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      Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy

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          Abstract

          Retinal oxidative damage, associated with an ATP-binding cassette, sub-family A, member 4, also known as ABCA4 gene mutation, has been implicated as a major underlying mechanism for Stargardt disease/fundus flavimaculatus (STG/FF). Recent findings indicate that saffron carotenoid constituents crocins and crocetin may counteract retinal oxidative damage, inflammation and protect retinal cells from apoptosis. This pilot study aimed to evaluate central retinal function following saffron supplementation in STG/FF patients carrying ABCA4 mutations. Methods: in a randomized, double-blind, placebo-controlled study (clinicaltrials.gov: NCT01278277), 31 patients with ABCA4-related STG/FF and a visual acuity >0.25 were randomly assigned to assume oral saffron (20 mg) or placebo over a six month period and then reverted to P or S for a further six month period. Full ophthalmic examinations, as well as central 18° focal electroretinogram (fERG) recordings, were performed at baseline and after six months of either saffron or placebo. The fERG fundamental harmonic component was isolated by Fourier analysis. Main outcome measures were fERG amplitude (in µV) and phase (in degrees). The secondary outcome measure was visual acuity. Results: supplement was well tolerated by all patients throughout follow-up. After saffron, fERG amplitude was unchanged; after placebo, amplitude tended to decrease from baseline (mean change: −0.18 log µV, p < 0.05). Reverting the treatments, amplitude did not change significantly. fERG phase and visual acuity were unchanged throughout follow-up. Conclusions: short-term saffron supplementation was well tolerated and had no detrimental effects on the electroretinographic responses of the central retina and visual acuity. The current findings warrant further long-term clinical trials to assess the efficacy of saffron supplementation in slowing down the progression of central retinal dysfunction in ABCA4-related STG/FF.

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          Most cited references 35

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          The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells.

          To determine whether the lipofuscin fluorophore A2E participates in blue light-induced damage to retinal pigmented epithelial (RPE) cells. Human RPE cells (ARPE-19) accumulated A2E from 10, 50, and 100 microM concentrations in media, the levels of internalized A2E ranging from less than 5 to 64 ng/10(5) cells, as assayed by quantitative high-performance liquid chromatography (HPLC). Restricted zones (0.5-mm diameter spots) of confluent cultures were subsequently exposed to 480 +/- 20-nm (blue) or 545 +/- 1-nm (green) light for 15 to 60 seconds. Phototoxicity was quantified at various periods after exposure by fluorescence staining of the nuclei of membrane-compromised cells, by TdT-dUTP terminal nick-end labeling (TUNEL) of apoptotic cells and by Annexin V labeling for phosphatidylserine exposure. Nonviable cells were located in blue light- exposed zones of A2E-containing RPE cells, whereas cells situated outside the illuminated areas remained viable. As shown by fluorescence labeling of the nuclei of membrane-damaged cells and by the presence of TUNEL-positive cells, the numbers of nonviable cells increased with exposure duration and as a function of the concentration of A2E used to load the cells before illumination. The numbers of blue light-induced TUNEL-positive cells also increased in advance of the increase in labeling of membrane-compromised cells, a finding that, together with Annexin V labeling, indicates an apoptotic form of cell death. Conversely, blue light- exposed RPE cells that did not contain A2E remained viable. In addition, illumination with green light resulted in the appearance of substantially fewer nonviable cells. These studies implicate A2E as an initiator of blue light-induced apoptosis of RPE cells.
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            Crocetin from saffron: an active component of an ancient spice.

             Mario Giaccio (2003)
            The known properties of saffron (Crocus sativus, L.) and its components have been examined. Recently, hormone like effects in green algae and the anti-cancerogenic and anti-toxic effects, have been observed. In particular, the effects of crocetin, a carotenoids (8,8'-diapo-8,8'-carotenoic acid) present in saffron and characterized by a diterpenic and symmetrical structure with seven double bonds and four methyl groups, have been taken into consideration. It has been found that this compound enhances the oxygen diffusivity through liquids, such as plasma. As a consequence of this property, it has been observed that crocetin increases alveolar oxygen transport and enhances pulmonary oxygenation. It improves cerebral oxygenation in hemorrhaged rats and positively acts in the atherosclerosis and arthritis treatment. It inhibits skin tumor promotion in mice (i.e., with benzo(a)pyrene); it has an inhibitory effect on intracellular nucleic acid and protein synthesis in malignant cells, as well as on protein-kinase-C and prorooncogene in INNIH/3T3 cells. This is most likely due to its anti-oxidant activity. Furthermore, crocetin protects against oxidative damage in rat primary hepatocytes. It also suppresses aflatoxin B1-induced hepatotoxic lesions and has a modulatory effect on aflatoxin, B1 cytotoxicity, and DNA adduct formation on C3H10/T1/2 fibroblast cells. It also has a protective effect on the bladder toxicity, induced by cyclophosphamide. The experiments reported in the scientific literature and the interesting results obtained have been carried out in vitro or on laboratory animals, but not yet on man.
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              Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo.

              Crocus sativus L. (saffron) has been used as a spice for flavoring and coloring food preparations, and in Chinese traditional medicine as an anodyne or tranquilizer. Our previous study demonstrated that crocin, a carotenoid pigment of saffron, can suppress the serum deprivation-induced death of PC12 cells by increasing glutathione (GSH) synthesis and thus inhibiting neutral sphingomyelinase (nSMase) activity and ceramide formation. The carotenoid pigments of saffron consist of crocetin di-(beta-d-glucosyl)-ester [dicrocin], crocetin-(beta-d-gentiobiosyl)-(beta-d-glucosyl)-ester [tricrocin] and crocetin-di-(beta-d-gentiobiosyl)-ester [crocin]. Saffron also contains picrocrocin, the substance causing saffron's bitter taste. In this study, to confirm whether neuroprotective effects of saffron are caused solely by crocin, we examined the antioxidant and GSH-synthetic activities of these crocins in PC12 cells under serum-free and hypoxic conditions. Measurements of cell viability, peroxidized membrane lipids and caspase-3 activity showed that the rank order of the neuroprotective potency at a concentration of 10 muM was crocin>tricrocin>dicrocin and picrocrocin (the latter two crocins had a little or no potency). In addition, we show that among these saffron's constituents, crocin most effectively promotes mRNA expression of gamma-glutamylcysteinyl synthase (gamma-GCS), which contributes to GSH synthesis as the rate-limiting enzyme, and that the carotenoid can significantly reduce infarcted areas caused by occlusion of the middle cerebral artery (MCA) in mice.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                15 October 2019
                October 2019
                : 11
                : 10
                Affiliations
                [1 ]Dipartimento di Scienze dell’Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli- IRCCS, 00168 Rome, Italy; piccmarc@ 123456tiscali.it (M.P.); dariomarangoni80@ 123456yahoo.it (D.M.); aminnella59@ 123456gmail.com (A.M.M.)
                [2 ]Dipartimento di Malattie Cardiovascolari, endocrino-metaboliche e invecchiamento, Istituto Superiore di Sanità, 00168 Rome, Italy; afadda@ 123456iss.it (A.F.); francesco.martelli@ 123456iss.it (F.M.)
                [3 ]Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
                [4 ]Dipartimento di Oftalmologia Pediatrica, Università di Salerno, 84084 Salerno, Italy; amagli@ 123456unisa.it
                [5 ]Istituto di Oftalmologia, Università Cattolica del S. Cuore, 00168 Rome, Italy
                [6 ]Laboratorio di Genetica Medica e Biologia Molecolare, MAGI, 38068 Rovereto, Italy; matteo.bertelli@ 123456assomagi.org
                [7 ]Dipartimento di Scienze Cliniche Applicate e Biotecnologie, Università dell’Aquila, 67100 L’Aquila, Italy; stefano.dimarco@ 123456univaq.it (S.D.M.); s.bisti@ 123456team.it (S.B.)
                [8 ]Istituto Nazionale Biosistemi e Biostrutture, 00168 Rome, Italy
                [9 ]Istituto Italiano di Tecnologia, NetS3 Laboratory, Neuroscience and Brain Technologies (NBT), 16100 Genova, Italy
                Author notes
                [* ]Correspondence: Benedetto.Falsini@ 123456unicatt.it ; Tel.: +39-6-30154929
                Article
                nutrients-11-02461
                10.3390/nu11102461
                6835540
                31618812
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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