Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa

Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro(~0.5-1.5°C).Electrical stimulation increased photoreceptor survival in human retinal explant cultures,particularly at the ramp waveform.Transcorneal electrical stimulation(rectangular+ramp)waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results.Histology and immunolabeling demonstrated increased photoreceptor survival,improved outer nuclear layer thickness,and increased bipolar cell sprouting in Rho^(-/-)mice.These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina,improves photoreceptor survival in both human and mouse retinas,and increases visual function in Rho^(-/-)mice.Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.

Phenotypical Aspects of a Familial Syndromic Retinitis Pigmentosa

Aim: To report a familial case of syndromic retinitis pigmentosa identified at Aristide Le Dantec Hospital in Dakar and to describe their clinical characteristics ophthalmic. Observation: We report a sibling group of nine children, four died at a young age from unknown causes. Three children were affected by retinitis pigmentosa, two cases were syndromic. A history of nyctalopia was found in all three affected children. The mean age of onset of decreased visual acuity was 6.6 years. Patient 1 affected by syndromic retinitis pigmentosa had an extraocular sign of cystic dilation of the main bile duct. Patient 2 had myoclonic epilepsy, psychomotor retardation, and the molar tooth sign on cerebral MRI (highly suggestive of Joubert syndrome). The third child had isolated retinitis pigmentosa. Ophthalmological examinations (fundus examination, electroretinogram, and visual evoked potentials) and pediatric examinations in the remaining two children were normal. Discussion and Conclusion: Retinitis pigmentosa is a rare degenerative disease that can be associated with several other malformations, highlighting the importance of screening for associated conditions. It presents a grim functional prognosis and a life prognosis dependent on extraocular manifestations. Molecular biology (karyotyping, next-generation sequencing) could have identified the implicated genes and allowed for a formal diagnosis and genetic counseling.

Retinitis pigmentosa and stem cell therapy

Retinitis pigmentosa(RP)is a group of genetic disorders characterized by progressive degeneration of photoreceptors and retinal pigment epithelium(RPE)cells.Its main clinical manifestations include night blindness and progressive loss of peripheral vision,making it a prevalent debilitating eye disease that significantly impacts patients’quality of life.RP exhibits significant phenotypic and genetic heterogeneity.For instance,numerous abnormal genes are implicated in RP,resulting in varying clinical presentations,disease progression rates,and pathological characteristics among different patients.Consequently,gene therapy for RP poses challenges due to these complexities.However,stem cells have garnered considerable attention in the field of RPE therapy since both RPE cells and photoreceptors can be derived from stem cells.In recent years,a large number of animal experiments and clinical trials based on stem cell transplantation attempts,especially cord blood mesenchymal stem cell(MSC)transplantation and bone marrow-derived MSC transplantation,have confirmed that stem cell therapy can effectively and safely improve the outer retinal function of the RP-affected eye.However,stem cell therapy also has certain limitations,such as the fact that RP patients may involve multiple types of retinal cytopathia,which brings great challenges to stem cell transplantation therapy,and further research is needed to solve various problems faced by this approach in the clinic.Through comprehensive analysis of the etiology and histopathological changes associated with RP,this study substantiates the efficacy and safety of stem cell therapy based on rigorous animal experimentation and clinical trials,while also highlighting the existing limitations that warrant further investigation.

AAV2-PDE6B restores retinal structure and function in the retinal degeneration 10 mouse model of retinitis pigmentosa by promoting phototransduction and inhibiting apoptosis

Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.

Cell replacement with stem cell-derived retinal ganglion cells from different protocols

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

Taurine: a promising nutraceutic in the prevention of retinal degeneration

Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.

A pedigree with retinitis pigmentosa and its concomitant ophthalmic diseases

AIM:To characterize the ophthalmic clinical phenotype of a family with retinitis pigmentosa(RP)and closed-angle glaucoma and to detect pathogenic genes and mutation sites causing RP in this family.METHODS:Ophthalmic clinic performance was examined in detail in 8 enrolled family members.Genomic DNA was extracted from the peripheral blood of 4 family members for whole-exome sequencing(WES)to select potential genetic mutations whose structures were identified by bioinformatics analysis.Then,Sanger sequencing was used in 12 family members and control group members to validate and confirm the disease-causing mutation loci,and we analyzed the genotype-phenotype relationships.RESULTS:The known c.512C>T(p.P171L)mutation in the rhodopsin(RHO)gene was only found in afflicted family members and was confirmed by WES and Sanger sequencing as the pathogenic mutation in this family.In addition to being diagnosed with RP,family member III:4 was found to have bilateral closed-angle glaucoma,high myopia,and concurrent cataracts,and family members II:2 and II:4 had pathological changes of anterior chamber angle narrowing.Family members IV:3 and IV:4 were found to have retinoschisis.CONCLUSION:Glaucoma and related pathological changes,such as retinoschisis,in family members are preliminarily considered RP complications caused by RHO mutation.

Overview of the immunological mechanisms in hepatitis B virus reactivation:Implications for disease progression and management strategies

Hepatitis B virus(HBV)reactivation is a clinically significant challenge in disease management.This review explores the immunological mechanisms underlying HBV reactivation,emphasizing disease progression and management.It delves into host immune responses and reactivation’s delicate balance,spanning innate and adaptive immunity.Viral factors’disruption of this balance,as are interac-tions between viral antigens,immune cells,cytokine networks,and immune checkpoint pathways,are examined.Notably,the roles of T cells,natural killer cells,and antigen-presenting cells are discussed,highlighting their influence on disease progression.HBV reactivation’s impact on disease severity,hepatic flares,liver fibrosis progression,and hepatocellular carcinoma is detailed.Management strategies,including anti-viral and immunomodulatory approaches,are critically analyzed.The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation.In conclusion,this compre-hensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation.With a dedicated focus on understanding its implic-ations for disease progression and the prospects of efficient management stra-tegies,this article contributes significantly to the knowledge base.The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches,ultimately enhancing disease management and elevating patient outcomes.The dynamic landscape of management strategies is critically scrutinized,spanning anti-viral and immunomodulatory approaches.The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Increased retinal venule diameter as a prognostic indicator for recurrent cerebrovascular events:a prospective observational study

Microvasculature of the retina is considered an alternative marker of cerebral vascular risk in healthy populations.However,the ability of retinal vasculature changes,specifically focusing on retinal vessel diameter,to predict the recurrence of cerebrovascular events in patients with ischemic stroke has not been determined comprehensively.While previous studies have shown a link between retinal vessel diameter and recurrent cerebrovascular events,they have not incorporated this information into a predictive model.Therefore,this study aimed to investigate the relationship between retinal vessel diameter and subsequent cerebrovascular events in patients with acute ischemic stroke.Additionally,we sought to establish a predictive model by combining retinal veessel diameter with traditional risk factors.We performed a prospective observational study of 141 patients with acute ischemic stroke who were admitted to the First Affiliated Hospital of Jinan University.All of these patients underwent digital retinal imaging within 72 hours of admission and were followed up for 3 years.We found that,after adjusting for related risk factors,patients with acute ischemic stroke with mean arteriolar diameter within 0.5-1.0 disc diameters of the disc margin(MAD_(0.5-1.0DD))of≥74.14μm and mean venular diameter within 0.5-1.0 disc diameters of the disc margin(MVD_(0.5-1.0DD))of≥83.91μm tended to experience recurrent cerebrovascular events.We established three multivariate Cox proportional hazard regression models:model 1 included traditional risk factors,model 2 added MAD_(0.5-1.0DD)to model 1,and model 3 added MVD0.5-1.0DD to model 1.Model 3 had the greatest potential to predict subsequent cerebrovascular events,followed by model 2,and finally model 1.These findings indicate that combining retinal venular or arteriolar diameter with traditional risk factors could improve the prediction of recurrent cerebrovascular events in patients with acute ischemic stroke,and that retinal imaging could be a useful and non-invasive method for identifying high-risk patients who require closer monitoring and more aggressive management.

A New Classification for Retinitis Pigmentosa Including Multifocal Electroretinography to Evaluate the Disease Severity

Aim: To establish a useful and objective classification for retinitis pigmentosa (RP) to evaluate the disease severity. Methods: This is a retrospective cross-sectional study. Visual acuity (VA), visual field (VF) width, ellipsoid zone width on optic cohorence tomography (OCT) and multifocal electroretinography (mf ERG) values were obtained from medical records of patients with RP. A scoring criterion was developed wherein each variable was assigned a score from 0 to 5 depending on its distribution. The cumulative score (from 0 to 20) was used to classify disease severity from grade 0 to 5. The scores were correlated with each other and the final grade. Results: Data of 152 eyes of 92 patients who had the results of all tests were reviewed. The mean age was 41.2 years. The mean VA of the patients was 0.13 ± 0.16 Snellen lines. The majority of patients had a VA less than 20/40 (88.6%), a visual field smaller than 20˚ (78%), and an ellipsoid zone width smaller than 7˚ (84.4%). The majority of the patients (85.4%) were in advanced stage of the disease (Grade 4 and 5). Conclusions: We present a simple, objective and easy to use disease severity classification for RP which can be used to categorize patients and to evaluate and compare treatment results.

Intelligent diagnosis of retinal vein occlusion based on color fundus photographs

AIM:To develop an artificial intelligence(AI)diagnosis model based on deep learning(DL)algorithm to diagnose different types of retinal vein occlusion(RVO)by recognizing color fundus photographs(CFPs).METHODS:Totally 914 CFPs of healthy people and patients with RVO were collected as experimental data sets,and used to train,verify and test the diagnostic model of RVO.All the images were divided into four categories[normal,central retinal vein occlusion(CRVO),branch retinal vein occlusion(BRVO),and macular retinal vein occlusion(MRVO)]by three fundus disease experts.Swin Transformer was used to build the RVO diagnosis model,and different types of RVO diagnosis experiments were conducted.The model’s performance was compared to that of the experts.RESULTS:The accuracy of the model in the diagnosis of normal,CRVO,BRVO,and MRVO reached 1.000,0.978,0.957,and 0.978;the specificity reached 1.000,0.986,0.982,and 0.976;the sensitivity reached 1.000,0.955,0.917,and 1.000;the F1-Sore reached 1.000,0.9550.943,and 0.887 respectively.In addition,the area under curve of normal,CRVO,BRVO,and MRVO diagnosed by the diagnostic model were 1.000,0.900,0.959 and 0.970,respectively.The diagnostic results were highly consistent with those of fundus disease experts,and the diagnostic performance was superior.CONCLUSION:The diagnostic model developed in this study can well diagnose different types of RVO,effectively relieve the work pressure of clinicians,and provide help for the follow-up clinical diagnosis and treatment of RVO patients.

Core fucosylation and its roles in gastrointestinal glycoimmunology

Glycosylation is a common post-translational modification in eukaryotic cells.It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function.Core fucosylation plays a vital role in the immune response.Most immune system molecules are core fucosylated glycoproteins such as complements,cluster differentiation antigens,immunoglobulins,cytokines,major histocompatibility complex molecules,adhesion molecules,and immune molecule synthesis-related transcription factors.These core fucosylated glycoproteins play important roles in antigen recognition and clearance,cell adhesion,lymphocyte activation,apoptosis,signal transduction,and endocytosis.Core fucosylation is dominated by fucosyltransferase 8(Fut8),which catalyzes the addition ofα-1,6-fucose to the innermost GlcNAc residue of N-glycans.Fut8 is involved in humoral,cellular,and mucosal immunity.Tumor immunology is associated with aberrant core fucosylation.Here,we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.

A novel pathogenic splicing mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa verified by minigene splicing assay

AIM:To report a novel splicing mutation in the RPGR gene(encoding retinitis pigmentosa GTPase regulator)in a three-generation Chinese family with X-linked retinitis pigmentosa(XLRP).METHODS:Comprehensive ophthalmic examinations including best corrected visual acuity,fundus photography,vision field,and pattern-visual evoked potential were performed to identify the disease phenotype of a six-yearold boy from the family(proband).Genomic DNA was extracted from peripheral blood of five available members of the pedigree.Whole-exome sequencing(WES),Sanger sequencing,and pSPL3-based exon trapping were used to investigate the aberrant splicing of RPGR.Human Splice Finder v3.1 and NNSPLICE v0.9 were used for in silico prediction of splice site variants.RESULTS:The proband was diagnosed as having retinitis pigmentosa(RP).He had severe symptoms with early onset.A novel splicing mutation,c.619+1G>C in RPGR was identified in the proband by WES and in four family members by Sanger sequencing.Minigene splicing assays verified that c.619+1G>C in RPGR would result in the formation of a damaging alternative transcript in which the last 91 bp of exon 6 were skipped,leading to the subsequent deletion of 623 correct amino acids(c.529_619del p.Val177Glnfs*16).CONCLUSION:We identify a novel splice donor site mutation causing aberrant splicing of RPGR.Our findings add to the catalog of pathological mutations of RPGR and further emphasize the functional importance of RPGR in RP pathogenesis and its complex clinical phenotypes.

NLRP3 and autophagy in retinal ganglion cell inflammation in age-related macular degeneration:potential therapeutic implications

Retinal degenerative diseases were a large group of diseases characterized by the primary death of retinal ganglion cells(RGCs).Recent studies had shown an interaction between autophagy and nucleotide-binding oligomerization domain-like receptor 3(NLRP3)inflammasomes,which may affect RGCs in retinal degenerative diseases.The NLRP3 inflammasome was a protein complex that,upon activation,produces caspase-1,mediating the apoptosis of retinal cells and promoting the occurrence and development of retinal degenerative diseases.Upregulated autophagy could inhibit NLRP3 inflammasome activation,while inhibited autophagy can promote NLRP3 inflammasome activation,which leaded to the accelerated emergence of drusen and lipofuscin deposition under the neurosensory retina.The activated NLRP3 inflammasome could further inhibit autophagy,thus forming a vicious cycle that accelerated the damage and death of RGCs.This review discussed the relationship between NLRP3 inflammasome and autophagy and its effects on RGCs in age-related macular degeneration,providing a new perspective and direction for the treatment of retinal diseases.

Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).

Single-cell RNA sequencing analysis of the retina under acute high intraocular pressure

High intraocular pressure causes retinal ganglion cell injury in primary and secondary glaucoma diseases,yet the molecular landscape characteristics of retinal cells under high intraocular pressure remain unknown.Rat models of acute hypertension ocular pressure were established by injection of cross-linked hyaluronic acid hydrogel(Healaflow■).Single-cell RNA sequencing was then used to describe the cellular composition and molecular profile of the retina following high intraocular pressure.Our results identified a total of 12 cell types,namely retinal pigment epithelial cells,rod-photoreceptor cells,bipolar cells,Müller cells,microglia,cone-photoreceptor cells,retinal ganglion cells,endothelial cells,retinal progenitor cells,oligodendrocytes,pericytes,and fibroblasts.The single-cell RNA sequencing analysis of the retina under acute high intraocular pressure revealed obvious changes in the proportions of various retinal cells,with ganglion cells decreased by 23%.Hematoxylin and eosin staining and TUNEL staining confirmed the damage to retinal ganglion cells under high intraocular pressure.We extracted data from retinal ganglion cells and analyzed the retinal ganglion cell cluster with the most distinct expression.We found upregulation of the B3gat2 gene,which is associated with neuronal migration and adhesion,and downregulation of the Tsc22d gene,which participates in inhibition of inflammation.This study is the first to reveal molecular changes and intercellular interactions in the retina under high intraocular pressure.These data contribute to understanding of the molecular mechanism of retinal injury induced by high intraocular pressure and will benefit the development of novel therapies.

The roles of macrophage migration inhibitory factor in retinal diseases

Macrophage migration inhibitory factor(MIF),a multifunctional cytokine,is secreted by various cells and participates in inflammatory reactions,including innate and adaptive immunity.There are some evidences that MIF is involved in many vitreoretinal diseases.For example,MIF can exacerbate many types of uveitis;measurements of MIF levels can be used to monitor the effectiveness of uveitis treatment.MIF also alleviates trauma-induced and glaucoma-induced optic nerve damage.Furthermore,MIF is critical for retinal/choroidal neovascularization,especially complex neovascularization.MIF exacerbates retinal degeneration;thus,anti-MIF therapy may help to mitigate retinal degeneration.MIF protects uveal melanoma from attacks by natural killer cells.The mechanism underlying the effects of MIF in these diseases has been demonstrated:it binds to cluster of differentiation 74,inhibits the c-Jun N-terminal kinase pathway,and triggers mitogen-activated protein kinases,extracellular signal-regulated kinase-1/2,and the phosphoinositide-3-kinase/Akt pathway.MIF also upregulates Toll-like receptor 4 and activates the nuclear factor kappa-B signaling pathway.This review focuses on the structure and function of MIF and its receptors,including the effects of MIF on uveal inflammation,retinal degeneration,optic neuropathy,retinal/choroidal neovascularization,and uveal melanoma.

Postnatal development of rat retina:a continuous observation and comparison between the organotypic retinal explant model and in vivo development

The organotypic retinal explant culture has been established for more than a decade and offers a range of unique advantages compared with in vivo experiments and cell cultures.However,the lack of systematic and continuous comparison between in vivo retinal development and the organotypic retinal explant culture makes this model controversial in postnatal retinal development studies.Thus,we aimed to verify the feasibility of using this model for postnatal retinal development studies by comparing it with the in vivo retina.In this study,we showed that postnatal retinal explants undergo normal development,and exhibit a consistent structure and timeline with retinas in vivo.Initially,we used SOX2 and PAX6 immunostaining to identify retinal progenitor cells.We then examined cell proliferation and migration by immunostaining with Ki-67 and doublecortin,respectively.Ki-67-and doublecortin-positive cells decreased in both in vivo and explants during postnatal retinogenesis,and exhibited a high degree of similarity in abundance and distribution between groups.Additionally,we used Ceh-10 homeodomain-containing homolog,glutamate-ammonia ligase(glutamine synthetase),neuronal nuclei,and ionized calcium-binding adapter molecule 1 immunostaining to examine the emergence of bipolar cells,Müller glia,mature neurons,and microglia,respectively.The timing and spatial patterns of the emergence of these cell types were remarkably consistent between in vivo and explant retinas.Our study showed that the organotypic retinal explant culture model had a high degree of consistency with the progression of in vivo early postnatal retina development.The findings confirm the accuracy and credibility of this model and support its use for long-term,systematic,and continuous observation.

Indirubin alleviates retinal neurodegeneration through the regulation of PI3K/AKT signaling

Retinal neurodegenerative disease is a leading cause of blindness among the elderly in developed countries,including glaucoma,diabetic retinopathy,traumatic optic neuropathy and optic neuritis,etc.The current clinical treatment is not very effective.We investigated indirubin,one of the main bioactive components of the traditional Chinese medicine Danggui Longhui Pill,in the present study for its role in retinal neurodegeneration.Indirubin exhibited no detectable tissue toxicity in vivo or cytotoxicity in vitro.Moreover,indirubin improved visual function and ameliorated retinal neurodegeneration in mice after optic nerve crush injury in vivo.Furthermore,indirubin reduced the apoptosis of retinal ganglion cells induced by oxidative stress in vitro.In addition,indirubin significantly suppressed the increased production of intracellular reactive oxygen species and the decreased activity of superoxide dismutase induced by oxidative stress.Mechanically,indirubin played a neuroprotective role by regulating the PI3K/AKT/BAD/BCL-2 signaling.In conclusion,indirubin protected retinal ganglion cells from oxidative damage and alleviated retinal neurodegeneration induced by optic nerve crush injury.The present study provides a potential therapeutic medicine for retinal neurodegenerative diseases.

OCTA characteristics in non-arteritic central retinal artery occlusion and correlation with visual acuity

AIM:To observe the retinal and choroidal circulations in patients with non-arteritic permanent central retinal artery occlusion(NA-CRAO)via optical coherence tomography angiography(OCTA)and analyze their correlation with visual acuity.METHODS:Sixty-two eyes with clinically confirmed acute NA-CRAO were included in the study and divided into:A type(mild n=29),B type(moderate n=27)and C type(severe n=6)based on the degree of visual loss,retinal edema,and arterial blood flow delay in fundus fluorescence angiography(FFA).Contralateral healthy eyes were used as the control group.Best-corrected visual acuity(BCVA),slit lamp microscopy,indirect ophthalmoscopy,fundus color photography,OCTA,and FFA were performed.Spearman’s correlation analysis was used to determine the correlations between retinal and choroidal vessels and visual acuity.RESULTS:There were no statistically significant differences in age,gender,and intraocular pressure among the three types and the control group(P>0.05).Vessel density in deep capillary plexus(VD-DCP)significantly decreased(P<0.05)in all three types of NA-CRAO patients compared to the control group.Vessel density in superficial vascular plexus(VD-SVP)significantly decreased(P<0.05)in type A patients and choriocapillaris flow area significantly decreased(P<0.05)in type B and type C patients compared to the control group;while outer retinal flow areas significantly increased in the type A(P<0.05)and decreased in type C patients(P<0.05).The retinal thickness significantly increased in type C group(P<0.05).The VD-SVP at fovea in the type A was significantly lower than both of type B and C.The VD-SVP at nasal parafovea in type A and B was significantly lower than type C(P<0.05).The logMAR BCVA of type A was significantly better than that of type B and C groups(P<0.05).Spearman’s correlation analysis showed that the logMAR BCVA was positively correlated with VD-SVP at fovea(r=0.679,P=0.031)and nasal parafovea(r=0.826,P=0.013).CONCLUSION:OCTA is valuable for assessing retinal ischemia,and evaluating visual impairment.Deep retinal vasculature is commonly affected in all NA-CRAO types.VDSVPs at fovea and nasal parafovea can serve as reliable markers of visual impairment in NA-CRAO.