Prostaglandin E2 promotes pathological retinal neovascularisation via EP4R-EGFR-Gab1-AKT signaling pathway.

Proliferative retinopathies, such as proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) are major causes of visual impairment and blindness in industrialized countries. Prostaglandin E2 (PGE2) is implicated in cellular proliferation and migration via E-prostanoid receptor (EP4R). The aim of this study was to investigate the role of PGE2/EP4R signaling in the promotion of retinal neovascularisation. In a streptozotocin (STZ)-induced diabetic model and an oxygen-induced retinopathy (OIR) model, rats received an intravitreal injection of PGE2, cay10598 (an EP4R agonist) or AH23848 (an EP4R antagonist). Optical coherence tomography, retinal histology and biochemical markers were assessed. Treatment with PGE2 or cay10598 accelerated pathological retinal angiogenesis in STZ and OIR-induced rat retina, which was ameliorated in rats pretreated with AH23848. Serum VEGF-A was upregulated in the PGE2-treated diabetic rats vs non-treated diabetic rats and significantly downregulated in AH23848-treated diabetic rats. PGE2 or cay10598 treatment also significantly accelerated endothelial tip-cell formation in new-born rat retina. In addition, AH23848 treatment attenuated PGE2-or cay10598-induced proliferation and migration by repressing the EGF receptor (EGFR)/Growth factor receptor bound protein 2-associated binder protein 1 (Gab1)/Akt/NF-κB/VEGF-A signaling network in human retinal microvascular endothelial cells (hRMECs). PGE2/EP4R signaling network is thus a potential therapeutic target for pathological intraocular angiogenesis.

Possible molecular mechanism of promotion of repair of acute achilles tendon rupture by low intensity-pulsed ultrasound treatment in a rat model / Posible mecanismo molecular de promoción de la ruptura aguda del tendón de aquiles por el tratamiento de ultrasonidos pulsados de baja intensidad en un modelo de rata

OBJECTIVE: This study investigated the effect of Low Intensity-pulsed Ultrasound (LIPUS) on the repair process of ruptured Achilles tendon using a rat model and also examined the regulation of a biological molecule that may contribute to this in vitro and in vitro. METHODS: To investigate the effect of LIPUS and its biological mechanism ofpromoting Achilles tendon repair after acute injury, ninety-eight male Sprague-Dawley (SD) rats (mean body weight, 258 ±9.8 g) aged 12 weeks were used in this study. To create the model, the Achilles tendon attachment site and musculotendinous junction were ruptured under direct vision. The leg on one side was exposed to LIPUS (frequency at 1.5 MHz, the repetition cycle at 1.0 kHz, the burst width at 200 msec and the power output at 45 mW/cm2), for 20 minutes daily with a 0.7 mm diameter probe. Results:Low Intensity-pulsed Ultrasound treatment accelerated the repair of the Achilles tendon compared to the untreated group, judged by electron microscopy. Both cyclo-oxygenase (COX)-2* and EP4* expressions were over-expressed in the LIPUS treated group in the inflammatory period, and TGFJ31* expression was markedly induced in LIPUS treated groups followed by collagen I* and III* expression in the repair and reconstitution process. CONCLUSION: These findings suggest that LIPUS is potentially able to accelerate the repair of acute ruptured Achilles tendon in several ways: by exaggerating inflammation by inducing COX-2 and EP4 and reconstituting tissue by inducing TGFJ31 followed by collagen I and III. (*: p < 0.05, **: 0.001).

OBJETIVO: Este estudio estuvo encaminado a investigar el efecto de los ultrasonidos pulsados de baja intensidad (LIPUS) sobre el proceso de reparación del tendón de Aquiles tras una ruptura, usando un modelo de rata. Asimismo, se examinó la regulación de una molécula biológica que puede contribuir a este proceso in vitro e in vitro. MÉTODOS: Con el fin de investigar el efecto de LIPUS y el mecanismo biológico por el cual este efecto promueve la reparación del tendón de Aquiles tras una lesión aguda, noventa y ocho ratas machos Sprague-Dawley (SD) (peso corporal promedio, 258 ± 9.8 g) de 12 semanas de edad fueron usadas en este estudio. Para crear el modelo, el sitio de ligazón microbiológica del tendón de Aquiles y la unión músculo-tendinosa fueron desgarrados bajo visión directa. La pierna de un lado fue expuesta a LIPUS (frecuencia de 1.5 MHz, ciclo de repetición de 1.0 kHz, ancho de ruptura de 200 msec, y potencia de salida de 45 mW/cm2), por 20 minutos diariamente con una sonda de 0.7 mm diámetro. RESULTADOS: El tratamiento de ultrasonidos pulsados de baja intensidad aceleró la reparación del tendón de Aquiles, en comparación con el grupo no tratado, según se apreció mediante el microscopio electrónico. Tanto la ciclo-oxygenasa (COX)-2* como las expresiones EP4* estuvieron sobe-expresadas en el grupo tratado con LIPUS en el periodo inflamatorio, y la expresión TGFfi1* fue marcadamente inducida en los grupos tratados con LIPUS seguidos por la expresión de colágeno I* y III* en el proceso de reparación y reconstitución. CONCLUSIÓN: Estos resultados sugieren que LIPUS puede potencialmente acelerar la reparación del tendón de Aquiles luego de un desgarramiento, de varias maneras: exagerando la inflamación mediante inducción de COX-2 y EP4 y reconstituyendo el tejido induciendo TGFfil seguido por colágeno I y III. (*: p < 0.05, **: 0.001).