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Editorial
Micro-RNA regulation of the angiogenic response in the diabetic retina
Regulación por micro RNA de la respuesta angiogénica en la retina diabética
H.C. Campos-Borgesa,b,1, S.M. Sanz-Gonzálezb,c,1, V. Zanón-Morenob,c,d, J.M. Millán Salvadore,f, M.D. Pinazo-Duranb,c,
Corresponding author
dolores.pinazo@uv.es

Corresponding author.
a Departamento de Química y Biomoléculas, Escuela Superior de Salud, Porto, Portugal
b Unidad de Investigación Oftalmológica “Santiago Grisolía”/FISABIO, Grupo de Oftalmobiología Celular y Molecular, Universidad de Valencia, Valencia, Spain
c Red Temática de Investigación Cooperativa en patología ocular (OFTARED), Instituto de Salud Carlos III, Madrid, Spain
d Universidad Internacional de Valencia, Valencia, Spain
e Unidad de Genómica Instituto Investigación Sanitaria La Fe, Valencia, Spain
f Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Diabetes mellitus &#40;DM&#41; prevalence is exponentially increasing worldwide&#44; constituting in Spain a serious problem for public health and social and sanitary expenditure&#46; Diabetic retinopathy &#40;DR&#41;&#44; the first cause of visual loss in working-age adults&#44; involves a multifactorial process where the main risk factor is chronic hyperglycemia&#44; which manifests as a microangiopathy that involves retinal and choroid neurodegeneration and requires early intervention&#44; both for diagnosis and medical and surgical treatment&#46; The main cellular and molecular mechanisms<span class="elsevierStyleSup">1</span> by which hyperglycemia damages the retinal and choroidal vessels include the following&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0010" class="elsevierStylePara elsevierViewall">Increased polyols pathways &#40;including sorbitol&#41; and hexosamine &#40;induces changes in the expression of genes and proteins related to microangiopathy&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0015" class="elsevierStylePara elsevierViewall">Activation of protein-kinase C isoforms &#40;nine of these are activated by diacyl glycerol as the second lipid messenger&#44; which alters vascular homeostasis&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0020" class="elsevierStylePara elsevierViewall">Increased advanced glycosylation products &#40;derived from intracellular autoxidation of glucose to 3-deoxyglucosone&#44; glyoxal and methylglyoxal&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4</span><p id="par0025" class="elsevierStylePara elsevierViewall">Endothelial reticulum stress can alter mitochondrial biogenesis producing reactive oxygen species &#40;ROS&#41; that damage lipids&#44; proteins and nucleic acids&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p></li></ul></p><p id="par0030" class="elsevierStylePara elsevierViewall">As previously mentioned&#44; chronic hyperglycemia is responsible for death by apoptosis of retinal ganglion cells &#40;RGC&#41;&#44; but it also induces changes in the rest of cellular phenotypes&#44; reducing the number of synapses and compacting&#44; demonstrated by optical coherence tomography &#40;OCT&#41; examination&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The initial stages of DR involve the alteration of the internal blood-retina barrier and thinning of vascular basal membranes as well as damage to pericytes and endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In fact&#44; pericyte loss is key to hypoxia and neovascularization&#44; mainly through vascular endothelial growth factor &#40;VEGF&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In addition&#44; the glia is activated giving rise to innate immunity mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Tumor necrosis factor alpha &#40;TNF&#945;&#41; and other proinflammatory interleukins &#40;IL&#41; &#40;IL-1&#946;&#44; IL-6&#44; IL-18&#41; are related to insulin resistance&#44; as in type 2 DM &#40;DM2&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Angiogenesis is a very complex process involving several genes that coexist in equilibrium for its promotion or inhibition&#44; and this in turn depends on many factors&#46; Chorioretinal circulation offers an excellent model to study angiogenesis&#44; both in physiological and pathological conditions&#44; the latter &#40;neovascularization&#41; responsible for various eye diseases and loss of vision&#44; mainly through VEGF and its receptors &#40;VEGFR&#41;&#44; an essential promoter in this process&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> but also of other molecules&#44; such as placental growth factors &#40;PGF&#41;&#44; derived from B-platelets &#40;PDGF-B&#41;&#44; derived from stroma-1 &#40;SDF-1&#41;&#44; inducible by hypoxia-1 &#40;HIF-1&#41;&#44; etc&#46; However&#44; VEGF is the most potent known vasoactive molecule&#44; and its presence is essential for the structural and functional maintenance of retinal cells&#44; although its excess can induce retinal angiogenesis in response to hypoxia and hyperglycemia&#46; VEGF is mainly synthesized by vascular endothelial cells&#44; pericytes&#44; various retinal phenotypes &#40;neurons&#44; astrocytes&#44; M&#252;ller cells and pigmentary epithelium&#41; and ciliary epithelium&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Data on the bioavailability of VEGF in plasma and serum of patients with DR are controversial&#46; However&#44; a recent meta-analysis demonstrates correlation between the serum concentration of VEGF &#40;and not in plasma&#41; determined by ELISA&#44; with the presence and severity of DR&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In addition&#44; the clinical efficiency of intravitreal treatment with anti-VEGF drugs is indisputable&#44; including diabetic macular edema &#40;DME&#41; and the neovascular form of age-associated macular degeneration &#40;AMD&#41;&#46; Anti-VEGFs are active in the nanomolar and picomolar range&#46; Intravitreal injections of ranibizumab and aflibercept&#44; which bind to all VEGFA isoforms&#44; have demonstrated their efficacy and safety showing significant improvements&#58; between 35 and 40&#37; visual acuity in patients with choroidal neovascularization&#44; although 60&#8211;65&#37; of these patients did not respond to therapy&#44; probably because &#171;something else&#187; is needed to block VEGF&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;7</span></a> It is known that transcriptional regulation of the genes involved in the process is essential to determine the balance between promoters&#47;inhibitors of neovascularization&#46; Moreover&#44; there is a silent phase prior to the appearance of clinical manifestations of DR&#44; in which important cellular and molecular changes take place that require the highest focus of clinicians and researchers&#46; Once DR is established&#44; progression towards proliferative forms characterized by neovascularization&#44; fibrosis&#44; the presence of vitreous and&#47;or preretinal hemorrhages and the ensuing complications thereof are the cause of diabetic blindness&#46; Therefore&#44; it is necessary to develop new diagnostic strategies and additional therapies to treat DR and prevent vision loss&#46; And it is here that micro-RNAs can play a supplementary role both in the diagnosis and design of new biotherapies for DR&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In the last decades&#44; interference RNA&#44; which regulates many biological functions such as cellular&#47;tissue architecture and cell signaling has broken into the scientific landscape&#46; The so-called &#171;micro-RNA&#187; are small molecules of single stranded RNA &#40;between 19 and 25<span class="elsevierStyleHsp" style=""></span>nt long&#41; involved in post-transcriptional gene regulation and probably also in DNA methylation&#46; They are non-coding and perform essential functions as regulators of numerous pathways and biological processes&#44; negatively controlling the expression of target genes&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> It is estimated that each micro-RNA can regulate about 200-messengers&#46; They can control up to 60&#37; of the expression of protein coding genes&#46; Changes in micro-RNA expression have been related to incidence&#44; risk factors and development&#47;progression of many diseases&#44; including ocular disorders&#46; The first publication relating micro-RNA and DR described the VEGF gene expression regulation by miR-200b in early and advanced stages&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Subsequent works demonstrated that hyperglycemia causes differences in the expression of micro-RNA related to the pathogenic mechanisms of the disease&#44; such as those associated with endothelial injury&#44; inflammation&#44; angiogenesis&#44; apoptosis and oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Preclinical research in humans has identified specific micro-RNAs&#44; such as the vitreous micro-RNA<span class="elsevierStyleHsp" style=""></span>200b of patients with proliferating DR &#40;PDR&#41; versus patients with macular hole as a comparative group&#44; determining VEGF by ELISA&#46; Both molecules were significantly increased in patients with PDR&#44; but they were not correlated&#46; For this reason researchers concluded that the mechanism of action of micro-RNA<span class="elsevierStyleHsp" style=""></span>200b is independent of VEGF&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In our opinion this is a very interesting topic that requires additional research&#46; Furthermore&#44; it has been described in animal models that micro-RNA<span class="elsevierStyleHsp" style=""></span>34a decreases VEGF and retinal angiogenesis through the Notch<span class="elsevierStyleHsp" style=""></span>1 pathway in a rat retinopathy model&#44; as well as in microvascular endothelial retinal cells stimulated with VEGF&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Micro<span class="elsevierStyleHsp" style=""></span>RNA<span class="elsevierStyleHsp" style=""></span>155 demonstrated anti-angiogenic properties in response to its blockade using lentivirus-mediated interference RNA&#44; attenuating retinal neovascularization via the phosphatidylinositol 3-kinase &#40;PI3K&#41;&#47;Akt pathway in in vivo and in vitro studies&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Collaborative studies between OFTARED and CIBERER groups and various hospitals and centers in Spain and Portugal have developed the tear extraction protocol for genetics and omic sciences studies of eye diseases&#46; In summary&#44; in 270 participants &#40;90 controls&#44; 90<span class="elsevierStyleHsp" style=""></span>DM2 with DR&#44; 90<span class="elsevierStyleHsp" style=""></span>DM2 without DR&#41; tears from the lower palpebral meniscus of both eyes were obtained through capillarity and were immediately frozen at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C to extract the total purified RNA &#40;with an appropriate quantity to continue the protocol&#41;&#44; using the RNeasy Mini Kit &#40;Qiagen&#41;&#44; from which the libraries were constructed using the NEBNext Ultra RNA Library Prep Kit &#40;New England Biolabs&#41;&#46; Once the cDNA libraries were obtained&#44; micro-RNA fragments and other species belonging to the &#171;small RNA&#187; fraction quality was examined&#46; The libraries were re-amplified and the desired fragments were quantified by polymerase chain reaction &#40;PCR&#41;&#46; Finally&#44; samples were diluted to a concentration of 2<span class="elsevierStyleHsp" style=""></span>nM&#44; equimolar pools were made and next generation sequencing &#40;NGS&#41; was carried out&#46; After bioinformatic analysis of the results and comparing them with databases &#40;miRBase&#44; microRNA&#46;org&#41; 64 micro-RNA were identified in tears of the study subjects&#46; Comparing DM2 tears with&#47;without DR&#44; 48 micro-RNA were identified&#46; Among them&#44; 14 stood out for their greater statistical significance in relation to the presence of DR&#46; Differential expression of micro-RNA among patients with&#47;without DR demonstrated that the most significant are related to angiogenesis&#46; To confirm the sequencing results&#44; a quantitative real-time PCR &#40;qRT-PCR&#41; was performed&#46; Likewise&#44; the expression of the <span class="elsevierStyleItalic">VEGFA</span> gene was analyzed by qRT-PCR&#44; using the <span class="elsevierStyleItalic">GAPDH</span> gene as <span class="elsevierStyleItalic">housekeeping</span>&#46; The <span class="elsevierStyleItalic">VEGFA</span> gene is located on chromosome<span class="elsevierStyleHsp" style=""></span>6 in 6p21&#46;1&#44; and is organized in 8 exons and 7 introns &#40;about 14<span class="elsevierStyleHsp" style=""></span>kb&#41;&#46; In our study&#44; VEGFA gene expression was significantly higher in diabetics with retinopathy compared to patients without DR&#46; These studies have revealed the potential of micro-RNA involved in the bioavailability of the <span class="elsevierStyleItalic">VEGFA</span> gene in DR as biomarkers for preclinical diagnosis&#44; and in monitoring the progression and response to anti-VEGF therapy in patients with DR&#46; Even so&#44; its potential to be used in the design of new biotherapies for DR requires a more in-depth investigation&#44; and so our groups continue this work&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0050" class="elsevierStylePara elsevierViewall">This work has been funded&#44; in part&#44; by the following institutions&#58; in collaboration with <span class="elsevierStyleGrantSponsor" id="gs0005">OFTARED</span> &#91;Thematic Network for Cooperative Research in Ocular Pathology RD16-0008&#93;&#44; Carlos III Health Institute&#44; Ministry of Science&#44; Innovation and Universities&#59; from Madrid &#40;Profs&#46; Jose M&#46; Ram&#237;rez&#44; Juan J&#46; Salazar&#44; and Ana I&#46; Ram&#237;rez&#41;&#44; from Valladolid &#40;Profs&#46; M&#46; Isabel L&#243;pez-G&#225;lvez and David Galarreta Mira&#41; and from Valencia &#40;Profs&#46; M&#46; Dolores Pinazo-Dur&#225;n&#44; Silvia M&#46; Sanz-Gonz&#225;lez&#44; Jose J&#46; Garc&#237;a-Medina&#44; Ricardo P&#46; Casaroli&#44; Elena Bendala and Vicente Zan&#243;n-Moreno&#41;&#93;&#44; and <span class="elsevierStyleGrantSponsor" id="gs0010">CIBERER</span> &#91;Center for Biomedical Research in Rare Diseases Network&#44; from Carlos Health Institute III&#44; Ministry of Science&#44; Innovation and Universities&#59; Valencia group &#40;Prof&#46; Jose M Mill&#225;n&#44; Dr&#46; Laila Pedrola&#44; Dr&#46; Teresa Jaijo and&#46; Dr&#46; Elena Aller&#41;&#93;&#46; It has also been funded&#44; in part&#44; by the <span class="elsevierStyleGrantSponsor" id="gs0015">European ERDF program and FIS research projects</span> PI13 &#47; 00480&#44; PI16 &#47; 00797 and Ocusensor-UPV &#47; FISABIO &#47; 2018-2019 &#40;Profs&#46; M&#46; Dolores Pinazo-Dur&#225;n and Jaime Garc&#237;a- Rup&#233;rez&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">There is no conflict of interest in this publication&#46;</p></span></span>"
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              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neurodegeneration in diabetic retinopathy&#58; does it really matter&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Sim&#243;"
                            1 => "A&#46;W&#46; Stitt"
                            2 => "T&#46;W&#46; Gardner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00125-018-4692-1"
                      "Revista" => array:7 [
                        "tituloSerie" => "Diabetologia&#46;"
                        "fecha" => "2018"
                        "volumen" => "61"
                        "numero" => "9"
                        "paginaInicial" => "1902"
                        "paginaFinal" => "1912"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30030554"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Valencia Study On Diabetic Retinopathy &#40;VSDR&#41;&#46; Enhanced Oxidative Stress and Other Potential Biomarkers for Retinopathy in Type 2 Diabetics&#58; Beneficial Effects of the Nutraceutic Supplements"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:22 [
                            0 => "M&#46;J&#46; Roig-Revert"
                            1 => "A&#46; Lle&#243;-P&#233;rez"
                            2 => "V&#46; Zan&#243;n-Moreno"
                            3 => "B&#46; Vivar-Llopis"
                            4 => "J&#46; Mar&#237;n-Montiel"
                            5 => "R&#46; Dolz-Marco"
                            6 => "L&#46; Alonso-Mu&#241;oz"
                            7 => "M&#46; Albert-Fort"
                            8 => "M&#46;I&#46; L&#243;pez-G&#225;lvez"
                            9 => "D&#46; Galarreta-Mira"
                            10 => "M&#46;F&#46; Garc&#237;a-Esparza"
                            11 => "C&#46; Galbis-Estrada"
                            12 => "C&#46; Marco-Ramirez"
                            13 => "K&#46; Shoaie-Nia"
                            14 => "S&#46;M&#46; Sanz-Gonz&#225;lez"
                            15 => "V&#46; Vila-Bou"
                            16 => "E&#46; Bendala-Tufanisco"
                            17 => "J&#46;J&#46; Garc&#237;a-Medina"
                            18 => "C&#46; Nucci"
                            19 => "R&#46; Gallego-Pinazo"
                            20 => "J&#46;F&#46; Ar&#233;valo"
                            21 => "M&#46;D&#46; Pinazo-Dur&#225;n"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1155/2015/408180"
                      "Revista" => array:5 [
                        "tituloSerie" => "Biomed Res Int"
                        "fecha" => "2015"
                        "volumen" => "2015"
                        "paginaInicial" => "408180"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26618168"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Correlaci&#243;n Anat&#243;mica de las Im&#225;genes de Tomograf&#237;a de Coherencia &#211;ptica&#46; Nomenclatura Internacional"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "N&#46; Cuenca"
                            1 => "I&#46; Pinilla"
                            2 => "M&#46;D&#46; Pinazo-Dur&#225;n"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:3 [
                        "editores" => "PinazoGallego"
                        "titulo" => "OCT&#46; Obtenci&#243;n e interpretaci&#243;n de im&#225;genes"
                        "serieFecha" => "2016"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic retinopathy and VEGF&#46; Diabetic retinopathy and VEGF"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:8 [
                            0 => "N&#46; Gupta"
                            1 => "S&#46; Mansoor"
                            2 => "A&#46; Sharma"
                            3 => "A&#46; Sapkal"
                            4 => "J&#46; Sheth"
                            5 => "P&#46; Falatoonzadeh"
                            6 => "B&#46; Kuppermann"
                            7 => "M&#46; Kenney"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2174/1874364101307010004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Open Ophthalmol J&#46;"
                        "fecha" => "2013"
                        "volumen" => "7"
                        "paginaInicial" => "4"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23459241"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "T Inflammation in Diabetic Retinopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Tang"
                            1 => "T&#46;S&#46; Kern"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.preteyeres.2011.05.002"
                      "Revista" => array:7 [
                        "tituloSerie" => "Prog Retin Eye Res&#46;"
                        "fecha" => "2011"
                        "volumen" => "30"
                        "numero" => "5"
                        "paginaInicial" => "343"
                        "paginaFinal" => "358"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21635964"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum vascular endothelial growth factor levels correlate with severity of retinopathy in diabetic patients&#58; a systematic review and meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Z&#46; Zhou"
                            1 => "H&#46; Ju"
                            2 => "M&#46; Sun"
                            3 => "H&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Dis Markers&#46;"
                        "fecha" => "2019"
                        "volumen" => "2019"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mehta H Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46; Hennings"
                            1 => "M&#46;K&#46; Gillies"
                            2 => "V&#46; Nguyen"
                            3 => "A&#46; Campain"
                            4 => "S&#46; Fraser&#8208;Bell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Cochrane Database Syst Rev&#46;"
                        "fecha" => "2018"
                        "volumen" => "2018"
                        "numero" => "4"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MicroRNA therapeutics&#58; discovering novel targets and developing specific therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46;F&#46; Christopher"
                            1 => "R&#46;P&#46; Kaur"
                            2 => "G&#46; Kaur"
                            3 => "A&#46; Kaur"
                            4 => "V&#46; Gupta"
                            5 => "P&#46; Bansal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4103/2229-3485.179431"
                      "Revista" => array:6 [
                        "tituloSerie" => "Perspect Clin Res&#46;"
                        "fecha" => "2016"
                        "volumen" => "7"
                        "paginaInicial" => "68"
                        "paginaFinal" => "74"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27141472"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "B&#46; Kovacs"
                            1 => "S&#46; Lumayag"
                            2 => "C&#46; Cowan"
                            3 => "S&#46; Xu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1167/iovs.10-6879"
                      "Revista" => array:6 [
                        "tituloSerie" => "Invest Ophthalmol Vis Sci&#46;"
                        "fecha" => "2011"
                        "volumen" => "52"
                        "paginaInicial" => "4402"
                        "paginaFinal" => "4409"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21498619"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulatory role of microRNA on inflammatory responses of diabetic retinopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Ye Eun-Ah"
                            1 => "J&#46;J&#46; Steinle"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4103/1673-5374.205095"
                      "Revista" => array:7 [
                        "tituloSerie" => "Neural Regen Res&#46;"
                        "fecha" => "2017"
                        "volumen" => "12"
                        "numero" => "4"
                        "paginaInicial" => "580"
                        "paginaFinal" => "581"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28553335"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MicroRNA-200b expression in the vitreous humor of patients with proliferative diabetic retinopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46;R&#46; Gomaa"
                            1 => "E&#46;T&#46; Elsayed"
                            2 => "R&#46;F&#46; Moftah"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000475671"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ophthalmic Res&#46;"
                        "fecha" => "2017"
                        "volumen" => "58"
                        "numero" => "3"
                        "paginaInicial" => "168"
                        "paginaFinal" => "175"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28571008"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MicroRNA-34a attenuates VEGF-mediated retinal angiogenesis via targeting Notch1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S&#46; Shi"
                            1 => "Y&#46; Jin"
                            2 => "H&#46; Song"
                            3 => "X&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1139/bcb-2018-0304"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biochem Cell Biol&#46;"
                        "fecha" => "2019"
                        "volumen" => "97"
                        "numero" => "4"
                        "paginaInicial" => "423"
                        "paginaFinal" => "430"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30571142"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Down-regulation of microRNA-155 attenuates retinal neovascularization via the PI3K&#47;Akt pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Z&#46; Zhuang"
                            1 => "Hu H&#46; Xiao-qin"
                            2 => "S&#46;Y&#46; Tian"
                            3 => "Z&#46;J&#46; Lu"
                            4 => "T&#46;Z&#46; Zhang"
                            5 => "Y&#46;L&#46; Bai"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Mol Vis&#46;"
                        "fecha" => "2015"
                        "volumen" => "21"
                        "paginaInicial" => "1173"
                        "paginaFinal" => "1184"
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
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Article information
ISSN: 21735794
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos