Resveratrol & Down Syndrome Abstracts
FASEB J. 28(6): 2551-65 (2014 Jun)
Miguel Alejandro Lopez-Ramirez, Dongsheng Wu, Gareth Pryce, Julie E. Simpson, Arie Reijerkerk, Josh King-Robson, Oliver Kay, Helga E. de Vries, Mark C. Hirst, Basil Sharrack, David Baker, David Kingsley Male, Gregory J. Michael and Ignacio Andres Romero
Department of Life, Health, and Chemical Sciences, Biomedical Research Network, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders.
Frontiers in Cellular Neuroscience 7: 41 (2013 Apr)
Wei-Hong Siew, Kai-Leng Tan, Maryam Abbaspour Babaei, Pike-See Cheah, and King-Hwa Ling
NeuroBiology and Genetics Group, Genetic Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang, Malaysia
Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)].
Neuroreport 23(3): 168-173 (2012 Feb 15)
YY Li, PN Alexandrov, AI Pogue, Y Zhao, S Bhattacharjee, and WJ Lukiw
LSU Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans LA 70112, USA
Down's syndrome, a congenital disorder associated with cognitive impairment and early onset Alzheimer's disease, is a progressive genetic pathology resulting from full or partial triplication of chromosome-21. Down's brain is typified by activated microglia, increases in inflammatory signaling and an aberrant immune system. In these studies, a screening of micro-RNA (miRNA) from Down's brain and peripheral tissues indicated an up-regulation of a chromosome-21-encoded miRNA-155, and a decrease in the abundance of the miRNA-155 mRNA target complement factor H (CFH), an important repressor of the innate immune response. Stressed primary human neuronal-glial cells indicated both miRNA-155 increases and CFH down-regulation, an effect that was reversed using anti-miRNA-155. These findings suggest that immunopathological deficits associated with Down's syndrome can in part be explained by a generalized miRNA-155-mediated down-regulation of CFH that may contribute to both brain and systemic immune pathology.
Carcinogenesis 31(9): 1561-6 (2010 Sep)
Esmerina Tili, Jean-Jacques Michaille, Brett Adair, Hansjuerg Alder, Emeric Limagne, Cristian Taccioli, Manuela Ferracin, Dominique Delmas, Norbert Latruffe and Carlo M. Croce
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Biomedical Tower, 460 West 12th Avenue, Columbus, OH 43210, USA.
An inflammatory component is present in the microenvironment of most neoplastic tissues, including those not causally related to an obvious inflammatory process. Several microRNAs, and especially miR-155, play an essential role in both the innate and adaptative immune response. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural antioxidant with anti-inflammatory properties that is currently at the stage of preclinical studies for human cancer prevention. Here, we establish that, in human THP-1 monocytic cells as well as in human blood monocytes, resveratrol upregulates miR-663, a microRNA potentially targeting multiple genes implicated in the immune response. In THP-1 cells, miR-663 decreases endogenous activator protein-1 (AP-1) activity and impairs its upregulation by lipopolysaccharides (LPS), at least in part by directly targeting JunB and JunD transcripts. We further establish that the downregulation of AP-1 activity by resveratrol is miR-663 dependent and that the effects of resveratrol on both AP-1 activity and JunB levels are dose dependent. Finally, we show that resveratrol impairs the upregulation of miR-155 by LPS in a miR-663-dependent manner. Given the role of miR-155 in the innate immune response and the fact that it is upregulated in many cancers, our results suggest that manipulating miR-663 levels may help to optimize the use of resveratrol as both an anti-inflammatory and anticancer agent against malignancies associated with high levels of miR-155.