Multifunctional nanogel loaded with cerium oxide nanozyme and CX3CL1 protein: Targeted immunomodulation and retinal protection in uveitis rat model.

Effectively addressing retinal issues represents a pivotal aspect of blindness-related diseases. Novel approaches involving reducing inflammation and rebalancing the immune response are paramount in the treatment of these conditions. This study delves into the potential of a nanogel system comprising polyethylenimine-benzene boric acid-hyaluronic acid (PEI-PBA-HA). We have evaluated the collaborative impact of cerium oxide nanozyme and chemokine CX3CL1 protein for targeted immunomodulation and retinal protection in uveitis models. Our nanogel system specifically targets the posterior segment of the eyes. The synergistic effect in this area reduces oxidative stress and hampers the activation of microglia, thereby alleviating the pathological immune microenvironment. This multifaceted drug delivery system disrupts the cycle of oxidative stress, inflammation, and immune response, suppressing initial immune cells and limiting local retinal structural damage induced by excessive immune reactions. Our research sheds light on interactions within retinal target cells, providing a promising avenue for the development of efficient and innovative drug delivery platforms.

Tamoxifen protects photoreceptors in the sodium iodate model.

Because the selective estrogen receptor modulator tamoxifen was shown to be retina-protective in the light damage and rd10 models of retinal degeneration, the purpose of this study was to test whether tamoxifen is retina-protective in a model where retinal pigment epithelium (RPE) toxicity appears to be the primary insult: the sodium iodate (NaIO3) model. C57Bl/6J mice were given oral tamoxifen (in the diet) or the same diet lacking tamoxifen, then given an intraperitoneal injection of NaIO3 at 25 mg/kg. The mice were imaged a week later using optical coherence tomography (OCT). ImageJ with a custom macro was utilized to measure retinal thicknesses in OCT images. Electroretinography (ERG) was used to measure retinal function one week post-injection. After euthanasia, quantitative real-time PCR (qRT-PCR) was performed. Tamoxifen administration partially protected photoreceptors. There was less photoreceptor layer thinning in OCT images of tamoxifen-treated mice. qRT-PCR revealed, in the tamoxifen-treated group, less upregulation of antioxidant and complement factor 3 mRNAs, and less reduction in the rhodopsin and short-wave cone opsin mRNAs. Furthermore, ERG results demonstrated preservation of photoreceptor function for the tamoxifen-treated group. Cone function was better protected than rods. These results indicate that tamoxifen provided structural and functional protection to photoreceptors against NaIO3. RPE cells were not protected. These neuroprotective effects suggest that estrogen-receptor modulation may be retina-protective. The fact that cones are particularly protected is intriguing given their importance for human visual function and their survival until the late stages of retinitis pigmentosa. Further investigation of this protective pathway could lead to new photoreceptor-protective therapeutics.

High-speed counter-current chromatography assisted preparative isolation of phenolic compounds from the flowers of Chrysanthemum morifolium cv. Fubaiju.

Chrysanthemum morifolium cv. Fubaiju is rich in phenolic compounds with various benefits such as anti-inflammatory, antioxidant, and cardiovascular protection. In this study, 12 phenolic compounds, including five flavonoid glycosides and seven quinic acid derivatives, were successfully separated from the flowers of Chrysanthemum morifolium cv. Fubaiju by high-speed counter-current chromatography and preparative high-performance liquid chromatography. Ethyl acetate-n-butanol-acetonitrile-water-acetic acid (5:0.5:2.5:5:0.25, v/v/v/v/v) was selected as solvent system to separate six fractions from the flowers of Chrysanthemum morifolium cv. Fubaiju, and 20% aqueous acetonitrile (containing 0.1% formic acid) was chosen to be the elution solvent in preparative high-performance liquid chromatography for purifying the fractions above. Luteolin-7-O-ß-D-glucoside (1), luteolin-7-O-ß-D-glucuronide (2), apigenin-7-O-ß-D-glucoside (3), luteolin-7-O-ß-D-rutinoside (4), diosmetin-7-O-ß-D-glucoside (5), chlorogenic acid (6), 1,5-dicaffeoylquinic acid (7), 1,4-dicaffeoylquinic acid (8), 3,4-dicaffeoylquinic acid (9), 3,4-dicaffeoyl-epi-quinic acid (10), 3,5-dicaffeoylquinic acid (11), and 4,5-dicaffeoylquinic acid (12) were isolated with purities all above 95%, respectively. In addition, all isolates were evaluated for their protective effects on H2 O2 -induced oxidative damage in adult retinal pigment epithelial cells.

Retinal protective effect of curcumin metabolite hexahydrocurcumin against blue light-induced RPE damage.

BACKGROUND: Age-related macular degeneration (AMD) is a disease of retinal pigment epithelium (RPE) cells. We have previously demonstrated that blue light can damage RPE cells and their underlying mechanisms. We found that hexahydrocurcumin (HHC), a metabolite of curcumin, had better retinal protection than curcumin. However, the involved mechanisms remain unclear. METHODS: By exposing ARPE-19 human RPE cells and mouse primary RPE cells to blue light, the intracellular mechanisms of HHC in cells were investigated, including the proliferation of RPE cells and the effects of HHC on activating intracellular protective mechanisms and related factors. Next-generation sequencing (NGS) RNA sequencing revealed the underlying mechanisms involved in the induction and regulation of HHC treatment following blue light exposure. RESULTS: HHC promoted autophagy by enhancing autophagic flux, reduced oxidative stress and endoplasmic reticulum (ER) stress, and effectively reversed blue light-induced cell death. RNA sequencing-based bioinformatics approaches comprehensively analyze HHC-mediated cellular processes. CONCLUSION: Our findings elucidate the mechanisms of HHC against blue light damage in RPE cells and are beneficial for the development of natural metabolite-based preventive drugs or functional foods.

Tsp-1 is involved in DNA stability through Tgf-ß1 activation domain in cone photoreceptor 661 W cells.

Thrombospondin-1 (Tsp-1), a matricellular protein, could protect retinal neurons from endogenous or exogenous insults; however, its underlying mechanism remains unclear. Thus, this study aimed to investigate Tsp-1-mediated neuron-protection effect in retinal cells. Our data showed that Tsp-1 downregulation would aggravate UV irradiation-induced DNA damage in 661 W cells and cone photoreceptor cells. The increasing levels of poly (ADP ribose) polymer (PAR) and γ-H2AX in Tsp-1-silenced 661 W cells indicate severe DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). By utilizing an error-prone substrate, Tsp-1 silencing significantly increased deleted DNA end joining in 661 W cells with spontaneous DNA damage (SDD). Moreover, Tsp-1 is indirectly involved in DNA stability in 661 W cells as UV treatment caused a significant Tsp-1 decreasing in cytoplasm, but no obvious Tsp-1 alteration in cell nuclear of 661 W cells. Furthermore, our data indicate that Tgf-ß1 activation domain in Tsp-1 plays a critical role in DNA stability in 661 W cells through expressing mutated exogenous Tsp-1 and Tgf-ß inhibitor, LSKL. Therefore, this study provides new insights into the mechanism of the neuroprotective action positively mediated by Tsp-1, which might be a therapeutic target for the treatment of retinal pathology.

Retinal Protection from LED-Backlit Screen Lights by Short Wavelength Absorption Filters.

(1) Background: Ocular exposure to intense light or long-time exposure to low-intensity short-wavelength lights may cause eye injury. Excessive levels of blue light induce photochemical damage to the retinal pigment and degeneration of photoreceptors of the outer segments. Currently, people spend a lot of time watching LED screens that emit high proportions of blue light. This study aims to assess the effects of light emitted by LED tablet screens on pigmented rat retinas with and without optical filters. (2) Methods: Commercially available tablets were used for exposure experiments on three groups of rats. One was exposed to tablet screens, the other was exposed to the tablet screens with a selective filter and the other was a control group. Structure, gene expression (including life/death, extracellular matrix degradation, growth factors, and oxidative stress related genes), and immunohistochemistry in the retina were compared among groups. (3) Results: There was a reduction of the thickness of the external nuclear layer and changes in the genes involved in cell survival and death, extracellular matrix turnover, growth factors, inflammation, and oxidative stress, leading decrease in cell density and retinal damage in the first group. Modulation of gene changes was observed when the LED light of screens was modified with an optical filter. (4) Conclusions: The use of short-wavelength selective filters on the screens contribute to reduce LED light-induced damage in the rat retina.

[Effect of retinal protective therapy on optical coherence tomography angiography (pilot study)]. / Vliyanie retinoprotektornoi terapii na pokazateli opticheskoi kogerentnoi tomografii s funktsiei angiografii (pilotnoe issledovanie).

PURPOSE: To assess the influence of the frequency of retinal protective therapy courses on the indicators of regional hemodynamics of the eye. MATERIAL AND METHODS: The study included 17 patients (34 eyes) with a diagnosis of primary open-angle glaucoma (POAG), advanced stage. The patients were divided into 2 groups: the first group received a course of retinal protective therapy with Retinalamin every 3 months, the second group received a course of retinal protective therapy with Retinalamin every 6 months. All patients underwent standard ophthalmological examination including standard automatic perimetry according to the 24-2 program, optical coherence tomography angiography (OCT-A) of the macular area and optic disc. RESULTS: The comparison of hemodynamic parameters of all vascular plexuses of the retina at the beginning and at the end of the study, as well as intergroup comparison did not reveal any statistically significant differences (p>0.05). However, when studying the density and fractal dimension of the vascular bed, multidirectional trends were observed. Specifically, in the peripapillary region, there was a decrease in the length from 19.8 (1/mm) to 19.0 (1/mm) (p=0.37) and the density from 36.6% to 35.7% (p=0.63) of the vascular bed of the peripapillary capillary plexus of the retina in patients of the first group. In the superficial vascular plexus, the trend in the density of the vascular bed in both groups slightly changed (in group 1 - 38.1% and 38.3%, p=0.97; group 2 - 37.8% and 38.7%, p=0.46). The fractal dimension of the vascular bed in the first group tended to increase during treatment from 18.8 (1/mm) to 19.1 (1/mm) (p=0.5), while in the second group, on the contrary, it had tendency to decrease from 18.6 (1/mm) to 17.9 (1/mm) (p=0.63). In the deep vascular plexus, the density of the vascular bed trended to decrease in both groups, but in group 2 (42.5% and 42.4%, p=1.0) it was more pronounced than in the first group (42.5% and 42.6%, p=0.82). However, the fractal dimension of the vascular bed increased in group 1 (21.0 (1/mm) and 21.3 (1/mm), p=0.43) and showed a slight tendency to decrease in group 2 (21.5 (1/mm) and 21.0 (1/mm), p=0.86). CONCLUSION: The general trend of changes in hemodynamic parameters demonstrates a potential positive effect, especially in the data related to the deep vascular plexus.

[Structural and functional changes in the retinal layers in patients with primary glaucoma and possible means of retinoprotection]. / Strukturno-funktsional'nye izmeneniia sloev setchatki pri pervichnoi glaukome i vozmozhnye puti retinoprotektsii.

Glaucoma is one of the most severe forms of ophthalmic pathology which can lead to low vision and blindness. Therapy aimed only at reducing intraocular pressure (IOP) may be insufficient in patients with this disease. PURPOSE: To study the structural and functional changes occurring in the retina and the effect of peptide bioregulator on the state of various retinal layers in patients with primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study included 62 patients (123 eyes) with POAG. The control group consisted of 25 people (50 eyes) of the same age. After the initial examination, patients of the glaucomatous group were divided into two equal subgroups. Patients of the first subgroup received 10 intramuscular injections of the peptide bioregulator; in the second subgroup, patients did not receive any retinoprotective therapy. The state of the visual analyzer was assessed using spectral optical coherence tomography (SOKT), electrophysiological research methods (ERG, PERG, flicker ERG), photostress test. RESULTS: Patients with POAG were found to have current and developing changes in the thickness and the configuration of various layers of the retina in the macular area as the disease progresses - particularly, in the nerve fiber layer (p=0.02), ganglion cells (p=0.002), inner nuclear layer (p=0.003) and the layer of pigment epithelium (p=0.049). Electrophysiological research methods helped reveal statistically significant changes in the functional parameters reflecting the generation and conduction of nerve impulses in retinal layers in patients with glaucoma. The patients undergoing peptide bioregulator therapy showed statistically significant positive changes in the state of ganglion cells observed as a decrease in the latency of the PERG N-95 wave (p=0.002) and stabilization of the structural indicators of SOCT (RNFL peripapillary zone). CONCLUSION: Patients with POAG exhibit progressive decrease in the thickness of not only the inner, but also the outer layers of the retinal macular area. According to objective structural and functional criteria, retinoprotective therapy leads to stabilization of the glaucomatous process.

Retinoprotective Effects of TAT-Bound Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Polypeptide.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) belong to the same peptide family and exert a variety of biological functions. Both PACAP and VIP have protective effects in several tissues. While PACAP is known to be a stronger retinoprotective peptide, VIP has very potent anti-inflammatory effects. The need for a non-invasive therapeutic approach has emerged and PACAP has been shown to be retinoprotective when administered in the form of eye drops as well. The cell penetrating peptide TAT is composed of 11 amino acids and tagging of TAT at the C-terminus of neuropeptides PACAP/VIP can enhance the traversing ability of the peptides through the biological barriers. We hypothesized that TAT-bound PACAP and VIP could be more effective in exerting retinoprotective effects when given in eye drops, by increasing the traversing efficacy and enhancing the activation of the PAC1 receptor. Rats were subjected to bilateral carotid artery occlusion (BCCAO), and retinas were processed for histological analysis 14 days later. The efficiency of the TAT-bound peptides to reach the retina was assessed as well as their cAMP increasing ability. Our present study provides evidence, for the first time, that topically administered PACAP and VIP derivatives (PACAP-TAT and VIP-TAT) attenuate ischemic retinal degeneration via the PAC1 receptor presumably due to a multifactorial protective mechanism.

Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina.

Calorie restriction (CR) being the most robust dietary intervention provides various health benefits. D-3-hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism.

Human bone marrow mesenchymal stem cells for retinal vascular injury.

PURPOSE: To examine the potential of intravitreally implanted human bone marrow-derived mesenchymal stem cells (BMSCs) to affect vascular repair and the blood-retina barrier in mice and rats with oxygen-induced retinopathy, diabetic retinopathy or retinal ischaemia-reperfusion damage. METHODS: Three study groups (oxygen-induced retinopathy group: 18 C57BL/6J mice; diabetic retinopathy group: 15 rats; retinal ischaemia-reperfusion model: 18 rats) received BMSCs injected intravitreally. Control groups (oxygen-induced retinopathy group: 12 C57BL/6J mice; diabetic retinopathy group: 15 rats; retinal ischaemia-reperfusion model: 18 rats) received an intravitreal injection of phosphate-buffered saline. We applied immunohistological techniques to measure retinal vascularization, spectroscopic measurements of intraretinally extravasated fluorescein-conjugated dextran to quantify the blood-retina barrier breakdown, and histomorphometry to assess retinal thickness and retinal ganglion cell count. RESULTS: In the oxygen-induced retinopathy model, the study group with intravitreally injected BMSCs as compared with the control group showed a significantly (p = 0.001) smaller area of retinal neovascularization. In the diabetic retinopathy model, study group and control group did not differ significantly in the amount of intraretinally extravasated dextran. In the retinal ischaemia-reperfusion model, on the 7th day after retina injury, the retina was significantly thicker in the study group than in the control group (p = 0.02), with no significant difference in the retinal ganglion cell count (p = 0.36). CONCLUSIONS: Intravitreally implanted human BMSCs were associated with a reduced retinal neovascularization in the oxygen-induced retinopathy model and with a potentially cell preserving effect in the retinal ischaemia-reperfusion model. Intravitreal BMSCs may be of potential interest for the therapy of retinal vascular disorders.