cytometry was performed to analyze cell cycle. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to detect apoptosis. 2,7-Dichlorofluorescin diacetate uptake was measured by confocal microscopy to determine free radicals. Level of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) were measured by biochemical methods.
RESULTS: IAA/HRP initiated growth inhibition of BXPC-3 cells in a dose- and time-dependent manner. Flow cytometry revealed that the cells treated for 48 h were arrested at G1/G0. After exposure to 80 µmol/L IAA plus 1.2 µg/mL HRP for 72 h, the apoptosis rate increased to 72.5, which was nine times that of control. Content of MDA and activity of SOD increased respectively after treatment compared to control. Meanwhile, IAA/HRP stimulated the formation of free radicals.
CONCLUSION: The combination of IAA and HRP can inhibit the growth of human pancreatic cancer BXPC-3 cells in vitro by inducing apoptosis.
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Affiliation(s)
- Chen Huang
- Department of Cytobiology and Medical Genetics, College of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
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Vallejo JG, Nemoto S, Ishiyama M, Yu B, Knuefermann P, Diwan A, Baker JS, Defreitas G, Tweardy DJ, Mann DL. Functional significance of inflammatory mediators in a murine model of resuscitated hemorrhagic shock. Am J Physiol Heart Circ Physiol 2005; 288:H1272-7. [PMID: 15706046 DOI: 10.1152/ajpheart.01003.2003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The mechanisms that underlie the development of myocardial dysfunction after resuscitated hemorrhagic shock (HS) are not known. Recent studies suggest that systemic activation of inflammatory mediators may contribute to cellular dysfunction and/or cell death in various organs, including the heart. However, the precise role that inflammatory mediators play in the heart in the setting of resuscitated HS is not known. Accordingly, the purpose of the present study was to use a well-defined murine model of resuscitated HS to characterize the functional significance of inflammatory mediators in the heart in vivo. Mice were subjected to sham operation or resuscitated HS. Left ventricular (LV) function was assessed by two-dimensional echocardiography 6 h after resuscitation. Myocardial TNF, IL-1β, and IL-6 proteins were measured 1 and 6 h after resuscitation. To determine the role of TNF in HS-induced LV dysfunction, mice were treated with a soluble TNF receptor antagonist (etanercept) before HS or at the time of resuscitation. LV fractional shortening was significantly depressed ( P < 0.05) in resuscitated HS mice (28 ± 1.5%) compared with sham controls (35.8 ± 1.0%). TNF and IL-1β levels were significantly increased ( P < 0.05) in resuscitated HS mice. Pretreatment with etanercept abrogated resuscitated HS-induced LV dysfunction, whereas treatment at the time of resuscitation significantly attenuated, but did not abrogate, LV dysfunction. Together, these data suggest that TNF plays a critical upstream role in resuscitated HS-induced LV dysfunction; however, once the deleterious consequences of reperfusion injury are initiated, TNF contributes to, but is not necessary for, the development of LV dysfunction.
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Affiliation(s)
- Jesus G Vallejo
- Winters Center for Heart Failure Research, Houston, Texas 77030, USA
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Han HJ, Lee YJ, Park JY, Kim EJ, Lee JH, Taub ML. Effect of EGF on H2O2-induced inhibition of ?-MG uptake in renal proximal tubule cells: Involvement of MAPK and AA release. J Cell Physiol 2005; 203:217-25. [PMID: 15368538 DOI: 10.1002/jcp.20214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Both oxidative stress and epidermal growth factor (EGF) contribute to the initiation and progression of renal proximal tubular dysfunction under pathophysiologic conditions. Thus, this study was performed (1) to examine both the individual, and the combined effects of H2O2 and EGF on alpha-methyl-D-glucopyranoside uptake (alpha-MG uptake) in the primary cultured renal proximal tubule cells (PTCs), and (2) to elucidate the involvement of p44/42 mitogen activated protein kinase (MAPK) and phospholipase A2 in mediating these actions. Both H2O2 and EGF inhibited alpha-MG uptake individually, while the combination of H2O2 and EGF further potentiated the inhibitory effect on alpha-MG uptake, which was elicited by each agent. H2O2 not only caused a rapid increase in the phosphorylation of p44/42 MAPK, but also promoted the translocation of cytosolic phospholipase A2 (cPLA2) from the cytosolic to particulate fraction, and stimulated cellular [3H]-arachidonic acid (AA) release. EGF similarly activates phosphorylation of p44/42 MAPK and stimulates [3H]-AA release. When PTCs were exposed to 100 microM H2O2 and 50 ng/ml EGF simultaneously, a further increase in the phosphorylation of p44/42 MAPK, of [3H]-AA release, and of prostaglandin E2 (PGE2) production was elicited as compared with the effects of each individual agonist alone. Moreover, the additive phosphorylation of p44/42 MAPK, [3H]-AA release, and PGE2 production by H2O2 and EGF was almost completely inhibited by the p44/42 MAPK inhibitor, PD 98059. In conclusion, these results are consistent with the hypothesis that under conditions of oxidative stress, the H2O2-induced inhibition of alpha-MG uptake in the renal proximal tubule is mediated through a modulation of the EGF signaling pathway, promoting further phosphorylation of p44/42 MAPK, activation of PLA2.
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Affiliation(s)
- Ho Jae Han
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
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Pawate S, Shen Q, Fan F, Bhat NR. Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. J Neurosci Res 2004; 77:540-51. [PMID: 15264224 DOI: 10.1002/jnr.20180] [Citation(s) in RCA: 368] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Astrocytes and microglia, the two immune-regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen-activated protein kinase (MAPK), nuclear factor (NF) kappaB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)-derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)- and interferon (IFN)gamma-induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNgamma resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNgamma-induced expression of cytokines, i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c-Jun N-terminal kinase and extracellular signal-regulated kinase), NFkappaB, and IFNgamma-induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47(phox) W(193)R, and primary astrocytes derived from Phox-deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNgamma, further strengthening the notion that Phox-derived ROS are crucial for proinflammatory gene expression in glial cells.
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Affiliation(s)
- Siddharama Pawate
- Department of Neurology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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50
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Affiliation(s)
- Henry Jay Forman
- School of Natural Sciences, University of California at Merced, Merced, CA 95344, USA.
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