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Faraji N, Ebadpour N, Abavisani M, Gorji A. Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases. Mol Neurobiol 2025; 62:3630-3652. [PMID: 39313658 PMCID: PMC11790780 DOI: 10.1007/s12035-024-04462-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024]
Abstract
Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer's disease and Parkinson's disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.
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Affiliation(s)
- Navid Faraji
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Ebadpour
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abavisani
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Gorji
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Epilepsy Research Center, Münster University, Münster, Germany.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
- Neurosurgery Department, Münster University, Münster, Germany.
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Oz T, Kaushik A, Kujawska M. Neural stem cells for Parkinson's disease management: Challenges, nanobased support, and prospects. World J Stem Cells 2023; 15:687-700. [PMID: 37545757 PMCID: PMC10401423 DOI: 10.4252/wjsc.v15.i7.687] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/27/2023] [Accepted: 05/16/2023] [Indexed: 07/25/2023] Open
Abstract
Parkinson's disease (PD), characterized by loss of nigrostriatal dopaminergic neurons, is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide. The concept of stem cell therapy in managing neurodegenerative diseases has evolved over the years and has recently rapidly progressed. Neural stem cells (NSCs) have a few key features, including self-renewal, proliferation, and multipotency, which make them a promising agent targeting neurodegeneration. It is generally agreed that challenges for NSC-based therapy are present at every stage of the transplantation process, including preoperative cell preparation and quality control, perioperative procedures, and postoperative graft preservation, adherence, and overall therapy success. In this review, we provided a comprehensive, careful, and critical discussion of experimental and clinical data alongside the pros and cons of NSC-based therapy in PD. Given the state-of-the-art accomplishments of stem cell therapy, gene therapy, and nanotechnology, we shed light on the perspective of complementing the advantages of each process by developing nano-stem cell therapy, which is currently a research hotspot. Although various obstacles and challenges remain, nano-stem cell therapy holds promise to cure PD, however, continuous improvement and development from the stage of laboratory experiments to the clinical application are necessary.
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Affiliation(s)
- Tuba Oz
- Department of Toxicology, Poznan University of Medical Sciences, Poznan 60-631, Poland
| | - Ajeet Kaushik
- NanoBioTech Laboratory, Health System Engineering, Department of Environmental Engineering, Florida Polytechnic University, Lakeland, FL 33805, United States
- School of Engineering, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Poznan 60-631, Poland.
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Paul A, Yadav KS. Parkinson's disease: Current drug therapy and unraveling the prospects of nanoparticles. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Sidorova YA, Volcho KP, Salakhutdinov NF. Neuroregeneration in Parkinson's Disease: From Proteins to Small Molecules. Curr Neuropharmacol 2019; 17:268-287. [PMID: 30182859 PMCID: PMC6425072 DOI: 10.2174/1570159x16666180905094123] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/16/2018] [Accepted: 08/30/2018] [Indexed: 01/07/2023] Open
Abstract
Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostria-tal dopamine neurons. There is no cure for PD and current therapy is limited to supportive care that partially alleviates dis-ease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopamine neurons, drugs restoring these neurons may significantly improve treatment of PD. Method: A literature search was performed using the PubMed, Web of Science and Scopus databases to discuss the pro-gress achieved in the development of neuroregenerative agents for PD. Papers published before early 2018 were taken into account. Results: Here, we review several groups of potential agents capable of protecting and restoring dopamine neurons in cul-tures or animal models of PD including neurotrophic factors and small molecular weight compounds. Conclusion: Despite the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biologicals and small molecules have been identified. Their further clinical development can eventually give rise to disease-modifying drugs for PD. Thus, inten-sive research in the field is justified.
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Affiliation(s)
- Yulia A Sidorova
- Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Konstantin P Volcho
- Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russian Federation.,Novosibirsk State University, Novosibirsk, Russian Federation
| | - Nariman F Salakhutdinov
- Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russian Federation.,Novosibirsk State University, Novosibirsk, Russian Federation
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NEUROPROTECTIVE IMMUNITY: Leukaemia Inhibitory Factor (LIF) as guardian of brain health. MEDICINE IN DRUG DISCOVERY 2019. [DOI: 10.1016/j.medidd.2019.100006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Leukemia Inhibitory Factor Receptor Is Involved in Apoptosis in Rat Astrocytes Exposed to Oxygen-Glucose Deprivation. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1613820. [PMID: 30937308 PMCID: PMC6415309 DOI: 10.1155/2019/1613820] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 02/12/2019] [Indexed: 11/30/2022]
Abstract
Leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (Lifr) protect CNS cells, specifically neurons and myelin-sheath oligodendrocytes, in conditions of oxygen-glucose deprivation (OGD). In the case of astrocyte apoptosis resulting from reperfusion injury following hypoxia, the function of the Lifr remains to be fully elucidated. This study established models of in vivo ischemia/reperfusion (I/R) using an in vitro model of OGD to investigate the direct impact of silencing the Lifr on astrocyte apoptosis. Astrocytes harvested from newborn Wistar rats were exposed to OGD. Cell viability and apoptosis levels were determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and annexin V/propidium iodide (PI) staining assays, respectively. Apoptosis was further investigated by the TdT-mediated dUTP nick-end labelling (TUNEL) assay. A standard western blotting protocol was applied to determine levels of the protein markers Bcl2, Bax, p-Akt/Akt, p-Stat3/Stat3, and p-Erk/Erk. The cell viability assay (MTT) showed that astrocyte viability decreased in response to OGD. Furthermore, blocking RNA to silence the Lifr further reduces astrocyte viability and increases levels of apoptosis as detected by annexin V/PI double staining. Likewise, western blotting after Lifr silencing demonstrated increased levels of the apoptosis-related proteins Bax and p-Erk/Erk and correspondingly lower levels of Bcl2, p-Akt/Akt, and p-Stat/Stat3. The data gathered in these analyses indicate that the Lifr plays a pivotal role in the astrocyte apoptosis induced by hypoxic/low-glucose environments. Further investigation of the relationship between apoptosis and the Lifr may provide a potential therapeutic target for the treatment of neurological injuries.
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Davis SM, Collier LA, Goodwin S, Lukins DE, Powell DK, Pennypacker KR. Efficacy of leukemia inhibitory factor as a therapeutic for permanent large vessel stroke differs among aged male and female rats. Brain Res 2018; 1707:62-73. [PMID: 30445025 DOI: 10.1016/j.brainres.2018.11.017] [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: 10/16/2018] [Revised: 11/07/2018] [Accepted: 11/12/2018] [Indexed: 01/19/2023]
Abstract
Preclinical studies using rodent models of stroke have had difficulty in translating their results to human patients. One possible factor behind this inability is the lack of studies utilizing aged rodents of both sexes. Previously, this lab showed that leukemia inhibitory factor (LIF) promoted recovery after stroke through antioxidant enzyme upregulation. This study examined whether LIF promotes neuroprotection in aged rats of both sexes. LIF did not reduce tissue damage in aged animals, but LIF-treated female rats showed partial motor skill recovery. The LIF receptor (LIFR) showed membrane localization in young male and aged rats of both sexes after stroke. Although LIF increased neuronal LIFR expression in vitro, it did not increase LIFR in the aged brain. Levels of LIFR protein in brain tissue were significantly downregulated between young males and aged males/females at 72 h after stroke. These results demonstrated that low LIFR expression reduces the neuroprotective efficacy of LIF in aged rodents of both sexes. Furthermore, the ability of LIF to promote motor improvement is dependent upon sex in aged rodents.
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Affiliation(s)
- Stephanie M Davis
- Department of Neurology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536, United States.
| | - Lisa A Collier
- Department of Neurology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536, United States.
| | - Sarah Goodwin
- Department of Neurology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536, United States.
| | - Douglas E Lukins
- Department of Radiology, University of Kentucky, 800 Rose St., Lexington, KY 40536, United States.
| | - David K Powell
- Spinal Cord and Brain Injury Research Center, 741 S. Limestone, Lexington, KY 40536, United States.
| | - Keith R Pennypacker
- Department of Neurology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536, United States; Department of Neuroscience, University of Kentucky, 800 Rose St., Lexington, KY 40536, United States.
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Metcalfe SM, Bickerton S, Fahmy T. Neurodegenerative Disease: A Perspective on Cell-Based Therapy in the New Era of Cell-Free Nano-Therapy. Curr Pharm Des 2018; 23:776-783. [PMID: 27924726 DOI: 10.2174/1381612822666161206141744] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Neurodegenerative diseases (NDD) result in irreversible loss of neurons. Dementia develops when disease-induced neuronal loss becomes sufficient to impair both memory and cognitive functioning and, globally, dementia is increasing to epidemic proportions as populations age. In the current era of regenerative medicine intense activity is asking, can loss of endogenous neurons be compensated by replacement with exogenously derived cells that have either direct, or indirect, neurogenic capacity? But, more recently, excitement is growing around an emerging alternative to the cell-based approach - here nanotechnology for targeted delivery of growth factor aims to support and expand resident central nervous system (CNS) stem cells for endogenous repair. The concept of a high volume, off-the-shelf nano-therapeutic able to rejuvenate the endogenous neuroglia of the CNS is highly attractive, providing a simple solution to the complex challenges posed by cell-based regenerative medicine. The role of inflammation as an underlying driver of NDD is also considered where anti-inflammatory approaches are candidates for therapy. Indeed, cell-based therapy and/or nanotherapy may protect against inflammation to support both immune quiescence and neuronal survival in the CNS - key targets for treating NDD with the potential to reduce or even stop the cascading pathogenesis and disease progression, possibly promoting some repair where disease is treated early. By design, nanoparticles can be formulated to cross the blood brain barrier (BBB) enabling sustained delivery of neuro-protective agents for sufficient duration to reset neuro-immune homeostasis. Proven safe and efficacious, it is now urgent to deliver nano-medicine (NanoMed) as a scalable approach to treat NDD, where key stakeholders are the patients and the global economy.
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Affiliation(s)
- Su M Metcalfe
- Cambridge University Hospitals Trust Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Sean Bickerton
- Yale School of Engineering and Applied Science and Yale School of Medicine, 55 Prospect Street, New Haven, CT, 06511, United States
| | - Tarek Fahmy
- Yale School of Engineering and Applied Science and Yale School of Medicine, 55 Prospect Street, New Haven, CT, 06511, United States
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LIF and multiple sclerosis: One protein with two healing properties. Mult Scler Relat Disord 2018; 20:223-227. [PMID: 29448112 DOI: 10.1016/j.msard.2018.01.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 01/20/2018] [Indexed: 11/21/2022]
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XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling. J Cardiovasc Pharmacol 2017; 68:414-424. [PMID: 27525574 DOI: 10.1097/fjc.0000000000000427] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Excessive proliferation, migration, and oxidative stress of vascular smooth muscle cells (VSMCs) are key mechanisms involved in intima formation, which is the basic pathological process of in stent restenosis. This study aims at exploring the role of XAV939 in proliferation, migration, and reactive oxygen species (ROS) generation of VSMCs, and hence evaluating its effects on intima formation. METHODS Carotid artery ligation models for C57BL/6 mice were established and gave them different intervention: saline, XAV939, Axin2 overexpression adenovirus, and negative control adenovirus. The intima formation was assayed by intima area and intima/media ratio. To investigate the underlying mechanisms, primary rat VSMCs were cultured and treated with XAV939 and platelet-derived growth factor-BB. EdU, direct cell counting, cell wound-healing assay, and flow cytometry were used to measure proliferation, migration, cell cycle, apoptosis, and ROS generation of VSMCs, respectively. By Western blot, we examined proliferating cell nuclear antigen, Cyclin D1, Cyclin E, p21, β-actin, JNK, phosphorylated JNK, Axin2 and β-catenin expression. Immunofluorescence staining and confocal microscopy were conducted to detect translocation of β-catenin. RESULTS XAV939 inhibited intima formation, which was exhibited by the loss of intima area and I/M ratio and attenuated proliferation, migration, and ROS generation, as well as promoted cell cycle arrest of VSMCs. Specifically, XAV939 inhibited Wnt pathway. CONCLUSIONS XAV939 attenuates intima formation because of its inhibition of proliferation, migration, and apoptosis of VSMCs through suppression of Wnt signaling pathway.
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Ganesan P, Ko HM, Kim IS, Choi DK. Recent trends in the development of nanophytobioactive compounds and delivery systems for their possible role in reducing oxidative stress in Parkinson's disease models. Int J Nanomedicine 2015; 10:6757-72. [PMID: 26604750 PMCID: PMC4631432 DOI: 10.2147/ijn.s93918] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Oxidative stress plays a very critical role in neurodegenerative diseases, such as Parkinson's disease (PD), which is the second most common neurodegenerative disease among elderly people worldwide. Increasing evidence has suggested that phytobioactive compounds show enhanced benefits in cell and animal models of PD. Curcumin, resveratrol, ginsenosides, quercetin, and catechin are phyto-derived bioactive compounds with important roles in the prevention and treatment of PD. However, in vivo studies suggest that their concentrations are very low to cross blood-brain barrier thereby it limits bioavailability, stability, and dissolution at target sites in the brain. To overcome these problems, nanophytomedicine with the controlled size of 1-100 nm is used to maximize efficiency in the treatment of PD. Nanosizing of phytobioactive compounds enhances the permeability into the brain with maximized efficiency and stability. Several nanodelivery techniques, including solid lipid nanoparticles, nanostructured lipid carriers, nanoliposomes, and nanoniosomes can be used for controlled delivery of nanobioactive compounds to brain. Nanocompounds, such as ginsenosides (19.9 nm) synthesized using a nanoemulsion technique, showed enhanced bioavailability in the rat brain. Here, we discuss the most recent trends and applications in PD, including 1) the role of phytobioactive compounds in reducing oxidative stress and their bioavailability; 2) the role of nanotechnology in reducing oxidative stress during PD; 3) nanodelivery systems; and 4) various nanophytobioactive compounds and their role in PD.
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Affiliation(s)
- Palanivel Ganesan
- Nanotechnology Research Center, Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea
| | - Hyun-Myung Ko
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea
| | - In-Su Kim
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea
| | - Dong-Kug Choi
- Nanotechnology Research Center, Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea
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Metcalfe SM. Stem cell therapy versus T lymphocytes: friend or foe? Stem Cells 2015; 33:622-5. [PMID: 25303042 DOI: 10.1002/stem.1863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 09/14/2014] [Indexed: 11/07/2022]
Affiliation(s)
- Su M Metcalfe
- University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, United Kingdom
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Rittchen S, Boyd A, Burns A, Park J, Fahmy TM, Metcalfe S, Williams A. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF). Biomaterials 2015; 56:78-85. [PMID: 25934281 PMCID: PMC4429967 DOI: 10.1016/j.biomaterials.2015.03.044] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 03/22/2015] [Accepted: 03/27/2015] [Indexed: 12/16/2022]
Abstract
Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS.
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Affiliation(s)
- Sonja Rittchen
- Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK
| | - Amanda Boyd
- Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK
| | - Alasdair Burns
- Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK
| | - Jason Park
- Department of Biomedical Engineering, Department of Immunobiology, Yale School of Engineering and Applied Science and Yale School of Medicine, 55 Prospect Street, New Haven, CT, 06511, USA
| | - Tarek M Fahmy
- Department of Biomedical Engineering, Department of Immunobiology, Yale School of Engineering and Applied Science and Yale School of Medicine, 55 Prospect Street, New Haven, CT, 06511, USA
| | - Su Metcalfe
- John van Geest Centre for Brain Repair, University of Cambridge, Addenbrooke's Hospital, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.
| | - Anna Williams
- Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK.
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Wnt/β-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells. Strahlenther Onkol 2015; 191:672-80. [PMID: 26072169 DOI: 10.1007/s00066-015-0858-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Accepted: 05/21/2015] [Indexed: 01/15/2023]
Abstract
BACKGROUND Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/β-catenin pathway in radiation-induced invasion of glioblastoma cells. METHODS U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/β-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of β-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/β-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of β-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography. RESULTS U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of β-catenin. Moreover, we found increased β-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/β-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/β-catenin pathway by XAV 939, which promotes degradation of β-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases. CONCLUSION Our data demonstrate a pivotal role of the Wnt/β-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting β-catenin is a promising therapeutic approach to overcoming glioma radioresistance.
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Metcalfe SM, Strom TB, Williams A, Fahmy TM. Multiple Sclerosis and the LIF/IL-6 Axis: Use of Nanotechnology to Harness the Tolerogenic and Reparative Properties of LIF. Nanobiomedicine (Rij) 2015; 2:5. [PMID: 29942371 PMCID: PMC5997376 DOI: 10.5772/60622] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 04/13/2015] [Indexed: 01/19/2023] Open
Abstract
Leukaemia inhibitory factor (LIF) plays a critical role in “stemness” versus “differentiation”, a property that underpins the core value of LIF as a therapeutic for both the treatment of autoimmune disease and for promoting tissue repair. This value can be realized using nano-engineering technology, where a new generation of tools can, with unprecedented ability, manipulate biological functions. One striking example is the treatment of multiple sclerosis (MS). The underpinning biology is the newly identified LIF/IL-6 axis in T lymphocytes, which can tilt the behaviour between immune tolerance versus immune attack. This LIF/IL-6 axis is ideally suited to nanotherapeutic manipulation, given its inherent mechanistic simplicity of two mutually opposing feed-forward loops that determine either tolerogenic (LIF) or inflammatory (IL-6) immunity. Using LIF that is formulated in biodegradable nanoparticles (LIF-NP) and targeted to CD4+ T cells, the axis is harnessed towards immune tolerance. This has implications for the treatment of autoimmune diseases, where the clinical burden is immense. It encompasses more than 100 diseases and, in the USA alone, costs more than $100 billion in direct health care costs annually. Other properties of LIF include the promotion of healthy neuro-glial interactions within the central nervous system (CNS), where, in addition to MS, LIF-NP therapy is relevant to inflammatory neurodegenerative diseases that represent a large and increasing need within aging populations. Thirdly, LIF is a reparative growth factor that can maintain genomic plasticity. LIF-NP supports the use of stem cell-based therapies in regenerative medicine plus augment therapeutic benefits within the patient. These core properties of LIF are greatly amplified in value by the advantage of being formulated as nanoparticles, namely (i) targeted delivery, (ii) exploitation of endogenous regulatory pathways and (iii) creation of surrogate micro-stromal niches. We discuss LIF-NP as a means to harness endogenous pathways for the treatment of MS, both to reset immune self-tolerance and to promote repair of myelin that is required to support health within the nervous system.
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Affiliation(s)
- Su M Metcalfe
- Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge Biomedical Campus, Cambridge, UK
| | - Terry B Strom
- The Transplant Institute, Beth Israel Deaconess Medical Center, Center for Life Science (CLS), East Campus, Boston, MA, USA
| | - Anna Williams
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Tarek M Fahmy
- Department of Biomedical Engineering, Department of Immunobiology Yale School of Engineering and Applied Science and Yale School of Medicine, New Haven, CT, USA
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