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LeVine SM. Exploring Potential Mechanisms Accounting for Iron Accumulation in the Central Nervous System of Patients with Alzheimer's Disease. Cells 2024; 13:689. [PMID: 38667304 PMCID: PMC11049304 DOI: 10.3390/cells13080689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 04/12/2024] [Accepted: 04/14/2024] [Indexed: 04/28/2024] Open
Abstract
Elevated levels of iron occur in both cortical and subcortical regions of the CNS in patients with Alzheimer's disease. This accumulation is present early in the disease process as well as in more advanced stages. The factors potentially accounting for this increase are numerous, including: (1) Cells increase their uptake of iron and reduce their export of iron, as iron becomes sequestered (trapped within the lysosome, bound to amyloid β or tau, etc.); (2) metabolic disturbances, such as insulin resistance and mitochondrial dysfunction, disrupt cellular iron homeostasis; (3) inflammation, glutamate excitotoxicity, or other pathological disturbances (loss of neuronal interconnections, soluble amyloid β, etc.) trigger cells to acquire iron; and (4) following neurodegeneration, iron becomes trapped within microglia. Some of these mechanisms are also present in other neurological disorders and can also begin early in the disease course, indicating that iron accumulation is a relatively common event in neurological conditions. In response to pathogenic processes, the directed cellular efforts that contribute to iron buildup reflect the importance of correcting a functional iron deficiency to support essential biochemical processes. In other words, cells prioritize correcting an insufficiency of available iron while tolerating deposited iron. An analysis of the mechanisms accounting for iron accumulation in Alzheimer's disease, and in other relevant neurological conditions, is put forward.
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Affiliation(s)
- Steven M LeVine
- Department of Cell Biology and Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 3043, Kansas City, KS 66160, USA
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2
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Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases. Drug Deliv Transl Res 2021; 12:1047-1079. [PMID: 34365576 PMCID: PMC8942947 DOI: 10.1007/s13346-021-01026-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 02/08/2023]
Abstract
Exosomes are extracellular vesicles with the diameter ranging from 50 to 100 nm and are found in different body fluids such as blood, cerebrospinal fluid (CSF), urine and saliva. Like in case of various diseases, based on the parent cells, the content of exosomes (protein, mRNA, miRNA, DNA, lipids and metabolites) varies and thus can be utilized as potential biomarker for diagnosis and prognosis of the brain diseases. Furthermore, utilizing the natural potential exosomes to cross the blood–brain barrier and by specifically decorating it with the ligand as per the desired brain sites therapeutics can be delivered to brain parenchyma. This review article conveys the importance of exosomes and their use in the treatment and diagnosis of brain/central nervous system diseases.
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Wang DS, Wang ZQ, Chen G, Peng JW, Wang W, Deng YH, Wang FH, Zhang JW, Liang HL, Feng F, Xie CB, Ren C, Jin Y, Shi SM, Fan WH, Lu ZH, Ding PR, Wang F, Xu RH, Li YH. Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer. Cancer Med 2019; 9:151-159. [PMID: 31724334 PMCID: PMC6943144 DOI: 10.1002/cam4.2693] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/04/2019] [Accepted: 10/24/2019] [Indexed: 01/04/2023] Open
Abstract
Background Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin‐based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin‐induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin‐based chemotherapy. Methods In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI‐CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTCQLQ‐CIPN20), time to grade 2 neurotoxicity (NCI‐CTCAE or the oxaliplatin‐specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3‐year disease‐free survival (DFS) and adverse events. Results There were no significant differences between the arms in the rate of NCI‐CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTCQLQ‐CIPN20 or time to grade 2 neurotoxicity using NCI‐CTCAE and the oxaliplatin‐specific neuropathy scale. GM1 substantially decreased participant‐reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3‐year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. Conclusion Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (http://ClinicalTrials.gov number, NCT02251977).
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Affiliation(s)
- De-Shen Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi-Qiang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Gong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | | | - Wei Wang
- The First People's Hospital of Foshan City, Foshan, China
| | - Yan-Hong Deng
- The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Feng-Hua Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jian-Wei Zhang
- The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | | | - Fen Feng
- The First People's Hospital of Foshan City, Foshan, China
| | - Chuan-Bo Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chao Ren
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Jin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Si-Mei Shi
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wen-Hua Fan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhen-Hai Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Pei-Rong Ding
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Feng Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu-Hong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
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4
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Han M, Ding S, Zhang Y, Lin Z, Li K. Serum Copper Homeostasis in Hypertensive Intracerebral Hemorrhage and its Clinical Significance. Biol Trace Elem Res 2018; 185:56-62. [PMID: 29322430 DOI: 10.1007/s12011-017-1227-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 12/18/2017] [Indexed: 02/05/2023]
Abstract
This study was to investigate the alterations of serum copper homeostasis after hypertensive intracerebral hemorrhage (ICH), which is not yet clear. We recruited 85 hypertensive ICH patients and determined their serum levels of total copper (TCu), small molecule copper (SMC), and ceruloplasmin (Cp). Sera from 32 healthy persons and 12 primary hypertension patients were collected and analyzed as well. Serum TCu levels in ICH patients were tested at three time points (on admission, day 3, and day 7) and found to be higher than that in hypertension patients (p < 0.05). The serum SMC levels in hypertension patients and ICH patients at three time points were higher than that in healthy controls (p < 0.05). Higher serum SMC levels on days 3 and 7 were associated with death in the hospital. Additionally, higher serum SMC levels on the seventh day were associated with poor outcome at discharge. High serum Cp levels on admission, as well as low serum Cp levels on the seventh day, were associated with death in the hospital (p = 0.002 and p = 0.034, respectively). Our findings indicated that declines in serum Cp and increases in serum SMC are correlated with lethal or poor outcome in hypertensive ICH patients, possibly as a result of contributions to secondary injury of brain after hemorrhage due to impairment of iron transport and enhanced oxidative stress.
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Affiliation(s)
- Ming Han
- Emergency Department of Second Affiliated Hospital, Shantou University Medical College, Shantou, China
- Department of Microbiology and Immunology, Shantou University Medical College, Shantou, 515041, China
| | - Shan Ding
- Craniocerebral Surgery Department of Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yuan Zhang
- Bio-analytical Laboratory, Shantou University Medical College, Shantou, China
| | - Zhexuan Lin
- Bio-analytical Laboratory, Shantou University Medical College, Shantou, China.
| | - Kangsheng Li
- Department of Microbiology and Immunology, Shantou University Medical College, Shantou, 515041, China.
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5
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Flygt J, Ruscher K, Norberg A, Mir A, Gram H, Clausen F, Marklund N. Neutralization of Interleukin-1β following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes. J Neurotrauma 2018; 35:2837-2849. [PMID: 29690837 PMCID: PMC6247990 DOI: 10.1089/neu.2018.5660] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Traumatic brain injury (TBI) commonly results in injury to the components of the white matter tracts, causing post-injury cognitive deficits. The myelin-producing oligodendrocytes (OLs) are vulnerable to TBI, although may potentially be replaced by proliferating oligodendrocyte progenitor cells (OPCs). The cytokine interleukin-1β (IL-1β) is a key mediator of the complex inflammatory response, and when neutralized in experimental TBI, behavioral outcome was improved. To evaluate the role of IL-1β on oligodendrocyte cell death and OPC proliferation, 116 adult male mice subjected to sham injury or the central fluid percussion injury (cFPI) model of traumatic axonal injury, were analyzed at two, seven, and 14 days post-injury. At 30 min post-injury, mice were randomly administered an IL-1β neutralizing or a control antibody. OPC proliferation (5-ethynyl 2'- deoxyuridine (EdU)/Olig2 co-labeling) and mature oligodendrocyte cell loss was evaluated in injured white matter tracts. Microglia/macrophages immunohistochemistry and ramification using Sholl analysis were also evaluated. Neutralizing IL-1β resulted in attenuated cell death, indicated by cleaved caspase-3 expression, and attenuated loss of mature OLs from two to seven days post-injury in brain-injured animals. IL-1β neutralization also attenuated the early, two day post-injury increase of microglia/macrophage immunoreactivity and altered their ramification. The proliferation of OPCs in brain-injured animals was not altered, however. Our data suggest that IL-1β is involved in the TBI-induced loss of OLs and early microglia/macrophage activation, although not the OPC proliferation. Attenuated oligodendrocyte cell loss may contribute to the improved behavioral outcome observed by IL-1β neutralization in this mouse model of diffuse TBI.
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Affiliation(s)
- Johanna Flygt
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden
| | - Karsten Ruscher
- 2 Novartis Institutes of Biomedical Research , Basel, Switzerland
| | - Amanda Norberg
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden
| | - Anis Mir
- 3 Lund University, Skane University Hospital , Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
| | - Hermann Gram
- 3 Lund University, Skane University Hospital , Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
| | - Fredrik Clausen
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden
| | - Niklas Marklund
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden .,3 Lund University, Skane University Hospital , Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
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Abstract
The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.
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Affiliation(s)
- Diana Boraschi
- Institute of Protein Biochemistry, National Research Council, Naples, Italy
| | - Paola Italiani
- Institute of Protein Biochemistry, National Research Council, Naples, Italy
| | - Sabrina Weil
- Immunology FB08, Justus-Liebig-Universitat Giessen, Giessen, Germany
| | - Michael U Martin
- Immunology FB08, Justus-Liebig-Universitat Giessen, Giessen, Germany
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7
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Bonaccorsi di Patti MC, Cutone A, Polticelli F, Rosa L, Lepanto MS, Valenti P, Musci G. The ferroportin-ceruloplasmin system and the mammalian iron homeostasis machine: regulatory pathways and the role of lactoferrin. Biometals 2018; 31:399-414. [PMID: 29453656 DOI: 10.1007/s10534-018-0087-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 02/14/2018] [Indexed: 02/08/2023]
Abstract
In the last 20 years, several new genes and proteins involved in iron metabolism in eukaryotes, particularly related to pathological states both in animal models and in humans have been identified, and we are now starting to unveil at the molecular level the mechanisms of iron absorption, the regulation of iron transport and the homeostatic balancing processes. In this review, we will briefly outline the general scheme of iron metabolism in humans and then focus our attention on the cellular iron export system formed by the permease ferroportin and the ferroxidase ceruloplasmin. We will finally summarize data on the role of the iron binding protein lactoferrin on the regulation of the ferroportin/ceruloplasmin couple and of other proteins involved in iron homeostasis in inflamed human macrophages.
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Affiliation(s)
| | - Antimo Cutone
- Department of Biosciences and Territory, University of Molise, C.da Fonte Lappone, 86090, Pesche, IS, Italy
| | - Fabio Polticelli
- Department of Sciences, University Roma Tre, Rome, Italy.,National Institute of Nuclear Physics, Roma Tre Section, Rome, Italy
| | - Luigi Rosa
- Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy
| | | | - Piera Valenti
- Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy
| | - Giovanni Musci
- Department of Biosciences and Territory, University of Molise, C.da Fonte Lappone, 86090, Pesche, IS, Italy.
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8
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Wu Y, Shen L, Wang R, Tang J, Ding SQ, Wang SN, Guo XY, Hu JG, Lü HZ. Increased ceruloplasmin expression caused by infiltrated leukocytes, activated microglia, and astrocytes in injured female rat spinal cords. J Neurosci Res 2018; 96:1265-1276. [PMID: 29377294 DOI: 10.1002/jnr.24221] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/21/2017] [Accepted: 01/11/2018] [Indexed: 12/17/2022]
Abstract
Ceruloplasmin (Cp), an enzyme containing six copper atoms, has important roles in iron homeostasis and antioxidant defense. After spinal cord injury (SCI), the cellular components in the local microenvironment are very complex and include functional changes of resident cells and the infiltration of leukocytes. It has been confirmed that Cp is elevated primarily in astrocytes and to a lesser extent in macrophages following SCI in mice. However, its expression in other cell types is still not very clear. In this manuscript, we provide a sensible extension of these findings by examining this system within a female Sprague-Dawley rat model and expanding the scope of inquiry to include additional cell types. Quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that the Cp mRNA and protein in SCI tissue homogenates were quite consistent with prior publications. However, we observed that Cp was expressed not only in GFAP+ astrocytes (consistent with prior reports) but also in CD11b+ microglia, CNPase+ oligodendrocytes, NeuN+ neurons, CD45+ leukocytes, and CD68+ activated microglia/macrophages. Quantitative analysis proved that infiltrated leukocytes, activated microglia/macrophages, and astrocytes should be the major sources of increased Cp.
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Affiliation(s)
- Yan Wu
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Lin Shen
- Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - Rui Wang
- Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - Jie Tang
- Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Shu-Qin Ding
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - Sai-Nan Wang
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Xue-Yan Guo
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
| | - Jian-Guo Hu
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China
| | - He-Zuo Lü
- Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Anhui Key Laboratory of Tissue Transplantation, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China.,Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, People's Republic of China
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9
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Saghazadeh A, Ferrari CC, Rezaei N. Deciphering variability in the role of interleukin-1β in Parkinson's disease. Rev Neurosci 2018; 27:635-50. [PMID: 27166719 DOI: 10.1515/revneuro-2015-0059] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 04/01/2016] [Indexed: 12/16/2022]
Abstract
Although the role of inflammation in neurodegeneration has been well acknowledged, less is known on the issue of each cytokine in specific neurodegenerative diseases. In this review, we will present evidence elucidating that interleukin-1β (IL-1β) has a multi-faceted character in pathogenesis of Parkinson's disease, which is a progressive neurodegenerative disorder. Increased levels of IL-1β were found in PD patients. Besides, PD symptoms were observed in IL-1β wild-type, but not deficient, animals. These lines of evidence suggest that IL-1β may contribute to the initiation or progression of PD. On the other hand, some studies reported decreased levels of IL-1β in PD patients. Also, genetic studies provided evidence suggesting that IL-1β may protect individuals against PD. Presumably, the broad range of IL-1β role is due to its interaction with both upstream and downstream mediators. Differences in IL-1β levels could be because of glia population (i.e. microglia and astrocytes), mitogen-activated protein kinase and nuclear factor κ light-chain-enhancer of activated B cells signaling pathways, and several mediators (including cyclooxygenase, neurotrophic factors, reactive oxygen species, caspases, heme oxygenase-1, and matrix metalloproteinases). Although far from practice at this point, unraveling theoretical therapeutic targets based on the up-down IL-1β neuroweb could facilitate the development of strategies that are likely to be used for pharmaceutical designs of anti-neurodegenerative drugs of the future.
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10
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Adiele RC, Adiele CA. Metabolic defects in multiple sclerosis. Mitochondrion 2017; 44:7-14. [PMID: 29246870 DOI: 10.1016/j.mito.2017.12.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 10/12/2017] [Accepted: 12/11/2017] [Indexed: 02/07/2023]
Abstract
Brain injuries in multiple sclerosis (MS) involve immunopathological, structural and metabolic defects on myelin sheath, oligodendrocytes (OLs), axons and neurons suggesting that different cellular mechanisms ultimately result in the formation of MS plaques, demyelination, inflammation and brain damage. Bioenergetics, oxygen and ion metabolism dominate the metabolic and biochemical pathways that maintain neuronal viability and impulse transmission which directly or indirectly point to mitochondrial integrity and adenosine triphosphate (ATP) availability indicating the involvement of mitochondria in the pathogenesis of MS. Loss of myelin proteins including myelin basic protein (MBP), proteolipid protein (PLP), myelin associated glycoprotein (MAG), myelin oligodendrocyte glycoproetin (MOG), 2, 3,-cyclic nucleotide phosphodiestarase (CNPase); microglia and microphage activation, oligodendrocyte apoptosis as well as expression of inducible nitric oxide synthase (i-NOS) and myeloperoxidase activities have been implicated in a subset of Balo's type and relapsing remitting MS (RRMS) lesions indicating the involvement of metabolic defects and oxidative stress in MS. Here, we provide an insighting review of defects in cellular metabolism including energy, oxygen and metal metabolism in MS as well as the relevance of animal models of MS in understanding the molecular, biochemical and cellular mechanisms of MS pathogenesis. Additionally, we also discussed the potential for mitochondrial targets and antioxidant protection for therapeutic benefits in MS.
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Affiliation(s)
- Reginald C Adiele
- Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada; Cameco MS Neuroscience Research Center, Saskatoon City Hospital, Saskatoon, SK, Canada; Department of Public Health, Concordia University of Edmonton, Edmonton, AB, Canada.
| | - Chiedukam A Adiele
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria
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11
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Lu C, Xia J, Bin W, Wu Y, Liu X, Zhang Y. Advances in diagnosis, treatments, and molecular mechanistic studies of traumatic brain injury. Biosci Trends 2016; 9:138-48. [PMID: 26166367 DOI: 10.5582/bst.2015.01066] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Traumatic brain injury (TBI) is a main cause of death and disability around the world especially in soldiers, children, and young men. Since its clinical diagnosis and treatment cannot predict its prognosis, novel diagnostic techniques need to be developed, insight into its molecular mechanisms needs to be gleaned, and alternative and complementary medicine (ACM) approaches to its treatment need to be developed. This review summarizes the new diagnostic methods used in clinical practice, such as imaging of structural abnormalities after TBI and measurement of prognosis-related biomarkers. This review also describes the cellular mechanisms of traditional Chinese medicine in terms of intracellular signaling pathways, the extracellular microenvironment, and stem cells. This review concludes by describing experimental and clinical studies of the use of traditional Chinese medicine as a form of ACM to treat TBI. This review helps to understand advances in the field of TBI diagnosis and treatment.
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Affiliation(s)
- Chunyu Lu
- Department of Neurosurgery, The People's Hospital of Huaibei
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12
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Taylor DD, Gercel-Taylor C. Exosome platform for diagnosis and monitoring of traumatic brain injury. Philos Trans R Soc Lond B Biol Sci 2015; 369:rstb.2013.0503. [PMID: 25135964 DOI: 10.1098/rstb.2013.0503] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We have previously demonstrated the release of membranous structures by cells into their extracellular environment, which are termed exosomes, microvesicles or extracellular vesicles depending on specific characteristics, including size, composition and biogenesis pathway. With activation, injury, stress, transformation or infection, cells express proteins and RNAs associated with the cellular responses to these events. The exosomes released by these cells can exhibit an array of proteins, lipids and nucleic acids linked to these physiologic events. This review focuses on exosomes associated with traumatic brain injury, which may be both diagnostic and a causative factor in the progression of the injury. Based on current data, exosomes play essential roles as conveyers of intercellular communication and mediators of many of the pathological conditions associated with development, progression and therapeutic failures and cellular stress in a variety of pathologic conditions. These extracellular vesicles express components responsible for angiogenesis promotion, stromal remodelling, signal pathway activation through growth factor/receptor transfer, chemoresistance, immunologic activation and genetic exchange. These circulating exosomes not only represent a central mediator of the pro-inflammatory microenvironment linked with secondary brain injury, but their presence in the peripheral circulation may serve as a surrogate for biopsies, enabling real-time diagnosis and monitoring of neurodegenerative progression.
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Affiliation(s)
- Douglas D Taylor
- Exosome Sciences, Inc., 11 Deer Park Drive, Suite 103, Monmouth Junction, NJ 08852, USA
| | - Cicek Gercel-Taylor
- Exosome Sciences, Inc., 11 Deer Park Drive, Suite 103, Monmouth Junction, NJ 08852, USA
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13
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Ceruloplasmin potentiates nitric oxide synthase activity and cytokine secretion in activated microglia. J Neuroinflammation 2014; 11:164. [PMID: 25224679 PMCID: PMC4174266 DOI: 10.1186/s12974-014-0164-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 09/04/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ceruloplasmin is a ferroxidase expressed in the central nervous system both as soluble form in the cerebrospinal fluid (CSF) and as membrane-bound GPI-anchored isoform on astrocytes, where it plays a role in iron homeostasis and antioxidant defense. It has been proposed that ceruloplasmin is also able to activate microglial cells with ensuing nitric oxide (NO) production, thereby contributing to neuroinflammatory conditions. In light of the possible role of ceruloplasmin in neurodegenerative diseases, we were prompted to investigate how this protein could contribute to microglial activation in either its native form, as well as in its oxidized form, recently found generated in the CSF of patients with Parkinson's and Alzheimer's diseases. METHODS Primary rat microglial-enriched cultures were treated with either ceruloplasmin or oxidized-ceruloplasmin, alone or in combination with lipopolysaccharide (LPS). Production of NO and expression of inducible nitric oxide synthase (iNOS) were evaluated by Griess assay and Western blot analysis, respectively. The productions of the pro-inflammatory cytokine IL-6 and the chemokine MIP-1α were assessed by quantitative RT-PCR and ELISA. RESULTS Regardless of its oxidative status, ceruloplasmin by itself was not able to activate primary rat microglia. However, ceruloplasmin reinforced the LPS-induced microglial activation, promoting an increase of NO production, as well as the induction of IL-6 and MIP-1α. Interestingly, the ceruloplasmin-mediated effects were observed in the absence of an additional induction of iNOS expression. The evaluation of iNOS activity in primary glial cultures and in vitro suggested that the increased NO production induced by the combined LPS and ceruloplasmin treatment is mediated by a potentiation of the enzymatic activity. CONCLUSIONS Ceruloplasmin potentiates iNOS activity in microglial cells activated by a pro-inflammatory stimulus, without affecting iNOS expression levels. This action might be mediated by the activation of a yet unknown Cp receptor that triggers intracellular signaling that cross-talks with the response elicited by LPS or other pro-inflammatory stimuli. Therefore, ceruloplasmin might contribute to pathological conditions in the central nervous system by exacerbating neuroinflammation.
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Musci G, Polticelli F, Bonaccorsi di Patti MC. Ceruloplasmin-ferroportin system of iron traffic in vertebrates. World J Biol Chem 2014; 5:204-215. [PMID: 24921009 PMCID: PMC4050113 DOI: 10.4331/wjbc.v5.i2.204] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 02/19/2014] [Indexed: 02/05/2023] Open
Abstract
Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin (SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasmin-ferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.
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Ayton S, Zhang M, Roberts BR, Lam LQ, Lind M, McLean C, Bush AI, Frugier T, Crack PJ, Duce JA. Ceruloplasmin and β-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron. Free Radic Biol Med 2014; 69:331-7. [PMID: 24509156 DOI: 10.1016/j.freeradbiomed.2014.01.041] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 01/10/2014] [Accepted: 01/31/2014] [Indexed: 10/25/2022]
Abstract
Traumatic brain injury (TBI) is in part complicated by pro-oxidant iron elevation independent of brain hemorrhage. Ceruloplasmin (CP) and β-amyloid protein precursor (APP) are known neuroprotective proteins that reduce oxidative damage through iron regulation. We surveyed iron, CP, and APP in brain tissue from control and TBI-affected patients who were stratified according to time of death following injury. We observed CP and APP induction after TBI accompanying iron accumulation. Elevated APP and CP expression was also observed in a mouse model of focal cortical contusion injury concomitant with iron elevation. To determine if changes in APP or CP were neuroprotective we employed the same TBI model on APP(-/-) and CP(-/-) mice and found that both exhibited exaggerated infarct volume and iron accumulation postinjury. Evidence supports a regulatory role of both proteins in defence against iron-induced oxidative damage after TBI, which presents as a tractable therapeutic target.
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Affiliation(s)
- Scott Ayton
- Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health
| | - Moses Zhang
- Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Blaine R Roberts
- Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health
| | - Linh Q Lam
- Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health
| | - Monica Lind
- Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health
| | - Catriona McLean
- Department of Pathology, and The University of Melbourne, Parkville, VIC 3010, Australia
| | - Ashley I Bush
- Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health; Department of Pathology, and The University of Melbourne, Parkville, VIC 3010, Australia
| | - Tony Frugier
- Department of Anatomy and Cell Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Peter J Crack
- Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC 3010, Australia
| | - James A Duce
- Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, North Yorkshire, UK.
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O'Brien ER, Howarth C, Sibson NR. The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches. Front Cell Neurosci 2013; 7:40. [PMID: 23596394 PMCID: PMC3627137 DOI: 10.3389/fncel.2013.00040] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 03/26/2013] [Indexed: 02/06/2023] Open
Abstract
Brain metastasis is a significant clinical problem, yet the mechanisms governing tumor cell extravasation across the blood-brain barrier (BBB) and CNS colonization are unclear. Astrocytes are increasingly implicated in the pathogenesis of brain metastasis but in vitro work suggests both tumoricidal and tumor-promoting roles for astrocyte-derived molecules. Also, the involvement of astrogliosis in primary brain tumor progression is under much investigation. However, translation of in vitro findings into in vivo and clinical settings has not been realized. Increasingly sophisticated resources, such as transgenic models and imaging technologies aimed at astrocyte-specific markers, will enable better characterization of astrocyte function in CNS tumors. Techniques such as bioluminescence and in vivo fluorescent cell labeling have potential for understanding the real-time responses of astrocytes to tumor burden. Transgenic models targeting signaling pathways involved in the astrocytic response also hold great promise, allowing translation of in vitro mechanistic findings into pre-clinical models. The challenging nature of in vivo CNS work has slowed progress in this area. Nonetheless, there has been a surge of interest in generating pre-clinical models, yielding insights into cell extravasation across the BBB, as well as immune cell recruitment to the parenchyma. While the function of astrocytes in the tumor microenvironment is still unknown, the relationship between astrogliosis and tumor growth is evident. Here, we review the role of astrogliosis in both primary and secondary brain tumors and outline the potential for the use of novel imaging modalities in research and clinical settings. These imaging approaches have the potential to enhance our understanding of the local host response to tumor progression in the brain, as well as providing new, more sensitive diagnostic imaging methods.
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Affiliation(s)
- Emma R. O'Brien
- Department of Oncology, CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital, University of OxfordOxford, UK
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Tiffany‐Castiglioni E, Hong S, Qian Y. Copper handling by astrocytes: Insights into neurodegenerative diseases. Int J Dev Neurosci 2011; 29:811-8. [DOI: 10.1016/j.ijdevneu.2011.09.004] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 09/13/2011] [Accepted: 09/14/2011] [Indexed: 12/14/2022] Open
Affiliation(s)
- Evelyn Tiffany‐Castiglioni
- Department of Veterinary Integrative BiosciencesTexas A&M UniversityCollege StationTexasTX77843United States
| | | | - Yongchang Qian
- Department of Veterinary Integrative BiosciencesTexas A&M UniversityCollege StationTexasTX77843United States
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Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties. ASN Neuro 2011; 3:e00062. [PMID: 21722095 PMCID: PMC3153963 DOI: 10.1042/an20100029] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hypoxic preconditioning reprogrammes the brain's response to subsequent H/I (hypoxia–ischaemia) injury by enhancing neuroprotective mechanisms. Given that astrocytes normally support neuronal survival and function, the purpose of the present study was to test the hypothesis that a hypoxic preconditioning stimulus would activate an adaptive astrocytic response. We analysed several functional parameters 24 h after exposing rat pups to 3 h of systemic hypoxia (8% O2). Hypoxia increased neocortical astrocyte maturation as evidenced by the loss of GFAP (glial fibrillary acidic protein)-positive cells with radial morphologies and the acquisition of multipolar GFAP-positive cells. Interestingly, many of these astrocytes had nuclear S100B. Accompanying their differentiation, there was increased expression of GFAP, GS (glutamine synthetase), EAAT-1 (excitatory amino acid transporter-1; also known as GLAST), MCT-1 (monocarboxylate transporter-1) and ceruloplasmin. A subsequent H/I insult did not result in any further astrocyte activation. Some responses were cell autonomous, as levels of GS and MCT-1 increased subsequent to hypoxia in cultured forebrain astrocytes. In contrast, the expression of GFAP, GLAST and ceruloplasmin remained unaltered. Additional experiments utilized astrocytes exposed to exogenous dbcAMP (dibutyryl-cAMP), which mimicked several aspects of the preconditioning response, to determine whether activated astrocytes could protect neurons from subsequent excitotoxic injury. dbcAMP treatment increased GS and glutamate transporter expression and function, and as hypothesized, protected neurons from glutamate excitotoxicity. Taken altogether, these results indicate that a preconditioning stimulus causes the precocious differentiation of astrocytes and increases the acquisition of multiple astrocytic functions that will contribute to the neuroprotection conferred by a sublethal preconditioning stress.
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Persichini T, Maio N, di Patti MCB, Rizzo G, Toscano S, Colasanti M, Musci G. Interleukin-1β induces ceruloplasmin and ferroportin-1 gene expression via MAP kinases and C/EBPβ, AP-1, and NF-κB activation. Neurosci Lett 2010; 484:133-8. [PMID: 20727382 DOI: 10.1016/j.neulet.2010.08.034] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2010] [Revised: 08/06/2010] [Accepted: 08/11/2010] [Indexed: 11/28/2022]
Abstract
Previously, we demonstrated that IL-1β was able to increase iron efflux from glial cells through a coordinate induction of both ferroportin-1 (Fpn) and ceruloplasmin (Cp) synthesis. In this study, we have investigated the signaling pathways that are involved in the transcriptional activation of the Cp and Fpn. Our data show that the expression of Cp and Fpn in response to IL-1β requires the activation of MAP kinase pathways as a consequence of an IL-1β receptor stimulation. Moreover, we have observed that IL-1β regulates the expression of Cp and Fpn genes through (i) p38 MAPK-mediated activation of C/EBP transcription factor, (ii) ERK1/2-, JNK1- and partially p38 MAPK-dependent activation of AP-1, and through (iii) activation of NF-κB partially mediated by p38 MAPK.
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20
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Dash PK, Redell JB, Hergenroeder G, Zhao J, Clifton GL, Moore A. Serum ceruloplasmin and copper are early biomarkers for traumatic brain injury-associated elevated intracranial pressure. J Neurosci Res 2010; 88:1719-26. [PMID: 20091772 DOI: 10.1002/jnr.22336] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
High intracranial pressure (ICP) is a prominent secondary pathology after traumatic brain injury (TBI) and is a major contributor to morbidity and mortality. Currently, there are no clinically proven methods for predicting which TBI patients will develop high ICP. In the present study, we examined whether the serum levels of the copper-binding protein ceruloplasmin are differentially altered in patients with elevated ICP (> or =25 mmHg) vs. those whose ICP remained below 20 mmHg throughout the study period. Consistent with its role as an acute-phase reactant, we found that ceruloplasmin levels were significantly increased by 3 days post-TBI compared with healthy volunteers. However, prior to this delayed increase, ceruloplasmin levels during the first 24 hr following injury were found to be significantly reduced in patients who subsequently developed high ICP. This decrease was found to have prognostic accuracy in delineating TBI patients based on their ICP status (cutoff of 140 microg/ml; sensitivity: 87%, specificity: 73%), Likewise, low total serum copper (below 1.32 microg/ml) was also found to be predictive of high ICP (sensitivity 86%, specificity 73%). These results suggest that initial serum ceruloplasmin/copper levels may have diagnostic value in predicting patients at risk for developing high intracranial pressure.
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Affiliation(s)
- Pramod K Dash
- Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, TX 77225, USA.
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21
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Taepavarapruk P, Song C. Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment. J Neurochem 2009; 112:1054-64. [PMID: 19968753 DOI: 10.1111/j.1471-4159.2009.06524.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Interleukin (IL)-1beta may play an important role in Alzheimer's disease. However, the relationships between glucocorticoids and acetylcholine (ACh), and between neurotrophins and ACh in IL-1-induced memory deficits are unknown. While ethyl-eicosapentaenoate (E-EPA) has recently been reported to reduce inflammation and improve memory, cholinergic and neurotrophic mechanisms by which E-EPA improves memory is unclear. This study evaluated: (i) the correlation between ACh release and memory impairment; (ii) the effect of glucocorticoids on ACh release; (iii) the relationship between nerve growth factor (NGF) and inflammation; and (iv) the effects of E-EPA treatment on IL-1beta-induced changes. Intracerebroventricular IL-1beta administrations produced a significant reduction in hippocampal ACh release in rats fed control diet, which was partially attenuated by mifepristone (RU 486) and completely blocked by IL-1 receptor antagonist. In eight-arm radial maze, significantly less ACh release was correlated with the memory deficits after IL-1beta administrations. mRNA expression of hippocampal NGF was lower, whereas IL-1beta was higher when compared with controls. E-EPA treatment significantly improved the memory, which was correlated with normalizing ACh release, and expressions of NGF and IL-1beta. This study revealed important mechanisms by which IL-1beta impairs, while E-EPA improves memory through IL-1-glucocorticoid-ACh release and IL-1-NGF-ACh release pathways.
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Affiliation(s)
- Pornnarin Taepavarapruk
- Department of Biomedical Sciences, AVC, University of Prince Edward Island, Charlottetown PEC1A4P3, Canada
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22
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Plasma interleukin-1beta concentration is associated with stroke in sickle cell disease. Cytokine 2009; 49:39-44. [PMID: 19900820 DOI: 10.1016/j.cyto.2009.10.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2008] [Revised: 05/11/2009] [Accepted: 10/06/2009] [Indexed: 12/15/2022]
Abstract
The pathogenesis of sickle cell disease (HbSS), which has numerous complications including stroke, involves inflammation resulting in alteration of plasma inflammatory protein concentration. We investigated HbSS children with abnormal cerebral blood flow detected by trans-cranial Doppler ultrasound (TCD) who participated in the multi-center stroke prevention (STOP) study, to determine if plasma inflammatory protein concentration is associated with the outcome of stroke. Thirty-nine plasma samples from HbSS participants with elevated TCD who had no stroke, HbSS-NS (n=13) or had stroke, HbSS-S (n=13), HbSS steady-state controls (n=7) and controls with normal hemoglobin, HbAA (n=6), were analyzed simultaneously for 27 circulating inflammatory proteins. Logistic regression and receiver operating characteristics curve analysis of stroke on plasma inflammatory mediator concentration, adjusted for age and gender, demonstrated that interleukin-1beta (IL-1beta) was protective against stroke development (HbSS-NS=19, 17-23, HbSS-S=17, 16-19 pg/mL, median and 25th-75th percentile; odds ratio=0.59, C.I.=0.36-0.96) and was a good predictor of stroke (area under curve=0.852). This result demonstrates a strong association of systemic inflammation with stroke development in HbSS via moderately increased plasma IL-1beta concentration, which is furthermore associated with a decreased likelihood of stroke in HbSS.
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23
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Schonberg DL, McTigue DM. Iron is essential for oligodendrocyte genesis following intraspinal macrophage activation. Exp Neurol 2009; 218:64-74. [PMID: 19374902 DOI: 10.1016/j.expneurol.2009.04.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 03/30/2009] [Accepted: 04/07/2009] [Indexed: 01/19/2023]
Abstract
Progenitor proliferation and differentiation are necessary for oligodendrocyte replacement. Previously, we showed that intraspinal activation of microglia and macrophages with the TLR4 agonist lipopolysaccharide (LPS) induced robust oligodendrocyte genesis. In this study we investigated whether this process involves iron since LPS can alter macrophage regulation of iron and its storage protein ferritin, and oligodendrocytes require iron for proper development and myelination. Further, activated macrophages can sequester and release iron and ferritin. We first examined whether iron or ferritin was present following LPS microinjection. Using Perl's stain, we noted a slight increase in iron at 1d, and peak iron levels 3d post-injection coincident with maximal macrophage activation. Ferritin+ cells were prevalent by 3d and included macrophages and NG2 cells (putative oligodendrocyte progenitors). At 7d, ferritin was mainly expressed by new oligodendrocytes prevalent throughout the lesions. Because of the timing and distribution of iron and ferritin after LPS, we next used an iron chelator to test whether free iron was necessary for maximal LPS-induced oligodendrocyte genesis. Chelating iron by Deferasirox (Exjade) after LPS microinjection significantly reduced the number of proliferating NG2 cells and new oligodendrocytes. Of the remaining oligodendrocytes, there was a 2-fold decrease in those expressing ferritin, revealing that the number of oligodendrocytes with high iron stores was reduced. Collectively, these results establish that iron accumulates after intraspinal TLR4 activation and is required for maximal TLR4-induced oligodendrogenesis. Since TLR4 agonists are abundant in CNS injury/disease sites, these results suggest that iron may be essential for macrophage/oligodendrocyte communication and adult glial replacement.
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Affiliation(s)
- David L Schonberg
- The Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH, USA
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24
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Swarup V, Ghosh J, Das S, Basu A. Tumor necrosis factor receptor-associated death domain mediated neuronal death contributes to the glial activation and subsequent neuroinflammation in Japanese encephalitis. Neurochem Int 2008; 52:1310-21. [DOI: 10.1016/j.neuint.2008.01.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Revised: 01/14/2008] [Accepted: 01/22/2008] [Indexed: 11/29/2022]
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Lee KH, Yun SJ, Nam KN, Gho YS, Lee EH. Activation of microglial cells by ceruloplasmin. Brain Res 2007; 1171:1-8. [PMID: 17727827 DOI: 10.1016/j.brainres.2007.07.053] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2007] [Revised: 07/26/2007] [Accepted: 07/31/2007] [Indexed: 12/20/2022]
Abstract
Ceruloplasmin (Cp) is the major copper transport protein in plasma and catalyzes the conversion of toxic ferrous iron to the safer ferric iron. As an acute-phase protein, Cp is induced during inflammation. It is synthesized primarily in the liver and is expressed in several other tissues, including the brain. Elevated Cp levels have been observed in the brain of patients with neurodegenerative conditions, including Alzheimer's, Parkinson's, and Huntington's diseases. However, the exact role(s) of Cp in inflammatory and neuropathological conditions remains unclear. Microglia are the prime effector cells involved in immune and inflammatory responses in the central nervous system (CNS). They are activated during pathological conditions to restore CNS homeostasis, but chronic microglial activation endangers neuronal survival. Consequently, it is important to identify the regulators of microglial activation and the underlying mechanisms. We sought to examine whether Cp might modulate microglial activation. We observed that Cp induced nitric oxide (NO) release and inducible NO synthase mRNA expression in BV2 microglial cells and rat brain microglia. Cp also increased levels of mRNAs encoding tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, and NADPH oxidase. Treatment of BV2 cells and primary microglia with Cp induced phosphorylation of p38 MAP kinase. Moreover, Cp induced nuclear factor (NF)-kappaB activation, showing a more sustained pattern than seen with bacterial lipopolysaccharide. Cp-stimulated NO induction was significantly attenuated by a p38 inhibitor, SB203580, and the NF-kappaB inhibitor SN50. Cp induced secretion of TNF-alpha and prostaglandin E(2) in primary microglial cultures. These results suggest that Cp may play an important role in neuropathological conditions by stimulating various proinflammatory and neurotoxic molecules in microglia.
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Affiliation(s)
- Kyung-Hee Lee
- Department of Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin-Si, Republic of Korea
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Dringen R, Bishop GM, Koeppe M, Dang TN, Robinson SR. The pivotal role of astrocytes in the metabolism of iron in the brain. Neurochem Res 2007; 32:1884-90. [PMID: 17551833 DOI: 10.1007/s11064-007-9375-0] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Accepted: 05/01/2007] [Indexed: 12/24/2022]
Abstract
Iron is essential for the normal functioning of cells but since it is also capable of generating toxic reactive oxygen species, the metabolism of iron is tightly regulated. The present article advances the view that astrocytes are largely responsible for distributing iron in the brain. Capillary endothelial cells are separated from the neuropil by the endfeet of astrocytes, so astrocytes are ideally positioned to regulate the transport of iron to other brain cells and to protect them if iron breaches the blood-brain barrier. Astrocytes do not appear to have a high metabolic requirement for iron yet they possess transporters for transferrin, haemin and non-transferrin-bound iron. They store iron efficiently in ferritin and can export iron by a mechanism that involves ferroportin and ceruloplasmin. Since astrocytes are a common site of abnormal iron accumulation in ageing and neurodegenerative disorders, they may represent a new therapeutic target for the treatment of iron-mediated oxidative stress.
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Affiliation(s)
- Ralf Dringen
- Center for Biomolecular Interactions Bremen, University of Bremen, P.O. Box 33 04 40, 28334 Bremen, Germany.
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Mishra MK, Koli P, Bhowmick S, Basu A. Neuroprotection conferred by astrocytes is insufficient to protect animals from succumbing to Japanese encephalitis. Neurochem Int 2007; 50:764-73. [PMID: 17353066 DOI: 10.1016/j.neuint.2007.01.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2006] [Revised: 01/19/2007] [Accepted: 01/22/2007] [Indexed: 10/23/2022]
Abstract
Astrocytes play a key role in regulating aspects of inflammation and in the homeostatic maintenance of the central nervous system (CNS). However, the role of astrocytes in viral encephalitis mediated inflammation is not well documented. As Japanese encephalitis virus (JEV) infection is localized to neurons and considering the importance of astrocytes in supporting neuronal survival and function, we have exploited an experimental model of Japanese encephalitis (JE) to better understand the role of astrocytes in JE. Suckling mice pups were inoculated with the virus and 2 and 4 days later we analyzed a panel of molecules characteristic of reactive astrogliosis. We show that JEV infection increases the expression of astrocyte-specific glial fibrillary acidic protein (GFAP), the glutamate aspartate transporter (GLAST), glutamate transporter-1 (GLT-1) and ceruloplasmin (CP). The transcript levels of growth factors produced predominantly by activated astrocytes such as nerve growth factor (NGF) and ciliary neurotrophin factor (CNTF) were elevated following JEV infection. The transcript level of brain-derived neurotrophic factor (BDNF) was also elevated following JEV infection. Both NGF and CNTF were capable of preventing ROS mediated neuronal death following in vitro JEV infection to a certain extent. Taken altogether, these data indicate that increased astrogliosis following JEV infection is accompanied by the enhanced ability of astrocytes to detoxify glutamate, inactivate free radical and produce neurotrophic factors that are involved in neuronal protection. However, this elevated physiological state of astrocyte is insufficient in conferring neuroprotection, as infected animals eventually succumb to infection. The response of astrocytes to JE can be amplified to modulate the adaptive response of brain to induce neuroprotection.
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Sharma V, Mishra M, Ghosh S, Tewari R, Basu A, Seth P, Sen E. Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 2007; 73:55-63. [PMID: 17499637 DOI: 10.1016/j.brainresbull.2007.01.016] [Citation(s) in RCA: 147] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2007] [Accepted: 01/29/2007] [Indexed: 11/30/2022]
Abstract
The proinflammatory cytokine interleukin-1beta (IL-1beta) contributes to inflammation and neuronal death in CNS injuries and neurodegenerative pathologies, and astrocytes have been implicated as the primary mediators of IL-1beta induced neuronal death. As astrocytes play an important role in supporting the survival and functions of neurons, we investigated the effect of plant flavonoids quercetin and luteolin, with known anti-inflammatory properties in modulating the response of human astrocytes to IL-1beta for therapeutic intervention. Flavonoids significantly decreased the release of reactive oxygen species (ROS) from astrocytes stimulated with IL-1beta. This decrease was accompanied by an increase in expression of superoxide dismutase (SOD-1) and thioredoxin (TRX1)-mediators associated with protection against oxidative stress. Flavonoids not only modulated the expression of astrocytes specific molecules such as glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and ceruloplasmin (CP) both in the presence and absence of IL-1beta but also decreased the elevated levels of proinflammatory cytokine interleukin-6 (IL-6) and chemokines interleukin-8 (IL-8), interferon-inducible protein (IP-10), monocyte-chemoattractant protein-1 (MCP-1), and RANTES from IL-1beta activated astrocytes. Significant decrease in neuronal apoptosis was observed in neurons cultured in conditioned medium obtained from astrocytes treated with a combination of IL-1beta and flavonoids as compared to that treated with IL-1beta alone. Our result suggests that by (i) enhancing the potential of activated astrocytes to detoxify free radical, (ii) reducing the expression of proinflammatory cytokines and chemokines, and (iii) modulating expression of mediators associated with enhanced physiological activity of astrocyte in response to injury, flavonoids confer (iv) protection against IL-1beta induced astrocyte mediated neuronal damage.
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Affiliation(s)
- Vivek Sharma
- National Brain Research Centre, Manesar, Haryana 122 050, India
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Getchell ML, Li H, Vaishnav RA, Borders AS, Witta J, Subhedar N, de Villiers W, Stromberg AJ, Getchell TV. Temporal gene expression profiles of target-ablated olfactory epithelium in mice with disrupted expression of scavenger receptor A: impact on macrophages. Physiol Genomics 2006; 27:245-63. [PMID: 16882882 DOI: 10.1152/physiolgenomics.00261.2005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Target ablation [removal of the olfactory bulb (OBX)] induces apoptotic death of olfactory sensory neurons (OSNs) and an immune response in which activation and recruitment of macrophages (ms) into the olfactory epithelium (OE) occupy a central role. Ms phagocytose apoptotic neurons and secrete cytokines/growth factors that regulate subsequent progenitor cell proliferation and neurogenesis. Scavenger receptor A (SR-A) is a pattern recognition receptor that mediates binding of ms to apoptotic cells and other relevant immune response functions. The aim of this study was to determine the impact of the absence of SR-A on the immune response to OBX. The immune response to OBX was evaluated in mice in which functional expression of the m scavenger receptor (MSR) was eliminated by gene disruption (MSR-/-) and wild-type (wt) mice of the same genetic background. OBX induced significant apoptotic death of mature OSNs in the two strains. However, subsequent m infiltration and activation and progenitor cell proliferation were significantly reduced in MSR-/- vs. wt mice. Gene expression profiling at short intervals after OBX demonstrated significant differences in temporal patterns of expression of several gene categories, including immune response genes. Many immune response genes that showed different temporal patterns of expression are related to m function, including cytokine and chemokine secretion, phagocytosis, and m maturation and activation. These studies suggest that impairment of the immune response to OBX in the OE of MSR-/- mice most likely resulted from decreased m adhesion and subsequent reduced infiltration and activation, with a resultant decrease in neurogenesis.
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Affiliation(s)
- M L Getchell
- Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
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Lin HW, Basu A, Druckman C, Cicchese M, Krady JK, Levison SW. Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury. J Neuroinflammation 2006; 3:15. [PMID: 16808851 PMCID: PMC1533808 DOI: 10.1186/1742-2094-3-15] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2006] [Accepted: 06/30/2006] [Indexed: 01/23/2023] Open
Abstract
The cytokines IL-1α and IL-1β are induced rapidly after insults to the CNS, and their subsequent signaling through the type 1 IL-1 receptor (IL-1R1) has been regarded as essential for a normal astroglial and microglial/macrophage response. To determine whether abrogating signaling through the IL-1R1 will alter the cardinal astrocytic responses to injury, we analyzed molecules characteristic of activated astrocytes in response to a penetrating stab wound in wild type mice and mice with a targeted deletion of IL-1R1. Here we show that after a stab wound injury, glial fibrillary acidic protein (GFAP) induction on a per cell basis is delayed in the IL-1R1-null mice compared to wild type counterparts. However, the induction of chondroitin sulfate proteoglycans, tenascin, S-100B as well as glutamate transporter proteins, GLAST and GLT-1, and glutamine synthetase are independent of IL-1RI signaling. Cumulatively, our studies on gliosis in the IL-1R1-null mice indicate that abrogating IL-1R1 signaling delays some responses of astroglial activation; however, many of the important neuroprotective adaptations of astrocytes to brain trauma are preserved. These data recommend the continued development of therapeutics to abrogate IL-1R1 signaling to treat traumatic brain injuries. However, astroglial scar related proteins were induced irrespective of blocking IL-1R1 signaling and thus, other therapeutic strategies will be required to inhibit glial scarring.
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Affiliation(s)
- Hsiao-Wen Lin
- Department of Neurology and Neuroscience, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA
| | - Anirban Basu
- National Brain Research Centre, Gurgaon – 122 050, India
| | - Charles Druckman
- Dept. of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Michael Cicchese
- Dept. of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - J Kyle Krady
- Dept. of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Steven W Levison
- Department of Neurology and Neuroscience, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA
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Nayak C, Nayak D, Raja A, Rao A. Time-level relationship between indicators of oxidative stress and Glasgow Coma Scale scores of severe head injury patients. Clin Chem Lab Med 2006; 44:460-3. [PMID: 16599841 DOI: 10.1515/cclm.2006.068] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
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Affiliation(s)
- Chandrika Nayak
- Department of Biochemistry, Melaka Manipal Medical College (Manipal Campus), Manipal, India.
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Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. ACTA ACUST UNITED AC 2005; 49:633-40. [PMID: 16269323 DOI: 10.1016/j.brainresrev.2005.03.003] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2004] [Revised: 03/14/2005] [Accepted: 03/14/2005] [Indexed: 11/19/2022]
Abstract
For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.
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Abstract
Interleukins 1alpha and 1beta (IL-1) are very potent signaling molecules that are expressed normally at low levels, but are induced rapidly in response to local or peripheral insults. IL-1 coordinates systemic host defense responses to pathogens and to injury and not surprisingly it has similar effects within the central nervous system (CNS). Numerous reports have correlated the presence of IL-1 in the injured or diseased brain, and its effects on neurons and nonneuronal cells in the CNS, but it is only recently that the importance of IL-1 signaling has been recognized. This article reviews studies that demonstrate that IL-1 is at or near the top of the hierarchical cytokine signaling cascade in the CNS that results in the activation of endogenous microglia and vascular endothelial cells to recruit peripheral leukocytes (i.e., neuroinflammation). The IL-1 system thus provides an attractive target for therapeutic intervention to ameliorate the destructive consequences of neuroinflammation.
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Affiliation(s)
- Anirban Basu
- National Brain Research Center, Manesar, Gurgaon, India.
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Ostrow LW, Sachs F. Mechanosensation and endothelin in astrocytes--hypothetical roles in CNS pathophysiology. ACTA ACUST UNITED AC 2004; 48:488-508. [PMID: 15914254 DOI: 10.1016/j.brainresrev.2004.09.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2003] [Revised: 08/19/2004] [Accepted: 09/09/2004] [Indexed: 01/23/2023]
Abstract
Endothelin (ET) is a potent autocrine mitogen produced by reactive and neoplastic astrocytes. ET has been implicated in the induction of astrocyte proliferation and other transformations engendered by brain pathology, and in promoting the malignant behavior of astrocytomas. Reactive astrocytes containing ET are found in the periphery/penumbra of a wide array of CNS pathologies. Virtually all brain pathology deforms the surrounding parenchyma, either by direct mass effect or edema. Mechanical stress is a well established stimulus for ET production and release by other cell types, but has not been well studied in the brain. However, numerous studies have illustrated that astrocytes can sense mechanical stress and translate it into chemical messages. Furthermore, the ubiquitous reticular meshwork formed by interconnected astrocytes provides an ideal morphology for sensing and responding to mechanical disturbances. We have recently demonstrated stretch-induced ET production by astrocytes in vitro. Inspired by this finding, the purpose of this article is to review the literature on (1) astrocyte mechanosensation, and (2) the endothelin system in astrocytes, and to consider the hypothesis that mechanical induction of the ET system may influence astrocyte functioning in CNS pathophysiology. We conclude by discussing evidence supporting future investigations to determine whether specific inhibition of stretch-activated ion channels may represent a novel strategy for treating or preventing CNS disturbances, as well as the relevance to astrocyte-derived tumors.
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Affiliation(s)
- Lyle W Ostrow
- Department of Physiology and Biophysics, S.U.N.Y. at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA
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di Patti MCB, Persichini T, Mazzone V, Polticelli F, Colasanti M, Musci G. Interleukin-1beta up-regulates iron efflux in rat C6 glioma cells through modulation of ceruloplasmin and ferroportin-1 synthesis. Neurosci Lett 2004; 363:182-6. [PMID: 15172111 DOI: 10.1016/j.neulet.2004.04.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2004] [Revised: 03/26/2004] [Accepted: 04/02/2004] [Indexed: 11/23/2022]
Abstract
A number of pathologies, including neurodegeneration and inflammation, have been associated with iron dysmetabolism in the brain. Hence, systems involved in iron homeostasis at the cellular level have aroused considerable interest in recent years. The iron exporter ferroportin-1 (FP) and the multicopper oxidase ceruloplasmin (CP) are essential for iron efflux from cells. By using RT-PCR, we demonstrate that FP and CP gene expression is up-regulated by treatment with the pro-inflammatory cytokine IL-1beta in rat C6 cells, taken as a glial cellular model. Following stimulation with IL-1beta, a higher expression level of CP and FP was also confirmed by Western blotting. Moreover, IL-1beta has been found to increase iron efflux from C6 cells, suggesting that both proteins may play a crucial role in iron homeostasis in pathological brain conditions, such as inflammatory and/or neurodegenerative diseases.
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