miR‐205‐5p is known to be involved in VEGF‐related angiogenesis and seems to regulate associated cell signalling pathways, such as cell migration, proliferation and apoptosis. Therefore, several studies have focused on the potential role of miR‐205‐5p as an anti‐angiogenic factor. Vascular proliferation is observed in diabetic retinopathy and the ‘wet’ form of age‐related macular degeneration. Today, the most common treatments against these eye‐related diseases are anti‐VEGF therapies. In addition, both AMD and DR are typically associated with oxidative stress; hence, the use of antioxidant agents is accepted as a co‐adjuvant therapy for these patients. According to previous data, ARPE‐19 cells release pro‐angiogenic factors when exposed to oxidative insult, leading to angiogenesis. Matching these data, results reported here, indicate that miR‐205‐5p is modulated by oxidative stress and regulates VEGFA‐angiogenesis. Hence, miR‐205‐5p is proposed as a candidate against eye‐related proliferative diseases.

ARPE-19 retinal pigment epithelial cells cultured in a medium containing 35 mM D-glucose led to an augmented ROS formation and release of vascular endothelial factor (VEGF)-containing exosomes compared to ARPE-19 cells cultured in a medium containing 5 mM D-glucose (standard medium). Exposing these cells to the melanocortin 5 receptor agonist (MCR 5) PG-901 (10 −10 M), for 9 d reduced ROS generation, the number of exosomes released and their VEGF content. In contrast, incubating the cells with the melanocortin receptor MCR 1 agonist BMS-470539 (10 −5 M) or with the mixed MCR 3/4 agonist MTII (0.30 nmol) did not produce any significant decrease in ROS levels. ARPE-19-derived VEGFcontaining exosomes promoted neovascularization in human umbilical vein endothelial cells (HUVEC), an effect that was markedly reduced by PG-901 (10 −10 M) but not by the MCR 3/4 agonist MTII (0.30 nmol) or the MCR 1 agonist BMS-470539 (10 −5 M). The MCR 5-related action in the ARPE-19 cells was accompanied by the increased expression of two coupled factors, cytochrome p4502E1 (CYP2E1) and nuclear factor kappa b (Nf-κB). These are both involved in high glucose signalling, in ROS generation and, interestingly, were reduced by the MCR 5 agonist in the ARPE-19 cells. Altogether, these data suggest that MCR 5 is a modulator of the responses stimulated by glucose in ARPE-19 cells, which might possibly be translated into a modulation of the retinal pigment epithelium response to diabetes in vivo.

Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction.

Retinitis Pigmentosa is a group of inherited neurodegenerative diseases that result in selective cell death of photoreceptors. In the developed world, RP is regarded as the main cause of blindness among the working age population. The precise mechanisms eventually leading to cell death remain unknown and to date no adequate treatment for RP is available. Poly ADP ribose polymerase (PARP) over activity is involved in photoreceptor degeneration and pharmacological inhibition or genetic knock-down PARP1 activity protect photoreceptors in mice models, the mechanism of neuroprotection is not clear yet. Our result indicated that olaparib, a PARP1 inhibitor, significantly rescued photoreceptor cells in rd10 retina. Extracellular vesicles (EVs) were previously recognized as a mechanism for discharging useless cellular components. Growing evidence has elucidated their roles in cell–cell communication by carrying nucleic acids, proteins and lipids that can, in turn, regulate behavior of the target cells. Recent research suggested that EVs extensively participate in progression of diverse blinding diseases, such as age-related macular (AMD) degeneration. Our study demonstrates the involvement of EVs activity in the process of photoreceptor degeneration in a PDE6 mutation. PARP inhibition protects photoreceptors via regulation of the EVs activity in rod photoreceptor degeneration in a PDE6b mutation.

Age related macular degeneration (AMD) is a common retina-related disease leading to blindness. Little is known on the origin of the disease, but it is well documented that oxidative stress generated in the retinal pigment epithelium and choroid neovascularization are closely involved. The study of circulating miRNAs is opening new possibilities in terms of diagnosis and therapeutics. miRNAs can travel associated to lipoproteins or inside small Extracellular Vesicles (sEVs). A number of reports indicate a significant deregulation of circulating miRNAs in AMD and experimental approaches, but it is unclear whether sEVs present a significant miRNA cargo. The present work studies miRNA expression changes in sEVs released from ARPE-19 cells under oxidative conditions (i.e. hydrogen peroxide, H 2 o 2). H 2 o 2 increased sEVs release from ARPE-19 cells. Moreover, 218 miRNAs could be detected in control and H 2 o 2 induced-sEVs. Interestingly, only two of them (hsa-miR-302a and hsa-miR-122) were significantly under-expressed in H 2 o 2-induced sEVs. Results herein suggest that the down regulation of miRNAs 302a and 122 might be related with previous studies showing sEVs-induced neovascularization after oxidative challenge in ARPE-19 cells. microRNA (miRNA) are small non-coding RNA sequences (21-25 nucleotides) able to regulate the expression of one or more mRNAs 1,2. miRNAs regulate protein translation by targeting their complementary mRNAs and by repressing translation or degrading a target mRNA. Nowadays, miRNA research has been rocketed from 214 publications in 2014 to 11,610 in 2018 (source: Pubmed). Many clinical fields are now focused on the study of miRNA for diagnosis or treatment purposes 3,4. Moreover, miRNAs play an important role in different cellular processes such as angiogenesis 5,6 , oxidative stress 7 , and immune responses 8. Most of the cells can release extracellular vesicles (EVs), which may interact with both neighbouring or distant target cells 9,10. EVs typically include genetic material and proteins, making these vesicles key in cell to cell communication 11. Among these EVs, are the small EVs (sEVs; <100 nm diameter) 12 , which were observed to carry miRNAs 13. Cargo of sEVs depends on the cellular origin and the homeostatic state 14. Recent studies analysed miRNA expression in biological samples from patients with age related macular degeneration (AMD), in order to identify those miRNAs related to the pathophysiology and progression of the disease. Among these, miR-9, miR-23a, miR-27a, miR-34a, miR-146a, miR-155 have been proposed as potential candidates 15-19. The "wet" form of AMD is characterized by neovascularization 20. The retinal pigment epithelium (RPE) plays a pivotal role between the photoreceptor cell layer and the choroid, the vascular network surrounding the eye. This interaction is critical for retinal homeostasis 21. Ren and collaborators analysed circulating miRNAs from AMD patients and proposed miR-27a-3p, miR-29b-3p, and miR-195-5p as candidate biomarkers for AMD diagnosis 19....