El tratamiento de la inflamacion en la retina: una nueva estrategia terapéutica en la retinopatía diabética

[EN]: Retinal diseases linked to inflammation, including diabetic retinopathy (DR), are often accompanied by resident macrophage/microglial cells activation. During DR, there are substantial changes in the polarization status of the microglia from the M2 (anti-inflammatory) to the M1 (pro-inflammatory) stage. However, the dynamics between M1 and M2 polarization of microglia during DR has not been investigated and it might be therapeutically useful. In this study, we have characterized the evolution of microglia polarizarion during the early stages of DR in the retina of diabetic db/db mice. Moreover, we have analyzed microglia polarization in response to pro-(bacterial lipopolysaccharide; LPS) or anti-(IL4/IL13 cytokines or the bicyclic nojirimycin derivative (1R)-1-dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (RDS-ONJ)) inflammatory stimuli. For this goal, we have performed in vitro experiments in Bv-2 murine microglial cells as well as ex vivo experiments in retinal explants from db/db mice. Treatment of Bv-2 cells with LPS together with IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards a M2 status at early stages of DR offers novel therapeutic interventions.[ES]: Las enfermedades retinianas, entre las que se encuentra la retinopatía diabética (RD), están vinculadas a un contexto inflamatorio en el cual existe una activación de los macrófagos residentes en la retina (microglia). Durante la retinopatía diabética se producen cambios de polarización de la microglia, definiéndose éstos como transiciones entre el estado M1 (proinflamatorio) y el estado M2 (anti-inflamatorio), estando aún por determinar los tiempos de aparición y actuación de la microglia en cada uno de ellos. La identificación espacio-temporal de la transición de la microglía de un estado a otro podría constituir una potente herramienta clínica para diferentes abordajes terapéuticos. En este trabajo se ha caracterizado el estado de polarización de la microgía en la retina durante las primeras fases de la RD en el modelo de ratón diabético db/db. Además, se ha estudiado la polarización de la microglia en presencia de estímulos pro-inflamatorios (lipopolisacárido bacteriano; LPS) o anti-inflamatorios (citoquinas IL4/IL13 o un compuesto natural derivado de la casternospermina, R-DS-ONJ). Para ello, se ha realizado un abordaje in vitro utilizando la línea celular de microglia murina Bv-2 y un abordaje ex vivo con explantes de retinas procedentes de ratones diabéticos db/db. El tratamiento de las células Bv-2 con LPS en combinación con IL4/IL13 o alternativamente con el compuesto R-DS-ONJ indujo la transición en la polarización de la microglia desde el estado proinflamatorio M1, inducido por el LPS, al estado antiinflamatorio M2. En los explantes de retinas de ratones db/db, el compuesto R-DS-ONJ indujo la respuesta M2 disminuyendo la respuesta M1. En conclusión, la polarización de la microglia hacía un estado M2 durante los estadíos tempranos de la RD ofrece una nueva ventana terapéutica de actuación.This work was supported by grants from the Spanish Ministry of Economy and Competitivity (SAF2015-65267-R and SAF2012-33283), Comunidad de Madrid S2010/BMD-2423 and S2010/BMD2439, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem, Instituto Carlos III, Spain), European Union (EUROCONDOR (FP7 HEALTH.2011.2.4.3.1.)).Peer Reviewe

El tratamiento de la inflamación en la retina: una nueva estrategia terapéutica en la retinopatía diabética

Retinal diseases linked to inflammation, including diabetic retinopathy (DR), are often accompanied by resident macrophage/microglial cells activation. During DR, there are substantial changes in the polarization status of the microglia from the M2 (anti-inflammatory) to the M1 (pro-inflammatory) stage. However, the dynamics between M1 and M2 polarization of microglia during DR has not been investigated and it might be therapeutically useful. In this study, we have characterized the evolution of microglia polarizarion during the early stages of DR in the retina of diabetic db/db mice. Moreover, we have analyzed microglia polarization in response to pro-(bacterial lipopolysaccharide; LPS) or anti-(IL4/IL13 cytokines or the bicyclic nojirimycin derivative (1R)-1-dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (R-DS-ONJ)) inflammatory stimuli. For this goal, we have performed in vitro experiments in Bv-2 murine microglial cells as well as ex vivo experiments in retinal explants from db/db mice. Treatment of Bv-2 cells with LPS together with IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards a M2 status at early stages of DR offers novel therapeutic interventions.Las enfermedades retinianas, entre las que se encuentra la retinopatía diabética (RD), están vinculadas a un contexto inflamatorio en el cual existe una activación de los macrófagos residentes en la retina (microglia). Durante la retinopatía diabética se producen cambios de polarización de la microglia, definiéndose éstos como transiciones entre el estado M1 (pro-inflamatorio) y el estado M2 (anti-inflamatorio), estando aún por determinar los tiempos de aparición y actuación de la microglia en cada uno de ellos. La identificación espacio-temporal de la transición de la microglía de un estado a otro podría constituir una potente herramienta clínica para diferentes abordajes terapéuticos.  En este trabajo se ha caracterizado el estado de polarización de la microgía en la retina durante las primeras fases de la RD en el modelo de ratón diabético db/db. Además,  se ha estudiado  la polarización de la microglia en presencia de estímulos pro-inflamatorios (lipopolisacárido bacteriano; LPS) o anti-inflamatorios (citoquinas IL4/IL13 o un compuesto natural derivado de la casternospermina, R-DS-ONJ). Para ello, se ha realizado un abordaje in vitro utilizando la línea celular de microglia murina Bv-2 y un abordaje ex vivo con explantes de retinas procedentes de ratones diabéticos db/db. El tratamiento de las células Bv-2 con LPS en combinación con IL4/IL13  o alternativamente con el compuesto R-DS-ONJ indujo la transición en la polarización de la microglia desde el estado pro-inflamatorio M1, inducido por el LPS, al estado anti-inflamatorio M2. En los explantes de retinas de ratones db/db, el compuesto R-DS-ONJ indujo la respuesta M2 disminuyendo la respuesta M1. En conclusión, la polarización de la microglia hacía un estado M2 durante los estadíos tempranos de la RD ofrece una nueva ventana terapéutica de actuación

Role of long non-coding RNAs in adipose tissue metabolism and associated pathologies

The incidence of obesity and its related disorders has increased dramatically in recent years and has become a pandemic. Adipose tissue is a crucial regulator of these diseases due to its endocrine capacity. Thus, understanding adipose tissue metabolism is essential to finding new effective therapeutic approaches. The 'omic' revolution has identified new concepts about the complexity of the signaling pathways involved in the pathophysiology of adipose tissue-associated disorders. Specifically, advances in transcriptomics have allowed its application in clinical practice and primary or secondary prevention. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipose tissue since they can modulate gene expression at the epigenetic, transcriptional, and post-transcriptional levels. They interact with DNA, RNA, protein complexes, other non-coding RNAs, and microRNAs to regulate a wide range of physiological and pathological processes. Here, we review the emerging field of lncRNAs, including how they regulate adipose tissue biology, and discuss circulating lncRNAs, which may represent a turning point in the diagnosis and treatment of adipose tissue-associated disorders. We also highlight potential biomarkers of obesity and diabetes that could be considered as therapeutic targets. Keywords: Adipose tissue; Biomarkers; Diabetes; Obesity; Therapeutics; lncRNA

Anti-Inflammatory (M2) Response Is Induced by a sp(2)-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (S (S),1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp(2)-iminosugar glycolipid (sp(2)-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (S (S))-DS-ONJ in microglia. (S (S))-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR

Proinsulin attenuates the loss of vision and delays apoptosis of photoreceptors in a mouse model of retinitis pigmentosa.

34 p. 8 fig. 2 supl. fig.purpose. Retinitis pigmentosa (RP) is a heterogeneous group of inherited conditions that lead to blindness and for which there is no effective therapy. Apoptosis of photoreceptors is a common feature in animal models of the disease. Thus, the authors studied the therapeutic potential of proinsulin, an antiapoptotic molecule active during retinal development. methods. Transgenic mice expressing human proinsulin (hPi) in the skeletal muscle were generated in a mixed C57BL/6:SJL background and were back-crossed to a C57BL/6 background. Two independent lineages of transgenic mice were established in which hPi production in muscle was constitutive and not regulated by glucose levels. hPi levels in serum, muscle, and retina were determined with a commercial ELISA kit, visual function was evaluated by electroretinographic (ERG) recording, and programmed cell death was assessed by TUNEL. Immunohistochemistry was used to evaluate retinal structure preservation and oxidative damage. results. Transgenic expression of hPi in the rd10 retinal degeneration mouse model led to prolonged vision, as determined by ERG recording, in a manner that was related to the level of transgene expression. This attenuation of visual deterioration was correlated with a delay in photoreceptor apoptosis and with the preservation of retinal cytoarchitecture, particularly that of the cones. conclusions. These results provide a new basis for possible therapies to counteract retinitis pigmentosa and a new tool to characterize the mechanisms involved in the progress of retinal neurodegenerationSupported by Spanish Ministerio de Educación y Ciencia Grants SAF2001-1038, SAF2004-05870, and SAF2007-66175 (EJdlR, PdlV); BFU2004-02352 (FdP); SAF2005-01262 (FB); Spanish Ministerio de Sanidad y Consumo Grant RETIC RD-06 (FdP, FB); Comunidad de Madrid Grants 8.5-0019.1/2001 (EJdlR) and 08.5-0049/2003 and CCG06-UAH/BIO-0711 (PdlV); Fundación Médica Mutua Madrileña (EJdlR); and Fundaluce (PdlV). SC and NR-M were supported by postgraduate fellowships from the Ministerio de Educación y Ciencia, PB by a Ramón y Cajal contract from the Ministerio de Educación y Ciencia, AIA by a postdoctoral contract from the Fondo de Investigaciones Sanitarias, and VG-V by an I3P postdoctoral contract from the European Social FundPeer reviewe

Inhibition of protein tyrosine phosphatase 1B improves IGF-I receptor signaling and protects against inflammation-induced gliosis in the retina

[Purpose]: Insulin-like growth factor-I receptor (IGF-IR) signaling mediates retinal growth and survival and its failure may contribute to aggravate diabetic retinopathy (DR). Protein tyrosine phosphatase 1B (PTP1B) negatively modulates IGF-IR signaling, but its involvement in inflammation during DR remains unknown. We investigated whether PTP1B participates in the cross-talk between proinflammatory signaling pathways and IGF-IR–mediated signaling in the retina. [Methods]: 661W photoreceptors or mouse retinal explants were treated with TNFa, IL6, and IL1b. Insulin-like growth factor-I receptor signaling cascade was evaluated in the absence or presence of PTP1B. db/db mice were used to test a PTP1B inhibitor in retinal gliosis. [Results]: 661W retinal cells and retinal explants responded to IGF-I by inducing IGF-IR tyrosine (13-fold) and Akt phosphorylations (7- and 3-fold for serine 473 and threonine 308, respectively). Cytokines triggered early activation of stress kinases (c-jun [NH2] terminal kinase [JNK] and p38 MAPK), resulting in insulin receptor substrate 1 (IRS1) serine 307 phosphorylation that precedes its degradation. Pretreatment of 661W cells or retinal explants with cytokines upregulated PTP1B protein levels (1.45- and 4.5-fold, respectively), induced IRS1 degradation and decreased IGF-I–mediated IGF-IR/Akt phosphorylation. Silencing or deficiency in PTP1B ameliorated the negative effects of cytokines on IGF-IR signaling. Cytokines increased glial fibrillary acidic protein (GFAP) expression in retinal explants by 4.5- fold, this response being reduced by 2-fold with a PTP1B inhibitor. Protein tyrosine phosphatase 1B protein levels increased by 3-fold in retinas from db/db mice and its inhibition reduced gliosis. [Conclusions]: Targeting PTP1B might be useful for modulating IGF-I effects in retinal cells during DR.Supported by grants from Spanish Ministry of Economy and Competitivity (SAF2012-33283; Madrid, Spain), Comunidad de Madrid S2010/BMD-2423 (Madrid, Spain), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBEDEM, Instituto Carlos III, Madrid, Spain), and European Union (EUROCONDOR; FP7 HEALTH.2011.2.4.3.1.; Barcelona, Spain).Peer Reviewe