RESUMEN
Diabetic retinopathy (DR) is the leading etiology of blindness in the working population of the USA. Its long-term management relies on effective glycemic control. Seven anti-diabetic classes have been introduced for patients with type 2 diabetes (T2D) in the past two decades, with different glucose-lowering and cardiovascular benefits. Yet, their effects specifically on DR have not been studied in detail. A systematic review of the literature was conducted to investigate this topic, focusing on the available clinical data for T2D. Published studies were evaluated based on their level of statistical evidence, as long as they incorporated at least one endpoint or adverse event pertaining to retinal health. Fifty nine articles met our inclusion criteria and were grouped per anti-diabetic class as follows: alpha-glucosidase inhibitors (1), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (8), amylin analogs (1), glucagon-like peptide-1 (GLP-1) receptor agonists (28), dipeptidyl peptidase 4 (DPP-4) inhibitors (9), and sodium glucose co-transporter-2 (SGLT-2) inhibitors (9), plus one retrospective study and two meta-analyses evaluating more than one of the aforementioned anti-diabetic categories. We also reviewed publicly-announced results of trials for the recently-introduced class of twincretins. The available data indicates that most drugs in the newer anti-diabetic classes are neutral to DR progression; however, there are subclasses differences in specific drugs and T2D populations. In particular, there is evidence suggesting there may be worse diabetic macular edema with PPAR-gamma agonists, potential slight DR worsening with semaglutide (GLP-1 receptor agonist), and potential slight increase in the incidence of retinal vein occlusion in elderly and patients with advanced kidney disease receiving SGLT-2 inhibitors. All these warrant further investigation. Longer follow-up and systematic assessment of at least one DR-related endpoint are highly recommended for all future trials in the T2D field, to ultimately address this topic.
Asunto(s)
Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Edema Macular , Anciano , Humanos , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios Retrospectivos , Hipoglucemiantes/uso terapéutico , GlucosaRESUMEN
Uveal melanoma (UM) is the most common primary intraocular cancer in the adult population. Recent studies suggested that the NLRP3 inflammasome could be a therapeutic target for cutaneous melanoma (CM), but the role of NLRP3 in UM remains unknown. Here, we analyzed the NLRP3-IL-1ß axis in 5 UM and 4 CM cell lines. Expression of NLRP3 mRNA in UM and CM was low, and expression in UM was lower than in CM (P < 0.001). NLRP3 protein levels were below detection limit for all cell lines. UM exhibited lower baseline IL-1ß secretion than CM, especially when compared to the Hs294t cell line (P < 0.05). Bioinformatic analysis of human tumor samples showed that UM has significantly lower expression of NLRP3 and IL-1ß compared with CM. In conclusion, our work shows evidence of extremely low NLRP3 expression and IL-1ß secretion by melanoma cells and highlight differences between CM and UM.
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Melanoma , Neoplasias Cutáneas , Adulto , Humanos , Inflamasomas/metabolismo , Melanoma/patología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neoplasias Cutáneas/patología , Interleucina-1beta/metabolismo , Melanoma Cutáneo MalignoRESUMEN
Ultraviolet light A (UVA) is the only UV light that reaches the retina and can cause indirect damage to DNA via absorption of photons by non-DNA chromophores. Previous studies demonstrate that UVA generates reactive oxygen species (ROS) and leads to programmed cell death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor interacting protein 1 and 3 (RIPK1 and RIPK3) kinases, key signaling molecules of PCD, in UVA-induced photoreceptor injury using in vitro and ex vivo models. UVA irradiation activated RIPK3 but not RIPK1 and mediated necroptosis through MLKL that lie downstream of RIPK3 and induced apoptosis through increased oxidative stress. Moreover, RIPK3 but not RIPK1 inhibition suppresses UVA-induced cell death along with the downregulation of MLKL and attenuates the levels of oxidative stress and DNA fragmentation. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced necroptosis cell death in photoreceptors and highlight RIPK3 potential as a neuroprotective target.
RESUMEN
Ultraviolet (UV) is one of the most energetic radiations in the solar spectrum that can result in various tissue injury disorders. Previous studies demonstrated that UVA, which represents 95% of incident photovoltaic radiation, induces corneal endothelial cells (CECs) death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor-interacting protein 3 kinase (RIPK3), a key signaling molecule of PCD, in UVA-induced injury using a short-term corneal endothelium (CE) culture model. UVA irradiation activated RIPK3 and mediated necroptosis both in mouse CE and primary human CECs (pHCECs). UVA irradiation was associated with upregulation of key necroptotic molecules (DAI, TRIF, and MLKL) that lie downstream of RIPK3. Moreover, RIPK3 inhibition or silencing in primary corneal endothelial cells suppresses UVA-induced cell death, along with downregulation of MLKL in pHCECs. In addition, genetic inhibition or knockout of RIPK3 in mice (RIPK3K51A and RIPK3-/- mice) similarly attenuates cell death and the levels of necroptosis in ex vivo UVA irradiation experiments. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced cell death in CE and indicate its potential as a future protective target.
RESUMEN
Progression of blinding diseases, such as age-related macular degeneration, is accelerated by light exposure. However, no particular intervention is applied to the photostress. Here, we report neuroprotective effects of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), on light-induced visual function impairment, photoreceptor disorders and death in mice. Increase in retinal ATP levels in response to photostress was transient, because oxygen consumption rate (OCR) and cytochrome c oxidase (CcO) activity were reduced under photostress. However, AICAR treatment preserved OCR, CcO activity, and high levels of retinal ATP after light exposure. AMPK knockdown in the photoreceptor-derived cell line revealed that AMPK targeted CcO activity. Further, our data indicated that photostress reduced mitochondrial respiratory function and ATP levels, while AICAR treatment promoted neuronal survival and retained visual function, stabilizing ATP levels through preserved CcO activity. The current study has provided proof of concept for providing cells with sufficient energy to promote cell survival in the presence of cellular stress. This is in contrast to the previous reports which primarily investigated therapeutic approaches to suppress stress signals. Hence, stabilization of the ATP supply may serve as a novel therapeutic approach to support tissue survival under stress and prevent neurodegeneration.
Asunto(s)
Adenosina Trifosfato/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Degeneración Macular/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Proteínas Quinasas/metabolismo , Ribonucleótidos/farmacología , Quinasas de la Proteína-Quinasa Activada por el AMP , Aminoimidazol Carboxamida/farmacología , Aminoimidazol Carboxamida/uso terapéutico , Animales , Línea Celular , Complejo IV de Transporte de Electrones/metabolismo , Degeneración Macular/etiología , Degeneración Macular/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Fármacos Neuroprotectores/uso terapéutico , Consumo de Oxígeno , Proteínas Quinasas/genética , Retina/efectos de los fármacos , Retina/metabolismo , Retina/efectos de la radiación , Ribonucleótidos/uso terapéutico , Rayos Ultravioleta/efectos adversosRESUMEN
We report a 60-year-old woman with posterior cortical atrophy (PCA) who presented with left homonymous hemianopsia persisting for 5 years; the patient's condition was observed using static, but not kinetic, perimetry. This statokinetic dissociation of hemianopsia, which is often called Riddoch syndrome, might have been caused by a dysfunction of the right primary visual and visual association cortices, representing a functional imbalance within a disturbed visual cortex. In patients with PCA and visual field defects, both static and kinetic perimetry may be useful for understanding the extent of degeneration in the visual cortex, in addition to examinations of unilateral neglect.
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Lutein slows the progression of age-related macular degeneration (AMD), a leading cause of blindness in ageing societies. However, the underlying mechanisms remain elusive. Here, we evaluated lutein's effects on light-induced AMD-related pathological events. Balb/c mice exposed to light (2000 lux, 3 h) showed tight junction disruption in the retinal pigment epithelium (RPE) at 12 h, as detected by zona occludens-1 immunostaining. Substantial disruption remained 48 h after light exposure in the vehicle-treated group; however, this was ameliorated in the mice treated with intraperitoneal lutein at 12 h, suggesting that lutein promoted tight junction repair. In the photo-stressed RPE and the neighbouring choroid tissue, lutein suppressed reactive oxygen species and increased superoxide dismutase (SOD) activity at 24 h, and produced sustained increases in sod1 and sod2 mRNA levels at 48 h. SOD activity was induced by lutein in an RPE cell line, ARPE19. We also found that lutein suppressed upregulation of macrophage-related markers, f4/80 and mcp-1, in the RPE-choroid tissue at 18 h. In ARPE19, lutein reduced mcp-1 mRNA levels. These findings indicated that lutein promoted tight junction repair and suppressed inflammation in photo-stressed mice, reducing local oxidative stress by direct scavenging and most likely by induction of endogenous antioxidant enzymes.
Asunto(s)
Antioxidantes/farmacología , Luteína/farmacología , Retina/efectos de los fármacos , Animales , Línea Celular , Coroides/efectos de los fármacos , Coroides/metabolismo , Humanos , Luz , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Retina/metabolismo , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Oxidative stress in the retinal pigment epithelium (RPE) is a well-accepted pathogenic change in vision-threatening diseases such as age-related macular degeneration. One source of oxidative stress is excessive light exposure, which causes excessive activation of the visual cycle. Because short wavelength light (blue light) has more energy, it is reported to be more harmful to photoreceptor cells than the other wavelengths of light. However, the biological effect of blue light in the RPE of living animals and the protective effect of a yellow intraocular lens (IOL) material that blocks blue light is still obscure. Therefore, we compared the pathogenic effect in the RPE-choroid complexes of mice exposed to light in a box made of a clear or a yellow IOL material. We measured the level of reactive oxygen species (ROS) using 2', 7'-dichlorodihydrofluorescein diacetate, the mRNA levels of inflammatory cytokines and a macrophage marker by real-time polymerase chain reaction, and the protein level of monocyte chemotactic protein-1 (MCP-1) by ELISA. The ROS level after light exposure was suppressed in the RPE-choroids of light-exposed mice in the yellow IOL material box. In parallel, all the inflammatory cytokines that we measured and a macrophage marker were also suppressed in the RPE-choroids of light-exposed mice in the yellow IOL material box. Therefore, a yellow IOL material suppressed, and thus blue light exacerbated, the increase in the ROS level and inflammatory cytokine expression as well as macrophage recruitment in the RPE-choroid in vivo after light exposure.
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Coroides/efectos de la radiación , Lentes Intraoculares , Luz/efectos adversos , Epitelio Pigmentado de la Retina/efectos de la radiación , Animales , Biomarcadores/metabolismo , Quimiocina CCL2/metabolismo , Coroides/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/fisiología , Estrés Oxidativo/efectos de la radiación , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
Exposure to light contributes to the development and progression of retinal degenerative diseases. However, the mechanisms underlying light-induced tissue damage are not fully understood. Here, we examined the role of angiotensin II type 1 receptor (AT1R) signaling, which is part of the renin-angiotensin system, in light-induced retinal damage. Light-exposed Balb/c mice that were treated with the AT1R blockers (angiotensin II receptor blockers; ARBs) valsartan, losartan, and candesartan before and after the light exposure exhibited attenuated visual function impairment, compared to vehicle-treated mice. This effect was dose-dependent and observed across the ARB class of inhibitors. Further evaluation of valsartan showed that it suppressed a number of light-induced retinal effects, including thinning of the photoreceptor cell layer caused by apoptosis, shortening of the photoreceptor cell outer segment, and increased levels of reactive oxygen species (ROS). The role of ROS in retinal pathogenesis was investigated further using the antioxidant N-acetyl-l-cysteine (NAC). Treatment of light-exposed mice with NAC before the light exposure suppressed the visual function impairment and photoreceptor cell histological changes due to apoptosis. Moreover, treatment with valsartan or NAC suppressed the induction of c-fos (a component of the AP-1 transcription factor) and the upregulation of fasl (a proapoptotic molecule whose transcript is regulated downstream of AP-1). Our results suggest that AT1R signaling mediates light-induced apoptosis, by increasing the levels of ROS and proapoptotic molecules in the retina. Thus, AT1R blockade may represent a new therapeutic approach for preventing light-induced retinal neural tissue damage.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Losartán/farmacología , Degeneración Retiniana/tratamiento farmacológico , Segmento Externo de las Células Fotorreceptoras Retinianas/efectos de los fármacos , Tetrazoles/farmacología , Valina/análogos & derivados , Acetilcisteína/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Compuestos de Bifenilo , Relación Dosis-Respuesta a Droga , Proteína Ligando Fas/agonistas , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Regulación de la Expresión Génica , Luz , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Proto-Oncogénicas c-fos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Segmento Externo de las Células Fotorreceptoras Retinianas/metabolismo , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Segmento Externo de las Células Fotorreceptoras Retinianas/efectos de la radiación , Transducción de Señal , Valina/farmacología , ValsartánRESUMEN
BACKGROUND: To elucidate the biological effects of blocking fluorescent light on the retina using specific blocking materials. METHODS: Seven- to 8-week-old BALB/c mice were divided into three groups and placed in one of the three boxes: one blocked ultraviolet and violet wavelengths of light (violet blockade), one blocked ultraviolet, violet, blue and some other visible wavelengths (blue-plus blockade), and one allowed most visible light to pass through (control). They were then exposed to a white fluorescent lamp for 1 h at 5.65E-05 mW/cm(2) /s. After treatment, the electroretinogram, retinal outer nuclear layer thickness and retinal outer segment length were measured. In addition, retinal apoptotic cells were quantified by TdT-mediated dUTP nick-end labelling assay and c-Fos messenger RNA, and protein levels were measured by real-time reverse-transcription polymerase chain reaction and immunoblot analyses, respectively. RESULTS: The blue-plus blockade group retained a significantly better electroretinogram response following light exposure than the control or violet blockade groups. The blue-plus blockade group also exhibited greater outer nuclear layer thickness and greater outer-segment length, and fewer apoptotic cells after light exposure than the other groups. The c-Fos messenger RNA and protein levels were substantially reduced in the blue-plus blockade group and reduced to a lesser extent in the violet blockade group. CONCLUSIONS: The blockade of blue plus additional visible wavelengths of light was most effective in protecting the retina from light-induced damage. The blockade of violet light alone was also effective in reducing intracellular molecular responses, but these effects were not sufficient for attenuating retinal degeneration.
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Luz/efectos adversos , Traumatismos Experimentales por Radiación/prevención & control , Protección Radiológica/métodos , Retina/fisiología , Degeneración Retiniana/prevención & control , Rayos Ultravioleta/efectos adversos , Animales , Apoptosis/efectos de la radiación , Electrorretinografía , Técnicas para Inmunoenzimas , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/genética , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Degeneración Retiniana/metabolismo , Degeneración Retiniana/fisiopatología , Neuronas Retinianas , Segmento Externo de las Células Fotorreceptoras Retinianas/patologíaRESUMEN
PURPOSE: To elucidate the influences of light exposure on the retinal pigment epithelium (RPE) in vivo that may be involved in the pathogenesis of AMD. METHODS: Six- to 7-week-old BALB/c mice were exposed to light at 2000 lux for 3 hours. Flat-mount RPE samples were immunostained with anti-ZO-1 antibody for evaluating tight junction, anti-N-cadherin, and anti-ß-catenin antibodies for adherens junction, and stained with phalloidin for actin cytoskeleton. The reactive oxygen species (ROS) level was measured using DCFH-DA; Rho-associated coiled-coil forming kinase (ROCK) activity was by ELISA. Cytokine expression was analyzed by real-time RT-PCR and/or ELISA in the RPE-choroid, and macrophage recruitment was by real-time RT-PCR and immunohistochemistry. Either an antioxidant, N-Acetyl-L-cysteine (NAC), or a ROCK inhibitor, Y-27632, were administered to analyze the roles of ROS and ROCK activation, respectively. RESULTS: Light exposure disrupted staining patterns of tight junctions, adherens junctions, and actin cytoskeleton in the RPE, where ROS was elevated. However, NAC treatment avoided the RPE changes, reducing ROS. ROCK activity increased after light exposure was suppressed by NAC, and the structural disruptions were suppressed by Y-27632. The levels of MCP-1, CCL11, and IL-6 increased after light exposure were suppressed by NAC. Light-induced MCP-1 and IL-6 were suppressed by Y-27632. Macrophage recruitment after light exposure was also suppressed either by NAC or Y-27632. CONCLUSIONS: Light exposure induced ROS and Rho/ROCK activation, which caused disruption of cell-cell junctions (tight junctions and adherens junctions) and actin cytoskeleton, the RPE's barrier structure, and induced AMD-associated pathological changes in the RPE-choroid.
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Citocinas/metabolismo , Uniones Intercelulares/efectos de la radiación , Luz/efectos adversos , Degeneración Macular/fisiopatología , Epitelio Pigmentado de la Retina/efectos de la radiación , Análisis de Varianza , Animales , Biomarcadores/metabolismo , Coroides , Citoesqueleto/efectos de la radiación , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Epitelio Pigmentado de la Retina/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
The process of aging involves the accumulating changes in the microenvironment that lead to cell senescence or apoptosis, and subsequent tissue or organ dysfunction. Multiple extrinsic and intrinsic events that cause DNA instability are associated with aging. Cells containing unstable DNA are biologically vulnerable, and if the DNA damage is too great for the cell to repair, it becomes senescent or dies by apoptosis. Thus, the cell's capacity to repair its DNA determines the progress of aging, at least in part. Here, we focus on the sirtuins, the mammalian homologs of the yeast life-span-extending molecule, Sir2. Among the sirtuin family proteins in mammals, the one most similar to yeast Sir2 is SIRT1, which is involved in multiple pathways, including the repair of DNA double-strand breaks. Although the role of SIRT1 in mammalian longevity is not clear, it is expressed throughout the retina, where it may suppress aging. In fact, a mutant mouse model of retinal degeneration shows an abnormal subcellular localization of SIRT1 protein and accelerated retinal cell apoptosis. Further analyses are required to elucidate the mechanism of DNA damage and repair, including the contributions of the sirtuins, in the aged or diseased retinas, which will help us understand the mechanisms of retinal aging.