**1. Introduction**

The proliferation of electronic devices (such as computers, widescreen phones, and televisions) and diverse lighting products has led to a dramatic increase in the incidences of light-induced photochemical eye damage and has become a major cause of visual health problems in modern society [1,2]. As the site of visual imaging and visible light focusing, retinal tissue is a vulnerable target for photochemical damage [3]. Not only does the retina metabolize and function under hyperoxic conditions, but the outer segments of its photoreceptors are also rich in photosensitizer molecules and polyunsaturated fatty acids (PUFAs) [4,5]. When the eyes are exposed to natural or artificial light sources for long periods of time, retinas become vulnerable to oxidative stress, thus greatly increasing the risk of retinopathy [6–8]. It is believed that excessive illumination can result in photoreceptor apoptosis, disturbance in the blood-retinal barrier, and inflammatory infiltration in the retina [9,10]. It has also been suggested that light-induced retinal injury can initiate age-related macular degeneration (AMD), which is a major cause of vision deterioration and blindness in the elderly [4,11]. Consequently, the prevention of retinal photo-oxidative damage through dietary nutritional supplementation has become a significant research focus for food scientists and nutritionists.

**Citation:** Liu, Y.; Guo, Z.; Wang, S.; Liu, Y.; Wei, Y. Fucoxanthin Pretreatment Ameliorates Visible Light-Induced Phagocytosis Disruption of RPE Cells under a Lipid-Rich Environment via the Nrf2 Pathway. *Mar. Drugs* **2022**, *20*, 15. https://doi.org/10.3390/ md20010015

Academic Editor: Hayato Maeda

Received: 26 November 2021 Accepted: 21 December 2021 Published: 23 December 2021

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As one of the main targets of retinal photo-oxidative damage, and due to their important role in maintaining the physiological function of the retina, retinal pigment epithelium (RPE) cells and the potential to improve vision by maintaining their health through dietary supplementation have garnered increasing scientific attention. There is considerable evidence to confirm that RPE cells act as part of the outer blood-retinal barrier (BRB), controlling the exchange of nutrients and waste products between choroidal vessels and photoreceptor cells, and thus supporting the survival and normal functioning of photoreceptor cells [12]. In fact, the recycling of the photoreceptor outer segments (POSs) damaged by oxidation is completed via the phagocytosis of RPE cells [13]. Lipid peroxidation of PUFAs in the POSs can subject RPE cells to intense oxidative stress [4] and, therefore, the inhibition of photo-oxidative damage in RPE cells through dietary antioxidants is increasingly emphasized in research. In one study, berry-derived anthocyanins were reported to efficiently scavenge intracellular reactive oxide species (ROS) and down-regulate the expression of vascular endothelial growth factor (VEGF) in RPE cells under visible light exposure [14]. In another, epigallocatechin-3-gallate, a polyphenolic compound found in green tea, displayed a regulatory role in ultraviolet light irradiation-induced autophagy in RPE cells [15], while quercetin-3-Oα-L-arabinopyranoside reportedly exhibited an inhibitory effect on blue light-induced cell apoptosis and inflammation in RPE cells [16]. However, few studies have investigated dietary active ingredients to ameliorate visible light and lipid peroxidation-induced phagocytic disorder in RPE cells. In addition, while the RPE is a polarized monolayer of highly differentiated epithelial cells in vivo, current in vitro RPE culture models are unable to preserve many of their specific properties or to reproduce the functional features and gene expression patterns that RPE exhibits in vivo [17].

Nuclear factor erythroid-derived 2-like 2 (Nrf2), also known as nuclear factor erythroid 2-related factor 2, plays an important role as a main antioxidant pathway in a variety of diseases [18]. Under oxidative or other stress conditions, Nrf2 in the cytoplasm is translocated to the nucleus, thus regulating antioxidant response element (ARE)-mediated phase II detoxification and the expression of antioxidant proteins/enzymes, including glutamatecysteine ligase (GCL), heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase (NQO1) [19,20]. There is growing evidence that the inhibition of Nrf2 signaling pathway activation further aggravates oxidative damage in cells [21]. It was recently reported that, after pigmented rabbits were exposed to visible light, the oral administration of dietary polyphenols could reduce light-induced retinal oxidative stress and further up-regulate the expression level of HO-1 mRNA [22]. Therefore, the regulation of Nrf2, as an upstream signaling molecule, would make it an attractive candidate gene as a regulatory target for improving phagocytosis in RPE cells during photo-oxidative stress.

Fucoxanthin, a special xanthophyll derived from edible brown seaweeds and some microalgae, has attracted attention due to its biological functions and unique structural properties, including epoxide, allenic, and acetyl groups [23,24]. In our earlier studies, fucoxanthin supplementation was found to provide comparatively superior performance to lutein in protecting the retina against visible light-induced damage, both in vitro and in vivo [23]. However, the mechanisms by which fucoxanthin ameliorates visible lightinduced retinal damage have not ye<sup>t</sup> been demonstrated. Accordingly, the aim of this study is to investigate the preventive effect of fucoxanthin on visible light-induced phagocytic dysfunction of RPE cells and the underlying mechanisms. In order to better mimic the tissue properties of pigment epithelium, differentiated RPE cell monolayers were employed in the construction of in vitro evaluation models. Additionally, as the most abundant polyunsaturated fatty acid (PUFA) in the POSs, docosahexaenoic acid (DHA) was used to create the lipid-rich environment to which the RPE cells are exposed in vivo. Under this in vitro model, the effects of the intensity and duration of visible light exposure on oxidative damage and phagocytic function of RPE cells were observed. Subsequently, the mechanism by which fucoxanthin improves the phagocytosis of RPE cells through the Nrf2 signaling pathway was elucidated. This study, thus, provides a theoretical basis for the use of marine fucoxanthin to prevent visual impairment caused by prolonged light exposure.
