Compact RNA editors with natural miniature Cas13j nucleases.

Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3D65N and SCN9AR896Q, to the wild-type forms. In addition, we developed an optimized system, Chi-RESCUE-S-mini3, which pioneered efficient in vivo C-to-U RNA editing of PCSK9 in mice through single-AAV delivery, resulting in reduced total cholesterol levels. These results highlight the potential of Cas13j to treat human diseases.

Measured Regional Division Optimization for Acoustic Tomography Velocity Field Reconstruction in a Circular Area.

The acoustic tomography (AT) velocity field reconstruction technique has become a research hotspot in recent years due to its noninvasive nature, high accuracy, and real-time measurement advantages. However, most of the existing studies are limited to the reconstruction of the velocity field in a rectangular area, and there are very few studies on a circular area, mainly because the layout of acoustic transducers, selection of acoustic paths, and division of measured regions are more difficult in a circular area than in a rectangular area. Therefore, based on AT and using the reconstruction algorithm of the Markov function and singular value decomposition (MK-SVD), this paper proposes a measured regional division optimization algorithm for velocity field reconstruction in a circular area. First, an acoustic path distribution based on the multipath effect is designed to solve the problem of the limited emission angle of the acoustic transducer. On this basis, this paper proposes an adaptive optimization algorithm for measurement area division based on multiple sub-objectives. The steps are as follows: first, two optimization objectives, the condition number of coefficient matrix and the uniformity of acoustic path distribution, were designed. Then, the weights of each sub-objective are calculated using the coefficient of variation (CV). Finally, the measured regional division is optimized based on particle swarm optimization (PSO). The reconstruction effect of the algorithm and the anti-interference ability are verified through the reconstruction experiments of the model velocity field and the simulated velocity field.

DTFusion: Infrared and Visible Image Fusion Based on Dense Residual PConv-ConvNeXt and Texture-Contrast Compensation.

Infrared and visible image fusion aims to produce an informative fused image for the same scene by integrating the complementary information from two source images. Most deep-learning-based fusion networks utilize small kernel-size convolution to extract features from a local receptive field or design unlearnable fusion strategies to fuse features, which limits the feature representation capabilities and fusion performance of the network. Therefore, a novel end-to-end infrared and visible image fusion framework called DTFusion is proposed to address these problems. A residual PConv-ConvNeXt module (RPCM) and dense connections are introduced into the encoder network to efficiently extract features with larger receptive fields. In addition, a texture-contrast compensation module (TCCM) with gradient residuals and an attention mechanism is designed to compensate for the texture details and contrast of features. The fused features are reconstructed through four convolutional layers to generate a fused image with rich scene information. Experiments on public datasets show that DTFusion outperforms other state-of-the-art fusion methods in both subjective vision and objective metrics.

Insights into geospatial heterogeneity of landslide susceptibility based on the SHAP-XGBoost model.

The spatial heterogeneity of landslide influencing factors is the main reason for the poor generalizability of the susceptibility evaluation model. This study aimed to construct a comprehensive explanatory framework for landslide susceptibility evaluation models based on the SHAP (SHapley Additive explanation)-XGBoost (eXtreme Gradient Boosting) algorithm, analyze the regional characteristics and spatial heterogeneity of landslide influencing factors, and discuss the heterogeneity of the generalizability of the models under different landscapes. Firstly, we selected different regions in typical mountainous hilly region and constructed a geospatial database containing 12 landslide influencing factors such as elevation, annual average rainfall, slope, lithology, and NDVI through field surveys, satellite images, and a literature review. Subsequently, the landslide susceptibility evaluation model was constructed based on the XGBoost algorithm and spatial database, and the prediction results of the landslide susceptibility evaluation model were explained based on regional topography, geology, and hydrology using the SHAP algorithm. Finally, the model was generalized and applied to regions with both similar and very different topography, geology, meteorology, and vegetation, to explore the spatial heterogeneity of the generalizability of the model. The following conclusions were drawn: the spatial distribution of landslides is heterogeneous and complex, and the contribution of each influencing factor on the occurrence of landslides has obvious regional characteristics and spatial heterogeneity. The generalizability of the landslide susceptibility evaluation model is spatially heterogeneous and has better generalizability to regions with similar regional characteristics. Further explanation of the XGBoost landslide susceptibility evaluation model using the SHAP method allows quantitative analysis of the differences in how much various factors contribute to disasters due to spatial heterogeneity, from the perspective of global and local evaluation units. In summary, the integrated explanatory framework based on the SHAP-XGBoost model can quantify the contribution of influencing factors on landslide occurrence at both global and local levels, which is conducive to the construction and improvement of the influencing factor system of landslide susceptibility in different regions. It can also provide a reference for predicting potential landslide hazard-prone areas and for Explainable Artificial Intelligence (XAI) research.

Effect of a TSPO ligand on retinal pigment epithelial cholesterol homeostasis in high-fat fed mice, implication for age-related macular degeneration.

Age-related Macular Degeneration (AMD) is a major cause of sight impairment in the elderly with complex aetiology involving genetics and environment and with limited therapeutic options which have limited efficacy. We have previously shown in a mouse-model of the condition, induced by feeding a high fat diet, that adverse effects of the diet can be reversed by co-administration of the TSPO activator, etifoxine. We extend those observations showing improvements in retinal pigment epithelial (RPE) cells with decreased lipids and enhanced expression of cholesterol metabolism and transport enzymes. Further, etifoxine decreased levels of reactive oxygen species (ROS) in RPE and inflammatory cytokines in RPE and serum. With respect to gut microbiome, we found that organisms abundant in the high fat condition (e.g. in the genus Anaerotruncus and Oscillospira) and implicated in AMD, were much less abundant after etifoxine treatment. The changes in gut flora were associated with the predicted production of metabolites of benefit to the retina including tryptophan and other amino acids and taurine, an essential component of the retina necessary to counteract ROS. These novel observations strengthen earlier conclusions that the mechanisms behind improvements in etifoxine-induced retinal physiology involve an interaction between effects on the host and the gut microbiome.

Protection by vitamin D against high-glucose-induced damage in retinal pigment epithelial cells.

Diabetic retinopathy (DR) is a diabetes-associated complication characterized by irreversible deterioration of the microvessels within the retina, leading subsequently to severe retinal damage and vision loss. Vitamin D (VITD), a steroid hormone, plays multiple physiological functions in cellular homeostasis. Deficiency of VITD has been suggested to be associated with DR. To study the potential protective function of VITD in DR, high-glucose-treated ARPE-19 cells and STZ-induced diabetic mice were used as in vitro and in vivo models. The protective effects of VITD were assessed based on the changes of expression of antioxidant enzymes and cytokines in high-glucose-treated retinal pigment epithelial (RPE) cells and in the retina and RPE of diabetic and VITD-treated diabetic mice. The present study demonstrated that exposure to a high level of glucose caused upregulation of pro-inflammatory cytokines and a decrease in anti-oxidant enzyme expression in both in vitro and in vivo models. VITD treatment increased cell viability, reduced reactive oxygen species (ROS) production and caspase-3/7 activities in high-glucose-treated RPE cells. Our data suggest that VITD can protect the retina and RPE from high-glucose-induced oxidative damage and inflammation.

Gypenosides attenuate retinal degeneration in a zebrafish retinitis pigmentosa model.

Retinitis pigmentosa (RP) is a collection of heterogenous genetic retinal disorders resulting in cumulative retinal deterioration involving progressive loss of photoreceptors and eventually in total blindness. Oxidative stress plays a central role in this photoreceptor loss. Gypenosides (Gyp) are the main functional component isolated from the climbing vine Gynostemma pentaphyllum and have been shown to defend cells against the effects of oxidative stress and inflammation, providing protection in experimentally-induced optic neuritis. The zebrafish model has been used to investigate a range of human diseases. Previously we reported early retinal degeneration in a mutant zebrafish line carrying a point-nonsense mutation in the retinitis pigmentosa GTPase regulator interacting protein 1 (rpgrip1) gene that is mutated in RP patients. The current study investigated the potential protective effects of Gyp against photoreceptor degeneration in the Rpgrip1 deleted zebrafish. Rpgrip1 mutant zebrafish were treated with 5 µg/ml of Gyp in E3 medium from 6 h post fertilization (hpf) till 1 month post fertilization (mpf). Rpgrip1 mutant zebrafish treated with 5 µg/ml of Gyp showed a significant decrease by 68.41% (p = 0.0002) in photoreceptor cell death compared to that of untreated mutant zebrafish. Expression of antioxidant genes catalase, sod1, sod2, gpx1, gclm, nqo-1 and nrf-2 was significantly decreased in rpgrip1 mutant zebrafish eyes by 61.51%, 77.40%, 60.11%, 81.17%, 72.07%, 78.95% and 85.42% (all p < 0.0001), respectively, when compared to that of wildtype zebrafish; superoxide dismutase and catalase activities, and glutathione levels in rpgrip1 mutant zebrafish eyes were significantly decreased by 87.21%, 21.55% and 96.51% (all p < 0.0001), respectively. There were marked increases in the production of reactive oxygen species (ROS) and malondialdehyde (MDA) by 2738.73% and 510.69% (all p < 0.0001), respectively, in rpgrip1 mutant zebrafish eyes; expression of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α was also significantly increased by 150.11%, 267.79% and 190.72% (all p < 0.0001), respectively, in rpgrip1 mutant zebrafish eyes, compared to that of wildtype zebrafish. Treatment with Gyp significantly counteracted these effects. This study indicates that Gyp has a potential role in the treatment of RP.

Retinal pigment epithelium cholesterol efflux mediated by the 18 kDa translocator protein, TSPO, a potential target for treating age-related macular degeneration.

Cholesterol accumulation beneath the retinal pigment epithelium (RPE) cells is supposed to contribute the pathogenesis of age-related macular degeneration (AMD). Cholesterol efflux genes (APOE and ABCA1) were identified as risk factors for AMD, although how cholesterol efflux influences accumulation of this lipid in sub-RPE deposits remains elusive. The 18 kDa translocator protein, TSPO, is a cholesterol-binding protein implicated in mitochondrial cholesterol transport. Here, we investigate the function of TSPO in cholesterol efflux from the RPE cells. We demonstrate in RPE cells that TSPO specific ligands promoted cholesterol efflux to acceptor (apo)lipoprotein and human serum, while loss of TSPO resulted in impaired cholesterol efflux. TSPO-/- RPE cells also had significantly increased production of reactive oxygen species (ROS) and upregulated expression of proinflammatory cytokines (IL-1ß and TNFα). Cholesterol (oxidized LDL) uptake and accumulation were markedly increased in TSPO-/- RPE cells. Finally, in aged RPE cells, TSPO expression was reduced and cholesterol efflux impaired. These findings provide a new pharmacological concept to treat early AMD patients by stimulating cellular cholesterol removal with TSPO specific ligands or by overexpression of TSPO in RPE cells.

Protection against oxidative stress by vitamin D in cone cells.

Photoreceptor degeneration (PD) refers to a group of heterogeneous outer retinal dystrophies characterized by the death of photoreceptors. Both oxidative stress and inflammation are involved in the pathogenesis of PD. We investigate whether vitamin D has a potential for the treatment of PD by evaluating the anti-oxidative stress and anti-inflammatory properties of the active form of vitamin D3 , 1,α, 25-dihydroxyvitamin D3 , in a mouse cone cell line, 661W. Mouse cone cells were treated with H2 O2 or a mixture of H2 O2 and vitamin D; cell viability was determined. The production of reactive oxygen species (ROS) in treated and untreated cells was measured. The expression of key anti-oxidative stress and inflammatory genes in treated and untreated cells was determined. Treatment with vitamin D significantly increased cell viability and decreased ROS production in 661W cells under oxidative stress induced by H2 O2 . H2 O2 treatment in 661W cells can significantly down-regulate the expression of antioxidant genes and up-regulate the expression of neurotoxic cytokines. Vitamin D treatment significantly reversed these effects and restored the expression of antioxidant genes. Vitamin D treatment also can block H2 O2 induced oxidative damages. The data suggested that vitamin D may offer a therapeutic potential for patients with PD.

Abnormal photoreceptor outer segment development and early retinal degeneration in kif3a mutant zebrafish.

Photoreceptors are highly specialized sensory neurons that possess a modified primary cilium called the outer segment. Photoreceptor outer segment formation and maintenance require highly active protein transport via a process known as intraflagellar transport. Anterograde transport in outer segments is powered by the heterotrimeric kinesin II and coordinated by intraflagellar transport proteins. Here, we describe a new zebrafish model carrying a nonsense mutation in the kinesin II family member 3A (kif3a) gene. Kif3a mutant zebrafish exhibited curved body axes and kidney cysts. Outer segments were not formed in most parts of the mutant retina, and rhodopsin was mislocalized, suggesting KIF3A has a role in rhodopsin trafficking. Both rod and cone photoreceptors degenerated rapidly between 4 and 9 days post fertilization, and electroretinography response was not detected in 7 days post fertilization mutant larvae. Loss of KIF3A in zebrafish also resulted in an intracellular transport defect affecting anterograde but not retrograde transport of organelles. Our results indicate KIF3A plays a conserved role in photoreceptor outer segment formation and intracellular transport.

Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity.

Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously.

CRISPR-Cas13: Pioneering RNA Editing for Nucleic Acid Therapeutics.

The CRISPR-Cas13 system has emerged as a revolutionary tool for RNA editing, offering new opportunities for the development of nucleic acid therapeutics. Unlike DNA-targeting CRISPR-Cas9, Cas13 targets and cleaves RNA, enabling gene silencing and preventing genomic instability. Its applications include suppressing disease-causing genes, correcting splicing errors, and modulating immune responses. Despite these advances, challenges persist, such as the need to refine specificity, mitigate off-target impacts, and ensure effective delivery. This review provides an overview of the CRISPR-Cas13 mechanism, elucidating its role in RNA-targeted therapies and its transformative potential for disease treatment. Furthermore, it addresses the ongoing challenges that the scientific community is striving to overcome.

Engineering Living Material for Controlled Fragrance Release Utilizing Kluyveromyces marxianus CBS6556 and Adaptive Hydrogel.

The demand for controllable fragrance materials is substantial owing to their potential to impart enduring scents in a variety of applications. However, the practical application of such materials has been limited by challenges in tunable morphogenesis, structural variability, and adaptability to diverse conditions. In our study, we introduce a hybrid living material that integrates a genetically engineered strain of Kluyveromyces marxianus CBS6556 with an adaptive hydrogel. The engineered K. marxianus achieved temperature stability in 2-phenylethanol (2-PE) and 2-phenylethyl acetate (2-PEAc) production by expressing relevant genes in the 2-PE metabolic pathway using the high-temperature preferential promoter SSE1. The enhanced water retention capacity supports the metabolic activities of the encapsulated yeast cells, ensuring their survival and functionality over an extended period. Fragrance-releasing living material (FLM) is designed to controllably emit fragrance 2-PE by adjusting the microbial concentration within the hydrogel matrix. The FLM exhibits versatile adhesion capabilities, effectively binding to a spectrum of surfaces such as wood, textiles, and glass as well as to natural substrates like leaves. This adaptability enhances the material's applicability across various settings. Furthermore, FLM can be crafted into various forms, including microbeads, fibers, and films. This research opens up new horizons for controlled fragrance release of living materials.

Chinese medicine, Qijudihuang pill, mediates cholesterol metabolism and regulates gut microbiota in high-fat diet-fed mice, implications for age-related macular degeneration.

Background: Traditional Chinese Medicines have been used for thousands of years but without any sound empirical basis. One such preparation is the Qijudihuang pill (QP), a mixture of eight herbs, that has been used in China for the treatment of various conditions including age-related macular degeneration (AMD), the most common cause of blindness in the aged population. In order to explain the mechanism behind the effect of QP, we used an AMD model of high-fat diet (HFD) fed mice to investigate cholesterol homeostasis, oxidative stress, inflammation and gut microbiota. Methods: Mice were randomly divided into three groups, one group was fed with control diet (CD), the other two groups were fed with high-fat-diet (HFD). One HFD group was treated with QP, both CD and the other HFD groups were treated with vehicles. Tissue samples were collected after the treatment. Cholesterol levels in retina, retinal pigment epithelium (RPE), liver and serum were determined using a commercial kit. The expression of enzymes involved in cholesterol metabolism, inflammation and oxidative stress was measured with qRT-PCR. Gut microbiota was analyzed using 16S rRNA sequencing. Results: In the majority of the lipid determinations, analytes were elevated by HFD but this was reversed by QP. Cholesterol metabolism including the enzymes of bile acid (BA) formation was suppressed by HFD but again this was reversed by QP. BAs play a major role in signaling between host and microbiome and this is disrupted by HFD resulting in major changes in the composition of colonic bacterial communities. Associated with these changes are predictions of the metabolic pathway complexity and abundance of individual pathways. These concerned substrate breakdowns, energy production and the biosynthesis of pro-inflammatory factors but were changed back to control characteristics by QP. Conclusion: We propose that the ability of QP to reverse these HFD-induced effects is related to mechanisms acting to lower cholesterol level, oxidative stress and inflammation, and to modulate gut microbiota.

Evaluation of okadaic acid toxicity in human retinal cells and zebrafish retinas.

Okadaic acid (OA, C44H68O13) is a neurotoxin and phosphatase inhibitor produced by several dinoflagellate species. OA is widely known to accumulate in black sponges and is associated with seafood poisoning. Humans can be exposed to OA by consuming contaminated shellfish that have accumulated toxins during algal blooms. Evidence from in vitro and in vivo studies demonstrate that OA exposure causes neurotoxicity in addition to diarrheal syndrome. It is unclear whether exposure to OA affects retinal function, a part of the central nervous system. We evaluated the toxicity of OA in human retinal pigment epithelial cells (ARPE-19) and in zebrafish retinas. Cell-based assays determined that OA significantly decreased cell viability in a dose-dependent manner and increased oxidative stress, inflammation and cell death compared to the untreated control group. In the in vivo study, zebrafish embryos at 24 h post fertilization (hpf) were treated with/without OA for four days, endpoint measurements including mortality, malformations, delayed hatching, altered heartbeat and reduced movement were performed. OA exposure increased mortality, decreased hatching, heartbeat rate, and caused morphological abnormalities. OA exposure also markedly decreased the expression of antioxidant genes and a significantly increased inflammation as well as evoking a loss of photoreceptors in zebrafish embryos. The data suggest that consuming OA-contaminated seafood can induce retinal toxicity.

Bioinformatical and Biochemical Analyses on the Protective Role of Traditional Chinese Medicine against Age-Related Macular Degeneration.

PURPOSE: Age-related macular degeneration (AMD) is the commonest cause of permanent vision loss in the elderly. Traditional Chinese medicine (TCM) has long been used to treat AMD, although the underlying functional mechanisms are not understood. This study aims to predict the active ingredients through screening the chemical ingredients of anti-AMD decoction and to elucidate the underlying mechanisms. METHODS: We collected the prescriptions for effective AMD treatment with traditional Chinese medicine and screened several Chinese medicines that were used most frequently in order to compose "anti-AMD decoction." The pharmacologically active ingredients and corresponding targets in this anti-AMD decoction were mined using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Subsequently, the AMD-related targets were identified through the GeneCards database. Network pharmacology was performed to construct the visual network of anti-AMD decoction-AMD protein-protein interaction (PPI). Further, the Autodock software was adopted for molecular docking on the core active ingredients and core targets. The function of core ingredients against oxidative stress and inflammation in retinal pigment epithelial cells was assessed using biochemical assays. RESULTS: We screened out 268 active ingredients in anti-AMD decoction corresponding to 258 ingredient targets, combined with 2160 disease targets in AMD, and obtained 129 drug-disease common targets. The key core proteins were predominantly involved in inflammation. Furthermore, molecular docking showed that four potential active ingredients (Quercetin, luteolin, naringenin and hederagenin) had good affinity with the core proteins, IL-6, TNF, VEGFA and MAPK3. Quercetin, luteolin and naringenin demonstrated capacities against oxidative stress and inflammation in human retinal pigment epithelial cells. CONCLUSIONS: The data suggests that anti-AMD decoction has multiple functional components and targets in treating AMD, possibly mediated by suppression of oxidative stress and inflammation.

Mobile Robot Path Planning Based on Time Taboo Ant Colony Optimization in Dynamic Environment.

This article aims to improve the problem of slow convergence speed, poor global search ability, and unknown time-varying dynamic obstacles in the path planning of ant colony optimization in dynamic environment. An improved ant colony optimization algorithm using time taboo strategy is proposed, namely, time taboo ant colony optimization (TTACO), which uses adaptive initial pheromone distribution, rollback strategy, and pheromone preferential limited update to improve the algorithm's convergence speed and global search ability. For the poor global search ability of the algorithm and the unknown time-varying problem of dynamic obstacles in a dynamic environment, a time taboo strategy is first proposed, based on which a three-step arbitration method is put forward to improve its weakness in global search. For the unknown time-varying dynamic obstacles, an occupancy grid prediction model is proposed based on the time taboo strategy to solve the problem of dynamic obstacle avoidance. In order to improve the algorithm's calculation speed when avoiding obstacles, an ant colony information inheritance mechanism is established. Finally, the algorithm is used to conduct dynamic simulation experiments in a simulated factory environment and is compared with other similar algorithms. The experimental results show that the TTACO can obtain a better path and accelerate the convergence speed of the algorithm in a static environment and can successfully avoid dynamic obstacles in a dynamic environment.

Ultrasonic Thermometry Algorithm Based on Inverse Quadratic Function.

At present, there are two ways to obtain temperature information: contact type and nonintrusive type. As a nonintrusive temperature measurement method, ultrasonic thermometry can be used to acquire the temperature distribution of complex fields conveniently. By measuring the time-of-flight (TOF) between ultrasonic transmitters and receivers, and according to the relationship between temperature and ultrasonic velocity, the temperature distribution can be reconstructed. Among the existing algorithms, the least square method (LSM) will lose much information near the edges of the temperature field, and the algebra reconstruction technique (ART) is time-consuming with low reconstruction accuracy. In this article, an improved reconstruction algorithm based on an inverse quadratic function and singular value decomposition (IQ-SVD) is proposed, which can effectively increase the reconstruction accuracy. The simulations of the real temperature data are conducted in ideal and noisy environments, respectively. Moreover, the influence of region division and shape parameters on reconstruction accuracy is discussed. The simulation results indicate that, compared with conventional algorithms, the proposed algorithm can accurately reflect the temperature distribution, and the root mean square error in the central region and the edge region is reduced by 0.49% at least, and 1.28% at most.

Oxysterols and retinal degeneration.

Retinal degeneration, characterised by the progressive death of retinal neurons, is the most common cause of visual impairment. Oxysterols are the cholesterol derivatives produced via enzymatic and/or free radical oxidation that regulate cholesterol homeostasis in the retina. Preclinical and clinical studies have suggested a connection between oxysterols and retinal degeneration. Here, we summarise early and recent work related to retina oxysterol-producing enzymes and the distribution of oxysterols in the retina. We examine the impact of loss of oxysterol-producing enzymes on retinal pathology and explore the molecular mechanisms associated with the toxic or protective roles of individual oxysterols in different types of retinal degeneration. We conclude that increased efforts to better understand the oxysterol-associated pathophysiology will help in the development of effective retinal degeneration therapies. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Overexpression of STARD3 attenuates oxidized LDL-induced oxidative stress and inflammation in retinal pigment epithelial cells.

Age-related macular degeneration (AMD) is the most common cause of visual disorder in aged people and may lead to complete blindness with ageing. The major clinical feature of AMD is the presence of cholesterol enriched deposits underneath the retinal pigment epithelium (RPE) cells. The deposits can induce oxidative stress and inflammation. It has been suggested that abnormal cholesterol homeostasis contributes to the pathogenesis of AMD. However, the functional role of defective cholesterol homeostasis in AMD remains elusive. STARD proteins are a family of proteins that contain a steroidogenic acute regulatory protein-related lipid transfer domain. There are fifteen STARD proteins in mammals and some, such as STARD3, are responsible for cholesterol trafficking. Previously there was no study of STARD proteins in retinal cholesterol metabolism and trafficking. Here we examined expression of the Stard3 gene in mouse retinal and RPE cells at ages of 2 and 20 months. We found that expression of Stard 3 gene transcripts in both mouse RPE and retina was significantly decreased at age of 20 months when compared to that of age 2 months old. We created a stable ARPE-19 cell line overexpressing STARD3 and found this resulted in increased cholesterol efflux, reduced accumulation of intracellular oxidized LDL, increased antioxidant capacity and lower levels of inflammatory cytokines. The data suggested that STARD3 is a potential target for AMD through promoting the removal of intracellular cholesterol and slowing the disease progression.