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      Attenuated neuroprotective effect of riboflavin under UV-B irradiation via miR-203/c-Jun signaling pathway in vivo and in vitro

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          Abstract

          Background

          Riboflavin (RF) or vitamin B2 is known to have neuroprotective effects. In the present study, we report the attenuation of the neuroprotective effects of RF under UV-B irradiation. Preconditioning of UV-B irradiated riboflavin (UV-B-RF) showed attenuated neuroprotective effects compared to that of RF in SH-SY5Y neuroblostoma cell line and primary cortical neurons in vitro and a rat model of cerebral ischemia in vivo.

          Results

          Results indicated that RF pretreatment significantly inhibited cell death and reduced LDH secretion compared to that of the UV-B-RF pretreatment in primary cortical neuron cultures subjected to oxygen glucose deprivation in vitro and cortical brain tissue subjected to ischemic injury in vivo. Further mechanistic studies using cortical neuron cultures revealed that RF treatment induced increased miR-203 expression which in turn inhibited c-Jun expression and increased neuronal cell survival. Functional assays clearly demonstrated that the UV-B-RF preconditioning failed to sustain the increased expression of miR-203 and the decreased levels of c-Jun, mediating the neuroprotective effects of RF. UV-B irradiation attenuated the neuroprotective effects of RF through modulation of the miR-203/c-Jun signaling pathway.

          Conclusion

          Thus, the ability of UV-B to serve as a modulator of this neuroprotective signaling pathway warrants further studies into its role as a regulator of other cytoprotective/neuroprotective signaling pathways.

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          Most cited references16

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          Pathobiology of ischaemic stroke: an integrated view.

          Brain injury following transient or permanent focal cerebral ischaemia (stroke) develops from a complex series of pathophysiological events that evolve in time and space. In this article, the relevance of excitotoxicity, peri-infarct depolarizations, inflammation and apoptosis to delayed mechanisms of damage within the peri-infarct zone or ischaemic penumbra are discussed. While focusing on potentially new avenues of treatment, the issue of why many clinical stroke trials have so far proved disappointing is addressed. This article provides a framework that can be used to generate testable hypotheses and treatment strategies that are linked to the appearance of specific pathophysiological events within the ischaemic brain.
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            c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms.

            c-Jun is a component of the transcription factor AP-1, which is activated by a wide variety of extracellular stimuli. The regulation of c-Jun is complex and involves both increases in the levels of c-Jun protein as well as phosphorylation of specific serines (63 and 73) by Jun N-terminal kinase (JNK). We have used fibroblasts derived from c-Jun null embryos to define the role of c-Jun in two separate processes: cell growth and apoptosis. We show that in fibroblasts, c-Jun is required for progression through the G1 phase of the cell cycle; c-Jun-mediated G1 progression occurs by a mechanism that involves direct transcriptional control of the cyclin D1 gene, establishing a molecular link between growth factor signaling and cell cycle regulators. In addition, c-Jun protects cells from UV-induced cell death and cooperates with NF-kappaB to prevent apoptosis induced by tumor necrosis factor alpha (TNFalpha). c-Jun mediated G1 progression is independent of phosphorylation of serines 63/73; however, protection from apoptosis in response to UV, a potent inducer of JNK/SAP kinase activity, requires serines 63/73. The results reveal critical roles for c-Jun in two different cellular processes and show that different extracellular stimuli can target c-Jun by distinct biochemical mechanisms.
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              MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration.

              MicroRNAs are small RNAs that function as regulators of posttranscriptional gene expression. MicroRNAs are encoded by genes, and processed to form ribonucleoprotein complexes that bind to messenger RNA (mRNA) targets to repress translation or degrade mRNA transcripts. The microRNAs are particularly abundant in the brain where they serve as effectors of neuronal development and maintenance of the neuronal phenotype. They are also expressed in dendrites where they regulate spine structure and function as effectors in synaptic plasticity. MicroRNAs have been evaluated for their roles in brain ischemia, traumatic brain injury, and spinal cord injury, and in functional recovery after ischemia. They also serve as mediators in the brain's response to ischemic preconditioning that leads to endogenous neuroprotection. In addition, microRNAs are implicated in neurodegenerative disorders, including Alzheimer's, Huntington, Parkinson, and Prion disease. The discovery of microRNAs has expanded the potential for human diseases to arise from genetic mutations in microRNA genes or sequences within their target mRNAs. This review discusses microRNA discovery, biogenesis, mechanisms of gene regulation, their expression and function in the brain, and their roles in brain ischemia and injury, neuroprotection, and neurodegeneration.
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                Author and article information

                Contributors
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central
                1021-7770
                1423-0127
                2014
                7 May 2014
                : 21
                : 1
                : 39
                Affiliations
                [1 ]Division of Endocrinology, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226031, India
                [2 ]Photobiology Division, Indian Institute of Toxicology Research, MG Marg, Lucknow 226001, India
                [3 ]Department of Obstetrics and Gynaecology, KGMU, Lucknow 226003, UP, India
                [4 ]Department of Biochemistry, Jamia Hamdard (Hamdard University, New Delhi, India
                [5 ]Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
                [6 ]Department of Meat, Fish & Poultry Technology, CSIR-Central Food Technological Research Institute, Mysore 570 020, India
                Article
                1423-0127-21-39
                10.1186/1423-0127-21-39
                4049496
                24884571
                5d823f3c-cb4f-4bdb-933e-b06a00e1e505
                Copyright © 2014 Tripathi et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 November 2013
                : 15 April 2014
                Categories
                Research

                Molecular medicine
                cerebral ischemia,riboflavin,uv-b,mir-203,c-jun,neuroprotection
                Molecular medicine
                cerebral ischemia, riboflavin, uv-b, mir-203, c-jun, neuroprotection

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