1. Nrf2 Signalling in Stress and Diseases
1.1. Nrf2 Signalling Pathway
The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway plays an essential role in antioxidation (Figure 1). The key regulatory factors involved in the Nrf2 pathway include Kelch-like ECH-associated protein 1 (Keap1), Cullin 3 (CUL3), and the small MAF subfamily (sMAFs) isoforms. Keap1 can be modified by electrophiles via massive reactive cysteine sulfhydration [1], preventing Nrf2 degradation in stress conditions [2,3]. Without stress, Keap1 binds to Nrf2, for which the complex is degraded via the CUL3-dependent ubiquitination proteasomal pathway [4]. As Nrf2 is unavailable to dimerise with sMAF in the nucleus, the transcription of the downstream antioxidative genes cannot be initiated. sMAFs can homodimerise with themselves and act as transcriptional repressors due to the competition of Maf-recognition elements (MAREs) [5]. sMAFs may also heterodimerise with cap’n’collar (CNC), activator protein 1 (AP-1), and Bach proteins to initiate the downstream transcription of various genes by binding to MAREs [5].
Nrf2 is degraded by a protein complex, named the Keap1/CUL3 ubiquitin ligase, under normal conditions (Figure 1) [6]. This degradation process is initiated by adding several ubiquitin molecules (polyubiquitination) to Nrf2, which marks it for destruction by the proteasome. The Keap1 protein acts as a receptor for Nrf2 and helps to bring it into the E3 complex, which is composed of the CUL3 protein and a RING box protein. The RING box protein is responsible for recruiting another set of proteins called ubiquitin-conjugating enzymes (E2), which work together with the E3 complex to transfer the ubiquitin molecules onto Nrf2. Once the E2 enzyme binds to the C-terminal of the CUL3 protein, it catalyses the transfer of the ubiquitin molecules onto Nrf2, leading to its degradation by the proteasome [6].
Under stress (Figure 1), Nrf2 dissociates from the complex of Nrf2–Keap1–CUL3 and moves into the nucleus to bind with sMAFs [2,3,7,8]. Consequently, the heterodimer of Nrf2–sMAFs binds to MAREs and activates the downstream antioxidants, including HO-1 (Heme Oxygenase-1), GCLC (the first rate-limiting enzyme in glutathione synthesis), GCLM (the second rate-limiting enzyme in glutathione synthesis), TXNRD1 (thioredoxin-coded gene), GPx (glutathione peroxidase), and MRP4 (glutathione efflux transporter 4) [7,9,10].
1.2. MAF Family
The MAF family contributes to an oncogene and was discovered in the avian musculoaponeurotic fibrosarcoma virus AS42, in the late 1990s [11]. The MAF family is classified into two subfamilies, per their protein size. One is the large MAF isoforms (lMAFs), including MAFA, MAFB, c-MAF, and NRL, which are characterised by the presence of an activation domain at the N-terminal [12]. lMAFs are about 240–340 amino acids in length. The other subfamily is sMAFs, including MAFF, MAFG, and MAFK, which are featured as 150–160 amino acids without activation domains [12].
lMAFs with activation domains independently regulate the transcription of downstream genes. For example, the MAFA and MAFB in beta cells activate the transcription of glucose-sensing genes [13]. Studies suggested that MAFA and MAFB are associated with maturing pancreatic beta cells [14]. In addition, MAFB is also involved in the differentiation of macrophages and monocytes [15] as well as podocyte formation [16]. c-MAF is primarily expressed in the immune system, facilitating interleukin transcription in T cells [17,18]. Moreover, c-MAF also plays a role in liver sinusoidal maturation [19] and lens formation [20]. The physiological role of NRL remains unclear; it specifically expresses in the retina and may be involved in visual function [21].
sMAFs have no activation domains. In stress conditions, they form heterodimers with CNC family members, particularly Nrf2. In the absence of stress, the homodimerisation of sMAFs acts as a transcriptional repressor [22]. sMAFs contribute to the progression of human diseases, such as cancers and cardiovascular diseases. MAFF is abundantly expressed in metastatic breast cancer cells [23]. It regulates the expression of low-density lipoprotein receptors (LDLR) [24]. The expression of LDLR is directly associated with cholesterol metabolism and inflammation, and the dysregulation of these processes leads to CVD [24]. Moreover, induction of MAFF by secretory inflammatory cytokines (IL-1β and TNF-α) can promote host defence against the hepatitis B virus (HBV) [25]. Similarly, MAFK is also highly expressed in triple-negative breast cancer [26]; the upregulation of MAFK influences a tumour’s susceptibility to salmonella mucosal infection [27]. MAFK is positively associated with the expression of nuclear factor kappa B (NF-κB) [28], a gene that is activated in cancers, inflammatory responses, and neurodegenerative diseases. The literature indicated that the expression of MAFG is associated with liver cancer [29] and osteosarcoma progression [30]. Overall, all sMAFs form heterodimers with Nrf2 to regulate antioxidative responses [31], which is closely related to the pathogenesis of human diseases.
1.3. Nrf2 in Diseases
Nrf2 is a potent transcription factor that controls around 250 genes that are widely involved in antioxidation and detoxification. Nrf2 was found to be involved in oncogenic events in the late 1990s. Tumour cells are susceptible to oxidative stress; the Nrf2–sMAFs complex is overexpressed in tumour cells in response to oxidative stress, to preserve the tumour microenvironment [5]. Mutations of Nrf2 or its repressor Keap1 are also found in cancer cells, resulting in Nrf2 overactivation and promoting cancer cell survival [32]. Nrf2 overactivation provides a satisfactory cancer cell microenvironment, but oxidative stress disfavours tumour growth. In response to oxidative stimuli, tumour cells further upregulate the Nrf2 antioxidative signalling pathway [33,34,35]. This continuous activation status of Nrf2 is closely related to a tumour’s prognosis. For example, the isocitrate dehydrogenase 1 or 2 genes (IDH1/2) of mutated glioma cells have decreased Nrf2 activity but a better prognosis [36]. Nrf2 is also reported to be anticarcinogenic in colorectal cancer and melanoma. Upregulating Nrf2 by activating the PERK/Nrf2/HO-1 pathway induces ferroptosis in colorectal cancer cells [37]. The knockdown of glutaryl-CoA dehydrogenase (GCDH) results in Nrf2 upregulation and promotes cancer cell apoptosis in melanoma [38]. Re-expression of Nrf2, which is deficient in prostate cancer, can protect prostate cells from tumorigenesis [39]. The Nrf2/KEAP1 signalling pathway is also reported to play a critical role in the response of several cancer types to chemotherapy [40,41,42].
In neurodegenerative diseases such as Huntington’s and Hippocampal sclerosis, Nrf2 is low in activity, producing an antioxidative effect. E3 ubiquitin-protein ligase 1 (HACE1) has low expression in Huntington’s, and its depletion decreases Nrf2 expression, leading to neurodegeneration [43]. Nrf2 is downregulated by increasing the activity of its repressor Keap1 in hippocampal sclerosis [44]. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are among the most prevalent age-related neurodegenerative diseases. The oxygen level is usually high in the brain due to the high consumption of coping signals. The continuous accumulation of biological products via lipid peroxidation, DNA oxidation, and free radical production gradually increases local oxidative stress [8]. A Ca2+ imbalance due to endoplasmic reticulum (ER) stress and ER-associated ROS production in peripheral blood mononuclear cells is observed in AD patients [45]. The Nrf2-associated antioxidative enzymes show a differential expression pattern in different locations of the brain, such as superoxide dismutase 1 (SOD1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and HO-1. The Nrf2-associated antioxidative enzymes show a differential expression pattern in different locations of the brain in AD patients, such as superoxide dismutase 1 (SOD1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and HO-1 [8]. There is also a change in the expression of Nrf2-related antioxidative enzymes in PD patients, with a similar pattern as that in AD patients [8]. Protein and lipid oxidation as well as iron accumulation are also observed in PD, indicating an impaired antioxidative system due to disrupted Nrf2 activity [8]. Sara et al. reported that Nrf2 is highly expressed in PD and is also detectable in leukocytes [46]. Nevertheless, it is recognised that Nrf2 is a potential therapeutic target to be further investigated in both AD and PD.
Nrf2 is also reported to be involved in many other diseases. For instance, Nrf2 is reported to be associated with Hutchinson-Gilford progeria syndrome (HGPS) [47]. This is a rare premature-ageing disease. Its pathogenesis is largely unknown but may result from progerin overproduction [47]. Via a high-throughput siRNA screening, Nrf2 is shown to be a potential risk factor for this disease [47]. In addition, diabetic kidney disease can be improved by β-hydroxybutyrate therapy by inhibiting glycogen synthase kinase-3 beta (GSK3β) and reactivating Nrf2 in glomerular podocytes [48]. An Nrf2 defect is shown in the disrupted homeostasis of ageing and redox system, contributing to fibroblast resistance to apoptosis in diabetic nephropathy [49] and phagocyte ageing and death in human immunity [50].
2. Nrf2 Signalling in the Retina
The retina is a complex, layered structure composed of multiple cell types. In mammals, it consists of five major neuronal cell types and glial cells distributed across five distinct layers (Figure 2). The outermost layer of the retina is the retinal pigment epithelium (RPE), which acts in concert with photoreceptors [51]. Two types of photoreceptors are found in the retina: cones and rods, both of which reside in the outer nuclear layer (ONL). Cones are responsible for daylight due to their lesser light sensitivity than rods [52] and are more concentrated in the fovea, where stronger light passes through [53]. Rods outnumber cones by about 20 fold and are present outside of the fovea [53]. The cell body of the horizontal cell is predominantly situated in the inner nuclear layer (INL) of the retina, and its axon extends into the outer plexiform layer (OPL). Horizontal cells manipulate the synaptic transmission between photoreceptors and bipolar cells [52]. The bipolar cells located in the INL can be divided into cone bipolar and rod bipolar, for their activity in processing information from cone and rod cells, respectively [52]. Amacrine cells are present in the INL and the ganglion cell layer (GCL). The axon of an amacrine cell is projected into the inner plexiform layer (IPL) to form synapses bipolar and ganglion cells [52]. The innermost layer of the retina is the GCL, which is mainly composed of ganglion cells that are the final output neurons to transform visual information from bipolar and amacrine cells to the optic nerve [54].
2.1. Nrf2 in Normal Retina
Nrf2 is a key regulator of oxidative stress in the retina. The retina is a metabolically active tissue with high oxygen consumption, which can lead to increased production of ROS. To protect against ROS-induced damage, the retina has an essential antioxidative defence system. Nrf2 plays a central role in regulating this system, particularly in response to stimuli such as ageing, exposure to sunlight, and inflammation. In a normal retina, Nrf2 is expressed in various retinal cell types, including RPE, Müller, and ganglion cells [55,56]. By activating the expression of various antioxidative enzymes, such as HO-1, SOD, and GSH-related enzymes [7,9,10], Nrf2 helps prevent ROS accumulation in the retina and maintain its normal function.
2.1.1. Retina Pigment Epithelium (RPE)
The RPE is located at the outermostof the retina and plays many roles in maintaining the retina structure and the visual cycle. Phagocytotic RPE cells can engulf the dead photoreceptor’s outer segments [57,58]. The RPE also controls the movement of ions, water, and other metabolic wastes out of the subretinal space, as part of the blood–retinal barrier (BRB) [58]. As critical steps involved in the visual cycle, an all-trans-retinal is formed in the photoreceptors; the RPE helps to re-isomerise it to 11-cis-retinal and transport it back to the photoreceptors [58]. Furthermore, the RPE creates a locally immunosuppressive and anti-inflammatory microenvironment essential for the eye’s immune privilege. This is achieved by secreting immunomodulatory cytokines, neuropeptides, and growth factors into the intraocular fluid [59].
The RPE is a protective shield for the retina, while oxidative stress damages the RPE, leading to aged-macular degeneration (AMD) and diabetic retinopathy (DR) [60,61]. The Nrf2 signalling pathway primarily mediates the crucial antioxidative response of the RPE against oxidative stress [56]. Studies report the altered protein expression of Nrf2 and its downstream targets in the RPE. The literature suggests that the protein level of Nrf2 decreases due to its downregulated mRNA expression in the ageing RPE [56]. Similarly, the disruption of Nrf2 signalling is widely found in diseased rodent models and human tissues [56]. A potential upstream regulator (microRNA-144) is positively related to oxidative stress, while the overexpression of microRNA-144 decreases Nrf2 and its downstream targets [62]. As such, it is postulated that Nrf2 may be the master regulator in the RPE to overcome oxidation-induced degeneration. In a recent study, Nrf2 overexpression in mice could successfully rescue the RPE from degeneration [9].
Overall, the RPE protects the human retina from oxidative stress and maintains its redox homeostasis in an Nrf2-dependent manner. The dysregulation of Nrf2 signalling leads to retinal diseases such as AMD and DR. Therefore, Nrf2 is a promising therapeutic target for degenerative retinal diseases. sMAF, as a key regulator of the Nrf2 pathway, is poorly understood in RPE cells, and little is known about its expression in different retinal cell types. However, RPE cells rely on the Nrf2 signalling pathway to protect them from oxidative stress and maintain redox homeostasis. The dysregulation in this pathway leads to retinal diseases such as AMD and DR.
2.1.2. Müller Cells
Müller cells were reported by Heinrich Müller in 1851. They are an essential type of glial cells in the retina, functionally similar to the RPE [63]. They penetrate through whole neuroretina layers. Each Müller cell is responsible for one cone cell [64]. The primate retina has a unique structure, called the macula, at the central posterior. Macular and peripheral Müller cells have distinguished morphologies [64] and transcriptional changes [65]. In mammals, each Müller cell column can contain up to 10 rods, and the arrangement of other cell types in the column depends on the peripheral and macular fovea regions [64]. Müller cells are involved in the inner BRB, which is different from the RPE. Müller cells are responsible for neuroprotection, neovascularisation, and the release of gliotransmitters [63,64]. They are also identified by their stem-like characteristics derived from the retina [66]. The essential physiological activities of Müller cells include maintaining retinal redox homeostasis and supporting neuroretina, due to their extensive distribution across the entire retina [65]. Müller cell dysfunction is associated with many retinal diseases, such as AMD, DR, and macular telangiectasia (MacTel) type 2 [65].
Similarly, Nrf2 also plays an essential role in the stress defence of Müller cells. “Nrf2-mediated oxidative stress response”, including an increase of Nrf2 and the sMAF family, is among the top cellular responses when Müller cells are exposed to strong light (a stress condition) compared to dim light (an unstressed condition) [67]. Nrf2 activation in Müller cells also rescues retinal ganglion cells (RGCs) from cell death [55], since Müller cells support other retinal neurons. In a co-culture model of Müller cells and RGCs, Nrf2 knockout results in a decreased number of RGCs. Nrf2 knockout leads to increasing RGC death and decreasing visual acuity [55]. Furthermore, a novel Nrf2 activator RS9 is reported to protect Müller cell death from light-induced stress [68]. This evidence highlights the crucial role of Müller cells in the retina, while Nrf2 is the key mediator in response to stress.
2.1.3. Photoreceptors
Photoreceptors are composites in the outer retina. Their primary function is to receive light signals and then convert and pass the signal to other neuronal cells by impulses (i.e., horizontal and bipolar cells) [53]. Rods and cones are the two types of photoreceptors that have different physiological characteristics and functions (Table 1). The phototransduction mechanism in rods was fully understood in the early 2000s, while the complex light signal pathway in cones was elucidated later on due to the difficulties of dissecting cones [53]. Cones and rods both rely on glutamate neurotransmission in the synapse, which is formed by horizontal and bipolar cells [53]. Rods have a single synaptic ribbon, whereas cones have many ribbons [53]. The rate of glutamate release in the synapse is primarily influenced by the strength of the light exposure. In the dark, there is a high and rapid release of glutamate, resulting in the photoreceptors hyperpolarising [53].
Photoreceptors also have protective responses against oxidative stress. Mitophagy is a process that degrades the damaged mitochondria to prevent stress and reinstate cellular homeostasis [69]. This mechanism is particularly important in ageing, while impaired mitophagy is largely associated with age-related diseases. Activation of mitophagy in photoreceptors is known to reduce oxidative damage through the Nrf2/p62 signalling pathway [70,71]. p62 has a competitive Nrf2-binding site with Keap1, which is a negative regulator of Nrf2 signalling [72]. By inhibiting Keap1 binding, p62 allows Nrf2 to translocate to the nucleus and initiate the transcription of downstream antioxidative genes, thus maintaining redox homeostasis in the photoreceptors. Overall, Nrf2 drives the mitophagy in photoreceptors to maintain redox homeostasis and protect against oxidative stress.
2.1.4. Bipolar Cells
Bipolar cells mediate the light signal transmission between photoreceptors and ganglion cells. There are various types of bipolar cells, with 13 distinct types in mammals that are classified into two main groups, ON- and OFF-bipolar cells [73]. Rod bipolar cells are a unique type of ON-bipolar cell that specifically receives signals from rods. They depend on amacrine cells as well as ON- and OFF-cone bipolar cells to process these signals and send them as output to ganglion cells [73,74]. Cone bipolar cells are the only type that makes direct contact with ganglion cells [73]. Although rods vastly outnumber cones in mammals, the number of rod bipolar cells is much less than that of cone bipolar cells [75]. This is because every rod pathway requires cone bipolar cells, and rod photoreceptors are 20-fold more than cone photoreceptors in mammals. The primary rod pathway is well-explored in mammals, with signalling transduction occurring through the rod photoreceptors—rod bipolar cells—amacrine cells—ON-cone bipolar cells—OFF-cone bipolar cells—ganglion cells [74,76]. Between the rod photoreceptors and rod bipolar cells, the light signal transduction is mediated by sign-inverting metabotropic glutamate receptor 6 (mGluR6). Then, the signal is passed onto amacrine cells via glutamatergic synapses. Upon receiving the signal, it is distributed to the terminal of the ON-cone bipolar cells via the gap junction and the OFF-cone bipolar cells through the glycinergic synapses [74]. The other two light signal transduction pathways are via cones (cone photoreceptors to cone bipolar cells) or rods that make direct contact with the OFF-cone bipolar cells [76].
Bipolar cells are known to survive after photoreceptor degeneration [77]. However, it is unclear if they are immune to stress. There is limited literature available on the Nrf2-dependent antioxidative signalling in bipolar cells. We suspect that their survival mechanism may not necessarily depend on Nrf2 signalling but rather on peroxisomal β-oxidation, which is crucial for maintaining their retinal functions [78].
2.1.5. Horizontal and Amacrine Cells
Horizontal cells are interneurons located in the inner nuclear layer of the retina that help to transmit signals between groups of cones and rods [79]. The function of horizontal cells depends on their location. The horizontal cell body is in the upper region of the INL, and its axon projects to the cone and rod terminals. At the terminals, the neurotransmitter gamma-aminobutyric acid (GABA) negatively regulates glutamate release [80].
Amacrine cells, like horizontal cells, are associated with the rod and cone pathways. Two types of amacrine cells have been found in mammals, with AII as the primary type. AII amacrines transfer electrical signals to ON-cone bipolar cells and chemical signals (glycine) to OFF-cone bipolar cells, while A17 amacrine cells provide inhibitory feedback (via GABA) to rod bipolar cells [81]. Both horizontal and amacrine cells are rarely associated with age-related diseases; however, natural mutations of the development-related genes in these two cells may result in genetic retinal diseases, such as retinoblastoma [82].
2.1.6. Ganglion Cells
RGCs are the last neuron to transmit visual information to the brain. In humans, a variety of ganglion cells have been identified. The exact clusters of ganglion cells in the human retina are yet to be defined. The two main types of RGCs, ON- and OFF-ganglion cells, respond differently to various light stimuli, such as light frequency and colour [83]. The process of light transduction in ganglion cells is complex. Melanopsin, a photopigment, is expressed in ganglion cells to help with light transduction, even though there are no photoreceptors [84]. As a part of the retina, damaged ganglion cells can impact visual ability.
Oxidative stress predominantly affects ganglion cells and promotes glaucoma [85] as well as other ocular neurodegenerative diseases [86]. Recent studies show that Nrf2 is expressed in RGCs and promotes cell survival under stress. For example, upregulating polo-like kinase 2 (PLK2) through the Nrf2 pathway protects ganglion cells from stress [85]. The literature also reports that Nrf2 upstream factors, including Sox2 overlapping transcript [86], serum response factor [87], and L-carnitine [88], affect the survival of RGCs. Knocking down these inducers leads to RGC loss. Mitochondrial dysfunction is also a primary cause of stress in RGCs, which may lead to glaucoma. RGCs require a high oxygen level and high metabolic activity, resulting in an increased number of mitochondria. The mitochondrial DNA damage is likely associated with ageing and ROS production [89]. The protective function of Nrf2 in mitochondria is widely reported, and Nrf2 activators are shown to support mitochondrial function and structure homeostasis when exposed to stress [71].
2.1.7. MAF Family in Retinal Cells
The exact function of MAF in the retina remains unclear, and the single-cell RNA sequencing data from the Human Protein Atlas (
2.2. Nrf2 in Ageing and Diseased Retina
Research suggests that the disruption of Nrf2 is a significant contributor to age-related and disease-related changes in the retina (Figure 3), including mitochondrial dysfunction and endoplasmic reticulum stress. In human retinal diseases, the activation of Nrf2 decreases, as discussed in the following section. However, currently there is limited knowledge on the role of the MAF family in ageing and retinal diseases.
2.2.1. Dysregulation of Nrf2 in the Ageing Retina—Mitochondria
The human retina is among the most metabolically active tissues in the body. Mitochondria are vital for the normal function of retina cells due to their high oxygen demand. Studies show that in an aged retina, there is a functional decline of the mitochondrial electron transport chain (ETC), leading to the accumulation of ROS that can damage the retina [92]. Mitochondria dysfunction is a key event leading to cell death, which results in retina degeneration. In the aged retina, the number, morphology, and enzymatic activity of the mitochondria are different from those in a healthy retina [93]. Particularly in the RPE cells, the mitochondria are typically regular and round-shaped in younger individuals compared to the larger, more irregular mitochondria found in older subjects [94].
Several mitochondria proteins maintain redox homeostasis, including mitochondria 70 kDa heat shock protein (mtHsp70), mitochondrial uncoupling protein 2 (UCP2), and superoxide dismutase 3 (SOD3). In aged RPE, these proteins have reduced expression [94], which may contribute to the pathogenesis of retina degeneration. Similarly, mitochondria dysfunction in photoreceptors also leads to retina degeneration. Photoreceptors have more mitochondria than the RPE does, predominantly in the inner segment and the axon terminals that are the sites of frequent signalling processing [95]. Oxidative stress is the primary cause of the deletion of photoreceptor mitochondria, further exacerbating the retina-degeneration progression.
Nrf2 responds to ROS accumulation in the mitochondria by mitigating mitochondrial-triggered cell death [96] and shielding against the toxicity and damage induced by the ETC [97,98]. Downstream, Nrf2 activation upregulates the expression of antioxidative genes [99,100,101]. For instance, ferroptosis is a type of cell death triggered by the accumulation of excess iron. The mitochondrial dysfunction in the aged retina leads to disrupted iron metabolism and increased ROS production, which is regulated through the Nrf2 pathway [96]. A study reveals that neuron cells lacking Nrf2 are more susceptible to cytotoxic events, such as the increased calcium resulting from the inhibition of mitochondrial complex I, compared to that of wild-type neurons [97]. The expression of Nrf2 in neurons also facilitates the detoxification of ROS accumulation by inhibiting mitochondrial complex II [98]. These findings suggest that Nrf2 may protect neurons from the toxic events induced by damaged mitochondria. Furthermore, the upregulation of the antioxidant response by Nrf2 may be crucial for protecting retinal cells from oxidative stress.
2.2.2. Dysregulation of Nrf2 in the Ageing Retina—Endoplasmic Reticulum
The endoplasmic reticulum (ER) is the site of protein synthesis and folding. ER stress happens when protein folding reaches its maximum capacity. ER stress also occurs when the retina is exposed to excessive light. The unfolded protein response (UPR) is modulated by stress sensors such as protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6) [102,103,104]. Suppressed PERK expression in photoreceptors and RPE cells could rescue the retina from light damage [105]. PERK downregulation consistently promotes the expression of the miR-106b-25 cluster to prevent the retina from oxidative stress [106]. The hyperactivation of the IRE1α induced by ER stress contributes to cell death [107]. ATF6 is the major regulator in the ER stress pathway and is associated with cone mitochondrial defects and Müller cell transcriptomic changes [108].
Several studies suggest that the Nrf2 pathway mediates ER stress. Nrf2 overexpression is shown to deactivate the ER stress sensors via the PERK/eIF2α/ATF4/CHOP pathway (i.e., the ER stress pathway), promoting RPE cell survival [109]. This is also evidenced in drug-related studies. The long-term use of minocycline in treating acne vulgaris is toxic to the retina by increasing ER stress and downregulating the Nrf2 pathway [110]. Plant-derived morin hydrate is reported to reduce ER stress in the RPE by activating the Nrf2 pathway [111].
2.2.3. Changes in Nrf2 Signalling in Retinal Diseases
AMD is a common condition, characterised by progressive vision loss, which typically affects individuals over the age of 55 [112]. A clinical hallmark of AMD is the formation of drusen, yellowish extracellular deposits containing lipids and proteins that can be visualised through optical coherence tomography (OCT) [113]. In addition to genetic and environmental factors, excessive ROS production is a known risk factor for AMD [114].
Diabetic retinopathy (DR) is a common complication of diabetes mellitus that is characterised by hyperglycaemia and dysfunction of the blood–retinal barrier (BRB) in the early stage. The high glucose levels in the retina trigger the utilisation of nicotinamide adenine dinucleotide phosphate (NADPH), leading to an increased demand for NADPH and a reduction in the biosynthesis of antioxidants such as GSH [115]. This results in an accumulation of ROS and oxidative stress, accelerating the progression of DR.
The central role of Nrf2 signalling is to maintain redox homeostasis in the retina. These diseases are associated with an imbalanced redox system such as ROS accumulation. In AMD, the expression of Nrf2 is reduced, which may contribute to the imbalanced redox system observed in the disease [56]. In DR, the DNA-binding capacity is reduced, resulting in the low activity of Nrf2 [115]. Furthermore, disruption of the Nrf2 pathway increases the production of the proinflammatory cytokines in relation to the NF-kB pathway [115], contributing to the pathogenesis of DR. More relevant studies about Nrf2 signalling and related retinal diseases are summarised in Table 3.
3. Nrf2 Signalling as a Therapeutic Target of Diseases
3.1. Manipulate Nrf2 Signalling in Disease Treatments
As previously mentioned, Nrf2 is often activated in cancer cells to promote their survival. Targeting Nrf2 has emerged as a potential strategy for cancer treatment. Several compounds that can suppress Nrf2 activation or promote its degradation are identified, showing improved efficacy in chemotherapies or radiotherapies. For example, brusatol enhances the efficacy of chemotherapy for lung cancer by reducing the Nrf2 level by increasing its degradation [130]. Trigonelline can also promote Nrf2 degradation, improving anticancer treatment [131]. Halofuginone, a derivative of febrifugine, efficiently reduces the Nrf2 protein and shows great potential in treating chemo- and radio-resistant cancers [132]. Ochratoxin A (OTA) is a common food toxin in many European countries, which can decrease Nrf2 by interfering with its DNA binding [133]. ML385 is a small molecule that shows anticancer activity by directly binding with Nrf2 and preventing its activation [134].
Nrf2 activation is considered a viable approach in the therapeutic development of neurodegenerative diseases, especially in treating AD [135] and PD [136]. Sulforaphane, a natural Nrf2 enhancer, is effective in treating epilepsy; however, its clinical applications are largely compromised due to off-target effects and its narrow therapeutic index [44]. In comparison, cyanoenone triterpenoids, with a higher specificity to Nrf2 and wider therapeutic windows, have progressed to clinical trials in epilepsy patients [44]. Withaferin A and amantadine restore the decreased Nrf2 level in dopaminergic neurons by targeting the DJ1–Nrf2–STING pathway, in order to compensate for the neuron loss in PD [137]. In addition, Nrf2 modulators also have potential therapeutic effects on other diseases such as autoimmune, metabolic, respiratory, and CVD [2].
3.2. Target Nrf2 Signalling to Treat Retinal Diseases
Dysfunction in Nrf2 signalling is closely associated with certain age-related retinal diseases, such as AMD and DR. Recent studies have attempted to investigate Nrf2-targeted therapies in these diseases. Chrysoeriol is a compound that acts as an Nrf2 inducer, which can increase Nrf2/HO-1 expression to potentially prevent dry AMD [101]. Isothiosynate sulforaphane interacts with the thiols group in Keap1, resulting in conformational changes that cannot suppress Nrf2 activation. This leads to increased expression of Nrf2, which can help resecure RPE and photoreceptors from stress [138]. Triterpenoids are small molecules that may also act on Keap1 to activate Nrf2 and treat AMD. The benefit of these molecules is that they can easily penetrate the BRB [138]. Betulinic acid derivatives protect the RPE and Müller cells via the Nrf2 dependent pathway [139]; lipid nanocarriers may improve the efficacy of compound delivery into these retinal cells [140]. Catapol, an Nrf2 activator, is widely used to treat degenerative diseases and AMD [141]. Chlorogenic acid improves DR resulting from BRB injury by inducing Nrf2 activation [123]. Moreover, herbal extracts/medicines such as ginkgo biloba extracts also demonstrate a cytoprotective effect in the RPE and Müller cells in an Nrf2-dependent manner [142]. Although cell experiments alone may not be sufficient to demonstrate the clinical usefulness of Nrf2 for treating DR and AMD, they do suggest that further research is warranted to determine whether it may have therapeutic potential for these conditions [143].
4. Conclusions and Future Studies
Nrf2 is a powerful oxidative defence system widely expressed in cells, which plays a critical role in maintaining cellular homeostasis. The upregulation of Nrf2 in cancers leads to drug resistance in cancer therapies. The downregulation of Nrf2 largely contributes to the pathogenesis of neurodegenerative diseases such as AD, PD, and AMD. Therefore, Nrf2 activity significantly influences the progression of many prevalent human diseases. sMAFs are the key chaperon proteins of Nrf2, which form heterodimers with Nrf2 to regulate downstream antioxidative gene expression. It is unclear whether the loss or low expression of sMAFs is associated with the dysregulation of the Nrf2 pathway in many diseases, especially retinal diseases. Future research is expected to investigate the role of sMAFs and other members of the MAF family in relation to Nrf2 signalling as well as their relationship with human diseases. This information will provide insights into elucidating the mechanism of antioxidative gene regulation and discovering novel therapeutic targets for retinal and age-related diseases.
Conceptualisation: L.Z., T.Z., S.Z. and J.Z.; writing, J.Z. and L.Z.; figure creation, J.Z.; editing and reviewing, M.C.G., F.Z., X.Z. and L.Z. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
The single-cell RNA sequencing data of MAFF expression in the eyes are from the Human Protein Atlas (
The authors declare no conflict of interest.
| Abbreviation | Meaning |
| AC | Amacrine cell |
| AD | Alzheimer’s disease |
| AMD | Age-related macular disease |
| AP-1 | Activator protein 1 |
| ATF4 | Activating transcription factor 4 |
| ATF6 | Activating transcription factor 6 |
| BC | Retinal bipolar cell |
| BRB | Blood–retinal barrier |
| bZIP | Basic-region leucine zipper |
| CHOP | C/EBP-homologous protein |
| CNC | Cap’n’collar |
| CUL3 | Cullin 3 |
| CVD | Cardiovascular diseases |
| DJ1 | Protein deglycase |
| DR | Diabetic retinopathy |
| eIF2α | Eukaryotic initiation factor 2 |
| ER | Endoplasmic reticulum |
| ETC | Electron transport chain |
| GABA | Gamma-aminobutyric acid |
| GCDH | Glutaryl-CoA dehydrogenase |
| GCL | Ganglion cell layer |
| GCLC | First rate-limiting enzyme in glutathione synthesis |
| GCLM | Second rate-limiting enzyme in glutathione synthesis |
| GSH | Glutathione |
| GSK3β | Glycogen synthase kinase-3 beta |
| HACE1 | E3 ubiquitin-protein ligase 1 |
| HBV | Hepatitis B virus |
| HGPS | Hutchinson-Gilford progeria syndrome |
| HO-1 | Heme oxygenase-1 |
| IDH1/2 | Isocitrate dehydrogenase 1 or 2 genes |
| INL | Inner nuclear layer |
| IPL | Inner plexiform layer |
| IRE1α | Inositol-requiring protein 1α |
| IS | Inner segement |
| Keap1 | Kelch-like ECH-associated protein 1 |
| LDLR | Low-density lipoprotein receptor |
| lMAF | Large MAF |
| MacTel | Macular telangiectasia |
| MAF | Avian musculoaponeurotic fibrosarcoma virus |
| MARE | Maf-recognition elements |
| MGC | Müller glial cell |
| MRP4 | Glutathione efflux transporter 4 |
| mtHsp70 | Mitochondria 70kDa heat shock protein |
| NADPH | Nicotinamide adenine dinucleotide phosphate |
| NF-κB | Nuclear factor kappa B |
| NQO1 | NAD(P)H quinone dehydrogenase 1 |
| Nrf2 | Nuclear factor-erythroid 2-related factor 2 |
| OCT | Optical coherence tomography |
| ONL | Outer nuclear layer |
| OPL | Outer plexiform layer |
| OS | Outer segement |
| OTA | Ochratoxin A |
| PD | Parkinson’s disease |
| PERK | Protein kinase RNA-like ER kinase |
| PLK2 | Polo-like kinase 2 |
| PR | Photoreceptor |
| RGC | Retinal ganglion cell |
| ROS | Reactive oxygen species |
| RPE | Retinal pigment epithelium |
| sMAF | Small MAF |
| SOD1 | Superoxide dismutase 1 |
| SOD3 | Superoxide dismutase 3 |
| Sox2 | SRY-box 2 |
| STING | Stimulator of interferon genes |
| TXNRD1 | Thioredoxin-coded gene |
| UCP2 | Mitochondrial uncoupling protein 2 |
| URP | Unfolded protein response |
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Enlarge this image.Figure 1. Nrf2 signalling pathway. In the normal condition, the complex of Nrf2–Keap1–CUL3 is degraded via the proteasomal pathway. Upon exposure to stress, Nrf2 is dissociated from the complex and freely moves into the nucleus to form a heterodimer with sMAFs. Upon binding to MARE, it initiates the transcription of antioxidant signalling.
Enlarge this image.Figure 2. The structure of the human retina. GCL: ganglion cell layer; IPL: inner plexiform layer; INL: inner nuclear layer; OPL: outer plexiform layer; ONL: outer nuclear layer; IS: inner segment; OS: outer segment; RPE: retinal pigment epithelium.
Enlarge this image.Figure 3. Nrf2 signalling in young and ageing retinas. Nrf2 signalling is initiated in response to stress in the young retina to mitigate the impact of stress factors, such as reactive oxygen species (ROS). This protective effect becomes compromised with ageing in the retina, resulting in a decline in antioxidative responses (indicated by the dashed line).
Differences between cone and rod photoreceptors.
| Rods | Cones | |
|---|---|---|
| Shape | Rod-shape in the outer segment | Cone-shape in the outer segment |
| Distribution | Mainly outside the fovea macular region | Mainly inside the fovea macular region |
| Numbers | 20-fold more than cones | Few |
| Responsibility | Dim light (sensitive to light) | Daylight (less sensitive to light); colour vision |
| Cell types | One | Three (L-, M-, or S-type) |
| Connected cells | Many rods to one bipolar cell | One cone to one bipolar cell |
| Visual acuity | Less | High |
| Speed for light response | Slow | Fast |
| Insufficiency of rhodopsin | Night blindness | Colour blindness |
A summary of MAF family expression in retinal cells from single-cell data [
| RPE | PR | BC | HC | AC | RGC | MGC | |
|---|---|---|---|---|---|---|---|
| MAF | ✔✔ | ✔ | N/A | N/A | ✔✔ | ||
| MAFA | ✔ | ✔ | N/A | N/A | |||
| MAFB | ✔✔ | ✔ | N/A | N/A | ✔✔ | ||
| RNL | ✔✔ | ✔ | N/A | N/A | ✔ | ||
| MAFF | ✔✔ | N/A | N/A | ✔✔ | |||
| MAFK | ✔✔ | ✔ | ✔ | N/A | N/A | ✔✔ | |
| MAFG | ✔ | ✔ | ✔ | N/A | N/A | ✔ |
A summary of Nrf2 signalling regulation in retinal disease model.
| Disease | Model | Nrf2-Related Signalling and Factors | Conclusion | Ref. |
|---|---|---|---|---|
| AMD | C57BL/6 mice | Nrf2/SLC7A11/HO-1 | HO-1 overexpression inhibition can inhibit RPE ferroptosis and prevent photoreceptor and RPE degeneration. | [ |
| DR | ARPE-19 cells | miR-138/Sirt1 */Nrf2 | Increased Sirt1/Nrf2 promotes cellular antioxidative response by reducing high glucose-induced ferroptosis-related processes. | [ |
| RD *; RP *; AMD | Rd mice | Nrf2-dependent antioxidative response | Activated Nrf2 by plasmid injection to mice reverses the degeneration of RPE cells. | [ |
| DR | In vitro (mouse and human retinal microvessels) | LncRNA MALAT1 */Keap1/Nrf2 | LncRNA MALAT1 downregulation prevents angiogenesis by regulating Keap1/Nrf2 pathway. | [ |
| AMD | ARPE-19 cells | NRF2/IDH * or PPP * |
Nrf2 is decreased in AMD patients, and NRF2 deficiency leads to cell death and impaired mitochondrial antioxidant response. | [ |
| Oxygen-induced retinopathy | C57BL/6J mice | Nrf2/HO-1 | Attenuation of retinal neovascularisation is partly affected by the activation of Nrf2/HO-1 signalling. | [ |
| DR | MIO-M1 Müller cell; REDD1 knockout B6; 129 mice | REDD1 *-mediated NRF2/GSK3 or Ser-351/Ser-356 | Inhibition of REDD1 enhances Nrf2-dependent signalling activity to prevent retinal oxidative stress. | [ |
| Dry AMD | C57BL/6 mice | Nrf2/(SOD orGSH-Px or HO-1 or NQO-1) | AP-SD * treatment promotes Nrf2 expression and Nrf2-related downstream gene activities such as SOD, GSH-Px, HO-1, and NQO-1 to reduce the retinal oxidative injury in dry AMD mice. | [ |
| Dry AMD | Kunming mice; ARPE-19 cells | Nrf2/HO-1 | Activation of Nrf2 signalling protects RPE cells from oxidative stress-induced injury by naringenin. | [ |
| DR | C57BL/6 mice; APRE19 cells | Nrf2-dependent antioxidative activity | Chlorogenic acid activates Nrf2 signalling to reduce BRB injury and retinal oxidative injury. | [ |
| DR | Wistar rats | Nrf2/xCT * | Elevating Nrf2 expression through system xc− increases xCT * expression in DR, which gives a potential treatment for DR progression. | [ |
| Non-infectious uveitis | Experimental autoimmune uveoretinitis C57BL/6J mice | Nrf2/HO-1 | Nrf2 provides an anti-inflammatory role, while the deficiency of it leads to neuroinflammation in the ocular autoimmunity. | [ |
| AMD; DR | Sodium iodate (SI)-induced C57BL/6J mice; ARPE-19 cells | miR-144/Nrf2 | Suppression of miR-144 may potentially protect RPE from oxidant-induced damage by activating the Nrf2-dependent redox signalling pathway. | [ |
| AMD | ARPE-19 cells | Nrf2/HO-1; NQO-1 | Nrf2 activator (luteolin) promotes Nrf2 translocation and, hence, upregulates HO-1 and NQO-1 expression to protect cells against oxidative stress. | [ |
| AMD | ARPE-19 cells | Sirt1 */PGC-1α/Nrf2 | Natural compound sulforaphane regulates the expression of Sirt1 and PGC-1α * by activating the Nrf2-dependent antioxidative response against blue light, which induces RPE damage. | [ |
| DR | Mouse retinal Müller cells; C57BL/6 mice | Nrf2-dependent inflammatory signalling | Natural antioxidant geniposide mediates Nrf2-dependent signalling, leading to the inhibition of ROS accumulation, NF-κB activation, Müller cell activation, and anti-inflammatory response. | [ |
| AMD | 661w cell line | HMGB2 */Nrf2 | HMGB2 is a negative regulator of Nrf2, and its knockdown has been linked to upregulation of Nrf2 signalling, which helps prevent photoreceptor death. | [ |
* Silent information regulator 1 (Sirt1), a protein that belongs to the sirtuin family proteins, has a role in regulating gene expression, DNA repairing, metabolism, and ageing; RD: retinal degeneration; RP: retinitis pigmentosa; long non-coding RNA (LncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a role in pre-mRNA splicing; IDH: isocitrate dehydrogenase; PPP: pentose phosphate pathway; regulated in development and DNA damage responses 1 (REDD1), a hypoxia-inducible factor-1 target gene, plays a role in inhibiting the mechanistic target of the rapamycin complex 1 (mTORC1) signalling pathway; solid dispersion of apigenin (AP-SD) is a flavonoid that has antioxidant activity; xCT is a subunit of cystine/glutamate exchanger, mediating the homeostasis of glutamate release and cysteine uptake; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; HMGB2: high-mobility group protein B2.
References
1. Xie, L.; Gu, Y.; Wen, M.; Zhao, S.; Wang, W.; Ma, Y.; Meng, G.; Han, Y.; Wang, Y.; Liu, G. et al. Hydrogen Sulfide Induces Keap1 S-Sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation. Diabetes; 2016; 65, pp. 3171-3184. [DOI: https://dx.doi.org/10.2337/db16-0020] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27335232]
2. Cuadrado, A.; Rojo, A.I.; Wells, G.; Hayes, J.D.; Cousin, S.P.; Rumsey, W.L.; Attucks, O.C.; Franklin, S.; Levonen, A.-L.; Kensler, T.W. et al. Therapeutic Targeting of the NRF2 and KEAP1 Partnership in Chronic Diseases. Nat. Rev. Drug Discov.; 2019; 18, pp. 295-317. [DOI: https://dx.doi.org/10.1038/s41573-018-0008-x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30610225]
3. Liu, S.; Pi, J.; Zhang, Q. Signal Amplification in the KEAP1-NRF2-ARE Antioxidant Response Pathway. Redox Biol.; 2022; 54, 102389. [DOI: https://dx.doi.org/10.1016/j.redox.2022.102389] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35792437]
4. Eggler, A.L.; Small, E.; Hannink, M.; Mesecar, A.D. Cul3-Mediated Nrf2 Ubiquitination and Antioxidant Response Element (ARE) Activation Are Dependent on the Partial Molar Volume at Position 151 of Keap1. Biochem. J.; 2009; 422, pp. 171-180. [DOI: https://dx.doi.org/10.1042/BJ20090471]
5. Katsuoka, F.; Yamamoto, M. Small Maf Proteins (MafF, MafG, MafK): History, Structure and Function. Gene; 2016; 586, pp. 197-205. [DOI: https://dx.doi.org/10.1016/j.gene.2016.03.058]
6. Ma, Q. Role of Nrf2 in Oxidative Stress and Toxicity. Annu. Rev. Pharmacol. Toxicol.; 2013; 53, pp. 401-426. [DOI: https://dx.doi.org/10.1146/annurev-pharmtox-011112-140320]
7. Schmidlin, C.J.; Dodson, M.B.; Madhavan, L.; Zhang, D.D. Redox Regulation by NRF2 in Aging and Disease. Free Radic. Biol. Med.; 2019; 134, pp. 702-707. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2019.01.016]
8. Fão, L.; Mota, S.I.; Rego, A.C. Shaping the Nrf2-ARE-Related Pathways in Alzheimer’s and Parkinson’s Diseases. Ageing Res. Rev.; 2019; 54, 100942. [DOI: https://dx.doi.org/10.1016/j.arr.2019.100942]
9. Wu, D.M.; Ji, X.; Ivanchenko, M.V.; Chung, M.; Piper, M.; Rana, P.; Wang, S.K.; Xue, Y.; West, E.; Zhao, S.R. et al. Nrf2 Overexpression Rescues the RPE in Mouse Models of Retinitis Pigmentosa. JCI Insight; 2021; 6, 4. [DOI: https://dx.doi.org/10.1172/jci.insight.145029]
10. Russel, F.G.M.; Koenderink, J.B.; Masereeuw, R. Multidrug Resistance Protein 4 (MRP4/ABCC4): A Versatile Efflux Transporter for Drugs and Signalling Molecules. Trends Pharmacol. Sci.; 2008; 29, pp. 200-207. [DOI: https://dx.doi.org/10.1016/j.tips.2008.01.006]
11. Nishizawa, M.; Kataoka, K.; Goto, N.; Fujiwara, K.T.; Kawai, S. V-Maf, a Viral Oncogene That Encodes a “Leucine Zipper” Motif. Proc. Natl. Acad. Sci. USA; 1989; 86, pp. 7711-7715. [DOI: https://dx.doi.org/10.1073/pnas.86.20.7711] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2554284]
12. Deng, Y.; Lu, L.; Zhang, H.; Fu, Y.; Liu, T.; Chen, Y. The Role and Regulation of Maf Proteins in Cancer. Biomark. Res.; 2023; 11, 17. [DOI: https://dx.doi.org/10.1186/s40364-023-00457-w]
13. Cataldo, L.R.; Vishnu, N.; Singh, T.; Bertonnier-Brouty, L.; Bsharat, S.; Luan, C.; Renström, E.; Prasad, R.B.; Fex, M.; Mulder, H. et al. The MafA-Target Gene PPP1R1A Regulates GLP1R-Mediated Amplification of Glucose-Stimulated Insulin Secretion in β-Cells. Metabolism; 2021; 118, 154734. [DOI: https://dx.doi.org/10.1016/j.metabol.2021.154734] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33631146]
14. Hang, Y.; Stein, R. MafA and MafB Activity in Pancreatic β Cells. Trends Endocrinol. Metab.; 2011; 22, pp. 364-373. [DOI: https://dx.doi.org/10.1016/j.tem.2011.05.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21719305]
15. Kelly, L.M.; Englmeier, U.; Lafon, I.; Sieweke, M.H.; Graf, T. MafB Is an Inducer of Monocytic Differentiation. EMBO J.; 2000; 19, pp. 1987-1997. [DOI: https://dx.doi.org/10.1093/emboj/19.9.1987]
16. Sadl, V.; Jin, F.; Yu, J.; Cui, S.; Holmyard, D.; Quaggin, S.; Barsh, G.; Cordes, S. The Mouse Kreisler (Krml1/MafB) Segmentation Gene Is Required for Differentiation of Glomerular Visceral Epithelial Cells. Dev. Biol.; 2002; 249, pp. 16-29. [DOI: https://dx.doi.org/10.1006/dbio.2002.0751]
17. Xu, M.; Pokrovskii, M.; Ding, Y.; Yi, R.; Au, C.; Harrison, O.J.; Galan, C.; Belkaid, Y.; Bonneau, R.; Littman, D.R. C-MAF-Dependent Regulatory T Cells Mediate Immunological Tolerance to a Gut Pathobiont. Nature; 2018; 554, pp. 373-377. [DOI: https://dx.doi.org/10.1038/nature25500]
18. Wu, H.; Deng, Y.; Long, D.; Yang, M.; Li, Q.; Feng, Y.; Chen, Y.; Qiu, H.; Huang, X.; He, Z. et al. The IL-21-TET2-AIM2-c-MAF Pathway Drives the T Follicular Helper Cell Response in Lupus-like Disease. Clin. Transl. Med.; 2022; 12, e781. [DOI: https://dx.doi.org/10.1002/ctm2.781]
19. Gómez-Salinero, J.M.; Izzo, F.; Lin, Y.; Houghton, S.; Itkin, T.; Geng, F.; Bram, Y.; Adelson, R.P.; Lu, T.M.; Inghirami, G. et al. Specification of Fetal Liver Endothelial Progenitors to Functional Zonated Adult Sinusoids Requires C-Maf Induction. Cell Stem Cell; 2022; 29, pp. 593-609.e7. [DOI: https://dx.doi.org/10.1016/j.stem.2022.03.002]
20. Fujino, M.; Tagami, A.; Ojima, M.; Mizuno, S.; Abdellatif, A.M.; Kuno, A.; Takahashi, S. C-MAF Deletion in Adult C57BL/6J Mice Induces Cataract Formation and Abnormal Differentiation of Lens Fiber Cells. Exp. Anim.; 2020; 69, pp. 242-249. [DOI: https://dx.doi.org/10.1538/expanim.19-0137]
21. Swaroop, A.; Xu, J.Z.; Pawar, H.; Jackson, A.; Skolnick, C.; Agarwal, N. A Conserved Retina-Specific Gene Encodes a Basic Motif/Leucine Zipper Domain. Proc. Natl. Acad. Sci. USA; 1992; 89, pp. 266-270. [DOI: https://dx.doi.org/10.1073/pnas.89.1.266]
22. Blank, V.; Andrews, N.C. The Maf Transcription Factors: Regulators of Differentiation. Trends Biochem. Sci.; 1997; 22, pp. 437-441. [DOI: https://dx.doi.org/10.1016/S0968-0004(97)01105-5]
23. Moon, E.J.; Mello, S.S.; Li, C.G.; Chi, J.-T.; Thakkar, K.; Kirkland, J.G.; Lagory, E.L.; Lee, I.J.; Diep, A.N.; Miao, Y. et al. The HIF Target MAFF Promotes Tumor Invasion and Metastasis through IL11 and STAT3 Signaling. Nat. Commun.; 2021; 12, 4308. [DOI: https://dx.doi.org/10.1038/s41467-021-24631-6]
24. Von Scheidt, M.; Zhao, Y.; de Aguiar Vallim, T.Q.; Che, N.; Wierer, M.; Seldin, M.M.; Franzén, O.; Kurt, Z.; Pang, S.; Bongiovanni, D. et al. The Transcription Factor MAFF Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism. Circulation; 2021; 143, pp. 1809-1823. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.050186]
25. Ibrahim, M.K.; Abdelhafez, T.H.; Takeuchi, J.S.; Wakae, K.; Sugiyama, M.; Tsuge, M.; Ito, M.; Watashi, K.; El Kassas, M.; Kato, T. et al. MafF Is an Antiviral Host Factor That Suppresses Transcription from Hepatitis B Virus Core Promoter. J. Virol.; 2021; 95, e00767-21. [DOI: https://dx.doi.org/10.1128/JVI.00767-21]
26. Okita, Y.; Kimura, M.; Xie, R.; Chen, C.; Shen, L.T.-W.; Kojima, Y.; Suzuki, H.; Muratani, M.; Saitoh, M.; Semba, K. et al. The Transcription Factor MAFK Induces EMT and Malignant Progression of Triple-Negative Breast Cancer Cells through Its Target GPNMB. Sci. Signal.; 2017; 10, eaak9397. [DOI: https://dx.doi.org/10.1126/scisignal.aak9397]
27. Xu, S.; Hu, G.; Wu, D.; Kan, X.; Oishi, H.; Takahashi, S.; Fu, S.; Liu, J.; Zhang, C. MafK Accelerates Salmonella Mucosal Infection through Caspase-3 Activation. Aging; 2022; 14, pp. 2287-2303. [DOI: https://dx.doi.org/10.18632/aging.203938]
28. Hwang, Y.-J.; Lee, E.-W.; Song, J.; Kim, H.-R.; Jun, Y.-C.; Hwang, K.-A. MafK Positively Regulates NF-ΚB Activity by Enhancing CBP-Mediated P65 Acetylation. Sci. Rep.; 2013; 3, 3242. [DOI: https://dx.doi.org/10.1038/srep03242] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24247732]
29. Liu, T.; Yang, H.; Fan, W.; Tu, J.; Li, T.W.H.; Wang, J.; Shen, H.; Yang, J.; Xiong, T.; Steggerda, J. et al. Mechanisms of MAFG Dysregulation in Cholestatic Liver Injury and Development of Liver Cancer. Gastroenterology; 2018; 155, pp. 557-571.e14. [DOI: https://dx.doi.org/10.1053/j.gastro.2018.04.032]
30. Shan, H.-J.; Zhu, L.-Q.; Yao, C.; Zhang, Z.-Q.; Liu, Y.-Y.; Jiang, Q.; Zhou, X.-Z.; Wang, X.-D.; Cao, C. MAFG-Driven Osteosarcoma Cell Progression Is Inhibited by a Novel MiRNA MiR-4660. Mol. Ther. Nucleic Acids; 2021; 24, pp. 385-402. [DOI: https://dx.doi.org/10.1016/j.omtn.2021.03.006]
31. Otsuki, A.; Yamamoto, M. Cis-Element Architecture of Nrf2–SMaf Heterodimer Binding Sites and Its Relation to Diseases. Arch. Pharm. Res.; 2020; 43, pp. 275-285. [DOI: https://dx.doi.org/10.1007/s12272-019-01193-2]
32. Zimta, A.-A.; Cenariu, D.; Irimie, A.; Magdo, L.; Nabavi, S.M.; Atanasov, A.G.; Berindan-Neagoe, I. The Role of Nrf2 Activity in Cancer Development and Progression. Cancers; 2019; 11, 1755. [DOI: https://dx.doi.org/10.3390/cancers11111755]
33. Karihtala, P.; Porvari, K.; Soini, Y.; Haapasaari, K.-M. Redox Regulating Enzymes and Connected MicroRNA Regulators Have Prognostic Value in Classical Hodgkin Lymphomas. Oxidative Med. Cell. Longev.; 2017; 2017, 2696071. [DOI: https://dx.doi.org/10.1155/2017/2696071] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28377796]
34. Luo, M.; Shang, L.; Brooks, M.D.; Jiagge, E.; Zhu, Y.; Buschhaus, J.M.; Conley, S.; Fath, M.A.; Davis, A.; Gheordunescu, E. et al. Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. Cell Metab.; 2018; 28, pp. 69-86.e6. [DOI: https://dx.doi.org/10.1016/j.cmet.2018.06.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29972798]
35. Romero, R.; Sayin, V.I.; Davidson, S.M.; Bauer, M.R.; Singh, S.X.; LeBoeuf, S.E.; Karakousi, T.R.; Ellis, D.C.; Bhutkar, A.; Sánchez-Rivera, F.J. et al. Keap1 Loss Promotes Kras-Driven Lung Cancer and Results in Dependence on Glutaminolysis. Nat. Med.; 2017; 23, pp. 1362-1368. [DOI: https://dx.doi.org/10.1038/nm.4407]
36. Kanamori, M.; Higa, T.; Sonoda, Y.; Murakami, S.; Dodo, M.; Kitamura, H.; Taguchi, K.; Shibata, T.; Watanabe, M.; Suzuki, H. et al. Activation of the NRF2 Pathway and Its Impact on the Prognosis of Anaplastic Glioma Patients. Neuro-Oncology; 2015; 17, pp. 555-565. [DOI: https://dx.doi.org/10.1093/neuonc/nou282]
37. Wei, R.; Zhao, Y.; Wang, J.; Yang, X.; Li, S.; Wang, Y.; Yang, X.; Fei, J.; Hao, X.; Zhao, Y. et al. Tagitinin C Induces Ferroptosis through PERK-Nrf2-HO-1 Signaling Pathway in Colorectal Cancer Cells. Int. J. Biol. Sci.; 2021; 17, pp. 2703-2717. [DOI: https://dx.doi.org/10.7150/ijbs.59404]
38. Verma, S.; Crawford, D.; Khateb, A.; Feng, Y.; Sergienko, E.; Pathria, G.; Ma, C.-T.; Olson, S.H.; Scott, D.; Murad, R. et al. NRF2 Mediates Melanoma Addiction to GCDH by Modulating Apoptotic Signalling. Nat. Cell Biol.; 2022; 24, pp. 1422-1432. [DOI: https://dx.doi.org/10.1038/s41556-022-00985-x]
39. Marzioni, D.; Mazzucchelli, R.; Fantone, S.; Tossetta, G. NRF2 Modulation in TRAMP Mice: An in Vivo Model of Prostate Cancer. Mol. Biol. Rep.; 2023; 50, pp. 873-881. [DOI: https://dx.doi.org/10.1007/s11033-022-08052-2]
40. Saw, C.L.L.; Kong, A.-N.T. Nuclear Factor-Erythroid 2-Related Factor 2 as a Chemopreventive Target in Colorectal Cancer. Expert Opin. Ther. Targets; 2011; 15, pp. 281-295. [DOI: https://dx.doi.org/10.1517/14728222.2011.553602]
41. Wang, P.; Long, F.; Lin, H.; Wang, T. Dietary Phytochemicals Targeting Nrf2 for Chemoprevention in Breast Cancer. Food Funct.; 2022; 13, pp. 4273-4285. [DOI: https://dx.doi.org/10.1039/D2FO00186A] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35373233]
42. Tossetta, G.; Marzioni, D. Targeting the NRF2/KEAP1 Pathway in Cervical and Endometrial Cancers. Eur. J. Pharmacol.; 2023; 941, 175503. [DOI: https://dx.doi.org/10.1016/j.ejphar.2023.175503] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36641100]
43. Rotblat, B.; Southwell, A.L.; Ehrnhoefer, D.E.; Skotte, N.H.; Metzler, M.; Franciosi, S.; Leprivier, G.; Somasekharan, S.P.; Barokas, A.; Deng, Y. et al. HACE1 Reduces Oxidative Stress and Mutant Huntingtin Toxicity by Promoting the NRF2 Response. Proc. Natl. Acad. Sci. USA; 2014; 111, pp. 3032-3037. [DOI: https://dx.doi.org/10.1073/pnas.1314421111] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24516159]
44. Shekh-Ahmad, T.; Eckel, R.; Dayalan Naidu, S.; Higgins, M.; Yamamoto, M.; Dinkova-Kostova, A.T.; Kovac, S.; Abramov, A.Y.; Walker, M.C. KEAP1 Inhibition Is Neuroprotective and Suppresses the Development of Epilepsy. Brain; 2018; 141, pp. 1390-1403. [DOI: https://dx.doi.org/10.1093/brain/awy071] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29538645]
45. Mota, S.I.; Costa, R.O.; Ferreira, I.L.; Santana, I.; Caldeira, G.L.; Padovano, C.; Fonseca, A.C.; Baldeiras, I.; Cunha, C.; Letra, L. et al. Oxidative Stress Involving Changes in Nrf2 and ER Stress in Early Stages of Alzheimer’s Disease. Biochim. Biophys. Acta Mol. Basis Dis.; 2015; 1852, pp. 1428-1441. [DOI: https://dx.doi.org/10.1016/j.bbadis.2015.03.015]
46. Petrillo, S.; Schirinzi, T.; Di Lazzaro, G.; D’Amico, J.; Colona, V.L.; Bertini, E.; Pierantozzi, M.; Mari, L.; Mercuri, N.B.; Piemonte, F. et al. Systemic Activation of Nrf2 Pathway in Parkinson’s Disease. Mov. Disord.; 2020; 35, pp. 180-184. [DOI: https://dx.doi.org/10.1002/mds.27878] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31682033]
47. Kubben, N.; Zhang, W.; Wang, L.; Voss, T.C.; Yang, J.; Qu, J.; Liu, G.-H.; Misteli, T. Repression of the Antioxidant NRF2 Pathway in Premature Aging. Cell; 2016; 165, pp. 1361-1374. [DOI: https://dx.doi.org/10.1016/j.cell.2016.05.017]
48. Fang, Y.; Chen, B.; Gong, A.Y.; Malhotra, D.K.; Gupta, R.; Dworkin, L.D.; Gong, R. The Ketone Body β-Hydroxybutyrate Mitigates the Senescence Response of Glomerular Podocytes to Diabetic Insults. Kidney Int.; 2021; 100, pp. 1037-1053. [DOI: https://dx.doi.org/10.1016/j.kint.2021.06.031]
49. Hecker, L.; Logsdon, N.J.; Kurundkar, D.; Kurundkar, A.; Bernard, K.; Hock, T.; Meldrum, E.; Sanders, Y.Y.; Thannickal, V.J. Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance. Sci. Transl. Med.; 2014; 6, 231ra47. [DOI: https://dx.doi.org/10.1126/scitranslmed.3008182]
50. Wang, P.; Geng, J.; Gao, J.; Zhao, H.; Li, J.; Shi, Y.; Yang, B.; Xiao, C.; Linghu, Y.; Sun, X. et al. Macrophage Achieves Self-Protection against Oxidative Stress-Induced Ageing through the Mst-Nrf2 Axis. Nat. Commun.; 2019; 10, 755. [DOI: https://dx.doi.org/10.1038/s41467-019-08680-6]
51. Belgio, B.; Salvetti, A.P.; Mantero, S.; Boschetti, F. The Evolution of Fabrication Methods in Human Retina Regeneration. Appl. Sci.; 2021; 11, 4102. [DOI: https://dx.doi.org/10.3390/app11094102]
52. Hoon, M.; Okawa, H.; Della Santina, L.; Wong, R.O.L. Functional Architecture of the Retina: Development and Disease. Prog. Retin. Eye Res.; 2014; 42, pp. 44-84. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2014.06.003]
53. Mustafi, D.; Engel, A.H.; Palczewski, K. Structure of Cone Photoreceptors. Prog. Retin. Eye Res.; 2009; 28, pp. 289-302. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2009.05.003]
54. Khatib, T.Z.; Martin, K.R. Protecting Retinal Ganglion Cells. Eye; 2017; 31, pp. 218-224. [DOI: https://dx.doi.org/10.1038/eye.2016.299]
55. Navneet, S.; Zhao, J.; Wang, J.; Mysona, B.; Barwick, S.; Ammal Kaidery, N.; Saul, A.; Kaddour-Djebbar, I.; Bollag, W.B.; Thomas, B. et al. Hyperhomocysteinemia-Induced Death of Retinal Ganglion Cells: The Role of Müller Glial Cells and NRF2. Redox Biol.; 2019; 24, 101199. [DOI: https://dx.doi.org/10.1016/j.redox.2019.101199]
56. Datta, S.; Cano, M.; Ebrahimi, K.; Wang, L.; Handa, J.T. The Impact of Oxidative Stress and Inflammation on RPE Degeneration in Non-Neovascular AMD. Prog. Retin. Eye Res.; 2017; 60, pp. 201-218. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2017.03.002]
57. Yang, S.; Zhou, J.; Li, D. Functions and Diseases of the Retinal Pigment Epithelium. Front. Pharmacol.; 2021; 12, 727870. [DOI: https://dx.doi.org/10.3389/fphar.2021.727870]
58. Strauss, O. The Retinal Pigment Epithelium in Visual Function. Physiol. Rev.; 2005; 85, pp. 845-881. [DOI: https://dx.doi.org/10.1152/physrev.00021.2004]
59. Streilein, J.W. Ocular Immune Privilege: Therapeutic Opportunities from an Experiment of Nature. Nat. Rev. Immunol.; 2003; 3, pp. 879-889. [DOI: https://dx.doi.org/10.1038/nri1224]
60. Hanus, J.; Anderson, C.; Wang, S. RPE Necroptosis in Response to Oxidative Stress and in AMD. Ageing Res. Rev.; 2015; 24, pp. 286-298. [DOI: https://dx.doi.org/10.1016/j.arr.2015.09.002]
61. Upadhyay, M.; Milliner, C.; Bell, B.A.; Bonilha, V.L. Oxidative Stress in the Retina and Retinal Pigment Epithelium (RPE): Role of Aging, and DJ-1. Redox Biol.; 2020; 37, 101623. [DOI: https://dx.doi.org/10.1016/j.redox.2020.101623] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32826201]
62. Jadeja, R.N.; Jones, M.A.; Abdelrahman, A.A.; Powell, F.L.; Thounaojam, M.C.; Gutsaeva, D.; Bartoli, M.; Martin, P.M. Inhibiting MicroRNA-144 Potentiates Nrf2-Dependent Antioxidant Signaling in RPE and Protects against Oxidative Stress-Induced Outer Retinal Degeneration. Redox Biol.; 2020; 28, 101336. [DOI: https://dx.doi.org/10.1016/j.redox.2019.101336] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31590045]
63. Devoldere, J.; Peynshaert, K.; De Smedt, S.C.; Remaut, K. Müller Cells as a Target for Retinal Therapy. Drug Discov. Today; 2019; 24, pp. 1483-1498. [DOI: https://dx.doi.org/10.1016/j.drudis.2019.01.023] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30731239]
64. Reichenbach, A.; Bringmann, A. New Functions of Müller Cells. Glia; 2013; 61, pp. 651-678. [DOI: https://dx.doi.org/10.1002/glia.22477]
65. Zhang, T.; Zhu, L.; Madigan, M.C.; Liu, W.; Shen, W.; Cherepanoff, S.; Zhou, F.; Zeng, S.; Du, J.; Gillies, M.C. Human Macular Müller Cells Rely More on Serine Biosynthesis to Combat Oxidative Stress than Those from the Periphery. eLife; 2019; 8, e43598. [DOI: https://dx.doi.org/10.7554/eLife.43598]
66. Eastlake, K.; Lamb, W.D.B.; Luis, J.; Khaw, P.T.; Jayaram, H.; Limb, G.A. Prospects for the Application of Müller Glia and Their Derivatives in Retinal Regenerative Therapies. Prog. Retin. Eye Res.; 2021; 85, 100970. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2021.100970]
67. Chen, Y.; Zhang, T.; Zeng, S.; Xu, R.; Jin, K.; Coorey, N.J.; Wang, Y.; Wang, K.; Lee, S.-R.; Yam, M. et al. Transketolase in Human Müller Cells Is Critical to Resist Light Stress through the Pentose Phosphate and NRF2 Pathways. Redox Biol.; 2022; 54, 102379. [DOI: https://dx.doi.org/10.1016/j.redox.2022.102379]
68. Inoue, Y.; Shimazawa, M.; Noda, Y.; Nagano, R.; Otsuka, T.; Kuse, Y.; Nakano, Y.; Tsuruma, K.; Nakagami, Y.; Hara, H. RS9, a Novel Nrf2 Activator, Attenuates Light-Induced Death of Cells of Photoreceptor Cells and Müller Glia Cells. J. Neurochem.; 2017; 141, pp. 750-765. [DOI: https://dx.doi.org/10.1111/jnc.14029]
69. Chen, G.; Kroemer, G.; Kepp, O. Mitophagy: An Emerging Role in Aging and Age-Associated Diseases. Front. Cell Dev. Biol.; 2020; 8, 200. [DOI: https://dx.doi.org/10.3389/fcell.2020.00200]
70. Zhou, B.; Fang, L.; Dong, Y.; Yang, J.; Chen, X.; Zhang, N.; Zhu, Y.; Huang, T. Mitochondrial Quality Control Protects Photoreceptors against Oxidative Stress in the H2O2-Induced Models of Retinal Degeneration Diseases. Cell Death Dis.; 2021; 12, 413. [DOI: https://dx.doi.org/10.1038/s41419-021-03660-5]
71. Dinkova-Kostova, A.T.; Abramov, A.Y. The Emerging Role of Nrf2 in Mitochondrial Function. Free Radic. Biol. Med.; 2015; 88, pp. 179-188. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2015.04.036]
72. Komatsu, M.; Kurokawa, H.; Waguri, S.; Taguchi, K.; Kobayashi, A.; Ichimura, Y.; Sou, Y.-S.; Ueno, I.; Sakamoto, A.; Tong, K.I. et al. The Selective Autophagy Substrate P62 Activates the Stress Responsive Transcription Factor Nrf2 through Inactivation of Keap1. Nat. Cell Biol.; 2010; 12, pp. 213-223. [DOI: https://dx.doi.org/10.1038/ncb2021]
73. Schneider, F.M.; Mohr, F.; Behrendt, M.; Oberwinkler, J. Properties and Functions of TRPM1 Channels in the Dendritic Tips of Retinal ON-Bipolar Cells. Eur. J. Cell Biol.; 2015; 94, pp. 420-427. [DOI: https://dx.doi.org/10.1016/j.ejcb.2015.06.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26111660]
74. Euler, T.; Haverkamp, S.; Schubert, T.; Baden, T. Retinal Bipolar Cells: Elementary Building Blocks of Vision. Nat. Rev. Neurosci.; 2014; 15, pp. 507-519. [DOI: https://dx.doi.org/10.1038/nrn3783]
75. Strettoi, E.; Novelli, E.; Mazzoni, F.; Barone, I.; Damiani, D. Complexity of Retinal Cone Bipolar Cells. Prog. Retin. Eye Res.; 2010; 29, pp. 272-283. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2010.03.005]
76. Tsukamoto, Y.; Morigiwa, K.; Ishii, M.; Takao, M.; Iwatsuki, K.; Nakanishi, S.; Fukuda, Y. A Novel Connection between Rods and ON Cone Bipolar Cells Revealed by Ectopic Metabotropic Glutamate Receptor 7 (MGluR7) in MGluR6-Deficient Mouse Retinas. J. Neurosci.; 2007; 27, pp. 6261-6267. [DOI: https://dx.doi.org/10.1523/JNEUROSCI.5646-06.2007]
77. Gilhooley, M.J.; Hickey, D.G.; Lindner, M.; Palumaa, T.; Hughes, S.; Peirson, S.N.; MacLaren, R.E.; Hankins, M.W. ON-Bipolar Cell Gene Expression during Retinal Degeneration: Implications for Optogenetic Visual Restoration. Exp. Eye Res.; 2021; 207, 108553. [DOI: https://dx.doi.org/10.1016/j.exer.2021.108553]
78. Swinkels, D.; Das, Y.; Kocherlakota, S.; Vinckier, S.; Wever, E.; van Kampen, A.H.C.; Vaz, F.M.; Baes, M. Cell Type-Selective Loss of Peroxisomal β-Oxidation Impairs Bipolar Cell but Not Photoreceptor Survival in the Retina. Cells; 2022; 11, 161. [DOI: https://dx.doi.org/10.3390/cells11010161]
79. Pycock, C.J. Retinal Neurotransmission. Surv. Ophthalmol.; 1985; 29, pp. 355-365. [DOI: https://dx.doi.org/10.1016/0039-6257(85)90111-0]
80. Grove, J.C.R.; Hirano, A.A.; de los Santos, J.; McHugh, C.F.; Purohit, S.; Field, G.D.; Brecha, N.C.; Barnes, S. Novel Hybrid Action of GABA Mediates Inhibitory Feedback in the Mammalian Retina. PLoS Biol.; 2019; 17, e3000200. [DOI: https://dx.doi.org/10.1371/journal.pbio.3000200]
81. Veruki, M.L.; Zhou, Y.; Castilho, Á.; Morgans, C.W.; Hartveit, E. Extrasynaptic NMDA Receptors on Rod Pathway Amacrine Cells: Molecular Composition, Activation, and Signaling. J. Neurosci.; 2019; 39, pp. 627-650. [DOI: https://dx.doi.org/10.1523/JNEUROSCI.2267-18.2018] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30459218]
82. Boije, H.; Shirazi Fard, S.; Edqvist, P.-H.; Hallböök, F. Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease. Front. Neuroanat.; 2016; 10, 77. [DOI: https://dx.doi.org/10.3389/fnana.2016.00077]
83. Reinhard, K.; Münch, T.A. Visual Properties of Human Retinal Ganglion Cells. PLoS ONE; 2021; 16, e0246952. [DOI: https://dx.doi.org/10.1371/journal.pone.0246952] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33592045]
84. Detwiler, P.B. Phototransduction in Retinal Ganglion Cells. Yale J. Biol. Med.; 2018; 91, pp. 49-52.
85. Li, Y.; Wang, Q.; Chu, C.; Liu, S. Astaxanthin Protects Retinal Ganglion Cells from Acute Glaucoma via the Nrf2/HO-1 Pathway. J. Chem. Neuroanat.; 2020; 110, 101876. [DOI: https://dx.doi.org/10.1016/j.jchemneu.2020.101876]
86. Liu, X.-F.; Zhou, D.-D.; Xie, T.; Hao, J.-L.; Malik, T.H.; Lu, C.-B.; Qi, J.; Pant, O.P.; Lu, C.-W. The Nrf2 Signaling in Retinal Ganglion Cells under Oxidative Stress in Ocular Neurodegenerative Diseases. Int. J. Biol. Sci.; 2018; 14, pp. 1090-1098. [DOI: https://dx.doi.org/10.7150/ijbs.25996]
87. Cao, Y.; Wang, L.; Zhao, J.; Zhang, H.; Tian, Y.; Liang, H.; Ma, Q. Serum Response Factor Protects Retinal Ganglion Cells Against High-Glucose Damage. J. Mol. Neurosci.; 2016; 59, pp. 232-240. [DOI: https://dx.doi.org/10.1007/s12031-015-0708-1]
88. Cao, Y.; Li, X.; Wang, C.-J.; Li, P.; Yang, B.; Wang, C.-B.; Wang, L.-X. Role of NF-E2-Related Factor 2 in Neuroprotective Effect of l-Carnitine against High Glucose-Induced Oxidative Stress in the Retinal Ganglion Cells. Biomed. Pharmacother.; 2015; 69, pp. 345-348. [DOI: https://dx.doi.org/10.1016/j.biopha.2014.12.030]
89. Almasieh, M.; Wilson, A.M.; Morquette, B.; Cueva Vargas, J.L.; Di Polo, A. The Molecular Basis of Retinal Ganglion Cell Death in Glaucoma. Prog. Retin. Eye Res.; 2012; 31, pp. 152-181. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2011.11.002]
90. Whitmore, S.S.; Wagner, A.H.; DeLuca, A.P.; Drack, A.V.; Stone, E.M.; Tucker, B.A.; Zeng, S.; Braun, T.A.; Mullins, R.F.; Scheetz, T.E. Transcriptomic Analysis across Nasal, Temporal, and Macular Regions of Human Neural Retina and RPE/Choroid by RNA-Seq. Exp. Eye Res.; 2014; 129, pp. 93-106. [DOI: https://dx.doi.org/10.1016/j.exer.2014.11.001]
91. Uhlén, M.; Fagerberg, L.; Hallström, B.M.; Lindskog, C.; Oksvold, P.; Mardinoglu, A.; Sivertsson, Å.; Kampf, C.; Sjöstedt, E.; Asplund, A. et al. Tissue-Based Map of the Human Proteome. Science; 2015; 347, 1260419. [DOI: https://dx.doi.org/10.1126/science.1260419]
92. Eells, J.T. Mitochondrial Dysfunction in the Aging Retina. Biology; 2019; 8, 31. [DOI: https://dx.doi.org/10.3390/biology8020031]
93. Harman, D. The Aging Process. Proc. Natl. Acad. Sci. USA; 1981; 78, pp. 7124-7128. [DOI: https://dx.doi.org/10.1073/pnas.78.11.7124]
94. He, Y.; Tombran-Tink, J. Mitochondrial Decay and Impairment of Antioxidant Defenses in Aging RPE Cells. Retinal Degenerative Diseases: Laboratory and Therapeutic Investigations; Advances in Experimental Medicine and Biology Anderson, R.E.; Hollyfield, J.G.; LaVail, M.M. Springer: New York, NY, USA, 2010; pp. 165-183. ISBN 978-1-4419-1399-9
95. Bravo-Nuevo, A.; Williams, N.; Geller, S.; Stone, J. Mitochondrial Deletions in Normal and Degenerating Rat Retina. Adv. Exp. Med. Biol.; 2003; 533, pp. 241-248. [DOI: https://dx.doi.org/10.1007/978-1-4615-0067-4_30] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15180270]
96. Chen, G.-H.; Song, C.-C.; Pantopoulos, K.; Wei, X.-L.; Zheng, H.; Luo, Z. Mitochondrial Oxidative Stress Mediated Fe-Induced Ferroptosis via the NRF2-ARE Pathway. Free Radic. Biol. Med.; 2022; 180, pp. 95-107. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2022.01.012]
97. Lee, J.-M.; Shih, A.Y.; Murphy, T.H.; Johnson, J.A. NF-E2-Related Factor-2 Mediates Neuroprotection against Mitochondrial Complex I Inhibitors and Increased Concentrations of Intracellular Calcium in Primary Cortical Neurons*. J. Biol. Chem.; 2003; 278, pp. 37948-37956. [DOI: https://dx.doi.org/10.1074/jbc.M305204200]
98. PNAS. Protection from Mitochondrial Complex II Inhibition in Vitro and in Vivo by Nrf2-Mediated Transcription. Available online: https://www.pnas.org/doi/full/10.1073/pnas.0408487101 (accessed on 10 March 2023).
99. Tang, X.; Li, X.; Zhang, D.; Han, W. Astragaloside-IV Alleviates High Glucose-Induced Ferroptosis in Retinal Pigment Epithelial Cells by Disrupting the Expression of MiR-138-5p/Sirt1/Nrf2. Bioengineered; 2022; 13, pp. 8240-8254. [DOI: https://dx.doi.org/10.1080/21655979.2022.2049471]
100. Ryoo, I.; Kwak, M.-K. Regulatory Crosstalk between the Oxidative Stress-Related Transcription Factor Nfe2l2/Nrf2 and Mitochondria. Toxicol. Appl. Pharmacol.; 2018; 359, pp. 24-33. [DOI: https://dx.doi.org/10.1016/j.taap.2018.09.014]
101. Kim, M.H.; Kwon, S.Y.; Woo, S.-Y.; Seo, W.D.; Kim, D.Y. Antioxidative Effects of Chrysoeriol via Activation of the Nrf2 Signaling Pathway and Modulation of Mitochondrial Function. Molecules; 2021; 26, 313. [DOI: https://dx.doi.org/10.3390/molecules26020313]
102. Hetz, C. The Unfolded Protein Response: Controlling Cell Fate Decisions under ER Stress and Beyond. Nat. Rev. Mol. Cell Biol.; 2012; 13, pp. 89-102. [DOI: https://dx.doi.org/10.1038/nrm3270]
103. Scheper, W.; Hoozemans, J.J.M. The Unfolded Protein Response in Neurodegenerative Diseases: A Neuropathological Perspective. Acta Neuropathol.; 2015; 130, pp. 315-331. [DOI: https://dx.doi.org/10.1007/s00401-015-1462-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26210990]
104. Walter, P.; Ron, D. The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation. Science; 2011; 334, pp. 1081-1086. [DOI: https://dx.doi.org/10.1126/science.1209038]
105. Song, J.-Y.; Fan, B.; Che, L.; Pan, Y.-R.; Zhang, S.-M.; Wang, Y.; Bunik, V.; Li, G.-Y. Suppressing Endoplasmic Reticulum Stress-Related Autophagy Attenuates Retinal Light Injury. Aging; 2020; 12, pp. 16579-16596. [DOI: https://dx.doi.org/10.18632/aging.103846] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32858529]
106. Ménard, C.; Wilson, A.M.; Dejda, A.; Miloudi, K.; Binet, F.; Crespo-Garcia, S.; Parinot, C.; Pilon, F.; Juneau, R.; MMA Andriessen, E. et al. MiR-106b Suppresses Pathological Retinal Angiogenesis. Aging; 2020; 12, pp. 24836-24852. [DOI: https://dx.doi.org/10.18632/aging.202404] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33361521]
107. Ghosh, R.; Wang, L.; Wang, E.S.; Perera, B.G.K.; Igbaria, A.; Morita, S.; Prado, K.; Thamsen, M.; Caswell, D.; Macias, H. et al. Allosteric Inhibition of the IRE1α RNase Preserves Cell Viability and Function during Endoplasmic Reticulum Stress. Cell; 2014; 158, pp. 534-548. [DOI: https://dx.doi.org/10.1016/j.cell.2014.07.002]
108. Lee, E.-J.; Diaz-Aguilar, M.S.; Min, H.; Choi, J.; Valdez Duran, D.A.; Grandjean, J.M.; Wiseman, R.L.; Kroeger, H.; Lin, J.H. Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Patients with Vision Loss. Am. J. Pathol.; 2022; [DOI: https://dx.doi.org/10.1016/j.ajpath.2022.12.002]
109. Huang, C.; Wang, J.J.; Ma, J.H.; Jin, C.; Yu, Q.; Zhang, S.X. Activation of the UPR Protects against Cigarette Smoke-Induced RPE Apoptosis through up-Regulation of Nrf2. J. Biol. Chem.; 2015; 290, pp. 5367-5380. [DOI: https://dx.doi.org/10.1074/jbc.M114.603738]
110. Xu, W.; Tao, M.; Hu, Z.; Chang, T.; Wang, Y. Minocycline Induces Apoptosis of Photoreceptor Cells by Regulating ER Stress. Exp. Eye Res.; 2020; 190, 107887. [DOI: https://dx.doi.org/10.1016/j.exer.2019.107887]
111. Kim, S.H.; Park, J.-W. Morin Hydrate Attenuates CSE-Induced Lipid Accumulation, ER Stress, and Oxidative Stress in RPE Cells: Implications for Age-Related Macular Degeneration. Free Radic. Res.; 2019; 53, pp. 865-874. [DOI: https://dx.doi.org/10.1080/10715762.2019.1637862]
112. Fleckenstein, M.; Keenan, T.D.L.; Guymer, R.H.; Chakravarthy, U.; Schmitz-Valckenberg, S.; Klaver, C.C.; Wong, W.T.; Chew, E.Y. Age-Related Macular Degeneration. Nat. Rev. Dis. Prim.; 2021; 7, 31. [DOI: https://dx.doi.org/10.1038/s41572-021-00265-2]
113. Khan, K.N.; Mahroo, O.A.; Khan, R.S.; Mohamed, M.D.; McKibbin, M.; Bird, A.; Michaelides, M.; Tufail, A.; Moore, A.T. Differentiating Drusen: Drusen and Drusen-like Appearances Associated with Ageing, Age-Related Macular Degeneration, Inherited Eye Disease and Other Pathological Processes. Prog. Retin. Eye Res.; 2016; 53, pp. 70-106. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2016.04.008]
114. Sachdeva, M.M.; Cano, M.; Handa, J.T. Nrf2 Signaling Is Impaired in the Aging RPE given an Oxidative Insult. Exp. Eye Res.; 2014; 119, pp. 111-114. [DOI: https://dx.doi.org/10.1016/j.exer.2013.10.024]
115. Kowluru, R.A.; Mishra, M. Epigenetic Regulation of Redox Signaling in Diabetic Retinopathy: Role of Nrf2. Free Radic. Biol. Med.; 2017; 103, pp. 155-164. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2016.12.030]
116. Tang, Z.; Ju, Y.; Dai, X.; Ni, N.; Liu, Y.; Zhang, D.; Gao, H.; Sun, H.; Zhang, J.; Gu, P. HO-1-Mediated Ferroptosis as a Target for Protection against Retinal Pigment Epithelium Degeneration. Redox Biol.; 2021; 43, 101971. [DOI: https://dx.doi.org/10.1016/j.redox.2021.101971]
117. Radhakrishnan, R.; Kowluru, R.A. Long Noncoding RNA MALAT1 and Regulation of the Antioxidant Defense System in Diabetic Retinopathy. Diabetes; 2021; 70, pp. 227-239. [DOI: https://dx.doi.org/10.2337/db20-0375]
118. Cano, M.; Datta, S.; Wang, L.; Liu, T.; Flores-Bellver, M.; Sachdeva, M.; Sinha, D.; Handa, J.T. Nrf2 Deficiency Decreases NADPH from Impaired IDH Shuttle and Pentose Phosphate Pathway in Retinal Pigmented Epithelial Cells to Magnify Oxidative Stress-Induced Mitochondrial Dysfunction. Aging Cell; 2021; 20, e13444. [DOI: https://dx.doi.org/10.1111/acel.13444]
119. Huang, Z.; Ng, T.K.; Chen, W.; Sun, X.; Huang, D.; Zheng, D.; Yi, J.; Xu, Y.; Zhuang, X.; Chen, S. Nattokinase Attenuates Retinal Neovascularization Via Modulation of Nrf2/HO-1 and Glial Activation. Investig. Ophthalmol. Vis. Sci.; 2021; 62, 25. [DOI: https://dx.doi.org/10.1167/iovs.62.6.25]
120. Miller, W.P.; Sunilkumar, S.; Giordano, J.F.; Toro, A.L.; Barber, A.J.; Dennis, M.D. The Stress Response Protein REDD1 Promotes Diabetes-Induced Oxidative Stress in the Retina by Keap1-Independent Nrf2 Degradation. J. Biol. Chem.; 2020; 295, pp. 7350-7361. [DOI: https://dx.doi.org/10.1074/jbc.RA120.013093]
121. Zhang, Y.; Yang, Y.; Yu, H.; Li, M.; Hang, L.; Xu, X. Apigenin Protects Mouse Retina against Oxidative Damage by Regulating the Nrf2 Pathway and Autophagy. Oxid. Med. Cell Longev.; 2020; 2020, 9420704. [DOI: https://dx.doi.org/10.1155/2020/9420704]
122. Chen, W.; Ye, Y.; Wu, Z.; Lin, J.; Wang, Y.; Ding, Q.; Yang, X.; Yang, W.; Lin, B.; Lin, B. Temporary Upregulation of Nrf2 by Naringenin Alleviates Oxidative Damage in the Retina and ARPE-19 Cells. Oxid. Med. Cell Longev.; 2021; 2021, 4053276. [DOI: https://dx.doi.org/10.1155/2021/4053276]
123. Ouyang, H.; Du, A.; Zhou, L.; Zhang, T.; Lu, B.; Wang, Z.; Ji, L. Chlorogenic Acid Improves Diabetic Retinopathy by Alleviating Blood-Retinal-Barrier Dysfunction via Inducing Nrf2 Activation. Phytother. Res.; 2022; 36, pp. 1386-1401. [DOI: https://dx.doi.org/10.1002/ptr.7401] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35133045]
124. Carpi-Santos, R.; Calaza, K.C. Alterations in System Xc− Expression in the Retina of Type 1 Diabetic Rats and the Role of Nrf2. Mol. Neurobiol.; 2018; 55, pp. 7941-7948. [DOI: https://dx.doi.org/10.1007/s12035-018-0961-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29488137]
125. Sato, Y.; Saito, S.; Nakayama, M.; Sugita, S.; Kudo, A.; Keino, H. Genetic Ablation of Nrf2 Exacerbates Neuroinflammation in Ocular Autoimmunity. Int. J. Mol. Sci.; 2022; 23, 11715. [DOI: https://dx.doi.org/10.3390/ijms231911715] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36233013]
126. Chen, L.; Zhu, Y.; Zhou, J.; Wu, R.; Yang, N.; Bao, Q.; Xu, X. Luteolin Alleviates Epithelial-Mesenchymal Transformation Induced by Oxidative Injury in ARPE-19 Cell via Nrf2 and AKT/GSK-3β Pathway. Oxid. Med. Cell Longev.; 2022; 2022, 2265725. [DOI: https://dx.doi.org/10.1155/2022/2265725] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35198094]
127. Yang, P.-M.; Cheng, K.-C.; Huang, J.-Y.; Wang, S.-Y.; Lin, Y.-N.; Tseng, Y.-T.; Hsieh, C.-W.; Wung, B.-S. Sulforaphane Inhibits Blue Light-Induced Inflammation and Apoptosis by Upregulating the SIRT1/PGC-1α/Nrf2 Pathway and Autophagy in Retinal Pigment Epithelial Cells. Toxicol. Appl. Pharmacol.; 2021; 421, 115545. [DOI: https://dx.doi.org/10.1016/j.taap.2021.115545]
128. Tu, Y.; Li, L.; Zhu, L.; Guo, Y.; Du, S.; Zhang, Y.; Wang, Z.; Zhang, Y.; Zhu, M. Geniposide Attenuates Hyperglycemia-Induced Oxidative Stress and Inflammation by Activating the Nrf2 Signaling Pathway in Experimental Diabetic Retinopathy. Oxid. Med. Cell Longev.; 2021; 2021, 9247947. [DOI: https://dx.doi.org/10.1155/2021/9247947]
129. Zhang, Y.; Zhao, Z.; Zhao, X.; Xie, H.; Zhang, C.; Sun, X.; Zhang, J. HMGB2 Causes Photoreceptor Death via Down-Regulating Nrf2/HO-1 and up-Regulating NF-ΚB/NLRP3 Signaling Pathways in Light-Induced Retinal Degeneration Model. Free Radic. Biol. Med.; 2022; 181, pp. 14-28. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2022.01.018]
130. Ren, D.; Villeneuve, N.F.; Jiang, T.; Wu, T.; Lau, A.; Toppin, H.A.; Zhang, D.D. Brusatol Enhances the Efficacy of Chemotherapy by Inhibiting the Nrf2-Mediated Defense Mechanism. Proc. Natl. Acad. Sci. USA; 2011; 108, pp. 1433-1438. [DOI: https://dx.doi.org/10.1073/pnas.1014275108]
131. Arlt, A.; Sebens, S.; Krebs, S.; Geismann, C.; Grossmann, M.; Kruse, M.-L.; Schreiber, S.; Schäfer, H. Inhibition of the Nrf2 Transcription Factor by the Alkaloid Trigonelline Renders Pancreatic Cancer Cells More Susceptible to Apoptosis through Decreased Proteasomal Gene Expression and Proteasome Activity. Oncogene; 2013; 32, pp. 4825-4835. [DOI: https://dx.doi.org/10.1038/onc.2012.493]
132. Tsuchida, K.; Tsujita, T.; Hayashi, M.; Ojima, A.; Keleku-Lukwete, N.; Katsuoka, F.; Otsuki, A.; Kikuchi, H.; Oshima, Y.; Suzuki, M. et al. Halofuginone Enhances the Chemo-Sensitivity of Cancer Cells by Suppressing NRF2 Accumulation. Free Radic. Biol. Med.; 2017; 103, pp. 236-247. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2016.12.041]
133. Limonciel, A.; Jennings, P. A Review of the Evidence That Ochratoxin A Is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity. Toxins; 2014; 6, pp. 371-379. [DOI: https://dx.doi.org/10.3390/toxins6010371]
134. Singh, A.; Venkannagari, S.; Oh, K.H.; Zhang, Y.-Q.; Rohde, J.M.; Liu, L.; Nimmagadda, S.; Sudini, K.; Brimacombe, K.R.; Gajghate, S. et al. Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. ACS Chem. Biol.; 2016; 11, pp. 3214-3225. [DOI: https://dx.doi.org/10.1021/acschembio.6b00651]
135. Zhang, W.; Feng, C.; Jiang, H. Novel Target for Treating Alzheimer’s Diseases: Crosstalk between the Nrf2 Pathway and Autophagy. Ageing Res. Rev.; 2021; 65, 101207. [DOI: https://dx.doi.org/10.1016/j.arr.2020.101207]
136. Barone, M.C.; Sykiotis, G.P.; Bohmann, D. Genetic Activation of Nrf2 Signaling Is Sufficient to Ameliorate Neurodegenerative Phenotypes in a Drosophila Model of Parkinson’s Disease. Dis. Model. Mech.; 2011; 4, pp. 701-707. [DOI: https://dx.doi.org/10.1242/dmm.007575]
137. Zhao, M.; Wang, B.; Zhang, C.; Su, Z.; Guo, B.; Zhao, Y.; Zheng, R. The DJ1-Nrf2-STING Axis Mediates the Neuroprotective Effects of Withaferin A in Parkinson’s Disease. Cell Death Differ.; 2021; 28, pp. 2517-2535. [DOI: https://dx.doi.org/10.1038/s41418-021-00767-2]
138. Cano, M.; Thimmalappula, R.; Fujihara, M.; Nagai, N.; Sporn, M.; Wang, A.L.; Neufeld, A.H.; Biswal, S.; Handa, J.T. Cigarette Smoking, Oxidative Stress, the Anti-Oxidant Response through Nrf2 Signaling, and Age-Related Macular Degeneration. Vis. Res.; 2010; 50, pp. 652-664. [DOI: https://dx.doi.org/10.1016/j.visres.2009.08.018]
139. Cheng, Z.; Li, Y.; Zhu, X.; Wang, K.; Ali, Y.; Shu, W.; Zhang, T.; Zhu, L.; Murray, M.; Zhou, F. The Potential Application of Pentacyclic Triterpenoids in the Prevention and Treatment of Retinal Diseases. Planta Med.; 2021; 87, pp. 511-527. [DOI: https://dx.doi.org/10.1055/a-1377-2596]
140. Cheng, Z.; Li, Y.; Wang, K.; Zhu, X.; Tharkar, P.; Shu, W.; Zhang, T.; Zeng, S.; Zhu, L.; Murray, M. et al. Compritol Solid Lipid Nanoparticle Formulations Enhance the Protective Effect of Betulinic Acid Derivatives in Human Müller Cells against Oxidative Injury. Exp. Eye Res.; 2022; 215, 108906. [DOI: https://dx.doi.org/10.1016/j.exer.2021.108906]
141. You, L.; Peng, H.; Liu, J.; Cai, M.; Wu, H.; Zhang, Z.; Bai, J.; Yao, Y.; Dong, X.; Yin, X. et al. Catalpol Protects ARPE-19 Cells against Oxidative Stress via Activation of the Keap1/Nrf2/ARE Pathway. Cells; 2021; 10, 2635. [DOI: https://dx.doi.org/10.3390/cells10102635] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34685615]
142. Li, Y.; Zhu, X.; Wang, K.; Zhu, L.; Murray, M.; Zhou, F. Ginkgo Biloba Extracts (GBE) Protect Human RPE Cells from t-BHP-Induced Oxidative Stress and Necrosis by Activating the Nrf2-Mediated Antioxidant Defence. J. Pharm. Pharmacol.; 2023; 75, pp. 105-116. [DOI: https://dx.doi.org/10.1093/jpp/rgac069] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36190376]
143. Li, Y.; Zhu, X.; Wang, K.; Zhu, L.; Murray, M.; Zhou, F. The Potential of Ginkgo Biloba in the Treatment of Human Diseases and the Relationship to Nrf2-Mediated Antioxidant Protection. J. Pharm. Pharmacol.; 2022; 74, pp. 1689-1699. [DOI: https://dx.doi.org/10.1093/jpp/rgac036] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36173884]
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; Zhang, Xinyuan 2
; Zhou, Fanfan 3 ; Gillies, Mark C 1 ; Zhu, Ling 1 1 Save Sight Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
2 Department of Ocular Fundus Diseases, Beijing Tongren Eye Centre, Tongren Hospital, Capital Medical University, Beijing 100073, China
3 Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia