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.
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.
Antimalarial drugs are used for the control of mild manifestations of autoimmune diseases due to their low toxicity. Hydroxychloroquine (HCQ), a alpha-hydroxylated derivative of chloroquine, is usually preferred because of its higher tolerability. Mild and unspecific gastrointestinal symptoms are the main secondary effects related to HCQ use. Less than 1% of subjects show liver enzyme increase, although the percentage can be as high as 50% in subjects with chronic liver disease. A woman with mixed connective tissue disease who developed a reversible acute hepatitis shortly after the initiation of low-dose HCQ is presented. Two previous cases of patients with acute liver failure have previously been published. All three cases have been reported in the absence of previous liver disease. It seems to be a dose-dependent, idiosyncratic, and molecule-specific toxic effect and must be considered, taking into account the potential bad prognosis.
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