Compartir
array:23 [ "pii" => "S0213485321000220" "issn" => "02134853" "doi" => "10.1016/j.nrl.2020.12.006" "estado" => "S300" "fechaPublicacion" => "2023-09-01" "aid" => "1573" "copyright" => "Sociedad Española de Neurología" "copyrightAnyo" => "2021" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Neurologia. 2023;38:486-94" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S0213485320303017" "issn" => "02134853" "doi" => "10.1016/j.nrl.2020.08.020" "estado" => "S300" "fechaPublicacion" => "2023-09-01" "aid" => "1522" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Neurologia. 2023;38:495-503" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVISIÓN</span>" "titulo" => "Microorganismos relacionados con un mayor riesgo de presentar la enfermedad de Parkinson" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "495" "paginaFinal" => "503" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Microorganisms associated with increased risk of Parkinson's disease" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1194 "Ancho" => 2172 "Tamanyo" => 164876 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Esquema que muestra los posibles mecanismos de acción patogénica de la bacteria <span class="elsevierStyleItalic">Helicobacter pylori</span> en la enfermedad de Parkinson. La bacteria <span class="elsevierStyleItalic">Helicobacter pylori</span> produce factores neurotóxicos y antigénicos con acción deletérea sobre neuronas dopaminérgicas de la sustancia negra. También induce inflamación gástrica e intestinal, que modifica la microbiota del intestino haciéndola patógena. Finalmente, la biodisponibilidad y la eficacia terapéutica de la levodopa están disminuidas en los pacientes infectados con <span class="elsevierStyleItalic">Helicobacter pylori</span>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Fernández-Espejo" "autores" => array:1 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Fernández-Espejo" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173580822000542" "doi" => "10.1016/j.nrleng.2020.08.023" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580822000542?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485320303017?idApp=UINPBA00004N" "url" => "/02134853/0000003800000007/v1_202309041924/S0213485320303017/v1_202309041924/es/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0213485321000232" "issn" => "02134853" "doi" => "10.1016/j.nrl.2021.01.007" "estado" => "S300" "fechaPublicacion" => "2023-09-01" "aid" => "1574" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Neurologia. 2023;38:475-85" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Auditory cortex hyperconnectivity before rTMS is correlated with tinnitus improvement" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "475" "paginaFinal" => "485" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Correlación entre hiperconectividad de la corteza auditiva antes del tratamiento con estimulación magnética transcraneal repetitiva y mejoría de los acúfenos" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1683 "Ancho" => 2175 "Tamanyo" => 288472 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Group differences between left A1-based connectivity maps. (A) The hot colormap represents the brain areas with significantly increased positive connectivity of the left A1 in the tinnitus group compared with the control group. These regions include the left middle temporal, cingulate, and postcentral areas. (B) The winter colormap represents the brain areas with significantly increased negative connectivity of the left A1 in the tinnitus group compared with the control group. These regions include the left superior, middle, and medial frontal and angular areas and right cerebellar areas.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Kim, H. Kang, T.-S. Noh, S.-H. Oh, M.-W. Suh" "autores" => array:5 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Kim" ] 1 => array:2 [ "nombre" => "H." "apellidos" => "Kang" ] 2 => array:2 [ "nombre" => "T.-S." "apellidos" => "Noh" ] 3 => array:2 [ "nombre" => "S.-H." "apellidos" => "Oh" ] 4 => array:2 [ "nombre" => "M.-W." "apellidos" => "Suh" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485321000232?idApp=UINPBA00004N" "url" => "/02134853/0000003800000007/v1_202309041924/S0213485321000232/v1_202309041924/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "486" "paginaFinal" => "494" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "H. Zhan-qiang, Q. Hai-hua, Z. Chi, W. Miao, Z. Cui, L. Zi-yin, H. Jing, W. Yi-wei" "autores" => array:8 [ 0 => array:3 [ "nombre" => "H." "apellidos" => "Zhan-qiang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Q." "apellidos" => "Hai-hua" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Z." "apellidos" => "Chi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "W." "apellidos" => "Miao" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Z." "apellidos" => "Cui" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "L." "apellidos" => "Zi-yin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "H." "apellidos" => "Jing" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 7 => array:4 [ "nombre" => "W." "apellidos" => "Yi-wei" "email" => array:1 [ 0 => "wangyiwei9511_cmc@163.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of General medicine, Affiliated Hospital of Chengde Medical College, Chengde 067000, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Dermatology, Affiliated Hospital of Chengde Medical College, Chengde 067000, China" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Neurology, Affilicated Hospital of Chengde Medical College, Chengde 067000, China" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "miR-146a empeora el deterioro cognitivo y la patología tipo Alzheimer al promover el estrés oxidativo a través de la vía de señalización MAPK" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 4080 "Ancho" => 2508 "Tamanyo" => 937558 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">miR-146a-5p promoted Aβ deposition by triggering oxidative stress via activation of MAPK signaling in Aβ<span class="elsevierStyleInf">1–42</span>-treated mice. (A) Relative transcription levels of miR-146a-5p among groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); (B) Relative escape latency in MWM are shown (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); (C) Immunohistochemistry analysis of Aβ in the hippocampus upon treatment as indicated, Scale bar: 200<span class="elsevierStyleHsp" style=""></span>μm; (D) Relative expression of DCHF-DA among groups, Scale bar: 50<span class="elsevierStyleHsp" style=""></span>μm; (E) Bar graphs show densitometric analysis of p-p38as indicated in western blots (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5). Each bar represents mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>S.E.M. * <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and *** <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the control group. ##<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and ###<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the AD group.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Alzheimer's disease (AD), the most common degenerative disorder of the nervous system, exhibits typical clinical pathological changes linked to the dysfunction of cognitive ability.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> The pathogenesis of AD is an extremely complicated process, of which multiple hypotheses have been proposed. The most usual is the amyloid deposition hypothesis which suggests the accumulation of the neurotoxic Aβ fragments derived from amyloid precursor protein (APP) by the action of β-secretase and γ-secretase proteases.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">2,3</span></a> Recently, a study revealed that Aβ deposition in the brain triggers oxidative stress, affecting the reduction ability of mitochondria, causing neuronal death.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">4</span></a> Besides, antioxidants are known to reverse neuronal cell apoptosis induced by Aβ.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">5</span></a> Therefore, these studies emphasize that oxidative stress is a significant factor in Aβ-triggered neuronal death, which gradually may turn to AD.</p><p id="par0010" class="elsevierStylePara elsevierViewall">MicroRNAs (miRNAs), a kind of small non-coding RNAs, are known to play a major post-transcriptional regulatory role in gene expression. Recently, the involvement of many miRNAs in modulating key disease genes, such as APP and BACE1, suggested that their dysfunction may also contribute to the pathology of AD.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">6</span></a> miR-146a-5p, the most widely studied miRNAs, is the key modulator of immune response and has been linked to a variety of neuroinflammation processes.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">7</span></a> The up-regulation of miR-146a-5p activates mitogen protein kinase to exacerbate neuroinflammation and oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> Interestingly, studies based on in vitro and in vivo models of AD found that gradual up-regulation of miR-146a-5p was linked to the progression of AD, while the other studies suggested that miR-146q-5p was closely related to Aβ deposition and synaptic pathological changes.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> Meanwhile, clinical studies also revealed that compared to the healthy elderly group, miR-146a-5p was significantly up-regulated in the brain tissue of AD patients.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> In general, both preclinical and clinical trials strongly put forward the role of miR-146a-5p in the pathogenesis of AD. Therefore, we conjectured that regulating miR-146a-5p could be a novel therapeutic strategy in AD.</p><p id="par0015" class="elsevierStylePara elsevierViewall">However, for that, the mechanistic details of miR-146a-5p role in oxidative stress-induced neuronal degeneration in AD need to be examined. Therefore, in this study, we evaluated whether the down-regulation of miR-146a-5p would cease the progression of AD. Also, we discussed the relevant pathological changes in AD resulting from the down-regulation of miR-146a-5p.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cell culture, transfection, and Aβ<span class="elsevierStyleInf">1-42</span> treatment</span><p id="par0020" class="elsevierStylePara elsevierViewall">SH-SY5Y cells were obtained from Procell (No.CM-0208, China) and cultured in MEM/F12 medium (Procell, No.PM151220, China) (Israel Biological Industries) with10% fetal bovine serum (FBS) at 37<span class="elsevierStyleHsp" style=""></span>°C. To induce cell differentiation, MEM/F12 medium with 1% FBS and 10<span class="elsevierStyleHsp" style=""></span>μM all-trans retinoic acid (RA) (Aladdin, No.CFLD-R106320, China) was used for 7 days, and the culture medium was changed every 3 days. After the RA treatment, the resultant morphological changes in SH-SY5Y cells were verified microscopically (200x magnification), and the differentiated cells were used for all subsequent studies. For transfection studies, SH-SY5Y cells were transfected with miR-146a-5p mimic (50<span class="elsevierStyleHsp" style=""></span>nM; RiboBio, No.miR10000449-1-5, China) or miR-146a-5p inhibitor (100<span class="elsevierStyleHsp" style=""></span>nM; RiboBio, No.miR20000449-1-5, China) using Lipofectamine3000 (Invitrogen, No.L3000-015, USA) according to the manufacturer's instructions. After incubation for 24<span class="elsevierStyleHsp" style=""></span>h, these cells were harvested and undergoing further tests, meanwhile, the transfection efficiency also was monitored. To establish the in vitro AD cell model, Aβ<span class="elsevierStyleInf">1–42</span> (GenScript, No.RP10017, USA) was dissolved in hexafluoroisopropanol (HFIP) for 10<span class="elsevierStyleHsp" style=""></span>min. The HFIP was pre-cooled in advance and after volatilization, the formed Aβ<span class="elsevierStyleInf">1–42</span> protein film was dissolved in DMSO, and the SH-SY5Y cells were treated with 1<span class="elsevierStyleHsp" style=""></span>μM Aβ<span class="elsevierStyleInf">1–42</span> for 24<span class="elsevierStyleHsp" style=""></span>h. To evaluate the effect of MAPK signaling, the SH-SY5Y cells were divided into the following groups with three replicates in each: (1) the control group without treatment, (2) the model group with Aβ<span class="elsevierStyleInf">1–42</span> treatmen, (3) the Model+miR-146a-5p mimic group with miR-146a-5p mimic transfection and Aβ<span class="elsevierStyleInf">1–42</span> treatmen, (4) the Model+miR-146a-5p mimic+ FGA-19 group was treated with Aβ<span class="elsevierStyleInf">1–42</span> to establish the in vitro AD cell model, and transfected with miR-146a-5p mimic, then FGA-19 (Aladdin, No.5.30486.0001, China) as the p38 MAPKinase inhibitor was added in the cells for 24<span class="elsevierStyleHsp" style=""></span>h with concentration of 50<span class="elsevierStyleHsp" style=""></span>μM, (5) the Model+miR-146a-5p mimic+ FGA-19+NAC group was treated similarly to the Model+miR-146a-5p mimic+ FGA-19 group, in addition, the cells were treated with N-Acetyl-cysteine (NAC, Abcam, No.AB60264, USA) of 1<span class="elsevierStyleHsp" style=""></span>mM for 2<span class="elsevierStyleHsp" style=""></span>h, as antioxidant to scavenge ROS.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Animals and treatment</span><p id="par0025" class="elsevierStylePara elsevierViewall">The animal experiment was approved by the Animal Ethics Committee of the Affiliated Hospital of Chengde Medical College (No.20200330-06). All animal studies strictly complied with the relevant regulations of the Animal Ethics Committee and abided by the 3R principle in the design and implementation of experiments. Six-month-old male C57bl/6J mice were randomly assigned into four groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5 per group), namely the control group without treatment, the AD group with Aβ<span class="elsevierStyleInf">1–42</span> treatment, the AD+miR-146 mimic group with miR-146a-5p mimic transfection and Aβ<span class="elsevierStyleInf">1–42</span> treatment, and the AD+miR-146 inhibitor group with miR-146a-5p inhibitor transfection and Aβ<span class="elsevierStyleInf">1–42</span> treatment. The lentiviral expression vectors of miR-146a-5p mimic, miR-146a-5p inhibitor and negative control were synthesized by Thermo Scientific company with their titer of 1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>PFU/mL. Except for the control group, the other three groups of animals were intracerebroventricular injected with Aβ<span class="elsevierStyleInf">1–42</span> which was prepared by dissolving in distilled water at 0.2<span class="elsevierStyleHsp" style=""></span>mg per mL. On contrary, the animals in the control group received the same volume of distilled water (vehicle control). Moreover, the mice in the AD+miR-146 mimic group were also intracerebroventricular injected with 3<span class="elsevierStyleHsp" style=""></span>μL lentiviral expression vector of miR-146a-5p mimic, the treatment in the AD+miR-146 inhibitor group was similar. After two weeks of the treatment period, the animals were examined for cognitive behavior using the Morris water maze (MWM) test. After that, all the mice with five in each group were anesthetized and sacrificed to obtain the hippocampal tissues for further study. Besides, three sections of hippocampal tissues per mouse were analyzed.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Surgical procedure</span><p id="par0030" class="elsevierStylePara elsevierViewall">The mice were placed in the isoflurane anesthesia device, adjusted to scale 2, with a 400cc/min air flow rate. Post-anesthesia, the mice were quickly fixed to the brain stereotaxic device and a wound was cut with a sterile scalpel blade. The brain surface was disinfected using an cotton swab dipped with alcohol. Then, an insertion point (coordinate: ML<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.0; AP 0.3) with 0.5<span class="elsevierStyleHsp" style=""></span>mm diameter aperture was drilled with a hand drill using a stereotactic instrument, and Aβ<span class="elsevierStyleInf">1–42</span> was injected to establish the animal model of AD.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Morris water maze (MWM)</span><p id="par0035" class="elsevierStylePara elsevierViewall">MWM behavioral experiment was performed on the 14th day after the operation. In the experiment, a circular pool (50<span class="elsevierStyleHsp" style=""></span>cm high and 20<span class="elsevierStyleHsp" style=""></span>cm in diameter) was filled with opaque water (22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>°C), and a circular platform (10<span class="elsevierStyleHsp" style=""></span>cm in diameter, 28<span class="elsevierStyleHsp" style=""></span>cm high) was placed 1<span class="elsevierStyleHsp" style=""></span>cm below the surface of the water. The MWM was theatrically divided into four quadrants, and the hidden platform was placed in one of the quadrants. The experiment was divided into two stages. Stage one, the first 5 days was used for the positioning and navigation, in which each mouse was tested 4 times a day. In each test, the mice were placed in the water from different quadrants and allowed to swim for up to 90<span class="elsevierStyleHsp" style=""></span>s to find the platform and rest on it for 10<span class="elsevierStyleHsp" style=""></span>s. If the mouse failed to find the platform within the specified time, it was guided to the platform and stand for 10<span class="elsevierStyleHsp" style=""></span>s, meanwhile, the escape latency was recorded as 90<span class="elsevierStyleHsp" style=""></span>s. In the second stage of free exploration, the platform was hidden on the 6th day. Then, the swimming time, distance of the mouse in the quadrant before the platform within 90<span class="elsevierStyleHsp" style=""></span>s, and the number of times it crosses the platform was recorded. The acquired data was analyzed.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Estimation of cellular reactive oxygen species (ROS) generation</span><p id="par0040" class="elsevierStylePara elsevierViewall">According to commercial regulations, the DCFH-DA method was used to estimate the production of cellular ROS. DCFH-DA is a fluorescent dye detecting ROS level, which can be converted to oxidized fluorescence dye 2’,7’-dichlorofluorescein (DCF) at the presence of ROS. First, SH-SY5Y (4<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">4</span>) cells were seeded into a 96-well plate and exposed to Aβ<span class="elsevierStyleInf">1–42</span> for 1day (25<span class="elsevierStyleHsp" style=""></span>μM). After this, the cells were incubated for 30<span class="elsevierStyleHsp" style=""></span>min in the DMEM medium containing 5<span class="elsevierStyleHsp" style=""></span>μ DCFH-DA (MedChemExpress, No.HY-D0940, USA) under dark conditions at room temperature (RT), and the cells were washed with PBS. Moreover, the nucleus with DAPI (Bio-Rad, No.1351303, USA) to distinguish apoptotic cells. Fluorescence images were captured immediately using a fluorescence microscope (Zeiss Axio Imager Z2, Germany) at 10× magnification.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Aβ<span class="elsevierStyleInf">1–42</span> ELISA</span><p id="par0045" class="elsevierStylePara elsevierViewall">Aβ<span class="elsevierStyleInf">1–42</span> analysis was performed according to the Aβ<span class="elsevierStyleInf">1–42</span> ELISA kit (Invitrogen, No.KHB3441, USA) operating instructions. Cell homogenates of the hippocampal tissue were prepared. Meanwhile, Aβ standard solution was prepared and the test samples were diluted with the standard dilution buffer provided in the kit. Then, 100<span class="elsevierStyleHsp" style=""></span>μL of standards was added to the appropriate microtiter wells in triplicates and incubated overnight at 4<span class="elsevierStyleHsp" style=""></span>°C. The next day, the liquid in the 96-well plate was completely removed and washed 3 times with washing buffer. Then, the Aβ<span class="elsevierStyleInf">1–42</span> antibody was added to the sample and incubated for 60<span class="elsevierStyleHsp" style=""></span>min at 37<span class="elsevierStyleHsp" style=""></span>°C. Again, 3 times washing was performed with the cleaning solution and incubation with the secondary antibody was carried out for 30<span class="elsevierStyleHsp" style=""></span>min at RT. Once again, after washing each well at least 3 times, 100<span class="elsevierStyleHsp" style=""></span>μL of stable color developing solution was added to each well. Lastly, the absorbance was recorded at 450<span class="elsevierStyleHsp" style=""></span>nm to calculate the concentration of Aβ<span class="elsevierStyleInf">1–42</span> in the corresponding samples using the standard curve.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> The antibodies and solutions were provided in the kit.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Immunohistochemistry</span><p id="par0050" class="elsevierStylePara elsevierViewall">Using the cryostat, coronal sections (thickness: 40<span class="elsevierStyleHsp" style=""></span>μm) of brain tissue were obtained. These were washed 3 times with 1% PBS for 5<span class="elsevierStyleHsp" style=""></span>min and then incubated with 5% bovine serum albumin in an incubator at RT for 0.5<span class="elsevierStyleHsp" style=""></span>h. Next, these were incubated with primary antibodies (in PBS, Anti-Aβ<span class="elsevierStyleInf">1–42</span>; 1:1000; Invitrogen, No.MA5-36246, USA) at RT for 60<span class="elsevierStyleHsp" style=""></span>min, and then overnight at 4<span class="elsevierStyleHsp" style=""></span>°C. After overnight incubation, tissue sections were bought to RT and washed 3 times with 1% PBS for 5<span class="elsevierStyleHsp" style=""></span>min. Followed by incubation with the secondary antibodies (goat anti-rabbit; 1:1000; Invitrogen, No.A32731, USA) at 37<span class="elsevierStyleHsp" style=""></span>°C for 1<span class="elsevierStyleHsp" style=""></span>h, the brain slices were washed 3 times with 1% PBS for 5<span class="elsevierStyleHsp" style=""></span>min. Lastly, the brain tissue sections were dipped in the DAB (Sigma, No.11718096001, USA) chromogenic solution with the deposition of Aβ<span class="elsevierStyleInf">1–42</span> stained dark brown and mounted on glass slides. After dried in a 37<span class="elsevierStyleHsp" style=""></span>°C incubator, tissue sections were dehydrated using ethanol gradient and turned transparent with xylene. Finally, the images were acquired using an optical microscope.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">RNA extraction</span><p id="par0055" class="elsevierStylePara elsevierViewall">The total RNA of each sample was extracted by the RNAiso Plus Reagent (Takara, No.M9108, Japan). The frozen cells were lysed using TRIZOL and placed at RT for 5<span class="elsevierStyleHsp" style=""></span>min for completed isolution. Then, 0.2<span class="elsevierStyleHsp" style=""></span>ml of chloroform was added to every 1<span class="elsevierStyleHsp" style=""></span>ml of the lysed sample and mixed vigorously for 15<span class="elsevierStyleHsp" style=""></span>s. The mixture was incubated at 15–30<span class="elsevierStyleHsp" style=""></span>°C for 2–3<span class="elsevierStyleHsp" style=""></span>min and then centrifuged at 12,000<span class="elsevierStyleHsp" style=""></span>rpm for 15<span class="elsevierStyleHsp" style=""></span>min at 4<span class="elsevierStyleHsp" style=""></span>°C. After centrifugation, the RNA, distributed in the water phase, was precipitated using an equal volume of isopropanol. After the precipitation, the RNA pellet was rinsed with at least 1<span class="elsevierStyleHsp" style=""></span>ml of 75% ethanol (75% ethanol prepared with DEPCH2O) and re-centrifuged at 7000<span class="elsevierStyleHsp" style=""></span>rpm at 4<span class="elsevierStyleHsp" style=""></span>°C for 5<span class="elsevierStyleHsp" style=""></span>min. Next, most of the ethanol solution was carefully removed and the RNA pellet was air-dried at RT for 5–10<span class="elsevierStyleHsp" style=""></span>min. Lastly, The RNA pellet was dissolved in 40<span class="elsevierStyleHsp" style=""></span>μl of RNase-free water and stored at −80<span class="elsevierStyleHsp" style=""></span>°C for later use.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">qRT-PCR Assay</span><p id="par0060" class="elsevierStylePara elsevierViewall">For qRT-PCR, cDNA synthesis was performed according to the manufactures’ instruction for the PrimeScriptTM RT Master Mix Kit (Takara, No.RR036B, Japan). The reverse transcriptase MMLV along with the reaction mixture was incubated at 70<span class="elsevierStyleHsp" style=""></span>°C for 3<span class="elsevierStyleHsp" style=""></span>min, and then immediately transferred to ice water. Then, 0.5<span class="elsevierStyleHsp" style=""></span>μl of reverse transcriptase was added and incubated at 37<span class="elsevierStyleHsp" style=""></span>°C for 60<span class="elsevierStyleHsp" style=""></span>min. Next, final incubation was performed at 95<span class="elsevierStyleHsp" style=""></span>°C for 3<span class="elsevierStyleHsp" style=""></span>min to obtain the cDNA which was stored at −80<span class="elsevierStyleHsp" style=""></span>°C. The housekeeping gene, β-actin was used as an internal standard. The specific primers used were: for miR-146<span class="elsevierStyleSup">a</span>-5p, 5’-3’ (forward) GGG GTG AGA ACT GAA TTC CAT and 5’-3’ (reverse) CAG TGC GTG TCG TGG AGT; for β-actin, 5’-3’ (forward) TGG CAC CCA GCA CAA TGA A and 5’-3’ (reverse) CTA AGT CAT AGT CCG CCT AGA AGC A. The target gene and housekeeping gene of each sample were designed and synthesized by Shanghai GenePharma Company (China), and subjected to real-time PCR by means of the SYBR@Premix Ex TaqTM (Tli RNaseH Plus) Kit (Takara, No.RR820A, Japan). Real-time PCR was performed with the following cycling conditions: 95<span class="elsevierStyleHsp" style=""></span>°C for 30<span class="elsevierStyleHsp" style=""></span>s, 40 cycles of 95<span class="elsevierStyleHsp" style=""></span>°C for 5<span class="elsevierStyleHsp" style=""></span>s, 60<span class="elsevierStyleHsp" style=""></span>°C for 30<span class="elsevierStyleHsp" style=""></span>s and, after that, 95<span class="elsevierStyleHsp" style=""></span>°C for 15<span class="elsevierStyleHsp" style=""></span>s, 60<span class="elsevierStyleHsp" style=""></span>°C for 1<span class="elsevierStyleHsp" style=""></span>min, 95<span class="elsevierStyleHsp" style=""></span>°C for 15<span class="elsevierStyleHsp" style=""></span>s. PCR products were electrophoresed on a 2% agarose gel, and stained with GoldView™ (Shanghai yuanye Bio-Technology, No.R20977, China) to detect the amplified product. The relative expression level was calculated using the 2-<span class="elsevierStyleSup">ΔΔCT</span> method.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Western blotting</span><p id="par0065" class="elsevierStylePara elsevierViewall">SH-SY5Y cells and hippocampal tissue were lysed with RIPA buffer (Abcam, No.AB156034, USA) under specific conditions and separated on SDS polyacrylamide gel (Abcam, No.AB139597, USA). The protein bands were then transferred onto a PVDF membrane (Sigma, No.3010040001, USA) which was blocked with 5% skimmed milk. After blocking, three times washing was performed with PBS. Then, the membrane was incubated overnight with the primary antibodies, APP antibody (1:500, Abclonal, No.A11912, China), Aβ<span class="elsevierStyleInf">1–42</span> antibody (1:200, Abcam, No.P05067, USA), p38 MAPK antibody (1:500, Abcam, No.AB170099, USA), p-p38 MAPK antibody (1:1000, Beijing Biolab, No.K22589-TZH, China) or GADPH antibody (1:5000, Cell Signaling Technology, No. 4967, USA) at 4<span class="elsevierStyleHsp" style=""></span>°C. On the second day, after rewarming for 30<span class="elsevierStyleHsp" style=""></span>min and 3 times washing with PBS, membranes were incubated with the corresponding HRP-conjugated goat anti-rabbit IgG or HRP-conjugated goat anti-mouse IgG (1:10,000, Sigma, No.A0545 and SAB3700986, USA) secondary antibodies for 30<span class="elsevierStyleHsp" style=""></span>min at RT. The membranes were again washed 3 times with PBS. Lastly, the ECL reagent (Sigma, No.WBULS0500, USA) was used to illuminate the target protein bands, and the quantitative analysis of protein was performed by a Gel-Pro-Analyzer imaging system.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">All experimental results are presented as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard error, and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 denotes the significant statistical difference. For statistical analysis, Student's <span class="elsevierStyleItalic">t</span>-test (comparison between two groups) and ANOVA test (comparison between multiple groups) were used. Also, Bonferroni correction was used for the post hoc test. Two-way ANOVA and repeated measures were used to determine the time differences between the two groups in the MWM and the group factors (based on the escape latency). The software SPSS version 21.0 was used for the statistical analysis.</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Results</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Upregulated miR-146a-5p elevated cognitive impairment in Aβ<span class="elsevierStyleInf">1–42</span>-treated mice</span><p id="par0075" class="elsevierStylePara elsevierViewall">miR-146a-5p is known to be involved in the pathogenesis of AD. In our study, we observed that the transcription of miR-146a-5p was significantly up-regulated in the Aβ<span class="elsevierStyleInf">1–42</span>-treated group compared to the control group (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Also, Aβ<span class="elsevierStyleInf">1–42</span>-treated mice exhibited higher escapes latency than the mice of the control group (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). Overall, these results indicated a strong positive correlation between cognitive impairment and increased levels of miR-146-5p in mice model of AD.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">miR-146a-5p promoted Aβ deposition by triggering oxidative stress via activation of MAPK signaling in Aβ<span class="elsevierStyleInf">1–42</span>-treated mice</span><p id="par0080" class="elsevierStylePara elsevierViewall">Next, we investigated the correlations between cognitive impairment and miR-146a-5p by using miR-146a-5p mimic and miR-146a-5p inhibitor. We first evaluated the cognitive ability among the groups. The MWM results showed that compared to the control group, the escape latency increased in the AD group, and was further aggravated in the miR-146a-5p-mimic group. However, the treatment with miR-146a-5p inhibitor markedly reversed this change (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). Also, when we examined the levels of miR-146a-5p and Aβ deposition, we observed that compared to the control group, the levels were significantly higher in the model group. Notably, the miR-146a-5p expression and Aβ deposition were further increased in the miR-146a-5p-mimic group. However, these levels were lowered upon treatment with miR-146a-5p-inhibitor (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and C). Next, we tested the role of MAPK signaling and ROS level. We observed that compared to the control group, a greater level of p-P38 was observed in the miR-146a-5p mimic group, and ROS were accumulated. However, a reverse was observed upon treatment with miR-146a-5p-inhibitor (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>D–E). These experiments suggested that miR-146a-5p promoted the deposition of Aβ by triggering oxidative stress via activation of the MAPK signaling pathway.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">miR-146a-5p upregulated APP by increasing ROS levels via activation of MAPK signaling in Aβ<span class="elsevierStyleInf">1–42</span> treatedSH-SY5Y cells</span><p id="par0085" class="elsevierStylePara elsevierViewall">Next, we verified the aforesaid in vivo observations at the cellular level. For this, SH-SY5Y cells were used. Since miR-146a-5p is known to participate in the pathogenesis processes of AD, we began by evaluating the adverse effect of miR-146a-5p in the control and treated groups of cells. We observed that compared to the control group, Aβ<span class="elsevierStyleInf">1–42</span> treatment significantly up-regulated the level of miR-146a-5p (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A) and APP (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>E). This suggested that the transcription levels of both miR-146a-5p and APP were influenced by Aβ<span class="elsevierStyleInf">1–42</span> treatment.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">ROS accumulation is an important pathological change in AD pathology and critical for the production of APP. To test whether the elevated level of APP was related to ROS, the DCFH-DA (a probe for indicating ROS) method was used. We found that ROS were immensely accumulated in the treated group rather than the control group (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>D). Next, we examined whether this was caused by miR-146a-5p. For this, we exploited miR-146a-5p mimic and miR-146a-5p inhibitor. We found that compared to the model group, in the miR-146a-5p mimic group, levels of miR-146a-5p, APP, Aβ<span class="elsevierStyleInf">1–42</span>, and ROS were highly up-regulated (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A, D, and F). Importantly, these effects were reversed in the miR-146a-5p inhibitor group. Meanwhile, we noticed that compared to the control group, the expression of p-P38 was elevated in the model group. Also, the miR-146-mimic group exhibited a higher level of p-p38 while the miR-146a-5p-inhibitor group displayed a lower level of p-p38 (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>C). Overall, these results indicated that the expression of APP and Aβ<span class="elsevierStyleInf">1–42</span> were influenced by miR-146 via activation of MAPK signaling and oxidative stress.</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">Most degenerative diseases of the nervous system are closely related to age.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> AD is a disease of severe dementia with a growing incidence in humans. Understanding the pathogenesis at the cellular can reveal novel insights for the prevention and treatment of AD. In our study, we firstly verified that miR-146a-5p promoted the development of AD by depositing Aβ in the animal model. This was also true in cell assays. We think that the potential mechanism could be related to increased oxidative stress via activation of MAPK signaling.</p><p id="par0100" class="elsevierStylePara elsevierViewall">miR-146a-5p is widely regarded as an inflammation-related microRNA with immunomodulatory effects.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> Multiple reports showed that miR-146a-5p could inhibit the interleukin-1 receptor-related kinase 1 (IRAK1) and down-regulate NF-κb activity in the cognitive and memory-related brain regions, such as the hippocampus and prefrontal cortex in AD model mice.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">17,18</span></a> Recently, other studies also implicated miR-146a-5p in aging processes using the experimental animal models of AD.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">19,20</span></a> From the postmortem brain autopsy of AD patients, studies found that miR-146a-5p was highly expressed in the CSF, serum, and plasma. Therefore, to verify the correlation between AD and miR-146a-5p, we first tested the level of miR-146a-5p in Aβ<span class="elsevierStyleInf">1–42</span> treated cells and animals. Notably, our findings are consistent with previous studies and found significantly higher levels of miR-146a-5p in the AD model group. Interestingly, we also found that reduced levels of miR-146 markedly decreased APP and deposition of Aβ in the hippocampus regions of the brain.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Several hypotheses put oxidative stress as the key factor in the pathophysiology of AD. With the accumulation of ROS, synaptic activity gradually decreases which leads to abnormal metabolism triggering the accumulation of Aβ and the hyper-phosphorylation of Tau protein. This ultimately causes mitochondrial dysfunction and neuronal cell death.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">5</span></a> The autopsy analysis of mouse models and AD patients revealed that an unbalanced redox state leads to increased ROS causing mitochondrial dysfunction and Aβ peptide aggregation.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">5,21</span></a> In our study, the ROS level were much higher in the model group than that of the control group, both in animal and cell studies, which also was consistent with the previous reports. Importantly, up-regulated miR-146a-5p further aggravated oxidative stress in the AD model group.</p><p id="par0110" class="elsevierStylePara elsevierViewall">MAPKs, belonging to the class of protein Ser/Thr kinases, can transform extracellular stimuli into intracellular responses, and thereby regulate many physiological processes.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">22</span></a> ERK1/2, p38 MAPK, and c-Jun N-terminal kinases (JNKs) are the most widely studied MAPKs. Notably, MAPK signaling is also known to regulate the generation of ROS. In our study, the miR-146a-5p-mimic group exhibited abnormally increased levels of ROS, though this could be reversed by using FGA-19 (a MAPK inhibitor). The elevated Aβ levels were caused by oxidative stress and the unbalanced redox state was triggered by miR-146a-5p-induced MAPK signaling. These results strongly indicate that in the Aβ-treated cells and animal models, ROS production is dependent on the activation of the MAPK signaling pathway. Also, we think that miR-146a-5p inhibitors can be used to block MAPK signaling. In addition, there are some limitations should be noted in our study. For example, it indeed is difficult to differentiate the administer Aβ from the generated with our study design, which limits the research about relationship of miR-146a-5p and Aβ. In this study, the mice model of AD is induced by the intracerebroventricular injection of the Aβ<span class="elsevierStyleInf">1–42</span>, however, there are relatively mature and widely used mice models of AD which can be purchased from company or research institution, and will be used directly in our future study.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">In conclusion, using the animal and cellular models, we reported that miR-146a-5p promotes the development of AD and aggravates Aβ deposition which is potentially caused by oxidative stress via activation of MAPK signaling.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Funding</span><p id="par0120" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interests</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1958082" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1685224" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1958083" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1685223" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:11 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Cell culture, transfection, and Aβ treatment" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Animals and treatment" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Surgical procedure" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Morris water maze (MWM)" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Estimation of cellular reactive oxygen species (ROS) generation" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Aβ ELISA" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Immunohistochemistry" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "RNA extraction" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "qRT-PCR Assay" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Western blotting" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0070" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Upregulated miR-146a-5p elevated cognitive impairment in Aβ-treated mice" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "miR-146a-5p promoted Aβ deposition by triggering oxidative stress via activation of MAPK signaling in Aβ-treated mice" ] 2 => array:2 [ "identificador" => "sec0085" "titulo" => "miR-146a-5p upregulated APP by increasing ROS levels via activation of MAPK signaling in Aβ treatedSH-SY5Y cells" ] ] ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0100" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-09-25" "fechaAceptado" => "2020-12-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1685224" "palabras" => array:5 [ 0 => "Alzheimer disease" 1 => "miR-146a-5p" 2 => "Reactive oxygen species" 3 => "MAPK signaling" 4 => "Amyloid-β" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1685223" "palabras" => array:5 [ 0 => "Enfermedad de Alzheimer" 1 => "miR-146a-5p" 2 => "Especies reactivas de oxígeno" 3 => "Señalización MAPK" 4 => "β-amiloide" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)<span class="elsevierStyleInf">1–42</span>.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To create a model of AD, SH-SY5Y cells were treated with Aβ<span class="elsevierStyleInf">1–42</span> and mice received intracerebroventricular injections of Aβ<span class="elsevierStyleInf">1–42</span>. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Aβ<span class="elsevierStyleInf">1–42</span>-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ<span class="elsevierStyleInf">1–42</span>, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">miR-146a-5p es un elemento regulador clave en la respuesta inmune. Sin embargo, estudios recientes sugieren que miR-146a-5p también está involucrado en el desarrollo de la enfermedad de Alzheimer (EA), aunque aún no se conoce con exactitud el mecanismo por el que esto sucede. Analizamos los efectos de miR-146a en un modelo animal y en células SH-SY5Y expuestas a β-amiloide (Aβ)<span class="elsevierStyleInf">1-42</span>.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Tratamos células SH-SY5Y con Aβ<span class="elsevierStyleInf">1-42</span> e inyectamos Aβ<span class="elsevierStyleInf">1-42</span> en los ventrículos cerebrales de ratones para generar un modelo celular y otro animal de EA. Estimamos los niveles transcripcionales de miR-146a mediante PCR en tiempo real. Al mismo tiempo, transfectamos temporalmente las células y los ratones con imitador/inhibidor de miR-146a<span class="elsevierStyleItalic">-</span>5p para evaluar el papel de miR-146a<span class="elsevierStyleItalic">.</span> Estudiamos el papel de algunas vías de señalización, como la de p38, y los niveles de especies reactivas de oxígeno (ERO) con inhibidores específicos. Los niveles de Aβ y de proteína precursora amiloidea (APP) se determinaron con inmunoblot. También se analizó la expresión de Aβ mediante inmunofluorescencia y análisis histoquímico.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Las células SH-SY5Y expuestas a Aβ<span class="elsevierStyleInf">1-42</span> mostraron altos niveles transcripcionales de miR-146a y APP. La vía de señalización p-38 MAPK y la producción de EROs se activaron al utilizar un imitador de miR-146a-5p<span class="elsevierStyleItalic">.</span> Sin embargo, el bloqueo de miR-146a-5p con un inhibidor redujo los niveles de APP, EROs y p-p38 MAPK. Se observó un fenómeno similar en los ratones tratados con Aβ<span class="elsevierStyleInf">1-42</span>: la sobrerregulación de miR-146a aumentó la expresión de Aβ, p-p38 y EROs, mientras que la inhibición de miR-146a tuvo el efecto contrario. Esto sugiere que miR-146a está involucrado en el aumento de acumulación de Aβ y de producción de EROs por medio de la vía de señalización p-p38.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestro estudio muestra que miR146a-5p aumenta la acumulación de Aβ al promover el estrés oxidativo a través de la activación de la vía de señalización MAPK.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 893 "Ancho" => 2508 "Tamanyo" => 103075 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The expression of miR-146a-5p and cognitive impairment were elevated in Aβ<span class="elsevierStyleInf">1–42</span>-treated mice. (A) Estimation of escape latency in Morris water maze in the control and Aβ<span class="elsevierStyleInf">1–42</span>-treated groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); (B) Relative expression of miR-146a-5p in the control and Aβ<span class="elsevierStyleInf">1–42</span>-treated groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5). Each bar represents mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>S.E.M. * <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and ***<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the control group.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 4080 "Ancho" => 2508 "Tamanyo" => 937558 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">miR-146a-5p promoted Aβ deposition by triggering oxidative stress via activation of MAPK signaling in Aβ<span class="elsevierStyleInf">1–42</span>-treated mice. (A) Relative transcription levels of miR-146a-5p among groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); (B) Relative escape latency in MWM are shown (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5); (C) Immunohistochemistry analysis of Aβ in the hippocampus upon treatment as indicated, Scale bar: 200<span class="elsevierStyleHsp" style=""></span>μm; (D) Relative expression of DCHF-DA among groups, Scale bar: 50<span class="elsevierStyleHsp" style=""></span>μm; (E) Bar graphs show densitometric analysis of p-p38as indicated in western blots (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5). Each bar represents mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>S.E.M. * <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and *** <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the control group. ##<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and ###<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the AD group.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 4175 "Ancho" => 2698 "Tamanyo" => 688613 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">miR-146a-5p up-regulated APP by increasing ROS levels via activation of MAPK signaling in the Aβ<span class="elsevierStyleInf">1–42</span>-treated SH-SY5Y cells. (A, B) Relative transcription levels of miR-146a-5p among groups (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3); (C) Immunoblotting of p-p38 in the hippocampus following the treatment as indicated. (D) Relative expression of DCFH-DA among groups, Scale bar: 50<span class="elsevierStyleHsp" style=""></span>μm; (E) Western blots showing the APP levels and the bar graphs show densitometric analysis of the same (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3). (F) Bar graphs showing the densitometric analysis of Aβ<span class="elsevierStyleInf">1–42</span> by ELISA (n3). * <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and *** <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the control group. ## <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 and ### <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 vs. the AD group.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0115" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alzheimer's disease: unique markers for diagnosis & new treatment modalities" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N.T. Aggarwal" 1 => "R.C. Shah" 2 => "B. DA" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Indian J Med Res" "fecha" => "2015" "paginaInicial" => "142" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0120" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of beta-site APP-cleaving enzyme 1 gene expression and its role in Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "X. Sun" 1 => "K. Bromley-Brits" 2 => "W. Song" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1471-4159.2011.07515.x" "Revista" => array:7 [ "tituloSerie" => "J Neurochem" "fecha" => "2012" "volumen" => "120" "numero" => "Suppl. 1" "paginaInicial" => "62" "paginaFinal" => "70" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22122349" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0125" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "W S. BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer's pathogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Zhang" 1 => "Z. Wang" 2 => "F. Cai" 3 => "M. Zhang" 4 => "Y. Wu" 5 => "J. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1523/JNEUROSCI.0340-17.2017" "Revista" => array:6 [ "tituloSerie" => "J Neurosci" "fecha" => "2017" "volumen" => "37" "paginaInicial" => "6915" "paginaFinal" => "6925" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28626014" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0130" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D. Praticò" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0002-9343(00)00547-7" "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "2000" "volumen" => "109" "paginaInicial" => "577" "paginaFinal" => "585" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11063960" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0135" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X. Wang" 1 => "B. Su" 2 => "S.L. Siedlak" 3 => "P.I. Moreira" 4 => "H. Fujioka" 5 => "Y. Wang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.0804871105" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci USA" "fecha" => "2008" "volumen" => "105" "paginaInicial" => "19318" "paginaFinal" => "19323" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19050078" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0140" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of miRNA expression profiles in individuals with chronic or aggressive periodontitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.A. Amaral" 1 => "T.S.F. Pereira" 2 => "J.A.R. Brito" 3 => "S.C. Cortelli" 4 => "J.R. Cortelli" 5 => "R.S. Gomez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/odi.12994" "Revista" => array:5 [ "tituloSerie" => "Oral Dis" "fecha" => "2019" "volumen" => "25" "paginaInicial" => "561" "paginaFinal" => "568" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0145" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Jiang" 1 => "Y. Hu" 2 => "S. Deng" 3 => "J. Deng" 4 => "X. Yu" 5 => "G. Huang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbadis.2017.12.035" "Revista" => array:6 [ "tituloSerie" => "Biochim Biophys Acta Mol Basis Dis" "fecha" => "2018" "volumen" => "1864" "paginaInicial" => "925" "paginaFinal" => "933" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29288795" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0150" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Selenium suppresses inflammation by inducing microRNA-146a in Staphylococcus aureus-infected mouse mastitis model" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Sun" 1 => "Q. Wang" 2 => "Y. Guo" 3 => "Y. Zhao" 4 => "X. Wang" 5 => "Z. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.18632/oncotarget.20740" "Revista" => array:6 [ "tituloSerie" => "Oncotarget" "fecha" => "2017" "volumen" => "8" "paginaInicial" => "110949" "paginaFinal" => "110964" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29340029" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0155" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Key aging-associated alterations in primary microglia response to beta-amyloid stimulation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Caldeira" 1 => "C. Cunha" 2 => "A.R. Vaz" 3 => "A.S. Falcao" 4 => "A. Barateiro" 5 => "E. Seixas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fnagi.2017.00277" "Revista" => array:5 [ "tituloSerie" => "Front Aging Neurosci" "fecha" => "2017" "volumen" => "9" "paginaInicial" => "277" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28912710" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0160" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Sierksma" 1 => "A. Lu" 2 => "E. Salta" 3 => "E.V. Eynden" 4 => "Z. Callaerts-Vegh" 5 => "R. D’Hooge" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s13024-018-0285-1" "Revista" => array:5 [ "tituloSerie" => "Mol Neurodegener" "fecha" => "2018" "volumen" => "13" "paginaInicial" => "54" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30314521" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0165" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "W S. Morris water maze test for learning and memory deficits in Alzheimer's disease model mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Bromley-Brits" 1 => "Y. Deng" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Vis Exp" "fecha" => "2011" "volumen" => "53" "paginaInicial" => "e2920" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0170" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "W S. Trehalose inhibits Aβ generation and plaque formation in Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Y. Liu" 1 => "J. Wang" 2 => "G.R. Hsiung" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Mol Neurobiol" "fecha" => "2020" "volumen" => "57" "paginaInicial" => "3150" "paginaFinal" => "3157" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0175" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anodal transcranial direct current stimulation can improve spatial learning and memory and attenuate Aβ42 burden at the early stage of Alzheimer's disease in APP/PS1 transgenic mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Y. Luo" 1 => "W.N.L. Yang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fnagi.2020.00134" "Revista" => array:5 [ "tituloSerie" => "Front Aging Neurosci" "fecha" => "2020" "volumen" => "12" "paginaInicial" => "134" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32595486" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0180" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Orchiectomy and letrozole differentially regulate synaptic plasticity and spatial memory in a manner that is mediated by SRC-1 in the hippocampus of male mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Zhao" 1 => "C. Bian" 2 => "M. Liu" 3 => "Y. Zhao" 4 => "T.F.X. Sun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jsbmb.2018.02.007" "Revista" => array:6 [ "tituloSerie" => "J Steroid Biochem Mol Biol" "fecha" => "2018" "volumen" => "178" "paginaInicial" => "354" "paginaFinal" => "368" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29452160" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0185" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D.N.D. Praticò" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0002-9343(00)00547-7" "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "2000" "volumen" => "109" "paginaInicial" => "577" "paginaFinal" => "658" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11063960" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0190" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of human natural killer cell IFN-gamma production by microRNA-146a via targeting the NF-kappaB signaling pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Wang" 1 => "Y. Zhang" 2 => "X. Wu" 3 => "Y. Wang" 4 => "H. Cui" 5 => "X. Li" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2018.00293" "Revista" => array:5 [ "tituloSerie" => "Front Immunol" "fecha" => "2018" "volumen" => "9" "paginaInicial" => "293" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29593706" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0195" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An enriched environment prevents diabetes-induced cognitive impairment in rats by enhancing exosomal miR-146a secretion from endogenous bone marrow-derived mesenchymal stem cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Kubota" 1 => "M. Nakano" 2 => "E. Kobayashi" 3 => "Y. Mizue" 4 => "T. Chikenji" 5 => "M. Otani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0204252" "Revista" => array:5 [ "tituloSerie" => "PLOS ONE" "fecha" => "2018" "volumen" => "13" "paginaInicial" => "e0204252" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30240403" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0200" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum microRNA profiles serve as novel biomarkers for the diagnosis of Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Dong" 1 => "J. Li" 2 => "L. Huang" 3 => "X. Chen" 4 => "D. Li" 5 => "T. Wang" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Dis Markers" "fecha" => "2015" "paginaInicial" => "e625659" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0205" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dysregulated expression of miR-146a contributes to age-related dysfunction of macrophages" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Jiang" 1 => "Y. Xiang" 2 => "D. Wang" 3 => "J. Gao" 4 => "D. Liu" 5 => "Y. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1474-9726.2011.00757.x" "Revista" => array:6 [ "tituloSerie" => "Aging Cell" "fecha" => "2012" "volumen" => "11" "paginaInicial" => "29" "paginaFinal" => "40" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21981419" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0210" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MicroRNA-146a induces lineage-negative bone marrow cell apoptosis and senescence by targeting polo-like kinase 2 expression" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Deng" 1 => "H. Wang" 2 => "C. Jia" 3 => "S. Zhu" 4 => "X. Chu" 5 => "Q. Ma" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/ATVBAHA.116.308378" "Revista" => array:6 [ "tituloSerie" => "Arterioscler Thromb Vasc Biol" "fecha" => "2017" "volumen" => "37" "paginaInicial" => "280" "paginaFinal" => "290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27908889" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0215" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "I M-J. Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.Y. Cha" 1 => "S.H. Han" 2 => "S.M. Son" 3 => "H.S. Hong" 4 => "Y.J. Choi" 5 => "J. Byun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0034929" "Revista" => array:5 [ "tituloSerie" => "PLoS ONE" "fecha" => "2012" "volumen" => "7" "paginaInicial" => "e34929" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22514691" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0220" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "C. Widmann" 1 => "S. Gibson" 2 => "M.B. Jarpe" 3 => "G.L. Johnson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/physrev.1999.79.1.143" "Revista" => array:6 [ "tituloSerie" => "Physiol Rev" "fecha" => "1999" "volumen" => "79" "paginaInicial" => "143" "paginaFinal" => "180" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9922370" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/02134853/0000003800000007/v1_202309041924/S0213485321000220/v1_202309041924/en/main.assets" "Apartado" => array:4 [ "identificador" => "9397" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Originales" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/02134853/0000003800000007/v1_202309041924/S0213485321000220/v1_202309041924/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485321000220?idApp=UINPBA00004N" ]
