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The morphology of retinal structure under light microscope (hematoxylin-eosin staining ×400). (a–c) Control group; (d–f) diabetic group. Numbers 1–6 represent layers of ganglion cell, inner plexiform, inner nuclear, outer plexiform, outer nuclear, rods, and cones.
Source publication
This paper aims to explore the relationship of retinal neuron apoptosis and manganese superoxidase dismutase (MnSOD) at early phase of diabetic retinopathy. Sprague-Dawley rats were grouped into normal controls and diabetics. Data were collected after 4, 8, and 12 weeks (n = 12). The pathological changes and ultrastructure of the retina, the apopto...
Citations
... Exendin-4 (a glucagon-like protein) increased GSH and magnesium superoxide dismutase levels, decreased NADPH oxidase levels, inhibited ROS production and cyt-c release, and prevented apoptosis in high glucose-induced adult human retinal pigment epithelial-19 cells by inhibiting p66Shc expression and activation (186). In a study on the relationship between retinal neuronal apoptosis and MnSOD in diabetic rats, it was noted that apoptosis increased in diabetic rats at 8 and 12 weeks, and the number of RGC cells decreased at 12 weeks, while MnSOD activity and mRNA levels decreased at 4, 8 and 12 weeks, indicating a close relationship between MnSOD and RGC apoptosis (187). Similarly, two other studies had shown that MnSOD overexpression inhibited the increase in 8-OHdG and nitrotyrosine levels, prevented the decrease in GSH and total antioxidant capacity caused by DR (188,189). ...
Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycaemia, with absolute insulin deficiency or insulin resistance as the main cause, and causes damage to various target organs including the heart, kidney and neurovascular. In terms of the pathological and physiological mechanisms of DM, oxidative stress is one of the main mechanisms leading to DM and is an important link between DM and its complications. Oxidative stress is a pathological phenomenon resulting from an imbalance between the production of free radicals and the scavenging of antioxidant systems. The main site of reactive oxygen species (ROS) production is the mitochondria, which are also the main organelles damaged. In a chronic high glucose environment, impaired electron transport chain within the mitochondria leads to the production of ROS, prompts increased proton leakage and altered mitochondrial membrane potential (MMP), which in turn releases cytochrome c (cyt-c), leading to apoptosis. This subsequently leads to a vicious cycle of impaired clearance by the body’s antioxidant system, impaired transcription and protein synthesis of mitochondrial DNA (mtDNA), which is responsible for encoding mitochondrial proteins, and impaired DNA repair systems, contributing to mitochondrial dysfunction. This paper reviews the dysfunction of mitochondria in the environment of high glucose induced oxidative stress in the DM model, and looks forward to providing a new treatment plan for oxidative stress based on mitochondrial dysfunction.
... In addition, ATP-gated cation channels, such as the P2X7 receptor (P2X7R), may also be the targets for RGC death after early-phase injury [23]. In STZ-injected rats, RGC apoptosis, as well as a decreased mRNA level of manganese superoxidase dismutase (MnSOD), a critical antioxidant enzyme, was observed in the retina only four weeks after DM induction [24]. Another example of early neuronal injury is that receptor of advanced glycation end-products (RAGE), a neuronal injuryassociated cytokine receptor, is upregulated in RGCs of high-fat-diet diabetic rats. ...
... In addition, ATP-gated cation channels, such as the P2X7 receptor (P2X7R), may also be the targets for RGC death after early-phase injury [23]. In STZ-injected rats, RGC apoptosis, as well as a decreased mRNA level of manganese superoxidase dismutase (MnSOD), a critical antioxidant enzyme, was observed in the retina only four weeks after DM induction [24]. Another example of early neuronal injury is that receptor of advanced glycation end-products (RAGE), a neuronal injury-associated cytokine receptor, is upregulated in RGCs of high-fat-diet diabetic rats. ...
Diabetic retinopathy (DR), the most common microvascular compilation of diabetes, is the leading cause of vision loss and blindness worldwide. Recent studies indicate that retinal neuron impairment occurs before any noticeable vascular changes in DR, and retinal ganglion cell (RGC) degeneration is one of the earliest signs. Axons of RGCs have little capacity to regenerate after injury, clinically leading the visual functional defects to become irreversible. In the past two decades, tremendous progress has been achieved to enable RGC axon regeneration in animal models of optic nerve injury, which holds promise for neural repair and visual restoration in DR. This review summarizes these advances and discusses the potential and challenges for developing optic nerve regeneration strategies treating DR.
... As mentioned previously, oxidative stress is prone to occur in cells under high glucose conditions. Antioxidant substances in retinal cells of diabetic individuals are reduced (e.g., MnSOD is reduced [133,134]), while the oxidative system is hyperactive (e.g., Nox2 is increased [135]), and a large amount of ROS is generated to cause mitochondrial damage. Mitochondrial damage can induce apoptosis of retinal capillary endothelial cells, pericytes, and neurons through content extravasation and activation of apoptosis-related signaling pathways [136][137][138][139]. ...
Diabetic Retinopathy (DR) is one of the most important microvascular complications of diabetes mellitus, which can lead to blindness in severe cases. Mitochondria are energy-producing organelles in eukaryotic cells, which participate in metabolism and signal transduction, and regulate cell growth, differentiation, aging, and death. Metabolic changes of retinal cells and epigenetic changes of mitochondria-related genes under high glucose can lead to mitochondrial dysfunction and induce mitochondrial pathway apoptosis. In addition, mitophagy and mitochondrial dynamics also change adaptively. These mechanisms may be related to the occurrence and progression of DR, and also provide valuable clues for the prevention and treatment of DR. This article reviews the mechanism of DR induced by mitochondrial dysfunction, and the prospects for related treatment.
... [35][36][37] Additionally, lipid oxidation may mediate oxidative stress in patients with DM, which leads to the occurrence and development of DR. 38,39 Mitochondria are the main source of intracellular reactive oxygen and the target of oxidative damage. Mitochondrial oxidative stress and decreased adenosine triphosphate concentration required for energy metabolism are believed to play an important role in the development of DR. 40,41 Lipids not only affect mitochondrial function but also directly affect phospholipids, causing changes in the lipid structure of cell membranes participating in the pathogenesis of DR. 42,43 Therefore, dyslipidemia is a risk factor for DR. ...
Purpose
We aimed to investigate the association between lipid profiles and diabetic retinopathy (DR).
Patients and Methods
This case-control study, which was conducted between November 2019 and August 2021, comprised 309 patients with DR, 186 patients with diabetes mellitus, and 172 healthy controls. Serum cholesterol (CHOL), triglyceride (TRIG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (SDLDL-C), apolipoprotein A (APOA), APOB, APOE and lipoprotein (a)(LPA) levels were assessed. Patients were divided into two groups according to median age and glycated hemoglobin (HbA1c) level. Linear and logistic regression analyses were performed to assess the association between lipid levels and DR.
Results
CHOL, TRIG, HDL-C, APOB, APOE, and SDLDL-C levels were significantly higher in the DR group than in the healthy control group, and TRIG levels were lower in the DR group than in the DM group (P < 0.05), especially in the ≤57-year-old and the HbA1c ≤7.2% subgroups. Linear regression analyses showed that CHOL, TRIG, APOA, APOB, APOE, and SDLDL-C levels were associated with HbA1c levels. Multivariable logistic regression analyses indicated that CHOL (odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.112–1.566), TRIG (OR = 1.269, 95% CI = 1.030–1.563), HDL-C (OR = 43.744, 95% CI = 17.12–111.769), APOB (OR = 7.037, 95% CI = 3.370–14.695), APOE (OR = 1.057, 95% CI = 1.038–1.077), and SDLDL-C (OR = 14.719, 95% CI = 8.304–26.088) levels were risk factors for DR (P < 0.05).
Conclusion
Increased lipid levels were risk factors for DR, and lipid level control should be strengthened, especially in younger adults or in patients with HbA1c ≤7.2%.
... Some studies have found that, after SOD1 aging, the cells of the inner and outer nuclear cell layers swell and the intracellular mitochondria are degraded. When the activity of manganese superoxide dismutase (MnSOD) and its mRNA expression were decreased, mitochondrial function was impaired, and the inner nuclear layer (INL) was thinned [8][9][10][11]. Reductions in mitochondrial volume and distribution may indicate that retinal ganglion cells in glaucoma are in a state of increased metabolic strain. Genomic analysis revealed that many instances of retinal endometrial cell apoptosis were caused by mutations in mitochondrial genes or nuclear genes encoding mitochondrial proteins [12]. ...
... OPA1 is a major gene that leads to optic nerve atrophy (DOA). OPA1 encodes dynamin in mitochondria, supports the intimal structure, and is widely expressed [8,9]. The glutamate receptor initiates acute intraocular hypertension, and ischemic injury induces the retinal mitochondria to release OPA1 and activate the cell death pathway, resulting in the apoptosis of inner retinal cells [15][16][17]. ...
Mitochondria are the energy factories of cells. Mitochondrial dysfunction directly affects the function and morphology of cells. In recent years, growing evidence has shown that mitochondrial dysfunction plays an important role in neurodegenerative diseases. In the eye, some age-related diseases are considered to be neurodegenerative diseases, such as primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). Here, we review the mechanisms of mitochondrial damage, post-injury repair, and the roles of mitochondria in various tissues of the eye. In the following sections, the potential for treating glaucoma by reducing mitochondrial damage and promoting post-injury repair is also discussed.
... Caspase-3 and -9 substrates were used for the assays of caspase-3 (c) and caspase-9 (d) (*p ≤ 0.05 vs control (Ctr) and GSH groups. **p ≤ 0.05 vs BEV group) [45,46]. We want to clarify changes of [Zn 2+ ] c in the ARPE-19 cells treated with BEV and GSH. ...
Purpose
Bevacizumab (BEV) is a blocker of circulating VEGF A generation. However, BEV has adverse apoptotic and cytotoxic effects via upregulation of mitochondrial reactive oxygen species (ROS) and TRPM2 activation, and downregulation of cytosolic glutathione (GSH) in neuronal cells. We investigated the possible protective effects of GSH treatment on BEV-induced oxidant and apoptotic adverse actions in the TRPM2 expressing adult retinal pigment epithelial-19 (ARPE-19) and SH-SY5Y neuronal cells.
Material and methods
The ARPE-19 and SH-SY5Y cells were divided into five main groups: Control, GSH (10 mM for 2 h), BEV (0.25 mg/ml for 24 h), BEV+GSH, and BEV+TRPM2 channel blockers (ACA or 2-APB). In the SH-SY5Y cells, the Ca²⁺ analyses (Fluo-3) were performed only, although Fluo-3 and the remaining analyses were performed in the ARPE-19 cells.
Results
The levels of apoptosis, cell death, mitochondrial ROS, lipid peroxidation, caspase-3, caspase-9, ADP-ribose-induced TRPM2 current density, cytosolic-free Zn²⁺, and Ca²⁺ were increased by BEV, although their levels were diminished by the treatments of GSH and TRPM2 blockers. The BEV-induced decreases of cell viability, GSH levels, and glutathione peroxidase activities were increased by the treatment of GSH. BEV-induced increase of TRPM2 expression was decreased by the treatment of GSH, although BEV-induced decrease of VEGF A expression was further decreased by the treatment of GSH.
Conclusion
Our data confirmed that BEV-induced mitochondrial ROS and apoptosis in the human retinal epithelial cells were modulated by GSH and TRPM2 inhibition. The treatment of GSH may be considered as a therapeutic approach to BEV-induced ARPE-19 cell injury.
... Degenerated mitochondria were present in GCs and some were shrunk and had condensed cytoplasm, decreased organelles with undefined nuclear membrane and cytoplasmic vacuoles [52] . Morphological changes in IPL due to neurodegenerative alterations displayed as neuronal apoptosis [54] . We can deduce that hyperglycaemia associated with metabolic disorders caused degenerative retinal changes in DR by inducing microvascular complications, neovascularization, and a breakdown of the blood-retinal barrier [2] . ...
... Moreover, a recent study showed that daily intraperitoneal injection of fenofibric acid significantly decreased retinal apoptosis in STZ-induced diabetes [40]. Hence, long-term studies will be needed to support the idea that pemafibrate has potential for treatment of diabetic retinopathy since apoptosis is involved in the pathophysiology of this disease [41]. Furthermore, more beneficial effects of pemafibrate include usefulness for patients who have renal dysfunction because it is metabolized in the liver [42]. ...
Excitotoxicity is involved in the retinal neuronal cell death in diabetic retinopathy. Although fenofibrate has been shown to ameliorate the progression of diabetic retinopathy, the effect of pemafibrate, which is highly selective for peroxisome proliferator-activated receptor α on retinal neuronal cell death has not been documented. Here, we investigated whether pemafibrate exerts a beneficial effect against retinal ganglion cell (RGC) death induced by N-methyl-D-aspartate (NMDA) in rats. Experiments were performed on adult male Wistar rats that received an intravitreal injection of 20 nmol NMDA. Fluoro-Gold labeled RGC morphometry showed that oral intake of pemafibrate once a day for 7 days resulted in significant protection on RGC death induced by NMDA. Phosphorylated c-Jun protein, which is involved in apoptosis, was upregulated after NMDA exposure, and this increase was significantly lessened by the systemic pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with Thy-1 immunopositive cells, and the increased these cells were ameliorated by the pemafibrate treatment. An increase in TUNEL-positive cells was significantly suppressed by the pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with TUNEL-positive cells, and they were decreased by pemafibrate treatment. These results suggest that the RGC protection achieved with pemafibrate appears to be associated with inhibition of phosphorylated c-Jun and its anti-apoptotic effect.
... In addition, impairment of RPE mitochondria is associated with increased oxidative stress, reduced ATP, and compromised autophagic and phagocytic capacities (142). Impairment of neuronal mitochondria contributes to the loss of retinal synapses and neuronal cell death in diabetes (143,144). ...
Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of diabetic complications, including diabetic retinopathy (DR). This review article provides an overview of the results of clinical trials evaluating the potential benefits of lipid lowering drugs, such as fibrates, omega 3 fatty acids, and statins, for the prevention and treatment of DR. Although several clinical trials demonstrated that treatment with fibrates leads to improvement of DR, there is a dissociation between the protective effects of fibrates in the retina, and the intended blood lipid classes, including plasma triglycerides, total cholesterol or HDL/LDL cholesterol ratio. Guided by these findings, plasma lipid and lipoprotein-independent mechanisms are addressed based on clinical, cell culture and animal model studies. Potential retinal-specific effects of fatty acids oxidation products, cholesterol, and ceramide, as well as lipid independent effects of PPAR alpha activation are summarized based on current literature. Overall, this review highlights promising potential of lipid-based treatment strategies further enhanced by the new knowledge of intra-retinal lipids and lipoproteins in DR.
... Decreasing oxidative stress in diabetic rodents with copper/zinc superoxide dismutase (Cu/Zn SOD) overexpression or lipoic acid administration corrected the diabetes-induced ion flux abnormalities in photoreceptors in the dark [145,193], suggesting that abnormalities in ion homeostasis are induced by increased oxidative stress. Studies showing that diabetes elevates oxidative stress in the retina by both promoting ROS production and suppressing the antioxidant defense [117] also provide strong support for this hypothesis. ...
Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease.
