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Citation: Cho, Y.-K.; Lee, S.-M.; Kang,

Y.-J.; Kang, Y.-M.; Jeon, I.-C.; Park,

D.-H. The Age-Related Macular

Degeneration (AMD)-Preventing

Mechanism of Natural Products.

Processes 2022, 10, 678. https://

doi.org/10.3390/pr10040678

Academic Editor: Bonglee Kim

Received: 2 March 2022

Accepted: 29 March 2022

Published: 30 March 2022

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Review

The Age-Related Macular Degeneration (AMD)-PreventingMechanism of Natural ProductsYeon-Kyoung Cho 1,†, Seung-Min Lee 2,†, Yeong-Ji Kang 1, Yeong-Mo Kang 1, In-Chul Jeon 1,*and Dae-Hun Park 3,*

1 College of Health and Welfare, Dongshin University, Naju 58245, Korea; yktender@naver.com (Y.-K.C.);yjkang0426@naver.com (Y.-J.K.); didiaos@naver.com (Y.-M.K.)

2 School of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea; smin0515@gmail.com3 Oriental Medicine, Dongshin University, Naju 58245, Korea* Correspondence: icjeon@dsu.ac.kr (I.-C.J.); dhj1221@hanmail.net (D.-H.P.); Tel.: +82-10-4372-0001 (I.-C.J.);

+82-10-9930-5494 (D.-H.P.)† These authors contributed equally to this work.

Abstract: Age-related macular degeneration (AMD) is related to central visual loss in elderly peopleand, based on the increment in the percentage of the aging population, the number of people sufferingfrom AMD could increase. AMD is initiated by retinal pigment epithelium (RPE) cell death, finallyleading to neovascularization in the macula lutea. AMD is an uncurable disease, but the symptomcan be suppressed. The current therapy of AMD can be classified into four types: device-basedtreatment, anti-inflammatory drug treatment, anti-vascular endothelial growth factor treatment, andnatural product treatment. All these therapies have adverse effects, however early AMD therapyused with products has several advantages, as it can prevent RPE cell apoptosis in safe doses. Celldeath (apoptosis) is caused by various factors, such as oxidative stress, inflammation, carbonylstress, and a deficiency in essential components for cells, and RPE cell death is related to oxidativestress, inflammation, and carbonyl stress. Some natural products have anti-oxidative effects, anti-inflammation effects, and/or anti-carbonylation effects. The AMD preventive mechanism of naturalproducts varies, with some natural products activating one or more anti-apoptotic pathways, suchas the Nrf2/HO-1 anti-oxidative pathway, the anti-inflammasome pathway, and the anti-carbonylpathway. As AMD drug candidates from natural products effectively inhibit RPE cell death, theyhave the potential to be developed as drugs for preventing early (dry) AMD.

Keywords: age-related macular degeneration (AMD); natural products; preventing mechanism;dry AMD

1. Introduction1.1. Definition and Classification of Age-Related Macular Degeneration (AMD)

There are several blindness causes/diseases, such as uncorrected refractive errors,cataracts, age-related macular degeneration, glaucoma, diabetic retinopathy, corneal opacity,and trachoma, and many cases of vision loss is strongly related to aging [1]. At least2.2 billion people suffer from visual impairment, and half of them, 1 billion people, havevision problems at a moderate level or worse [2]. Age-related macular degeneration (AMD)is one of the causes of blindness that are related to aging; its representative symptomis the loss of central vision [3], and it is caused by retinal pigment epithelial cell death(apoptosis) [4]. AMD can be classified into three categories: normal, geographic atrophy(dry) and exudative (wet) [4]; the dry AMD is divided into early and intermediate, andthe exudate AMD can be called advanced [5]. The classification of AMD is based onatrophy occurrence, angiogenesis, and the size/location of drusens [6]. In this review, wediscuss the advantages of natural products as treatment methods for geographic atrophy

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(early/dry) AMD and their therapeutic mechanisms, which are related to anti-oxidative,anti-inflammatory, and anti-carbonyl effects.

1.2. Statistics of AMD

AMD is the fourth most common cause of vision loss worldwide [7]. Worldwide, in2019, the population aged 65 years was 703 million (9 percent), a number that is expected todouble to 1.5 billion in 2050 (16 percent) [8]. In 2020, there were 196 million AMD patients,but in 2040, this population is forecast to grow to 288 million [9], as the prevalence of AMDin the population aged 80 years or over is 66% and the severity of AMD occurrence shouldincrease [10]. Furthermore, as the percentage of elderly people rapidly increases, the risk ofAMD occurrence might be thought of as more severe.

1.3. Problems of Current Treatments

The current treatment for AMD can be classified into four categories, device-basedtreatment, anti-inflammatory drug treatment, anti-vascular endothelial growth factor (anti-VEGF) treatment, and nutritional treatment [11], and there are several adverse effectsin device-based treatment, anti-inflammatory drug treatment, and anti-VEGF treatment(Table 1).

Table 1. Current treatments for age-related macular degeneration and the adverse effects of eachtreatment.

Treatment Principles of Treatment Adverse Effects References

Device-basedtreatment

(1) To eliminate the drusen(2) To inhibit the choroidalvascularization

Macular edema,retinovascular disease

[12][13]

Anti-inflammatorydrug treatment

(1) To block the inflammatorypathway(2) To inactivate cyclo-oxygenaseor/and lipoxygenase

Hypertension, insulinresistance, insomnia,skin thinning, gastric

ulceration

[14]

Anti-vascularendothelial growthfactor (anti-VEGF)

treatment

(1) To prohibit VEGF activation(2) To bind to the VEGF receptor(3) To block the tyrosine kinasepathway

Bleeding andinfection risk by

intravitreal injection[15]

2. Pathogenesis of Age-Related Macular Degeneration (AMD)2.1. The Basic Structure of the Eye

In order to keep clear, visible sight, the macula has four component parts, including aphotoreceptor, retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris;the photoreceptor converts light into a signal, it can firmly fix on the RPE, and the Bruch’smembrane supplies blood and exchanges gases (O2 and CO2) between the choriocapillarisand the RPE to support the photoreceptor’s maintenance [4]. RPE death (apoptosis)increases AMD severity, as it makes it difficult to supply nutrition and to exchange gases.

2.2. The Pathogenic Factors of AMD

The important pathogenic factors of AMD are bis-retinoid N-retinyl-N-retinylideneethanolamine (A2E), especially A2E-epoxides [16] and blue light (in the wavelength rangeof 480 ± 20 nm) [17]. A2E is a hydrophobic quaternary amine form of lipofuscin [18],which consists of aging pigments and lipofuscins that are distributed in many regions ofbio-organisms, such as neurons, the heart, and the retinal pigment epithelium (RPE) [19].A2E is a very unstable pigment, which easily changes to its oxidized form (A2E-epoxide)and, during A2E oxidization, many reactive oxygen species (ROSs) are produced [20]. Bluelight can induce rapid A2E oxidization and then cause irreversible injury to the visionsystem [21]. A2E is easily cleaved by light, and then photocleaved A2E accumulates tomake drusen [22].

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2.3. The Relation of Age-Related Macular Degeneration (AMD) and Retinal Pigment EpithelialCell Death (Apoptosis)

RPE is one of the very useful structures for the visible system, as it not only maintainsthe photoreceptor’s normal status through supplying blood and exchanging gases (O2 andCO2) from the choriocapillaris [4], but also preserves the immune function via defendingagainst various harmful stimulators, such as reactive oxygen species (ROS), carbonylatedmetabolites, and inflammatory factors [23]. It has high levels of superoxide dismutase(SOD) [24–26] and catalase [27] for chelating ROS. As polyunsaturated fatty acids (PUFAs)are plentiful in the RPE membrane, it is very vulnerable to reactive oxygen species [28] and,due to aging, the balance between the level of the ROS and that of anti-oxidants can easilybe disrupted [29]. Many ROS, such as hydrogen peroxide (H2O2), superoxide anion radical(O2−), hydroxyl radical (OH·), and nitric oxide (NO), are toxic to the cytoplasmic membrane,

as they can initiate oxidization, which destroys the membrane structure [20,29]; however, inthe case of NO, which is one of the most harmful ROS, the relation between AMD occurrenceand NO’s function is unclear, as some groups reported that the level of serum NO washigher in AMD patients than in normal people [30], but other groups presented the oppositeresults [31]. When the ROS destroy the RPE layer, many ophthalmological problems, suchas AMD and blindness, can occur. A2E can be changed to A2E-epoxide by blue light, and,at the same time, many ROS, such as H2O2, O2

−, and OH·, can be synthesized and startthe oxidization of RPEs, thus destroying them [16,20,32,33]. Although drusen is one of thehallmarks for discriminating AMD [34], there are many debates regarding drusen formation.However, it is related to both RPE cell death and ROS synthesis via A2E oxidization [35].

Accumulated drusen not only induces central region blindness, but also stimulatesinflammation in RPE [36], and the exacerbation of an inflammatory response is a trigger ofAMD occurrence [35]. Although inflammation is one of the homeostasis responses of bio-organisms and is an important immune defense mechanism against foreign bodies [37], andinflammation is necessary to effectively control abnormal situations, when an exacerbatedinflammatory situation occurs, the inflammatory cells can stimulate ROS synthesis andcan cause excessive oxidative stress on the inflammatory regions [38]. In order to maintainthe immune balance, there is a network among immune cells that can modulate cytokines,including pro-inflammatory ones (interleukin (IL)-1β, IL-6, IL-13, and tumor necrosis factor(TNF)-α) [39] and anti-inflammatory ones (IL-10 and tumor growth factor (TGF)-1) [40]. Theoxidative stress is closely connected with inflammation, and, in particular, A2E stimulatesRPE cell inflammation by increasing the level of IL-1β via the NLRP3 inflammasome [34].

Carbonyl stress means that, without the oxidative stress during the Maillard reaction,carbonylated products, such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and4-hydroxyhexanal (4-HHE), are synthesized from some compounds, such as lipids, protein,and DNA, via carbonylation [41]. PUFAs in the membrane layer in RPE cells consist of50% docosahexaenoic acid (DHA), 10% oleic acid (OA), and 8% arachidonic acid (AA) [42],carbonylated products are derived from PUFAs in RPE cells [43], and many diseases arerelated to their functions [42]. The chemical structures of 4-HNE and 4-HHE are similar,and both of them have cytotoxicity based on similar pathogenic pathways, such as blockingsome enzymes’ functions and stimulating cell cycle arrest and cell death, and, as theycan be derived from PUFAs in RPE cell membranes, they are important biomarkers forevaluating AMD [43,44]. For example, the level of serum MDA in patients who suffer fromwet-type AMD is higher [45], and the levels of MDA and 4-HNE in the retina are higher innormal mice than in intravitreal paraquat-injected mice used as AMD models [44].

From the toxicological point of view, although each type of stress can induce RPE cellsto be damaged by itself, all of them participate via their toxicological network in AMDoccurrence via RPE cell apoptosis (Figure 1).

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Figure 1. Age-related macular degeneration (AMD) occurrence caused by oxidative stress, carbonylstress, and inflammation. A2E-epoxide and reactive oxygen species (ROS) are synthesized by A2Eand the blue light reaction. The synthesized ROS attack the cell membrane of the retinal pigmentepithelium (RPE) and destroy it via oxidative stress. The gathered ROS recruit the immune cellsand secrete immune mediators, such as IL-1β, IL-6, IL-13, TNF-α, and IFN-γ (inflammation). Theattack of ROS on the cell membrane in RPE initiates the carbonylation of (1) the cell membrane’s lipidlayer and (2) DNA, and carbonylated products, such as malondialdehyde (MDA), 4-hydroxynonenal(4-HNE), and 4-hydroxyhexanal (4-HHE), disrupting the cell membrane and DNA (carbonyl stress).The correlation of these stresses induces RPE cell death (apoptosis). ©: carbohydrate.

3. Three Stresses and the Mechanism of Natural Products to Prevent Retinal PigmentEpithelial Cell Death (Apoptosis)3.1. Anti-Oxidative Stress and Natural Products3.1.1. Nuclear Factor Erythroid-Derived-2-like (Nrf2)/Heme Oxygenase-1(HO-1)-Antioxidant Responsive Element (ARE) System

The nuclear factor erythroid-derived-2-like (Nrf2)/heme oxygenase-1 (HO-1)-antioxidantresponsive element (ARE) system is one of the representative antioxidant systems, and itis an effective defensive pathway in RPE against oxidative stress [46]. Nrf2 binds to theKelch domain of Keap1 [47], but when oxidative stress occurs, this combination can be dis-sociated, inducing the transcription of several genes protecting against hazards, producinganti-cancer, anti-oxidative, anti-inflammatory, and detoxifying effects. [48–51]. HO-1, whichis transcribed by Nrf2, has several biological effects, such as oxidative stress prevention,apoptosis regulation, and inflammation modulation [52]. Within natural products, thereare many Nrf2/HO-2 modulators that can regulate various diseases, such as Alzheimer’sdisease [53], cerebral ischemia [54,55], chronic obstructive pulmonary disease [56], dia-betes [57,58], Parkinson’s disease [59,60], and stroke [61]. Recently, there has been anincreasing study of natural product-derived controllers on the Nrf2/HO-1-ARE systemfor preventing AMD occurrence/severity (Figure 2). The chemical formula of canolol is4-vinyl-2,6-dimethoxyphenol, which is isolated from canola oil and has Nrf2/HO-1-relatedanti-oxidative effects in RPE cell apoptosis via the ERK pathway [62]; genipin is a glycosidicligand that is included in Mast and Eucommia ulmoides, regulates Nrf2/HO-1 signalingfor suppressing oxidative stress, and finally inhibits RPE cell death through the regula-tion of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (BAX), and capsase-3 [63];hesperetin, which can be isolated from Citrus aurantium L’s peel, increases Nrf2/HO-1-ARE’s activation and upregulates levels of both SOD and glutathione [64]; narigenin,4′,5,7-trihydroxyflavanone is a component that is plentiful in grapefruit and increases the ac-tivations of Nrf2 and HO-1, which can decrease intracellular ROS [65]; and salvianolic acidA is the water extract of Saliva miltiorrhiza, which stimulates Nrf2/HO-2 activation and hasprotective effects against RPE cell death through phosphoinositide 3-kinase (PI3K)/AMP-

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activated protein kinase (AKT)/mammalian target of rapamycin complex 1 (mTORC1)signaling [66].

Figure 2. The anti-oxidative mechanism of natural products through the Nrf2/HO-1-ARE system.Nrf2 and the Keap 1 complex are dissociated by ERK/JNK/p38MAPK signals, and Nrf2 entersthe nucleus in order to function as an HO-1 transcription factor. This ARE system is initiated byseveral natural products, such as canolol, genipin, Eucommia ulmoides, hesperetin, narigenin, andSaliva miltiorrhiza. Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; ARE,antioxidant response element; Keap 1, Kelch-like ECH-associated protein 1; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; and p38MAPK, p38 mitogen-activated proteinkinase.

3.1.2. Other Anti-Oxidative Stress Pathways

There are many natural anti-oxidants that can alleviate AMD occurrence or decreaseAMD severity, and there are many natural products related to controlling AMD, suchas carotenoids, including β-carotene; vitamin E, including tocopherols and tocotrienols;vitamin C, which is known as ascorbic acid and ascorbate; and selenium [67,68]. An ethanolextract of Arctium lappa L. leaves contains large amounts of polyphenols and flavonoidsand prevents RPE cell death via down-regulating intracellular ROS levels [69]. Delpinidinis one of the anthocyanidins, which are a class of polyphenols in fruits and vegetablesand consist of six components, including cyanidin, delphinidin, malvidin, pleargonidin,peonidin, and petunidin [70], with anti-apoptotic effects on H2O2-damaged RPE cellsvia the modulation of the Bcl family [71]. Glabridin is one of the isoflavonoids, whichoriginates from Glycyrrhiza glabra L. root and prevents NaIO3-induced RPE cell death viathe extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated proteinkinase (MAPK) pathway [72].

3.2. Anti-Inflammatory Effects of Natural Products3.2.1. Inflammasome and Inflammation

Inflammasomes are multiprotein oligomers in the cytoplasm and are produced duringinflammatory responses [73]. They are usually observed in the epithelial barrier tissues,which act as the first line of bio-organisms’ defense; when foreign bodies enter the host,pattern recognition receptors (PRRs) in the host’s epithelial tissues respond to microbe-derived pathogen-associated molecular patterns (PAMPs) or danger-associated molecularpatterns (DAMPs), which are generated by the host cells. Recently, the study of inflamma-some and natural products has increased (Figure 3) [74]. The recognition of the entranceof PAMPs or DAPs is initiated by PRRs’ binding, including Toll-like receptors (TLRs),retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), NOD-like receptors (NLRs), andC-type lectin receptors (CLRs) [75]. As a result of inflammasomes’ activation, monocytesare recruited around the foreigners’ entrance site, changed to macrophages or dendriticcells, and secrete cytokines and chemokines, such as IL-1β, TNF-α, IL-6, and IL-12 (se-creted by M1 macrophages) or IL-4 and IL-13 (secreted by M2 macrophages) [76–79].

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Baicalin is an isolated flavonoid from Scutellaria baicalensis Georgi that suppresses the NLR3inflammasome-induced pyroptosis of RPE cells [80]; Lycium barbarum polysaccharidesinhibits pyroptosis, which is induced by an NLRP3/caspase-1/membrane N-terminalcleavage product of GSDMD (GSDMD-N) [81]; puerarin is an isolated constituent from thePueraria montana root that suppresses NLRP3 inflammasome activation [82]; grape seedproanthocyanidin extract was found to alleviate RPE cell senescence, which was causedthrough the nicotinamide phosphoribosyltransferase (NAMP)/SIRTI/NLRP3 pathway [83];and cyanidin-3-glucoside (C3G), which is plentiful in purple-colored fruits/vegetables,down-regulates NLRP3 inflammasome activation [84].

Figure 3. The inflammasome synthesis/activation and the anti-inflammasome effect of naturalproducts. (1) PRRs in the cell membrane bind to PAMPs or DAMPs. (2) After the recognition ofPRRs, NF-κB p65/p55 and IκB can be separated from each other and NF-κB p65 enters the nucleusin order to function as a transcription factor for both NLRP3 and pro-IL-1β (3). (4) A2E producesphagosomes and they release cathepsin B. (5) ROS are generated and stimulate the complex formationof NLRP3, active IL-1β, and cathepsin B to activate caspase-1. (6) Active caspase-1 binds to IL-18 toproduce the inflammasome. Natural products, such as baicalin, Lycium barbarum, puerarin, grapeseed, and cyanidin-3-glucoside, can block inflammasome formation to ameliorate inflammationin PRE cells. PRRs, pattern recognition receptors; PAMPs, microbe-derived pathogen-associatedmolecular patterns; DAMPs, danger-associated molecular patterns; NLRP3, NLR family pyrin domaincontaining 3; and A2E, N-retinylidene-N-retinyl-ethanolamine.

3.2.2. Other Anti-Inflammatory Pathways

Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione], which isone of the major constituents in Curcuma longa, has several biological effects, includinganti-allergy, anti-oxidative, and anti-inflammatory effects; in particular, it suppresses bcl-2family-related RPE cell death through the extracellular signal-regulated kinase (ERK)/NF-κB-COX-2 signaled anti-inflammation pathway [85]. Nepetin, which is called eupafolin or6-methoxyluteolin, a flavonoid isolated from several herbs, such as Eupatorium ballotaefolium,Rosmarinus officinalis, and Clerodendrum petasites [86–88], decreases inflammation-relatedcytokines, such as IL-6 and IL-8, via the NF-κB/MAPK (ERK1/2, JNK and p38MAPK)pathway [89]. Resveratrol [3,4′,5 trihydroxy-stilbene], which is one of the components ingrapes, can suppress the levels of inflammatory cytokines, such as IL-1β, IL-6, TNF-α,and TGF-β, via the NF-κB pathway in RPE cells [90]. Saffron is one of the componentsof Crocus sativus L.’s stigma and has anti-inflammatory effects [91] through modulatingboth inflammation-related cytokines such as proinflammatory cytokines (IL-1β, IL-17,IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-4 and IL-10) [92]. Wogonin [5,7-

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dihydroxy-8-methoxyflavone], which is isolated from Scutellaria baicalensis Georgi root,down-regulates LPS-induced inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNF-α,through the TLR4-NF-κB/COX-2 signal [93].

3.3. Anti-Carbonyl Stress Effects and Natural Products

Allicin is an organosulfur compound isolated from Allium sativum L. It has severalbiological effects, such as antimicrobial effects, immune-regulation, and anti-cancer ef-fects [94]; in an H2O2-induced AMD in vitro model, it decreased the level of MDA [95].Flavonoid-rich fractions from blueberries suppressed active carbonyl compounds, such asMDA and 4-HHE, and the lipid oxidative compound lipid hydroperoxide (LOOH) [42].Freeze-dried grapes, which contain resveratrol, flavans, flavonols, anthocyanins, and sim-ple phenolics, effectively prevented 4-HNE in RPE cells and then blocked blindness causedby RPE actin’s damage [96]. Quercetin and C3G, which are plentiful in various fruits andvegetables, prevented RPE cell damage through lipid oxidation and carbonyl stress via4-HNE [97]. Tomatoes have many constituents, including carotenoids, such as lycopene,phytoene, phytofluene, β-carotene, γ-carotene, δ-carotene, and lutein, and polyphenols,such as naringenin chalcone, rutin, quercetin, and chlorogenic acid [98]; tomato extractcontains high levels of β-carotene, lycopene, and traces of lutein, which decreased proteincarbonyls in H2O2-treated RPE cells by 30% [99]. Based on a human study, a nutritionalsupplement containing 408 mg of vitamin C, 241 mg of vitamin E, 30 mg of zinc, and 9 mgof lutein once a day for 3 months effectively reduced serum MDA levels [100].

4. Discussion

AMD is related to aging and the percentage of AMD patients is higher in older people.In 2020, the United Nations reported that, in 2019, the number of people aged 65 yearsor more was 703 million worldwide, and in 2050, this number could almost double toreach 1.5 million [8]. In 2020, 196 million people suffered from AMD, and in 2040, thisnumber is expected to rise to 288 million [9]. Depending on aging, the severity and theoccurrence of AMD might increase, and although there are several treatment methods,such as device-based therapy, anti-inflammatory drug therapy, and anti-VEGF treatment,because AMD is an incurable disease, the best treatment is to prevent its occurrence. Thecurrent incidence rate of AMD in young and juvenile people has been rapidly increasing asthe usage time of smart devices increases [101]; in order to reduce morbidity, smart devices’usage time should be reduced [102].

AMD is initiated by RPE cell death and, as it is difficult to supply blood to photore-ceptors, angiogenesis finally occurs from the choroid vessel to photoreceptors [103]. RPEcell death is related to oxidative stress, inflammatory stress, and carbonyl stress [23], andalthough each type of stress is harmful to cells, all three stresses influence RPE cell death asall occur simultaneously. It is difficult to completely cure AMD, and thus its prevention isthe best therapeutic strategy. In this study, the relation between AMD and the suppressionof the three types of stress by natural products was reviewed. These natural products in-clude anti-oxidants, including Nrf2/HO-1 stimulators, namely, canolol, genipin, hesperetin,narigenin, salvianolic acid, carotenoids, Arctium lappa L. leaves, delpinidin, polyphenols,and glabridin [62–72]; anti-inflammatory agents, such as baicalin, Lycium barbarum polysac-charides, puerarin, grape seed proanthocyanidin, C3G, curcumin, nepetin, resveratrol,saffron, and wogonin [80–87,90,91,93]; and anti-carbonyl stress suppressors, such as allicin,blueberries, grapes, quercetin, tomatoes, and nutritional supplements containing vitamin C,vitamin E, zinc, and lutein [42,82,94,96,98–100]. However, there are several AMD-preventedmechanisms of natural products excluding anti-oxidation, anti-inflammation, and anti-carbonylation. Docosa-hexaenoic acid, which is a major compound in omega-3 fatty acid,inhibited RPE cell death through the down-regulation of pro-apoptotic factors, such asBax and Bad, and the up-regulation of anti-apoptotic factors, such as Bcl-2 and Bcl-xL [33].Dietary lutein, which originates from fruits and vegetables, such as kiwi fruit, grapes,orange juice, maize, spinach, and zucchini [104], significantly decreased AMD incidence in

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humans [105,106], and the anti-AMD mechanism can be supposed to inhibit ROS-inducedRPE cell damage via the 25C cycle and cyclin B1-related G2/M phase arrest [107]. Tauro-cholic acid, which is a yellowish crystalline bile acid and is called cholaic acid, cholytaurine,or acidum cholatauricum [108], inhibited both VEGF-induced tube formation and the migra-tion of choroidal endothelial cells (RF/6A cells) in a study of anti-angiogenesis effects [109].Vaccinium uliginosum L. fractions, which contain a large amount of polyphenol, preventedblue-light-induced ARPE 19 cell damage [110]. In 2022, de Guimaraes et al. [111] reportedthat drug candidates for early (dry) AMD treatment were undergoing a clinical study(Table 2). Based on the therapeutic target, they can be classified as antioxidants, reducers oftoxic byproducts, visual cycle modulators, anti-inflammatory and complement inhibitiondrugs, neuroprotection, gene therapy, cell-based therapies, mitochondrial enhancers, andnanosecond laser therapy.

Table 2. Ongoing clinical trials for early (dry) AMD drugs.

Category/Name Clinical TrialID (NCT #)

StudyPhase

Route ofDelivery Status Sponsor

AntioxidativeAge-related eye disease study

(AREDS) 00000145 III Oral Completed National Eye Institute

AREDS2 00345176 III Oral Completed National Eye Institute

OT-551 00306488 II Topical Completed National Institutes of HealthClinical Center

Reduction in toxicbyproductsGSK933776 01342926 II IV Completed GlaxoSmithKline

RN6G 01577381 II IV Terminated Pfizer

Visual cycle modulatorsACU-4429 01802866 IIb/III Oral Completed Kutoba Vision, Inc.Fenretinide 00429936 II Oral Completed Sirion Therapeutics, Inc.

C20-D3-vitamin A (ALK-001) 03845582 III Oral Ongoing/recruiting Aleus Pharmaceuticals, Inc.

Anti-inflammatory andcomplement inhibition

Eculizumab 00935883 II IV Completed Philip J. Rosenfeld, MDLampalizumab 02247531 III Intravitreal Terminated Hoffman-La Roche

Sirolimus (rapamycin) 00766649 I/II Subconjunctival Completed National Eye InstituteAvacincaptad pegol (Zimura) 02686658 II/III Intravitreal Completed IVERIC bio, Inc.

Pegcetacoplan (APL-2) 03525613 III Intravitreal Completed/notrecruiting Apellis Pharmaceuticals, Inc.

Tedisolumab (LFG316) 01527500 II Intravitreal Completed Novartis Pharmaceuticals, Inc.Risuteganib 03626636 I Intravitreal Completed Allegro Ophthalmics

NeuroprotectionCiliary nerve trophic factor 00447954 II Intravitreal Completed National Eye Institute

Brimonidine tartrate 02087085 IIB Intravitreal Terminated Allergan

Gene therapyAAVCAGsCD59 03144999 I Intravitreal Completed Hemera Biosciences

GT005 03846193 I/II Subretinal Ongoing/recruiting Gyroscope Therapeutics

Cell-based therapies

Palucorcel (CNTO-2476) 01226628 I/II Subretinal Completed Janssen Research &Development, LLC

MA09-hRPE 01344993 I/II Subretinal Completed Astelas Institute forRegenerative Medicine

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Table 2. Cont.

Category/Name Clinical TrialID (NCT #)

StudyPhase

Route ofDelivery Status Sponsor

CPCB-RPE1 02590692 I/IIa Subretinal Ongoing/notrecruiting

Regenerative PatchTechnologies

Mitochondrial enhancersElamipretide 03891875 II Subcutaneous Ongoing/recruiting Stealth Biotechnologies, Inc.

Recently, trials to develop stem cell therapy for AMD have increased [112]; stem celltherapy for AMD uses the microsurgical method to replace damaged RPE cells using severalcell types, such as embryonic stem cells (ESCs) [113], pluripotent stem cells (PSCs) [114],and mesenchymal stem cells (MSCs) [115]. An RPE monolayer patch using human ESCshas been evaluated in a clinical phase I trial in order to use microsurgical tools in subretinalspace, and the study was deemed successful [116]. Human PSCs have the ability todifferentiate most cell types, and many studies have been conducted to find therapeuticconditions for AMD [117]. Intravitreal MSCs injection increased the survival of both RPEcells and photoreceptors in a retinitis pigmentosa model [118]. Although there have beenmany trials of stem cell usage on AMD patients, there are still several obstacles to their useas AMD therapeutics. One is that stem cells have a pluripotency to differentiate betweenmany types of cell, which means that it is difficult to control the making of a proper celltype, namely RPE [119]. Other problems are that the safety of the stem cell method is notcompletely confirmed, and that, in order to successfully settle cells down on the subretinalspace after the operation, the immunosuppressor should be treated, but the systemicimmunosuppression could inhibit the stem cells’ effective settling down [120]. Anotherstudy found that, in order to clinically apply stem cell therapy to AMD patients, there aremany obstacles still to be solved, including safety, the differentiation of the proper cell type,and the effective usage of immunosuppressors [121].

Especially in the early and intermediated stages of AMD (dry AMD), natural productsupplements, such as nutritional materials (antioxidants, anti-inflammatory materials, andanti-carbonyl ones), are effective for decreasing AMD occurrence.

Author Contributions: Conceptualization, I.-C.J. and D.-H.P.; writing—original draft preparation;Y.-K.C. and S.-M.L.; writing—review and editing, I.-C.J. and D.-H.P.; visualization, Y.-J.K. and Y.-M.K.;supervision, D.-H.P. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.

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