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MicroRNA-409-5p promotes retinal neovascularization in diabetic retinopathy
No full textBackground: Retinal neovascularization, which is characterized by the increased proliferation, migration, and tube formation of retinal microvascular endothelial cells (RMECs), contributes to the progression of diabetic retinopathy (DR). MiR-409-5p has been reported to be upregulated in peripheral blood of DR patients and in vascular endothelial growth factor (VEGF)-induced RMECs. However, the role of miR-409-5p in retinal neovascularization of DR remains unelucidated. Method: The expression of miR-409-5p was measured in retinal tissues of streptozocin-induced and db/db diabetic mice, in high glucose-induced mouse RMECs (mRMECs), and in vitreous fluid of proliferative DR patients. Antagomir of miR-409-5p was intravitreally injected into diabetic mice. Proliferation, migration, and tube formation were detected using cell counting kit-8 assay, transwell assay, and microscope observation, respectively. Luciferase reporter assay was used to detect the direct interaction between miR-409-5p and peroxisome proliferator-activated receptor-α (PPARα). Result: MiR-409-5p was upregulated in retinal tissues of diabetic mice, in high glucose-induced mRMECs, and in vitreous fluid of proliferative DR patients. The knockdown of miR-409-5p attenuated retinal neovascularization in vivo. The overexpression of miR-409-5p promotes the proliferation, migration, and tube formation, and increased VEGF expression and secretion, while the knockdown of miR-409-5p suppressed the VEGF-induced retinal neovascularization in vitro. PPARα is a downstream target of miR-409-5p, and PPARα overexpression negated the promotion of miR-409-5p overexpression on the proliferation, migration, and tube formation of mRMECs. Conclusion: Our findings demonstrated that miR-409-5p acted as a neovasculogenic factor in DR, and anti-miR-409-5p therapy may provide a novel strategy in treating DR.</p
Data_Sheet_3_MiR-409-5p as a Regulator of Neurite Growth Is Down Regulated in APP/PS1 Murine Model of Alzheimer’s Disease.pdf
No full textAlzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aβ1–42-induced pathologies. In this study, we found that Aβ1–42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aβ, which may be used as a potential early biomarker of AD.</p
Data_Sheet_1_MiR-409-5p as a Regulator of Neurite Growth Is Down Regulated in APP/PS1 Murine Model of Alzheimer’s Disease.pdf
No full textAlzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aβ1–42-induced pathologies. In this study, we found that Aβ1–42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aβ, which may be used as a potential early biomarker of AD.</p
Data_Sheet_2_MiR-409-5p as a Regulator of Neurite Growth Is Down Regulated in APP/PS1 Murine Model of Alzheimer’s Disease.pdf
No full textAlzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aβ1–42-induced pathologies. In this study, we found that Aβ1–42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aβ, which may be used as a potential early biomarker of AD.</p
Table_1_MiR-409-5p as a Regulator of Neurite Growth Is Down Regulated in APP/PS1 Murine Model of Alzheimer’s Disease.pdf
No full textAlzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aβ1–42-induced pathologies. In this study, we found that Aβ1–42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aβ, which may be used as a potential early biomarker of AD.</p
Resolución UNRN N° 409/2009. Contratación Directa N° 14/2009.
No full textFil: Universidad Nacional de Río Negro (U). Universidad Nacional de Río Negro. Río Negro, ArgentinaResolución UNRN N° 409/2009. Contratación Directa N° 14/2009.fals
Image_1_miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity.PDF
No full textThe evolutionary emergence of the corticospinal tract and corpus callosum are thought to underpin the expansion of complex motor and cognitive abilities in mammals. Molecular mechanisms regulating development of the neurons whose axons comprise these tracts, the corticospinal and callosal projection neurons, remain incompletely understood. Our previous work identified a genomic cluster of microRNAs (miRNAs), Mirg/12qF1, that is unique to placental mammals and specifically expressed by corticospinal neurons, and excluded from callosal projection neurons, during development. We found that one of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the transcriptional regulator Lmo4. Here we show that miR-409-3p also directly represses the transcriptional co-regulator Cited2, which is highly expressed by callosal projection neurons from the earliest stages of neurogenesis. Cited2 is highly expressed by intermediate progenitor cells (IPCs) in the embryonic neocortex while Mirg, which encodes miR-409-3p, is excluded from these progenitors. miR-409-3p gain-of-function (GOF) in IPCs results in a phenocopy of established Cited2 loss-of-function (LOF). At later developmental stages, both miR-409-3p GOF and Cited2 LOF promote the expression of corticospinal at the expense of callosal projection neuron markers in layer V. Taken together, this work identifies previously undescribed roles for miR-409-3p in controlling IPC numbers and for Cited2 in controlling callosal fate. Thus, miR-409-3p, possibly in cooperation with other Mirg/12qF1 miRNAs, represses Cited2 as part of the multifaceted regulation of the refinement of neuronal cell fate within layer V, combining molecular regulation at multiple levels in both progenitors and post-mitotic neurons.</p
VHE gamma-ray discovery and multiwavelength study of the blazar 1ES 2322-409
No full textA hotspot at a position compatible with the BL Lac object 1ES 2322−409 was serendipitously detected with H.E.S.S. during observations performed in 2004 and 2006 on the blazar
PKS 2316−423. Additional data on 1ES 2322−409 were taken in 2011 and 2012, leading to a total live-time of 22.3 h. Point-like very-high-energy (VHE; E > 100 GeV) γ -ray
emission is detected from a source centred on the 1ES 2322−409 position, with an excess
of 116.7 events at a significance of 6.0σ. The average VHE γ -ray spectrum is well described with a power law with a photon index = 3.40 ± 0.66stat ± 0.20sys and an integral
flux (E > 200 GeV) = (3.11 ± 0.71stat ± 0.62sys) × 10−12 cm−2 s−1, which corresponds to
1.1 per cent of the Crab nebula flux above 200 GeV. Multiwavelength data obtained with
Fermi LAT, Swift XRT and UVOT, RXTE PCA, ATOM, and additional data from WISE,
GROND, and Catalina are also used to characterize the broad-band non-thermal emission of
1ES 2322−409. The multiwavelength behaviour indicates day-scale variability. Swift UVOT
and XRT data show strong variability at longer scales. A spectral energy distribution (SED) is
built from contemporaneous observations obtained around a high state identified in Swift data.
A modelling of the SED is performed with a stationary homogeneous one-zone synchrotronself-Compton leptonic model. The redshift of the source being unknown, two plausible values
were tested for the modelling. A systematic scan of the model parameters space is performed,
resulting in a well-constrained combination of values providing a good description of the
broad-band behaviour of 1ES 2322−409
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