Alleviate oxidative stress in diabetic retinopathy: antioxidant therapeutic strategies

ABSTRACT
 Objectives This review outlines the function of oxidative stress in DR and discusses therapeutic strategies to treat DR with antioxidants. Methods Published papers on oxidative stress in DR and therapeutic strategies to treat DR with antioxidants were collected and reviewed via database searching on PubMed. Results The abnormal development of DR is a complicated process. The pathogenesis of DR has been reported to involve oxidative stress, despite the fact that the mechanisms underlying this are still not fully understood. Excessive reactive oxygen species (ROS) accumulation can damage retina, eventually leading to DR. Increasing evidence have demonstrated that antioxidant therapy can alleviate the degeneration of retinal capillaries in DR. Conclusion Oxidative stress can play an important contributor in the pathogenesis of DR. Furthermore, animal experiments have shown that antioxidants are a beneficial therapy for treating DR, but more clinical trial data is needed.


Introduction
Diabetes is now considered a rapidly expanding worldwide health emergency in the twenty-first century, with a global adult prevalence of 8.8% of the world's population in 2017 and a further increase to 9.9% projected by 2045 [1].According to the report of World Health Organization (WHO), DR is responsible for at least 5% of the 37 million instances of blindness globally, making it the primary cause of visual impairment in adults.Furthermore, the WHO predicts that diabetes will be the 7th leading cause of mortality by 2030 [2,3].Diabetes can be classified into two types: type 1 mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [4].DR is a severe microvascular complication of both T1DM and T2DM, which has been linked to the production of free radicals, oxidative stress and chronic inflammation [5].
Elevated oxidative stress is becoming more widely recognized of a critical factor in the pathogenesis of diabetes and its complications [6].Reactive oxygen species (ROS) are produced in excess, which results in oxidative stress, a biological process that aids in the etiology of many diseases and associated complications.ROS cause cell injury by interacting with various cellular components.Fortunately, organisms are shielded against ROS by an antioxidant mechanism [7][8][9].Despite the retina's efficient antioxidant defense mechanism, which consists of free radical scavengers and antioxidant enzymes, sustained hyperglycemia leads to a decrease in these defenses and an increase in oxidative stress [10][11][12].Multiple antioxidants are currently being tested in clinical trials, but the outcomes remain inconclusive.Although this topic has been discussed in previous reviews, this review highlights the most recent antioxidant treatments based on what our research team has published on DR in recent years and updates readers on how oxidative stress contributes to the development of DR.

Diabetic retinopathy
The primary cause of vision loss and blindness in individuals of working age is diabetic retinopathy (DR), as well as one of the most serious microvascular consequences of diabetes mellitus (DM) [13].According to clinical and research findings, hyperglycemia represents the primary cause of complications in diabetes [14].By 2045, the number of persons worldwide with DR is projected to grow to 160.50 million from 129.84 million in 2030 [15].The DR is a serious global public health and economic problem as a result of this disturbing future [16].DR is clinically characterized by damage to the retinal microvasculature, which can result in hemorrhaging, angiogenesis, microaneurysms, and even retinal detachment and blindness in the worst cases [17].Despite numerous studies, the precise mechanisms by which hyperglycemia contributes to retinal pathology still obscure.It has been postulated that aberrations in various metabolic pathways are significantly linked to the development of hyperglycemia-mediated retinopathy.As depicted in Figure 1, four main pathwaysthe polyol pathway, the advanced glycation end-products (AGE) pathway, the hexosamine biosynthetic pathway (HBP), and the protein kinase C (PKC) pathwayare thought to be responsible for the retinal damage brought on by hyperglycemia [18,19].However, clinical trials testing inhibitors of each of these distinct pathways have produced disappointing outcomes in terms of slowing the effects of DR [17].
The treatment for DR is dependent on its stage or type [20].DR is a progressive disease that progresses in stages and can be defined as non-proliferative (NPDR) and proliferative (PDR) types with or without macular oedema depending on whether retinal neovascularization is present [21,22].Diabetic macular edema (DME) is another complication of DR, which is induced by a breakdown of the external bloodretinal barrier (BRB) and subsequent fluid accumulation [23].Recent studies have identified three highly effective treatments for DR that can significantly reduce vision loss caused by the disease.If treated before the retina is seriously injured, even those with advanced DR have a 90% chance of preserving their eyesight [7].The normative treatment for DR commonly involves anti-vascular endothelial growth factor (VEGF) drugs or corticosteroids.Anti-vascular endothelial growth factor (VEGF) drugs or corticosteroids are commonly used as the standard treatment for DR.In the clinic, intravitreal injections of anti-VEGF medications such bevacizumab, aflibercept, and ranibizumab are administered [24].Combination therapy including laser photocoagulation and vitreoretinal surgery may be used for different stages in DR [25].However, while these treatments may alleviate symptoms, it is crucial to identify novel therapeutic targets for the prevention and treatment of DR progression.

Oxidative stress and ROS
Over the past 40 years, various of medical fields, including ophthalmology, have extensively studied the concept of 'oxidative stress' [26].Oxidative stress specifically refers to an imbalance between free radicals, which are highly reactive molecules produced in our bodies through a variety of pathways, and intrinsic antioxidant capacity [27].Oxidative stress is extremely complicated, connected to other types of stress, and has impacts on different cell types [28].Therefore, antioxidant therapy may be beneficial in preventing retinal damage,  as oxidative stress plays a significant role in the pathogenesis of DR [29].
Currently, ROS involvement is well acknowledged as a crucial causal element in the rise of DR. [30].Chronic hyperglycemia makes microvessels in the retina more susceptible to oxidative stress, which increases the production of ROS [5,31].ROS are free radicals, which are extremely unstable and reactive oxidant molecules due to the presence of an extra electron.In order to restore stability, they obtain electrons from nearby molecules, resulting in the formation of an oxidative chain.[32].Notably, free radicals are constantly produced during normal metabolic processes, and intracellular antioxidants work to balance the production and neutralization of these ROS.However, pathological conditions can disrupt this delicate equilibrium by either increasing ROS production or decreasing their removal, resulting in an excessive bioavailability of ROS (Figure 2).
As is apparent from the above results, DR is associated with elevated ROS levels.Reduced antioxidant enzyme activity, hyperglycemia-induced metabolic pathways, mitochondrial oxidative phosphorylation, and nicotinamide adenine dinucleotide phosphate-(NADPH-) oxidase (Nox) are all common contributors to ROS elevation.[33,34].In hyperglycemic conditions, the excessive production of superoxide (including superoxide radical anion, hydroxyl radical, H 2 O 2 and singlet oxygen) can activate various abnormal biochemical metabolic pathways due to mitochondria being the main endogenous source of ROS [35,36].Extensive scientific reports have also shown, due to alterations in the biomechanisms that are involved in the recovery and progression of microvascular complications, ROS play a crucial role in the pathological processes that occur in the retina of DR [32,37].ROS are capable of causing the development of DR, but are not the only cause, e.g.ROS interact with other pathways and crosstalk with each other.Therefore, more critical points need to be taken into account to prevent or treat these diseases by combining ROS antioxidants with other drugs.Herein, the alleviation elimination of ROS formation presents a potential antioxidative approach for DR-induced blindness.

Antioxidant therapeutic strategies
In prior chapters, we have shown that oxidative stress is crucial for the development of DR, and excessive accumulation of ROS can damage the tissue surrounding and within retinal vessels, ultimately resulting in DR.Therefore, by preventing the generation of ROS, eliminating free radicals, or strengthening the antioxidant defense system, antioxidants are postulated to mitigate aberrant metabolism and decelerate the progression of DR [19].Thus, these elements are the focus for treating DR.The classification of various antioxidant compounds in the prevention and treatment of oxidative stress in DR is covered in the section that follows.

Drugs
A specific inhibitor of branched chain amino transferase (BCATc), gabapentin is a leucine analogue.Gabapentin, via suppressing glutamate excitotoxicity, has the potential to be a therapeutic treatment for reducing oxidative stress and apoptosis in diabetic retinas, which may be achieved through its ability to decrease branched chain amino acids (BCAAs) levels via inhibition of BCATc, leading to reduced glutamate synthesis and increased in the rate of glutamate oxidation [38].Ola et al. suggested that gabapentin-stimulated glutamate clearance improved retinal cell apoptosis and oxidative stress in diabetic rats [39].
A peroxisome proliferator-activated receptor type α (PPAR-α) agonist called fenofibrate is employed for the treatment of hypertriglyceridemia and hyperlipidemia in the clinic.Fenofibrate has been demonstrated to considerably halt the progression of DR and decrease the need for laser therapy in DR [40].Hsu et al. have confirmed that fenofibrate can decelerate the advancement in DR via regulating signaling pathways involving apoptosis and stress [41].
A mixture called sulodexide, which combines dermatan sulfate with low-molecular-weight heparin, exhibits potential as a target of therapy for a number of vascular disorders [42].In vivo, sulodexide has been shown to enhance the retinal arterioles' glycocalyx, decrease vascular permeability and inhibit retinal neovascularization, indicating its potential to act as a promising DR therapeutic treatment [43,44].Strikingly, sulodexide protected from hyperglycemia-induced ROS vascular wall production and endothelial dysfunction in a dependent on concentration manner.From a clinical perspective, sulodexide could be used to decrease oxidative stress in treating DR [45].
Bilobalide, the pharmacologically active sesquiterpene trilactone found in Ginkgo biloba leaves, has been shown to exhibit various pharmacological effects such as antioxidant, anti-inflammatory and anti-cancer properties [46].In diabetic rats induced by STZ, several researches indicated that bilobalide protects retinal ganglion cells (RGCs) and exerts an antihyperglycemic effect [47,48].Sun et al. then suggested that bilobalide increased erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1(HO-1) expression while inhibiting oxidative stress by reducing inflammatory mediators.Notably, all products of HO-1 activity are biologically active, and the products include biliverdin and bilirubin, both of which are putative antioxidants, as well as CO, which is also biologically active.Therefore, bilobalide may effectively against DR by mitigating oxidative stress and inflammation [49].
Carvedilol (CAR), an adrenergic receptor blocking agent, is widely used in the management of cardiovascular diseases.CAR has been shown to possess anti-oxidative stress and anti-inflammatory properties [50].For instance, CAR inhibits inflammatory and oxidative mediators to prevent pancreatic cell damage and the development of T1DM in mice.An example is that CAR prevents pancreatic β cell damage and T1DM development in mice by inhibiting inflammatory and oxidative mediators [51].Zhang and co. reported that CAR reduces oxidative stress and apoptosis induced by HG in retinal pigment epithelial (RPE) cells through activation of the Nrf2/ARE pathway.Therefore, it is a prospective molecule for DR treatment in the future [52].
Conbercept is a novel anti-vascular endothelial growth factor (VEGF) drug that has been independently developed by China in recent years [53].Conbercept's effectiveness as an adjuvant to vitrectomy is mostly attributable to its capacity to target various members of VEGF family (VEGF-A, B, C, and PIGF), preventing the development of neovascularization and decreasing vascular permeability in the retina [54].Xia et al. demonstrated that conbercept exerts prominent suppressive effects on oxidative stress in mice with DR, providing further insight into the molecular mechanisms underlying its therapeutic efficacy [55].Scutellarin (SC), a natural flavonoid, serves as the chemical biomarker for quality control of certain traditional Chinese medicines such as Scutellariae barbatae Herba and Erigerontis Berba listed in China Pharmacopoeia.The Scutellariae barbatae Herba has been reported to possess antioxidant property [56].Additionally, an earlier study revealed that an ethanol extract from this herb attenuated DR development [57].Mei et al. demonstrated that SC mitigates BRB breakdown by inhibiting retinal inflammatory responses and subsequent oxidative stress damage triggered by hyperglycemia-activated microglia cells during DR progression [58].
Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, is indicated for the treatment of peripheral vascular occlusive disorders as well as intermittent claudication in diabetes patients [59].Previous research has indicated that cilostazol may exert effective anti-inflammatory and anti-oxidative functions through multiple pathways.Yeh et al. indicated that cilostazol can mitigate oxidative stress and inflammatory respones during the development of DR.Thus, cilostazol may be valuable for preventing the growth of DR [60].

Phytoestrogens
In RPE cells, the bioactive flavonoid component quercetin has been demonstrated to exert anti-inflammatory and protective effects against oxidative stress-induced cell apoptosis [61].This compound may efficiently prevent diabetic retinal neurodegeneration and oxidative stress damage by increasing the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase in rat retinas with diabetes and suppressing the expression of NF-B and Caspase-3 [62].Our research team discovered ultrasmall Fe-Quercetin nanozymes particles by combining quercetin with low-toxic iron ions to prevent and delay the development and progression of DR.It possesses strong ROS scavenging capabilities, effective relief of early DR symptoms, suppression of DR progression and multitarget-specific beneficial effects for DR suggest their potential for clinical translation [63].
A coumestan isoflavone known as coumestrol (CMS) is vital for treating diseases linked to estrogen, like DM [64].The effectiveness of 10-hydroxy-CMS as an antihyperlipidemic drug in STZ-induced diabetes has been demonstrated in a prior investigation [65].Subsequently, CMS alleviated DR by reducing inflammation, apoptosis, and oxidative stress via SIRT1 activation, according to Xu et al [66].

Polyphenols
Dihydromyricetin (DMY), a flavonoid found in Ampelopsis grossedentata, has antioxidant, anti-angiogenic, and antiinflammatory properties that suggest it may be beneficial for inhibiting the progression of diabetes and treating related complications [67].A previous study has shown that DHM protects against HG-induced oxidative stress and apoptotic damage in RPE cell line cells via inhibiting miR-34a expression [68].Our laboratory has reported for the firstever the construction of ultra-small Fe-DMY nanoparticles (Fe-DMY NCPs), which are composed of DMY combined with low-toxicity iron ions.Fe-DMY NCPs protect vascular endothelial cells from oxidative stress induced by high glucose levels, scavenge excess ROS, and ameliorate the pathogenic symptoms of DR.The Poldip2-Nox4-H 2 O 2 signaling pathway can be inhibited by Fe-DMY NCPs, which can also downregulate important vascular function markers.These results imply that Fe-DMY NCPs possess the potential to be a new multimeric drug for DR therapy, acting as a safe and efficient antioxidant and micro angio-protective agent [69].
Tricin, a flavone derived from rice bran, has demonstrated diverse bioeffects encompassing anti-cancer, anti-atherogenic and anti-inflammatory properties [70].Tricin reduces ROS production in endothelial cells, leading to downregulation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling and inhibition of HIF-1α accumulation in tumor cells, resulting in decreased expression of VEGF [71].Yang et al. discovered that tricin inhibit angiogenesis and oxidative stress in retinal epithelial cells of DR rats by reinforces the Sestrin2/Nrf2 signaling pathway [72].
Curcumin, an active phytochemical found in Curcuma Longa, exhibits outstanding antioxidant effect by suppressing HIF-1 and inhibiting hypoxia-induced angiogenesis [73].Numerous animal studies have demonstrated that curcumin can activate the Nrf2 antioxidant pathway, which mitigates cellular oxidative damage [74].Moreover, curcumin may reduce diabetic retinal damage by acting as an antioxidant, as reported by Xie et al.Through its antioxidant, hypoglycemic and anti-inflammatory properties, it may have therapeutic promise for preventing the development of DR [75].
Proanthocyanidins (PACs) are polyphenolic compounds present in a variety of plant and fruit extracts that have been shown to exhibit effective antioxidant, anti-inflammatory and immunosuppressive properties [76].By increasing the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax), lowering caspase cleavage, attenuating ROS production and decreasing the rate of apoptosis, the research has shown that PACs might defend the RPE from vitamin A dimermediated photooxidation damage [77].In diabetic rats, PAC treatment decreased apoptosis and enhanced retinal structure [78].Moreover, Li et al. demonstrated that PACs have the potential to protect RPE cells from high glucoseinduced damage by inhibiting ROS generation, indicating their candidacy for DR management [79].
Licorice root contains a bioactive flavonoid named isoliquiritigenin (ISL), which has been shown to possess antiinflammatory and antioxidant properties.Moreover, Alzahrani et al. indicated that ISL would be a useful therapeutic approach for both DR prevention and treatment.Additionally, it appears that the miR-195/SIRT-1/NF-B pathways are involved in mediating the positive effects of ISL therapy [80].
Rhaponticin (RN), a natural polyphenolic flavonoid, is recognized for its pharmacological properties, particularly as an anti-diabetic agent.Moreover, the RN metabolite rhapontigenin exhibits antioxidant activity and protects against oxidative stress-induced cell injury.Shi et al revealed that treatment of RN to diabetic rats prevented the development of diabetic retinal alterations via exerting antioxidant, antiinflammatory and hypoglycemic properties [81].
Kaempferol belongs to the flavonol subclass, which is abudant in numerous traditional herbs and edible plants.Kaempferol has been identified as a potent scavenger of superoxide, and its capacity to lower superoxide levels concentrations may have a significant impact on its antioxidant properties.This is due to the fact that the formation of superoxide radical anion is a necessary step in the generation of the majority of reactive oxygen and nitrogen species that contribute to oxidative stress [82].Du et al. revealed that kaempferol possesses antioxidant and antiapoptotic properties, which can protect from damage induced by oxidative stress in human RPE cells.These results suggest that kaempferol may be used therapeutically to prevent and treat DR mediated by oxidative stress [83].

Lipids
Oxidized low-density lipoprotein is primarily composed of lysophosphatidylcholine (LPC) [84].LPC induces endothelial cell dysfunction by generating ROS in the vascular endothelium and triggering oxidative stress through elevating free Ca 2+ concentration in the cytoplasm of muscle cells, macrophages, and leukocytes.[85].Plasma levels of LPC, which prevents glucose absorption in heart, muscle and liver tissues and can result in postprandial hyperglycemia, were significantly elevated in DR [86].Furthermore, the research has demonstrated that LPC counteracts the beneficial impacts of bone marrow mesenchymal stem cells (BMSCs) on oxidative stress damage in human retinal microvascular endothelial cells (HRMECs) through TLR4/NF-κB signaling pathway [87].
Long-chain n-3 fatty acids, also referred to as omega-3 fatty acids, are essential for the healthy development of neurological structures in both the brain and eye.Previous studies have demonstrated the potential benefits of supplementation with n-3 fatty acid in inhibiting ocular diseases, probably through their anti-inflammatory and antioxidant properties.According to Suzumura et al., n-3 fatty acids may be useful for both preclinical DR prevention and DR progression slowing [88].

Vitamins
Vitamin B9, often known as Folic acid (FA), acts as a crucial player in single-carbon metabolism that is indispensable for multiple biological processes.A study has shown that serum homocysteine (hcy) levels in patients with T2D are negatively correlated with FA, indicating that FA may have beneficial effects in both the prevention and treatment of DR through alleviating hyperhomocysteinemia (Hhcy) [89].Lei et al. further suggested that FA has the potential to serve as a therapeutic drug for DR by inhibiting oxidative stress, inflammation and angiogenesis [90].
Vitamin C can shield against the onset of DR by avoiding lipid peroxidation, scavenging free radicals and lowering the formation of ROS.As a result, taking vitamin C supplements is thought to be effective for the relief of DR.Research has shown that vitamin C improves retinal vascular endothelial dysfunction and reduces leukocyte adhesion in diabetic rats [19].
Vitamin D, widely recognized as an important component for bone metabolism, has also been in studies to possess potent antioxidant properties [91].Previous studies have shown that vitamin D treatment with vitamin D can decrease oxidative stress damage in diabetic rats and DR under high glucose conditions, as well as confer cellular and tissue protection against it.Furthermore, a study has indicated that vitamin D possesses anti-inflammatory properties and enhances antioxidant defense, which may protect the retina [92].
Vitamin E, the main antioxidant in lipids, has been demonstrated to scavenge free radicals outside cells through non-enzymatic mechanisms in DR.Further research has demonstrated that vitamin E may serve as an adjunctive therapy for individuals with DR by reducing oxidative stress and possibly preventing complications of diabetes mellitus in the future [93].

Carotenoids
Zeaxanthin, a dietary carotenoid found only in the retina, has been demonstrated to reduce inflammation and oxidative stress in the retina of diabetic rats.Furthermore, zeaxanthin can prevent neovascularization caused by VEGF in the human retina through activating a Nox4-dependent mechanism [18].
Astaxanthin is a xanthophyll carotenoid that exhibits potent in vitro and in vivo antioxidant capacity.Notably, retinal cells are shielded from damage caused by oxidative stress through the protective effects of astaxanthin [94].By activating antioxidant enzymes via the PI3 K/Akt/Nrf2 pathway, astaxanthin effectively protects retinal photoreceptor cells from the oxidative stress caused by high glucose levels, as demonstrated in research conducted by Lai et al [95].
Lutein, a xanthophyll carotenoid found in egg yolk and leafy vegetables, possesses antioxidant properties by scavenging ROS like lipid peroxy radicals and singlet oxygen [96].Relevant studies have demonstrated that lutein can effectively suppress oxidative stress-induced apoptosis of RGCs and RPEs, as well as protect the inner retina from ischemiareperfusion injury due to its capacity to scavenge endogenous ROS [97].

Proteins
Superoxide dismutase-3 (SOD3) is a Cu/Zn-containing homotetrameric superoxide dismutase that is secreted and mostly localized on cell surfaces and in the extracellular matrix (ECM).In order to anchor itself to the ECM, it interacts with collagen and heparan sulfate proteoglycans (HSPGs) [98].Notably, SOD enzymes regulate the levels of a variety of ROS, minimizing their potential toxicity and regulating important cellular processes that are governed by their signaling activities [99].SOD3 functions as an antioxidant in the human vitreous, where it is concentrated in a special matrix structure that opposes the inner retina in the vitreous base and cortex.Wert et al. reported that SOD3 antioxidant dysregulation or deficiency in the vitreous base and cortex leads to elevated tissue damage and oxidative stress in the inner retina, thereby contributing to the cause of DR [100].
Transforming growth factor-beta (TGF-β) is a family of multifunctional regulatory proteins with structural similarities that exert pleiotropic effects on different organs.TGF-β is thought to possess an antioxidative cytoprotective action against cellular injury in certain kinds of cell types.Chen et al. indicated that TGF-β promotes the activation of antioxidant pathways, thereby protecting RGCs from hyperglycemia-induced harm and indicating that it could serve as an anti-diabetic treatment for DR [101].
The neuroprotective effects of glucagon-like peptide 1 (GLP-1) on the nervous system, including the retina, suggest its potential as a preventive or therapeutic agent for retinal neurodegeneration in DR.Increasing evidence further supports the advantageous impacts of GLP-1 in experimental DR [102].Ramos et al. demonstrated that GLP-1 regulates the antioxidant defense system in the diabetic retina, exerting a neuroprotective effect that promotes neuronal proliferation and DNA repair [103].
The pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) belongs to the PHLPP protein family, which exerts a pivotal influence on various physiological and pathological processes [104].A study has suggested that PHLPP1 is essential for influencing cell viability by reducing oxidative stress and regulating the Nrf2 signaling pathways during diverse pathogenic processes [105].Zhang et al. demonstrated that the inhibition of PHLPP1 stimulates Nrf2/ARE signaling, thereby protecting RGCs from oxidative stress and apoptosis induced by high glucose levels.This work suggests that PHLPP1 may improve high glucose-induced damage to retinal ganglion cells during the onset and progression of DR [106].

Other antioxidants
Capsaicin is a main active compound in chili and serves as a transient receptor potential vanillic 1 (TRPV1) agonist.It has anti-inflammatory, cardiovascular-protective and antioxidant effects and activates TRPV1 [107].An earlier investigation showed that upregulation of CGRP by CAP can reduce apoptosis in diabetic retinal cells [108].Our laboratory has recently reported that CAP may ameliorate DR by activating TRPV1 and suppressing the PPARγ/poldip2/Nox4/H 2 O 2 regulatory pathway.The results of their study imply that capsaicin may serve as a novel therapeutic option for DR in clinical trials [109].
Captopril is an organic compound normally utilized for the management hypertension and as a prophylactic measure against DR.Previous research suggested that angiotensin II plays a major role in the mechanism of action of captopril in DR [110,111].Our laboratory has revealed through in vivo and in vitro experiments that captopril can slow the progression of DR by reducing oxidative stress [112].
The synthesized phenolic antioxidant Tert-butylhydroquinone (tBHQ) is extensively utilized as a food preservative to prolong the shelf life of food products [113].Accumulating evidence indicated that tBHQ effectively prevents cell disturbance caused by OS inducers [114].Notably, the recent study has demonstrated that tBHQ activates the PI3 K/Akt/ eNOS pathway to prevent DR-induced OS, providing preclinical evidence for future prevention and treatment of DR.In the future, it has potential as both a treatment and prevention for DR due to its antioxidant properties [115].
Paeonol, a phenolic metabolite found in plants, has been shown to be effective in treating various diseases [116].Liu and coworkers found that paeonol has both antidiabetic and antioxidant effects in diabetic rats induced by streptozotocin (STZ), as evidenced by a decrease in blood glucose levels with paeonol treatment [117].Recently, Adki et al. discovered that paeonol attenuates STZ-induced DR in rats through regulating oxidative stress and the polyol pathway [118].
Geniposide (GEN) is a native extract from the fruit of gardenia with various biological properties, including antiinflammatory and antioxidant effects [119].Findings have shown that GEN protects diabetic rats' myocardium from damage caused by myocardial ischemia reperfusion by preventing oxidative stress through the Nrf2/HO-1 signal pathway [120,121].Tu et al. subsequently demonstrated that GEN can alleviate hyperglycemia-induced oxidative stress and inflammation in DR by activating the Nrf2 signaling pathway, indicating its potential as an effective therapeutic approach for DR treatment [122].
Melatonin, also known as N-acetyl-5-methoxytryptamine, is mainly produced in the pineal gland and is essential in regulating various physiological processes [123].The study has demonstrated a decrease in serum melatonin levels in DM patients, suggesting its potential involvement in the pathogenesis of DR [124].Following these discoveries, Tu et al. also found that melatonin can mitigate inflammation and oxidative stress in Müller cells of DR through activation of the Sirt1 pathway [125].Furthermore, there are many other compounds that also have some antioxidant properties.Table 1 summarizes antioxidant therapies for DR caused by oxidative stress.

Conclusions and future perspectives
In both type 1 and type 2 diabetes, oxidative stress plays a crucial role in the etiology of DR.It has been considered a contributor in the onset and progression of DR, and may be regarded as the primary initiator and prevalent etiological factor among the multiple molecular mechanisms involved with DR [126].Notably, DR is associated with ROS by regulating signaling pathways involved in apoptosis and stress.DR is also a multifactorial and progressive disease characterized by the accumulation of neuronal and vascular damage, resulting in microaneurysms, neurodegeneration, edemas, neovascularization, BRB breakage and hemorrhages.It is currently one of the main global contributors to vision loss and blindness [127].Oxidative stress is a key factor in DR development.
Furthermore, an imbalance between the production and elimination of free radicals contributes to the condition known as oxidative stress [128,129].Thus, oxidative stress has been one of the most studied therapeutic approaches for DR [130].Due to its high capacity for oxygen uptake, the retina is particularly vulnerable to oxidative stress in diabetes.The diabetic environment promotes oxidative stress, and molecules or medicines with antioxidant properties could be suitable candidates for attenuating DR [72].These research' findings can facilitate the development of cost-effective therapeutic agents for preventing and treating DR.Therefore, antioxidative intervention is imperative and pressing for DR, offering a glimmer of hope to enhance patients' quality of life by improving functional vision.Currently, animal experiments provide most of the evidence, but their clinical therapeutic outcomes are unclear.As a result, further studies are necessary in the future.

Figure 1 .
Figure 1.Diabetes metabolic dysfunction caused by hyperglycemia.The primary pathways contributing to the pathogenesis of retinopathy by promoting oxidative stress and generating ROS include the polyol pathway, hexosamine biosynthesis pathway, formation of advanced glycation end products (AGEs), and activation of protein kinase C (PKC).

Figure 2 .
Figure 2. Diabetes disrupts Redox balance in retina induced by hyperglycemia.There exists a delicate balance between the formation of free radicals and the antioxidant defense mechanisms under normal physiological conditions.Hyperglycemia induced by diabetes disrupts this equilibrium by promoting ROS production while simultaneously suppressing retinal antioxidant response.

Table 1 .
Application of antioxidant therapeutic strategies for DR.