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Localization of chaperone molecules in the mouse retina 3 days after treatment with bilberry extract.
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Purpose
To investigate the effect of bilberry extract anthocyanins on retinal ganglion cell (RGC) survival after optic nerve crush. Additionally, to determine details of the mechanism of the neuroprotective effect of bilberry extract anthocyanins and the involvement of endoplasmic reticulum stress suppression in the mouse retina.
Materials and met...
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Purpose
Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene...
Citations
... In a recent study on mice [93], anthocyanins in bilberry extract (100 mg/kg/day or 500 mg/kg/day) were administered orally, and the expression levels of various molecular chaperones and RGC survival were appraised. This study showed that oral bilberry extract administration could suppress RGC death and increase glucose-regulated protein 78 (Grp78) and Grp94 protein levels, an effect which may underlie the neuroprotective effect of bilberry extract after optic nerve damage. ...
... Neuroprotective effects through retinal microcirculation improvement both in animal and human models [93] Slight IOP reduction if administered orally in patients with ocular hypertension [94][95][96] No data on POAG and NTG patients Ribes nigrum L. ...
Glaucoma causes the degeneration of the retinal ganglion cells (RGCs) and their axons, inducing a tissue reshaping that affects both the retina and the optic nerve head. Glaucoma care especially focuses on reducing intraocular pressure, a significant risk factor for progressive damage to the optic nerve. The use of natural treatments, such as herbs, vitamins, and minerals, is becoming increasingly popular today. While plants are a rich source of novel biologically active compounds, only a small percentage of them have been phytochemically examined and evaluated for their medicinal potential. It is necessary for eye care professionals to inform their glaucoma patients about the therapy, protection, and efficacy of commonly used herbal medicines, considering the widespread use of herbal medicines. The purpose of this review is to examine evidence related to the most widely used herbal medicines for the management and treatment of glaucoma, to better understand the potential benefits of these natural compounds as supplementary therapy.
... Grp78 and Grp94 increased in the ganglion cell layer and the inner nuclear layer of the retina after the administration of anthocyanins. At the same time, elevated levels of BAX, Chop, and Atf4 expression, which were observed after optic nerve crush, experienced a significant decline (Nakamura et al. 2017). Thus, anthocyanins may play a potential role in neuroprotective treatment for glaucoma. ...
Neurodegenerative ocular disorders mostly develop with aging and present great complications in the quality of life. Glaucoma and age-related macular degeneration (ARMD) rank as the third and fourth leading causes of blindness and low vision. Oxidative stress is one factor in the pathogenesis of neurodegenerative eye disease. In addition, ocular ischemia and neuroinflammation play an important role. It can be hypothesized that the influence of antioxidants through diet or oral supplementation can counteract the harmful effects of reactive oxygen species accumulated secondary to oxidative stress, ischemia, and inflammation. A range of studies has been published over the past decades focusing on the possible adjuvant effect of antioxidants in ARMD, while there were fewer reports on the potential role of antioxidants in glaucoma. Although certain reports demonstrated positive results, others were discouraging. As there is a controversy between the studies favoring and disfavoring supplementation with different types of antioxidants, it is important to revise the existing evidence on the role of antioxidants in neurodegenerative ocular disorders with a special focus on glaucoma and ARMD.
... Rd10 mice (RP) [375] Prph2/rds mouse [376] Ganglion cell damage models: Glaucoma model in rats [377] Mouse, ischemia/reperfusion [378] (rasagiline + idebenone) Others: Retinal detachment: NCT02068625 (Macula off-retinal detachment) [379] Norgestrel/ Progesterone IRD and retinal damage models: Pde6b Rd10 mouse [380][381][382] Rd1 mice (L + Z + lipoic acid + glutathione + Lycium barbarum) Rd1 mouse [383] Rd10 mice [384] Acute light-induced degeneration model in mice [382,385] Ganglion cell damage models: Rat models of ocular ischemia [386] Review: [387] IRD and retinal damage models: Light-induced photoreceptor degeneration in rats (+L) [390] Light damage in rabbits [391] MNU-induced damage in rats [392] Other retinal disease models: Oxygen-induced retinopathy in mice [393] IRD and retinal damage models: Photo-stressed murine model [394] Light damage in rabbits [395] AMD models: OXYS rats [396] DR models: STZ rats [397] Other retinal disease models: Oxygen-induced retinopathy in mice [398] Ganglion cell damage models: Optic nerve crush in mice [399] Uveitis models: Endotoxin-induced uveitis in mice [400] Metabolism and Clearance of Cyanidin ...
Inherited retinal dystrophies (IRDs) are a large group of genetically and clinically heterogeneous diseases characterized by the progressive degeneration of the retina, ultimately leading to loss of visual function. Oxidative stress and inflammation play fundamental roles in the physiopathology of these diseases. Photoreceptor cell death induces an inflammatory state in the retina. The activation of several molecular pathways triggers different cellular responses to injury, including the activation of microglia to eliminate debris and recruit inflammatory cells from circulation. Therapeutical options for IRDs are currently limited, although a small number of patients have been successfully treated by gene therapy. Many other therapeutic strategies are being pursued to mitigate the deleterious effects of IRDs associated with oxidative metabolism and/or inflammation, including inhibiting reactive oxygen species’ accumulation and inflammatory responses, and blocking autophagy. Several compounds are being tested in clinical trials, generating great expectations for their implementation. The present review discusses the main death mechanisms that occur in IRDs and the latest therapies that are under investigation.
... Recent studies have shown that anthocyanin extract and C3G ameliorate the abnormal ER stress responses in various disease conditions (Liu et al., 2020;Sukprasansap, Chanvorachote, & Tencomnao, 2020). Purple rice and bilberry anthocyanin extracts protect retinal ganglion cells by increasing BiP protein levels during ER stress (Nakamura et al., 2017;Tanaka et al., 2013), which may be promising functional ingredients to prevent glaucoma. C3G alleviates the destruction of periodontitis by downregulating ligation-activated ER stress (Tu et al., 2022). ...
Excessive exposure to blue light from smartphones, computers, and other video equipment causes retinal degeneration. Cyanidin-3-glucoside (C3G) exerts protective effects on retinal cells. However, the mechanism by which C3G enhances the barrier function of retinal pigment epithelial (RPE) cells remains unclear. This study investigated the effects of C3G on blue light-irradiated A2E-containing RPE cells and explored whether or not the endoplasmic reticulum (ER) stress and downstream nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways are involved in the mechanism. Results showed that C3G (10 and 25 μM) observably increased the viability and inhibited the apoptosis of RPE cells. Furthermore, C3G enhanced the barrier function of RPE cells and upregulated the expression of tight junction proteins. Blue light irradiation triggered ER stress, but C3G significantly suppressed the PERK/eIF2α/ATF4/CHOP pathway and maintained normal ER morphology in RPE cells. C3G also activated the Nrf2 pathway to promote RPE survival, which was independent of ER stress modulating Nrf2 activity. This study suggests that C3G promotes the barrier function of RPE cells by regulating ER stress-induced apoptosis, thereby offering a new approach to preventing retinal diseases. Thus, C3G is a potential functional food ingredient to improve visual health.
... The natural anthocyanins delphinidin, luteolinidin and peonidin were shown to be non-toxic to human retinal pigment epithelial (ARPE19) and RGC-5 cells, with luteolinidin and peonidin increasing the survival rates of the RGC-5 cells following exposure to H 2 O 2 [207]. Administration of oral bilberry extracts rich in anthocyanins was shown to suppress RGC death following an optic nerve injury mouse model [208]. Bilberry extract administration increased chaperone molecule (Grp78 and Grp94) protein levels, an effect which may underlie the neuroprotective effect of bilberry extract after optic nerve crush [208]. ...
... Administration of oral bilberry extracts rich in anthocyanins was shown to suppress RGC death following an optic nerve injury mouse model [208]. Bilberry extract administration increased chaperone molecule (Grp78 and Grp94) protein levels, an effect which may underlie the neuroprotective effect of bilberry extract after optic nerve crush [208]. In a model of light-induced retinal damage in pigmented rabbits, administration of bilberry anthocyanin extract at dosages of 250 and 500 mg/kg/day for 7 days significantly inhibited retinal dysfunction, as evidenced by the increased retinal outer nuclear layer thicknesses and lengths of the outer segments of the photoreceptor cells, compared to untreated rabbits with retinal degeneration [209]. ...
Glaucoma is one of the leading causes of irreversible blindness. It is generally caused by increased intraocular pressure, which results in damage of the optic nerve and retinal ganglion cells, ultimately leading to visual field dysfunction. However, even with the use of intraocular pressure-lowering eye drops, the disease still progresses in some patients. In addition to mechanical and vascular dysfunctions of the eye, oxidative stress, neuroinflammation and excitotoxicity have also been implicated in the pathogenesis of glaucoma. Hence, the use of natural products with antioxidant and anti-inflammatory properties may represent an alternative approach for glaucoma treatment. The present review highlights recent preclinical and clinical studies on various natural products shown to possess neuroprotective properties for retinal ganglion cells, which thereby may be effective in the treatment of glaucoma. Intraocular pressure can be reduced by baicalein, forskolin, marijuana, ginsenoside, resveratrol and hesperidin. Alternatively, Ginkgo biloba, Lycium barbarum, Diospyros kaki, Tripterygium wilfordii, saffron, curcumin, caffeine, anthocyanin, coenzyme Q10 and vitamins B3 and D have shown neuroprotective effects on retinal ganglion cells via various mechanisms, especially antioxidant, anti-inflammatory and anti-apoptosis mechanisms. Extensive studies are still required in the future to ensure natural products’ efficacy and safety to serve as an alternative therapy for glaucoma.
... However, treatment with purple sweet potato extract entirely mitigated this effect, returning these markers to normal levels and preventing ER stress-induced apoptosis. It has also been shown that anthocyanin-rich bilberry extract up-regulates chaperone proteins associated with inhibition of ER stress-induced apoptosis in a mouse model of optic nerve-crush injury, preventing the death of retinal ganglion cells [114]. Though to our knowledge, these are the only studies to date exploring the effects of anthocyanin extracts on neuronal ER stress in vivo, they demonstrate that these compounds may show some benefit in neurodegenerative disorders for which ER stress and concomitant protein dysregulation is an underlying factor ( Figure 6). ...
... However, treatment with purple sweet potato extract entirely mitigated this effect, returning these markers to normal levels and preventing ER stress-induced apoptosis. It has also been shown that anthocyanin-rich bilberry extract up-regulates chaperone proteins associated with inhibition of ER stress-induced apoptosis in a mouse model of optic nerve-crush injury, preventing the death of retinal ganglion cells [114]. Though to our knowledge, these are the only studies to date exploring the effects of anthocyanin extracts on neuronal ER stress in vivo, they demonstrate that these compounds may show some benefit in neurodegenerative disorders for which ER stress and concomitant protein dysregulation is an underlying factor ( Figure 6). . ...
Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), are characterized by the death of neurons within specific regions of the brain or spinal cord. While the etiology of many neurodegenerative diseases remains elusive, several factors are thought to contribute to the neurodegenerative process, such as oxidative and nitrosative stress, excitotoxicity, endoplasmic reticulum stress, protein aggregation, and neuroinflammation. These processes culminate in the death of vulnerable neuronal populations, which manifests symptomatically as cognitive and/or motor impairments. Until recently, most treatments for these disorders have targeted single aspects of disease pathology; however, this strategy has proved largely ineffective, and focus has now turned towards therapeutics which target multiple aspects underlying neurodegeneration. Anthocyanins are unique flavonoid compounds that have been shown to modulate several of the factors contributing to neuronal death, and interest in their use as therapeutics for neurodegeneration has grown in recent years. Additionally, due to observations that the bioavailability of anthocyanins is low relative to that of their metabolites, it has been proposed that anthocyanin metabolites may play a significant part in mediating the beneficial effects of an anthocyanin-rich diet. Thus, in this review, we will explore the evidence evaluating the neuroprotective and therapeutic potential of anthocyanins and their common metabolites for treating neurodegenerative diseases.
... Other than our study on AION, differential regulation of GRP78 and CHOP expression, that is, reduced GRP78 and increased CHOP expression, has been found in RGCs in animal models of optic neuritis and traumatic optic neuropathy. 77 Similarly, successful treatment of experimental optic neuropathies and improved RGC survival 77,78 have also been associated with differential expression of GRP78 and CHOP in the opposite direction, that is, increased GRP78 79 and decreased CHOP expression in cells in the RGC layer. Nakamura et al. 78 showed that RGC loss after optic nerve crush animal model was associated with decreased GRP78 and increased CHOP expression and that treatment with bilberry extract anthocyanins led to improved RGC survival, increased GRP78 and decreased CHOP expressions, along with reduced expression of BAX and ATF4, which are downstream of DDIT3 (CHOP). ...
... 77 Similarly, successful treatment of experimental optic neuropathies and improved RGC survival 77,78 have also been associated with differential expression of GRP78 and CHOP in the opposite direction, that is, increased GRP78 79 and decreased CHOP expression in cells in the RGC layer. Nakamura et al. 78 showed that RGC loss after optic nerve crush animal model was associated with decreased GRP78 and increased CHOP expression and that treatment with bilberry extract anthocyanins led to improved RGC survival, increased GRP78 and decreased CHOP expressions, along with reduced expression of BAX and ATF4, which are downstream of DDIT3 (CHOP). Jiang et al. 77 showed that transplantation of human umbilical cord cells as treatment for traumatic optic neurop- There was significant thickening of GCC at day 1 in both groups and significant preservation of GCC thickness in the 4-PBA-treated AION eyes (n ¼ 9-10, *P ¼ 0.01, 1-way ANOVA with Tukey multiple comparison test). ...
Purpose:
Increased endoplasmic reticulum (ER) stress is one of the earliest subcellular changes in neuro-ophthalmic diseases. In this study, we investigated the expression of key molecules in the ER stress pathways following nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults over 50, and assessed the impact of chemical chaperon 4-phenylbutyric acid (4-PBA) in vivo.
Methods:
We induced AION using photochemical thrombosis in adult mice and performed histologic analyses of key molecules in the ER stress pathway in the retina and optic nerve. We also assessed the effects of daily intraperitoneal injections of 4-PBA after AION.
Results:
In the retina at baseline, there was low proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) and high prosurvival chaperon glucose-regulated protein 78 (GRP78) expression in retinal ganglion cells (RGCs). One day after AION, there was significantly increased CHOP and reduced GRP78 expressions in the ganglion cell layer. In the optic nerve at baseline, there was little CHOP and high GRP78 expression. One day after AION, there was significantly increased CHOP and no change in GRP78 expression. Treatment immediately after AION using daily intraperitoneal injection of chemical chaperone 4-PBA for 19 days significantly rescued Brn3A+ RGCs and Olig2+ optic nerve oligodendrocytes.
Conclusions:
We showed for the first time that acute AION resulted in increased ER stress and differential expression of ER stress markers CHOP and GRP78 in the retina and optic nerve. Rescue of RGCs and oligodendrocytes with 4-PBA provides support for ER stress reduction as possible treatment for AION.
... В экспериментальных исследованиях in vitrо и in vivo показано, что активация молекулярных шаперонов способствует сохранению клеток при стрессе ЭПР. В особенности это касается шаперона Grp78, который играет важную роль в ослаблении процесса апоптоза, и шаперона Grp94, подавляющего гибель нейронов при ишемии/реперфузии [9,10]. Эти данные подтверждают, что молекулярные шапероны Grp78 и Grp94 задействованы в защите поврежденных клеток при стрессе ЭПР. ...
... В настоящее время в литературе описаны результаты экспериментального и клинического изучения влияния антоцианозидов экстракта черники на сохранение функциональной активности сетчатки и зрительного нерва при нейродегенеративных заболеваниях [10]. ...
... В связи с этим огромный интерес представляет исследование O. Nakamura и соавт. [10], которые изучали нейропротекторное действие антоци-Молекулярные механизмы повреждения зрительного нерва: роль антоцианозидов в профилактике гибели ганглиозных клеток Ðîññèéñêèé îôòàëüìîëîãè÷åñêèé aeóðíàë, 2018; 3: 101-106 104 анозидов черники на ГКС при моделировании травматического повреждения зрительного нерва у мышей С57BL/6J в эксперименте in vivo. Все животные были разделены на группы: в 1-ю группу вошли мыши, получавшие буферный раствор, мыши 2-й и 3-й групп получали экстракт черники с кормом (100 и 500 мг/кг соответственно) за 3 дня до травмы и в течение 7 дней после травмы. ...
The literary review focuses on the dysfunction of endoplasmic reticulum (EPR), the role of EPR stress and oxidative stress in the pathogenesis of optic nerve damage. The data on the molecular mechanisms of optic nerve damage are given: these include the expression of genes and molecular chaperones, which are related to EPR stress and antioxidant protection. The studies into oral administration of bilberry extract anthocyanosides showed elevated levels of molecular chaperones in retinal ganglion cells (RGC). The chaperones suppress EPR stress and produce a positive effect on the metabolic activity of the cells. Thus, bilberry extract anthocyanosides may be considered as neuroprotectors in combined treatment of retinal pathology and glaucoma. For citation: Neroev V.V., Kiseleva T.N., Zaitsev М.S. Molecular mechanisms of optic nerve damage: the role of anthocyanozides in the prevention of retinal ganglion cell death. Russian ophthalmological journal. 2018; 11 (3): 101-6 (In Russian). doi: 10.21516/2072-0076-2018-11-3-101-106
When the eyes work intensively, it is easy to have eye discomfort such as blurred vision, soreness, dryness, and tearing, that is, visual fatigue. Visual fatigue not only affects work and study efficiency, but long-term visual fatigue can also easily affect physical and mental health. In recent years, with the popularization of electronic products, although it has brought convenience to the office and study, it has also caused more frequent visual fatigue among people who use electronic devices. Moreover, studies have reported that the number of people with visual fatigue is showing a trend of increasing year by year. The range of people involved is also extensive, especially students, people who have been engaged in computer work and fine instruments (such as microscopes) for a long time, and older adults with aging eye function. More and more studies have proposed that supplementation with the proper nutrients can effectively relieve visual fatigue and promote eye health. This review discusses the physiological mechanisms of visual fatigue and the design ideas of animal experiments from the perspective of modern nutritional science. Functional food ingredients with the ability to alleviate visual fatigue are discussed in detail.
Glaucoma is a neurodegenerative disease leading to visual loss. Since glaucoma is associated with chronic renal diseases (RDs) their rate is higher in patients with RDs, and end-stage RDs (ESRDs) than in the general population and kidney transplant recipients.
Objective
To explore the molecular mechanism of diabetic internal environment in regulating the endoplasmic reticulum stress of the retinal ganglion cells (RGCs).
Methods
Thirty-six SPF grade type 2 diabetes models were divided into 3 groups: Diabetes mellitus (DM), DM + glaucoma and 4-phenylbutyric acid-DM (4-PBA-DM) + glaucoma group. C57BL6 mice of the same week age were taken as the negative control (NC) group. The morphology of RGCs and their axon in the 4 groups were labeled by fluorescent reactive dye Dil. The apoptosis situation of RGCs was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The protein expression values of RTN4IP1, Protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2A (eIF2a) and X-box-binding Protein 1 (XBP1) were determined by western blot. The relative mRNA levels of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), Caspase12 and Bax were determined by quantitative real-time polymerase chain reaction (qRT-PCR).
Results
Glaucoma promotes the apoptosis of RGCs. The protein expression values of RTN4IP1, PERK and XBP1 in DM mouse models with glaucoma were much higher compared to only DM mouse models. Further injection of endoplasmic reticulum stress inhibitor 4-PBA decreased the expression values. The relative mRNA levels of CHOP, Cysteine aspartic acid specific protease12 (Caspase12) and BCL2-associated X protein (Bax) in DM + glaucoma were significantly higher compared to those in DM group. Further injection of endoplasmic reticulum stress inhibitor 4-PBA decreased the mRNA levels.
Conclusion
Endoplasmic reticulum stress (ERS) is the underlying cause of glaucoma, which could promote the apoptosis of RGCs in diabetic mice.
