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The human retina is facing a big challenge of reactive oxygen species (ROS) from endogenous and exogenous sources. Excessive ROS can cause damage to DNA, lipids, and proteins, triggering abnormal redox signaling, and ultimately lead to cell death. Thus, oxidative stress has been observed in inherited retinal diseases as a common hallmark. To counte...
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... human retina (Fig. 2), without exception, is facing the challenge of ROS. As a part of the central nervous system (CNS), retina shares the same metabolic property as the brain that a huge amount of energy is needed [12]. There are several evolutionary examples that animals inhabiting in the darkness generally regress their vision systems as an ...
Citations
... Persistent OS not only accelerates the aging process of the body but also further induces the occurrence of aging-related diseases by damaging important cell structures such as mitochondria, DNA, and telomeres. These diseases include retinal disease [7], neurodegenerative disease [8,9], DNA, and telomeres. These diseases include retinal disease [7], neurodegenerative disease [8,9], osteoarthritis [10,11], cardiovascular diseases (CVDs) [12], cancer [13], and a variety of reproductive diseases [14,15], which seriously affect the quality of life and life expectancy of elderly individuals. ...
... These diseases include retinal disease [7], neurodegenerative disease [8,9], DNA, and telomeres. These diseases include retinal disease [7], neurodegenerative disease [8,9], osteoarthritis [10,11], cardiovascular diseases (CVDs) [12], cancer [13], and a variety of reproductive diseases [14,15], which seriously affect the quality of life and life expectancy of elderly individuals. ...
... These conditions are characterized by progressive neuronal degeneration or death of neurons, resulting in a gradual decline in everyday functions such as cognition and movement [69]. OS has been reported to be a key mechanism in the development of neurodegenerative disease [7]. ...
Under normal physiological conditions, reactive oxygen species (ROS) are produced through redox reactions as byproducts of respiratory and metabolic activities. However, due to various endogenous and exogenous factors, the body may produce excessive ROS, which leads to oxidative stress (OS). Numerous studies have shown that OS causes a variety of pathological changes in cells, including mitochondrial dysfunction, DNA damage, telomere shortening, lipid peroxidation, and protein oxidative modification, all of which can trigger apoptosis and senescence. OS also induces a variety of aging-related diseases, such as retinal disease, neurodegenerative disease, osteoarthritis, cardiovascular diseases, cancer, ovarian disease, and prostate disease. In this review, we aim to introduce the multiple internal and external triggers that mediate ROS levels in rodents and humans as well as the relationship between OS, aging, and aging-related diseases. Finally, we present a statistical analysis of effective antioxidant measures currently being developed and applied in the field of aging research.
... Antioxidants are molecules or compounds that neutralize or neutralize harmful free radicals formed in chemical reactions called oxidation or oxidative stress. Oxidation is a normal metabolic process in our body and serves many important functions [29,34]. ...
Natural compounds play an important role among antioxidants that protect the human body against oxidative stress. Many plants may have high levels of antioxidant capacity through the compounds they contain. In line with this information, in the current study, we aimed to evaluate the antioxidant properties of Galanthus elwesii Hook.f. In this context, we tested the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging and metal chelating activities of different concentrations (12.5-400 mg/L) of methanol and water extracts obtained from the bulb part of this plant. A concentration-dependent increase in activity was observed for both extracts. DPPH scavenging (87.10%) and metal chelating (72.99%) activities demonstrated by 400 mg/L concentration applications came to the fore. In addition, it was determined that these data were significantly (p < 0.05) higher than the activity rates revealed by other applications. Considering the IC50 values, low values for DPPH scavenging and metal chelating activities (110.88 mg/L and 132.40 mg/L, respectively) were detected in water extracts. As a result, the importance of G. elwesii among plants that have the potential to be a rich source of antioxidants was revealed in this study.
... Strategies aimed at reducing oxidative stress and enhancing the antioxidant defense system have been investigated as potential therapeutic approaches for RP [62]. These include the use of antioxidants, such as vitamins C and E, and other compounds that can mitigate ROS-induced damage [63,64]. ...
Retinitis pigmentosa, defined more properly as cone–rod dystrophy, is a paradigm of inherited diffuse retinal dystrophies, one of the rare diseases with the highest prevalence in the worldwide population and one of the main causes of low vision in the pediatric and elderly age groups. Advancements in and the understanding of molecular biology and gene-editing technologies have raised interest in laying the foundation for new therapeutic strategies for rare diseases. As a consequence, new possibilities for clinicians and patients are arising due to the feasibility of treating such a devastating disorder, reducing its complications. The scope of this review focuses on the pathomolecular mechanisms underlying RP better to understand the prospects of its treatment using innovative approaches.
... Strategies aimed at reducing oxidative stress and enhancing the antioxidant defence system have been investigated as potential therapeutic approaches for RP. These include the use of antioxidants, such as vitamins C and E, and other compounds that can mitigate ROS-induced damage (51) (52). ...
Retinitis Pigmentosa, defined more properly as rod-cone dystrophy, is the paradigm of diffuse inherited retinal dystrophies, one of the rare diseases with the highest prevalence in the worldwide population and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and gene editing technologies raised the interest in putting the basis for new therapeutic strategies in rare diseases. As a consequence, new possibilities for clinicians and patients are arising due to the feasibility of treating such a devastating disorder reducing its complications. The scope of this review is to focus on the pathomolecular mechanisms underlying RP better to understand the prospective for its treatment with innovative approaches.
... The ONL thickness in our in vivo experiment partially recovered in the group treated with T-MSC EVs compared to the no-treatment control group, indicating that T-MSC EVs exert a preventive effect on the retinal destruction in the Pde6b knockout rats. As mentioned earlier, the mutation of the Pde6b gene is contributed to the abnormal cGMP accumulation in rod photoreceptors followed by excessive intracellular Ca 2? , resulting the metabolic overload with increased oxidative stress and the apoptosis of photoreceptors [78,79]. In addition, rd1 mice, a representative animal RP model containing Pde6b mutant alleles, showed a prominent mitochondrial oxidative stress in the retina and a significant decrease in the retina by almost 50% of the level of reduced glutathione (GSH), an essential intracellular antioxidant [79,80]. ...
... As mentioned earlier, the mutation of the Pde6b gene is contributed to the abnormal cGMP accumulation in rod photoreceptors followed by excessive intracellular Ca 2? , resulting the metabolic overload with increased oxidative stress and the apoptosis of photoreceptors [78,79]. In addition, rd1 mice, a representative animal RP model containing Pde6b mutant alleles, showed a prominent mitochondrial oxidative stress in the retina and a significant decrease in the retina by almost 50% of the level of reduced glutathione (GSH), an essential intracellular antioxidant [79,80]. Furthermore, oxidative DNA damage in the photoreceptors is confirmed by a marked increase of 8-hydroxy deoxyguanosine in the retina of rd1 mice, and the superoxide radicals, one of ROS, gradually accumulate in the retina of rd1 mice as the disease progresses [81,82]. ...
Background:
Retinal degenerative disease (RDD), one of the most common causes of blindness, is predominantly caused by the gradual death of retinal pigment epithelial cells (RPEs) and photoreceptors due to various causes. Cell-based therapies, such as stem cell implantation, have been developed for the treatment of RDD, but potential risks, including teratogenicity and immune reactions, have hampered their clinical application. Stem cell-derived extracellular vesicles (EVs) have recently emerged as a cell-free alternative therapeutic strategy; however, additional invasiveness and low yield of the stem cell extraction process is problematic.
Methods:
To overcome these limitations, we developed therapeutic EVs for the treatment of RDD which were extracted from tonsil-derived mesenchymal stem cells obtained from human tonsil tissue discarded as medical waste following tonsillectomy (T-MSC EVs). To verify the biocompatibility and cytoprotective effect of T-MSC EVs, we measured cell viability by co-culture with human RPE without or with toxic all-trans-retinal. To elucidate the cytoprotective mechanism of T-MSC EVs, we performed transcriptome sequencing using RNA extracted from RPEs. The in vivo protective effect of T-MSC EVs was evaluated using Pde6b gene knockout rats as an animal model of retinitis pigmentosa.
Results:
T-MSC EVs showed high biocompatibility and the human pigment epithelial cells were significantly protected in the presence of T-MSC EVs from the toxic effect of all-trans-retinal. In addition, T-MSC EVs showed a dose-dependent cell death-delaying effect in real-time quantification of cell death. Transcriptome sequencing analysis revealed that the efficient ability of T-MSC EVs to regulate intracellular oxidative stress may be one of the reasons explaining their excellent cytoprotective effect. Additionally, intravitreally injected T-MSC EVs had an inhibitory effect on the destruction of the outer nuclear layer in the Pde6b gene knockout rat.
Conclusions:
Together, the results of this study indicate the preventive and therapeutic effects of T-MSC EVs during the initiation and development of retinal degeneration, which may be a beneficial alternative for the treatment of RDD.
... When oxygen accepts one electron, it becomes O − 2 , and if it subsequently takes another electron and two protons, it becomes H 2 O 2 , and an additional electron splits H 2 O 2 , into OH • and a hydroxyl anion ( OH − ) via Fenton reaction 16 . Apart from ROS being created as a result of oxidative glucose metabolism, the constant exposure of retinal cells to sunlight and artificial light triggers the production of ROS 16,17 , especially with photosensitizers present, such as retinoids 16,18 , and leads to photo-oxidation 19 . Though the cornea and lens absorb most of the ultraviolet (UV) radiation, a small fraction of it can reach the retina. ...
... NADPH, derived from glucose via the PPP, is the ultimate electron donor that reduces the downstream proteins in the GSH antioxidant system. Thus, in addition to being a preferred energy substrate of retinal neurons, glucose is also a key driver of the redox system 16 . Consistent with this, glucose, defined as G in our model, is the substrate for the reaction rate in the production of [G6P] (Eq. ...
... (5) below), which is modeled as an allosteric reaction. As mentioned in the Introduction, there are many factors that contribute to ROS including oxygen and blue light that can penetrate the cornea and lens and induce photochemical damage 16,20 . However, in this study we are not explicitly modeling how ROS is created from photo-oxidation; our mathematical model incorporates in the term r all the factors that contribute to ROS and that are not part of the metabolism of glucose. ...
The retina is highly susceptible to the generation of toxic reactive oxygen species (ROS) that disrupt the normal operations of retinal cells. The glutathione (GSH) antioxidant system plays an important role in mitigating ROS. To perform its protective functions, GSH depends on nicotinamide adenine dinucleotide phosphate (NADPH) produced through the pentose phosphate pathway. This work develops the first mathematical model for the GSH antioxidant system in the outer retina, capturing the most essential components for formation of ROS, GSH production, its oxidation in detoxifying ROS, and subsequent reduction by NADPH. We calibrate and validate the model using experimental measurements, at different postnatal days up to PN28, from control mice and from the rd1 mouse model for the disease retinitis pigmentosa (RP). Global sensitivity analysis is then applied to examine the model behavior and identify the pathways with the greatest impact in control compared to RP conditions. The findings underscore the importance of GSH and NADPH production in dealing with oxidative stress during retinal development, especially after peak rod degeneration occurs in RP, leading to increased oxygen tension. This suggests that stimulation of GSH and NADPH synthesis could be a potential intervention strategy in degenerative mouse retinas with RP.
... Lutein has recently been proposed to act in mice via multiple antioxidant pathways in response to light-induced oxidative stress [217], reducing oxidant generation and, in parallel, promoting the expression of superoxide dismutase coding genes Sod1 and Sod2 and of superoxide dismutase (SOD) and reducing markers of macrophages recruitment to the RPE-choroid. A recent review covers antioxidant enzymatic pathways that protect photoreceptors and RPE cells from degeneration [218]. ...
The retina is an oxidative stress-prone tissue due to high content of polyunsaturated lipids, exposure to visible light stimuli in the 400–480 nm range, and high oxygen availability provided by choroidal capillaries to support oxidative metabolism. Indeed, lipids’ peroxidation and their conversion into reactive species promoting inflammation have been reported and connected to retinal degenerations. Here, we review recent evidence showing how retinal polyunsaturated lipids, in addition to oxidative stress and damage, may counteract the inflammatory response triggered by blue light-activated carotenoid derivatives, enabling long-term retina operation despite its prooxidant environment. These two aspects of retinal polyunsaturated lipids require tight control over their synthesis to avoid overcoming their protective actions by an increase in lipid peroxidation due to oxidative stress. We review emerging evidence on different transcriptional control mechanisms operating in retinal cells to modulate polyunsaturated lipid synthesis over the life span, from the immature to the ageing retina. Finally, we discuss the antioxidant role of food nutrients such as xanthophylls and carotenoids that have been shown to empower retinal cells’ antioxidant responses and counteract the adverse impact of prooxidant stimuli on sight.
... Previous studies have demonstrated that ROS and other important enzymes related to the redox system are altered during glaucoma pathology. For example, glutathione (GSH) activity is significantly downregulated in the peripheral blood of patients with several types of glaucoma [40] and in the retinas of ph-IOP mouse model [26], and a study concluded that the redox proteins thioredoxin(TXN)1 and TXN2 support RGCs survival in experimental glaucoma [41]. In addition, NADHP and others enzymes have been shown to show changes in models of ph-IOP. ...
Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular pressure (ph-IOP) is an important risk factor for glaucoma, and it triggers molecularly distinct cascades that control RGC death and axonal degeneration. Dynamin-related protein 1 (Drp1)-mediated abnormalities in mitochondrial dynamics are involved in glaucoma pathogenesis; however, little is known about the precise pathways that regulate RGC injury and death. Here, we aimed to investigate the role of the ERK1/2-Drp1-reactive oxygen species (ROS) axis in RGC death and the relationship between Drp1-mediated mitochondrial dynamics and PANoptosis in ph-IOP injury. Our results suggest that inhibiting the ERK1/2-Drp1-ROS pathway is a potential therapeutic strategy for treating ph-IOP-induced injuries. Furthermore, inhibiting Drp1 can regulate RGC PANoptosis by modulating caspase3-dependent, nucleotide-binding oligomerization domain-like receptor-containing pyrin domain 3(NLRP3)-dependent, and receptor-interacting protein (RIP)-dependent pathways in the ph-IOP model. Overall, our findings provide new insights into possible protective interventions that could regulate mitochondrial dynamics to improve RGC survival.
Cardiac fibrosis, characterized by excessive collagen accumulation in heart tissues, poses a significant clinical challenge in various heart diseases and complications. Although salvianolic acid A (Sal A) from Danshen ( Salvia miltiorrhiza ) has shown promise in the treatment of ischemic heart disease, myocardial infarction, and atherosclerosis, its effects on cardiac fibrosis remain unexplored. Our study investigated the efficacy of Sal A in reducing cardiac fibrosis and elucidated its underlying molecular mechanisms. We observed that Sal A demonstrated significant cardioprotective effects against Angiotensin II (Ang II)-induced cardiac remodeling and fibrosis, showing a dose-dependent reduction in fibrosis in mice and suppression of cardiac fibroblast proliferation and fibrotic protein expression in vitro . RNA sequencing revealed that Sal A counteracted Ang II-induced upregulation of Txnip, and subsequent experiments indicated that it acts through the inflammasome and ROS pathways. These findings establish the anti-fibrotic effects of Sal A, notably attenuated by Txnip overexpression, and highlight its significant role in modulating inflammation and oxidative stress pathways. This underscores the importance of further research on Sal A and similar compounds, especially regarding their effects on inflammation and oxidative stress, which are key factors in various cardiovascular diseases.
Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to vision impairment and finally blindness. This is a rare disease with mutations in several genes and high genetic heterogeneity. A challenging effort has been the characterization of the molecular mechanisms underlying photoreceptor cell death during the progression of the disease. Some of the cell death pathways have been identified and comprise stress events found in several neurodegenerative diseases such as oxidative stress, inflammation, calcium imbalance and endoplasmic reticulum stress. Other cell death mechanisms appear more relevant to photoreceptor cells, such as high levels of cGMP and metabolic changes. Here we review some of the cell death pathways characterized in the RP mutant retina and discuss preclinical studies of therapeutic approaches targeting the molecular outcomes that lead to photoreceptor cell demise.
