Age-related macular degeneration(AMD)is the leading cause of irreversible vision loss in older adults,with early-stage features including subretinal lipid deposits and progressing to retinal geographic atrophy and cho...Age-related macular degeneration(AMD)is the leading cause of irreversible vision loss in older adults,with early-stage features including subretinal lipid deposits and progressing to retinal geographic atrophy and choroidal neovascularization in advanced stages.The dysregulation of ocular lipid metabolism,oxidative stress,and inflammation are critical risk factors for AMD pathogenesis.7-ketocholesterol(7-KC),a hallmark of ocular lipid metabolism disorders,is a significant component of subretinal lipid deposits in AMD patients,exhibiting toxicity to retinal cells and exacerbating lipotoxic aging.This review elaborates on the biosynthesis and metabolism of 7-KC in the retina,investigates its detoxification mechanisms by examining its binding proteins,and summarizes recent progress on kinase signaling pathways induced by 7-KC through inflammatory cytokines and intracellular effectors.The aim is to pinpoint potential pharmacological targets,nutritional compounds,and synthetic molecules to explore the potential of targeting 7-KC for AMD treatment.展开更多
Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages.Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and m...Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages.Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration,which is a prerequisite for nerve regeneration,we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis.Herein,we found low expression of microRNA-301a in intact sciatic nerves,with no impact of the microRNA-301a knockout on nerve structure and function.By contrast,we found significant upregulation of microRNA-301a in injured sciatic nerves.We established a sciatic nerve crush model in microRNA-301a knockout mice,which exhibited attenua9ted morphological and functional regeneration following sciatic nerve crush injury.The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model.Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration,which was reversible under transfection with microRNA-301a mimics.Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C-X-C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C-X-C motif receptor 4 pathway in the role of microRNA-301a.Combined with our previous findings in macrophages,we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C-X-C motif receptor 4 pathway.展开更多
Photoreceptor degeneration is a major cause of vision impairment in retinal diseases,for which no effective treatment currently exists.Previous research by our team demonstrated that Lycium barbarum glycopeptide and l...Photoreceptor degeneration is a major cause of vision impairment in retinal diseases,for which no effective treatment currently exists.Previous research by our team demonstrated that Lycium barbarum glycopeptide and luteolin can independently promote photoreceptor survival and function in degenerated mouse retinas,although with limited efficacy.This study evaluated whether a combination of Lycium barbarum glycopeptide and luteolin provides enhanced therapeutic benefits compared with either compound alone.Wild-type mice received a daily oral gavage of Lycium barbarum glycopeptide and luteolin for 7 days prior to intraperitoneal injection of N-nitroso-N-methylurea to induce photoreceptor damage.The treatment continued for an additional week after injury.Retinal structure and function were subsequently assessed using electroretinogram recordings,visual behavior testing,and immunostaining.Western blot analysis was conducted to investigate the underlying protective mechanisms.The results showed that the Lycium barbarum glycopeptide-luteolin mixture significantly increased photoreceptor survival,improved retinal light response,and enhanced visual behavior.Importantly,the combination outperformed either compound alone in protective efficacy.Mechanistic analysis indicated that the mixture suppressed retinal inflammation and modulated the extracellular signal-regulated kinase and Bcl-2-associated X protein/B-cell lymphoma 2 signaling pathways.These findings suggest that the combination of Lycium barbarum glycopeptide and luteolin represents a promising therapeutic strategy for photoreceptor degeneration.展开更多
Neurodegenerative diseases account for a large and increasing health and economic burden worldwide.With an increasingly aged population,this burden is set to increase.Optic neuropathies make up a large proportion of n...Neurodegenerative diseases account for a large and increasing health and economic burden worldwide.With an increasingly aged population,this burden is set to increase.Optic neuropathies make up a large proportion of neurodegenerative diseases with glaucoma being highly prevalent.Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells and their axons which make up the optic nerve.It is the leading cause of irreversible vision loss and affects an estimated 80 million people.The mammalian central nervous system is non-regenerative and,once lost or injured,retinal ganglion cells cannot regenerate an axon into the optic nerve under basal conditions.Thus,strategies that provide neuroprotection to stressed,dysfunctional,or dying retinal ganglion cells are likely to be of high therapeutic and translational value.Advancing age,genetics,and elevated intraocular pressure are all major risk factors for glaucoma,however,all clinically available glaucoma treatments focus on intraocular pressure management and do not directly address the neurodegenerative component of glaucoma.展开更多
Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Ret...Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.展开更多
Background:Lumbar disc degeneration(LDD)displays considerable heterogeneity in terms of clinical features and pathological changes.However,researchers have not clearly determined whether the transcriptome variations i...Background:Lumbar disc degeneration(LDD)displays considerable heterogeneity in terms of clinical features and pathological changes.However,researchers have not clearly determined whether the transcriptome variations in LDD could be used to identify or interpret the causes of heterogeneity in clinical features.This study aimed to identify the transcriptomic classification of degenerated discs in LDD patients and whether the molecular subtypes of LDD could be accurately predicted using clinical features.Methods:One hundred and twenty-two nucleus pulposus(NP)tissues from 108 patients were consecutively collected for bulk RNA sequencing(RNA-seq).An unsupervised clustering method was employed to analyze the bulk RNA matrix.Differential analysis was performed to characterize the transcriptional signatures and subtype-specific extracellular matrix(ECM)dysregulation.The cell subpopulation states of each subtype were inferred by integrating bulk and single-cell sequencing datasets.Transwell and dual-luciferase reporter gene assays were employed to investigate possible molecular mechanisms involved.Machine learning algorithm diagnostic prediction models were developed to correlate molecular classification with clinical features.Results:LDD was classified into 4 subtypes with distinct molecular signatures and ECM remodeling:C1 with collagenesis,C2 with ossification,C3 with low chondrogenesis,and C4 with fibrogenesis.Chond1-3 in C1 dominated disc collagenesis via the activation of the mechanosensors TRPV4 and PIEZO1;NP progenitor cells in C2 exhibited chondrogenic and osteogenic phenotypes;Chond1 in C3 was linked to a disrupted hypoxic microenvironment leading to reduced chondrogenesis;Macrophages in C4 played a crucial role in disc fibrogenesis via the secretion of tumor necrosis factor-α(TNF-α).Furthermore,the random forest diagnostic prediction model was proven to have a robust performance[area under the receiver operating characteristic(ROC)curve:0.9312;accuracy:0.84]in stratifying the molecular subtypes of LDD based on 12 clinical features.Conclusions:Our study delineates 4 distinct molecular subtypes of LDD that can be accurately stratified on the basis of clinical features.The identification of these subtypes would facilitate precise diagnostics and guide the development of personalized treatment strategies for LDD.展开更多
Existing evidence suggests residential greenness is beneficial to human,while no research to date explored the associations of greenness with age-related macular degeneration(AMD).To evaluate the association of greenn...Existing evidence suggests residential greenness is beneficial to human,while no research to date explored the associations of greenness with age-related macular degeneration(AMD).To evaluate the association of greenness with AMD,modification and mediation effect of air pollution,we conducted this prospective study.We con-structed weighted quantile sum(WQS)index as co-exposure to nitrogen oxides(NO_(x)),particulate matter<2.5μm(PM_(2.5)),particulate matter<10μm(PM10).Stratified Cox regression models were applied to test the effect of exposure.Effect modification of air pollution was assessed.Stratified Cox models through the indirect method and Aalen additive risk models were used in mediation analysis.Over median follow-up of 11.67 years,4596 AMD events were ascertained.Hazard ratios(HRs)and 95%confidence intervals(95%CIs)of incident AMD for pollution per interquartile range(IQR)increment were 1.10(1.04–1.16)for nitrogen dioxide(NO_(2)),1.09(1.03–1.15)for NO_(x),1.14(1.05–1.24)for PM_(2.5),1.13(1.05–1.21)for PM10.The HR(95%CI)of AMD associated with greenness 1000 m buffer per IQR increment was 0.91(0.86–0.97),300 m buffer was 0.94(0.89–0.99).The as-sociation between greenness 1000 m and AMD was 28.59%,44.77%,35.59%,32.31%and 27.08%mediated by the decreased WQS index,NO_(2),NO_(x),PM_(2.5) and PM10,respectively.Increased greenness was associated with lower AMD incidence,and air pollution partly mediate it,which implies that interventions aimed at improving air quality and increasing greenness could have a dual benefit in mitigating AMD risk.展开更多
Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal deg...Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal degenerative diseases.However,the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored.Bioinformatics and biochemical analyses in this study revealed xC^(–),solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model.This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway,through which cystine depletion,iron ion accumulation,and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment.We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo.Conversely,solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H_(2)O_(2)-induced ferroptosis of 661W cells.These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.展开更多
A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to ...A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.展开更多
Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain.While the etiological factors for disc degeneration vary,age is still one of the most important risk factors.Recen...Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain.While the etiological factors for disc degeneration vary,age is still one of the most important risk factors.Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health,however its role in the intervertebral disc health remains unexplored.We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc(AcanCreERT2;Sirt6fl/fl).Histological studies showed a degenerative phenotype in knockout mice compared to Sirt6fl/fl control mice at 12 months,which became pronounced at 24 months.RNA-Seq analysis of NP and AF tissues,in vitro quantitative histone analysis,and RNA-seq with ATAC-seq multiomic studies revealed that SIRT6-loss resulted in changes in acetylation and methylation status of specific Histone 3 lysine residues and affected DNA accessibility and transcriptomic landscape.A decrease in autophagy and an increase in DNA damage were also noted in Sirt6-deficient cells.Further mechanistic insights revealed that loss of SIRT6 increased senescence and SASP burden in the disc characterized by increased p21,p19,γH2AX,IL-6,IL-1β,and TGF-βabundance.Taken together,our study highlights the contribution of SIRT6 in modulating DNA damage,autophagy,and cell senescence and its importance in maintaining disc health during aging,thereby underscoring it as a potential therapeutic target to treat intervertebral disc degeneration.展开更多
Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulp...Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.展开更多
Intervertebral disc degeneration(IDD)is a progressive and dynamic process in which the senescence-associated secretory phenotype(SASP)of nucleus pulposus cells(NPC)plays a significant role.While impaired chaperone-med...Intervertebral disc degeneration(IDD)is a progressive and dynamic process in which the senescence-associated secretory phenotype(SASP)of nucleus pulposus cells(NPC)plays a significant role.While impaired chaperone-mediated autophagy(CMA)has been associated with inflammation and cellular senescence,its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood.Through LAMP2A knockout in NPC,we identified a significant upregulation of DYRK1A,a core mediator of premature senescence in Down syndrome.Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC.Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition,elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation,initiating transcriptional activation of cell cycle arrest.Intriguingly,CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC,thereby augmenting their survival fitness.Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis,mediated by decreased glutamine flux via GLUL degradation.Therefore,CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis.This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits,providing novel therapeutic insights for IDD and other age-related pathologies.展开更多
AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized g...AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized genome-wide association study(GWAS)summary statistics derived from the IEU OpenGWAS repositories.The investigation focused on 11 oxidative stress markers and AMD phenotypes,encompassing both wet and dry subtypes.The MR methodology incorporated inverse-variance weighted(IVW)calculations,MR-Egger statistical regression,weighted median approximation,and weighted mode assessments to estimate causative relationships.Sensitivity evaluations were conducted to verify result robustness and identify potential pleiotropy.RESULTS:Genetically predicted elevated catalase(CAT)concentrations demonstrated significant associations with heightened risks of overall AMD(IVW OR=1.084,95%CI:1.021-1.151,P=0.008)and wet AMD phenotype(IVW OR=1.113,95%CI:1.047-1.247,P=0.007).Higher genetically predicted albumin concentrations corresponded with reduced AMD risk(IVW OR=0.827,95%CI:0.715-0.957,P=0.013)but increased wet AMD risk(IVW OR=1.229,95%CI:1.036-1.458,P=0.018).Reverse MR analysis revealed that genetically predicted dry AMD exhibited significant association with reduced albumin levels(IVW OR=0.987,95%CI:0.979-0.996,P=0.004),while wet AMD corresponded with decreased total bilirubin(TBIL)and paraoxonase(PON)activity.CONCLUSION:The results offer strong support for a causal link between markers of oxidative stress and the development of AMD,indicating that oxidative processes play a role in driving the disease progression.展开更多
Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are...Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are consequently lacking.The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host.The intestinal microbiome undergoes dynamic changes owing to age,diet,genetics,and other factors.Such dysregulation of the intestinal flora can disrupt the microecological balance,resulting in immunological and metabolic dysfunction in the host,and affecting the development of many diseases.In recent decades,significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract,including the brain.Indeed,several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.Similarly,the role of the“gut-eye axis”has been confirmed to play a role in the pathogenesis of many ocular disorders.Moreover,age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies.As such,the intestinal flora may play an important role in age-related macular degeneration.Given the above context,the present review aims to clarify the gut-brain and gut-eye connections,assess the effect of intestinal flora and metabolites on age-related macular degeneration,and identify potential diagnostic markers and therapeutic strategies.Currently,direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited,while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration.Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions,while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.展开更多
Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as ...Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
Intervertebral disc degeneration is a degenerative disease where inflammation and immune responses play significant roles.Macrophages,as key immune cells,critically regulate inflammation through polarization into diff...Intervertebral disc degeneration is a degenerative disease where inflammation and immune responses play significant roles.Macrophages,as key immune cells,critically regulate inflammation through polarization into different phenotypes.In recent years,the role of macrophages in inflammation-related degenerative diseases,such as intervertebral disc degeneration,has been increasingly recognized.Macrophages construct the inflammatory microenvironment of the intervertebral disc and are involved in regulating intervertebral disc cell activities,extracellular matrix metabolism,intervertebral disc vascularization,and innervation,profoundly influencing the progression of disc degeneration.To gain a deeper understanding of the inflammatory microenvironment of intervertebral disc degeneration,this review will summarize the role of macrophages in the pathological process of intervertebral disc degeneration,analyze the regulatory mechanisms involving macrophages,and review therapeutic strategies targeting macrophage modulation for the treatment of intervertebral disc degeneration.These insights will be valuable for the treatment and research directions of intervertebral disc degeneration.展开更多
Fibrotic remodeling of nucleus pulposus(NP)leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration,leading to low back pain incidence and disability.Emergence of fibroblastic ce...Fibrotic remodeling of nucleus pulposus(NP)leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration,leading to low back pain incidence and disability.Emergence of fibroblastic cells in disc degeneration has been reported,yet their nature and origin remain elusive.In this study,we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens.We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype,characterized by CD45 and collagen I dual positivity,and expression of myofibroblast markerα-smooth muscle actin.Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells-and immunocytes-clusters,expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β.In injury-induced mouse disc degeneration model,fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype.Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs,and prevent disc height loss and histomorphological abnormalities.Marker analysis supports that disc degeneration progression is dependent on a function of CD45^(+)COL1A1^(+)andαSMA^(+)cells.Our findings reveal that myeloid-derived fibrocytes play a pivotal role in NP fibrosis and may therefore be a target for modifying disc degeneration and promoting its repair.展开更多
Rice yield is heavily reliant on the number of spikelets per panicle,a factor determined by the processes of spikelet differentiation and degeneration.In rice cultivars with large panicles,spikelet degeneration negate...Rice yield is heavily reliant on the number of spikelets per panicle,a factor determined by the processes of spikelet differentiation and degeneration.In rice cultivars with large panicles,spikelet degeneration negates the advantages of large panicle and constrains yield potential.Environmental stress-induced metabolic disorders in plants aggravate spikelet degeneration,with the sensitive period for this process commencing approximately 15‒20 d before panicle heading.Notable positional variations occur within the panicle,with significantly higher spikelet degeneration rates at the basal than at the upper positions.An imbalance of carbon and nitrogen metabolism represents the primary physiological basis for aggravated spikelet degeneration under abiotic stress.Impaired carbon and nitrogen metabolism leads to disordered energy metabolism and disrupted respiratory electron transport,which accelerates the apoptosis of young spikelets through excessive reactive oxygen species accumulation.Sucrose serves as the main carbohydrate source for spikelet development,demonstrating an apical dominance pattern that favors spikelet formation.However,under abiotic stress,the inhibition of sucrose decomposition,rather than sucrose transport impairment,predominantly contributes to aggravated spikelet degeneration at the basal panicle positions.Brassinolide and auxin have a significant relationship with spikelet formation,potentially mediating apical dominance.Specifically,brassinolide enhances sucrose accumulation and utilization,thereby alleviating spikelet degeneration.At present,the mechanisms underlying rice spikelet degeneration have not been fully revealed,and the joint effects of hormones,carbohydrates,and carbon and nitrogen metabolism on this process require further investigation.To reduce the spikelet degeneration,the strategic application of water and fertilizer to establish a stable rice population can enhance the rice plants’resilience to abiotic stress.An effective approach to reducing spikelet degeneration is to increase the dry matter occupancy of each spikelet during the panicle initiation period.展开更多
文摘Age-related macular degeneration(AMD)is the leading cause of irreversible vision loss in older adults,with early-stage features including subretinal lipid deposits and progressing to retinal geographic atrophy and choroidal neovascularization in advanced stages.The dysregulation of ocular lipid metabolism,oxidative stress,and inflammation are critical risk factors for AMD pathogenesis.7-ketocholesterol(7-KC),a hallmark of ocular lipid metabolism disorders,is a significant component of subretinal lipid deposits in AMD patients,exhibiting toxicity to retinal cells and exacerbating lipotoxic aging.This review elaborates on the biosynthesis and metabolism of 7-KC in the retina,investigates its detoxification mechanisms by examining its binding proteins,and summarizes recent progress on kinase signaling pathways induced by 7-KC through inflammatory cytokines and intracellular effectors.The aim is to pinpoint potential pharmacological targets,nutritional compounds,and synthetic molecules to explore the potential of targeting 7-KC for AMD treatment.
基金supported by the National Natural Science Foundation of China,No.82071386(to JG).
文摘Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages.Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration,which is a prerequisite for nerve regeneration,we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis.Herein,we found low expression of microRNA-301a in intact sciatic nerves,with no impact of the microRNA-301a knockout on nerve structure and function.By contrast,we found significant upregulation of microRNA-301a in injured sciatic nerves.We established a sciatic nerve crush model in microRNA-301a knockout mice,which exhibited attenua9ted morphological and functional regeneration following sciatic nerve crush injury.The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model.Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration,which was reversible under transfection with microRNA-301a mimics.Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C-X-C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C-X-C motif receptor 4 pathway in the role of microRNA-301a.Combined with our previous findings in macrophages,we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C-X-C motif receptor 4 pathway.
基金Natural Science Foundation of Guangdong Province,No.2023A1515012397(to YX)the National Natural Science Foundation of China,No.82074169(to XM)+2 种基金the Guangdong Basic and Applied Basic Research Foundation,No.2021A1515012473(to XM)and Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045(to XM)Aier Eye Hospital Group,No.AF2019001(to ST,KFS,YX,and XM).
文摘Photoreceptor degeneration is a major cause of vision impairment in retinal diseases,for which no effective treatment currently exists.Previous research by our team demonstrated that Lycium barbarum glycopeptide and luteolin can independently promote photoreceptor survival and function in degenerated mouse retinas,although with limited efficacy.This study evaluated whether a combination of Lycium barbarum glycopeptide and luteolin provides enhanced therapeutic benefits compared with either compound alone.Wild-type mice received a daily oral gavage of Lycium barbarum glycopeptide and luteolin for 7 days prior to intraperitoneal injection of N-nitroso-N-methylurea to induce photoreceptor damage.The treatment continued for an additional week after injury.Retinal structure and function were subsequently assessed using electroretinogram recordings,visual behavior testing,and immunostaining.Western blot analysis was conducted to investigate the underlying protective mechanisms.The results showed that the Lycium barbarum glycopeptide-luteolin mixture significantly increased photoreceptor survival,improved retinal light response,and enhanced visual behavior.Importantly,the combination outperformed either compound alone in protective efficacy.Mechanistic analysis indicated that the mixture suppressed retinal inflammation and modulated the extracellular signal-regulated kinase and Bcl-2-associated X protein/B-cell lymphoma 2 signaling pathways.These findings suggest that the combination of Lycium barbarum glycopeptide and luteolin represents a promising therapeutic strategy for photoreceptor degeneration.
基金supported by St.Erik Eye Hospital philanthropic donations,Vetenskapsrådet 2022-00799(to PAW).
文摘Neurodegenerative diseases account for a large and increasing health and economic burden worldwide.With an increasingly aged population,this burden is set to increase.Optic neuropathies make up a large proportion of neurodegenerative diseases with glaucoma being highly prevalent.Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells and their axons which make up the optic nerve.It is the leading cause of irreversible vision loss and affects an estimated 80 million people.The mammalian central nervous system is non-regenerative and,once lost or injured,retinal ganglion cells cannot regenerate an axon into the optic nerve under basal conditions.Thus,strategies that provide neuroprotection to stressed,dysfunctional,or dying retinal ganglion cells are likely to be of high therapeutic and translational value.Advancing age,genetics,and elevated intraocular pressure are all major risk factors for glaucoma,however,all clinically available glaucoma treatments focus on intraocular pressure management and do not directly address the neurodegenerative component of glaucoma.
文摘Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.
基金supported by the National Natural Science Foundation of China(32270887,82272507,32200654,82430079,and 82472519)the National Key Research and Development Program of China(2022YFA1103202)+7 种基金the Chongqing High-End Medical Talents for Middle-aged and Young(YXGD202408)the Army Scientific and Technological Innovation Talents Prioritized Suppor t Program(2023-124)the Natural Science Foundation of Chongqing(CSTB2023NSCQ-ZDJO008)the Postdoctoral Innovative Talent Support Program(BX20220397)the Open Project of State Key Laboratory of TraumaBurns and Combined Injury(SFLKF202201)the Project for Enhancing Innovation of Army Medical University(2023XJS39)the Talent Innovation Training Program at the Army Medical Center(ZXZYTSYS09)。
文摘Background:Lumbar disc degeneration(LDD)displays considerable heterogeneity in terms of clinical features and pathological changes.However,researchers have not clearly determined whether the transcriptome variations in LDD could be used to identify or interpret the causes of heterogeneity in clinical features.This study aimed to identify the transcriptomic classification of degenerated discs in LDD patients and whether the molecular subtypes of LDD could be accurately predicted using clinical features.Methods:One hundred and twenty-two nucleus pulposus(NP)tissues from 108 patients were consecutively collected for bulk RNA sequencing(RNA-seq).An unsupervised clustering method was employed to analyze the bulk RNA matrix.Differential analysis was performed to characterize the transcriptional signatures and subtype-specific extracellular matrix(ECM)dysregulation.The cell subpopulation states of each subtype were inferred by integrating bulk and single-cell sequencing datasets.Transwell and dual-luciferase reporter gene assays were employed to investigate possible molecular mechanisms involved.Machine learning algorithm diagnostic prediction models were developed to correlate molecular classification with clinical features.Results:LDD was classified into 4 subtypes with distinct molecular signatures and ECM remodeling:C1 with collagenesis,C2 with ossification,C3 with low chondrogenesis,and C4 with fibrogenesis.Chond1-3 in C1 dominated disc collagenesis via the activation of the mechanosensors TRPV4 and PIEZO1;NP progenitor cells in C2 exhibited chondrogenic and osteogenic phenotypes;Chond1 in C3 was linked to a disrupted hypoxic microenvironment leading to reduced chondrogenesis;Macrophages in C4 played a crucial role in disc fibrogenesis via the secretion of tumor necrosis factor-α(TNF-α).Furthermore,the random forest diagnostic prediction model was proven to have a robust performance[area under the receiver operating characteristic(ROC)curve:0.9312;accuracy:0.84]in stratifying the molecular subtypes of LDD based on 12 clinical features.Conclusions:Our study delineates 4 distinct molecular subtypes of LDD that can be accurately stratified on the basis of clinical features.The identification of these subtypes would facilitate precise diagnostics and guide the development of personalized treatment strategies for LDD.
基金supported by the High-level Talents Introduction Plan from Central South University(No.502045003)the National Natural Science Foundation of China(No.42277438)Hunan Provincial Natural Science Foundation for Distinguished Young Scholars(No.2024JJ2082)to Fang Xiao,and the Postgraduate Independent Exploration and Innovation Project of Central South University,China(Nos.2024ZZTS0557 and 2023ZZTS0993)。
文摘Existing evidence suggests residential greenness is beneficial to human,while no research to date explored the associations of greenness with age-related macular degeneration(AMD).To evaluate the association of greenness with AMD,modification and mediation effect of air pollution,we conducted this prospective study.We con-structed weighted quantile sum(WQS)index as co-exposure to nitrogen oxides(NO_(x)),particulate matter<2.5μm(PM_(2.5)),particulate matter<10μm(PM10).Stratified Cox regression models were applied to test the effect of exposure.Effect modification of air pollution was assessed.Stratified Cox models through the indirect method and Aalen additive risk models were used in mediation analysis.Over median follow-up of 11.67 years,4596 AMD events were ascertained.Hazard ratios(HRs)and 95%confidence intervals(95%CIs)of incident AMD for pollution per interquartile range(IQR)increment were 1.10(1.04–1.16)for nitrogen dioxide(NO_(2)),1.09(1.03–1.15)for NO_(x),1.14(1.05–1.24)for PM_(2.5),1.13(1.05–1.21)for PM10.The HR(95%CI)of AMD associated with greenness 1000 m buffer per IQR increment was 0.91(0.86–0.97),300 m buffer was 0.94(0.89–0.99).The as-sociation between greenness 1000 m and AMD was 28.59%,44.77%,35.59%,32.31%and 27.08%mediated by the decreased WQS index,NO_(2),NO_(x),PM_(2.5) and PM10,respectively.Increased greenness was associated with lower AMD incidence,and air pollution partly mediate it,which implies that interventions aimed at improving air quality and increasing greenness could have a dual benefit in mitigating AMD risk.
基金supported by the National Natural Science Foundation of China,Nos.82171076(to XS)and U22A20311(to XS),82101168(to TL)Shanghai Science and technology Innovation Action Plan,No.23Y11901300(to JS)+1 种基金Science and Technology Commission of Shanghai Municipality,No.21ZR1451500(to TL)Shanghai Pujiang Program,No.22PJ1412200(to BY)。
文摘Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal degenerative diseases.However,the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored.Bioinformatics and biochemical analyses in this study revealed xC^(–),solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model.This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway,through which cystine depletion,iron ion accumulation,and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment.We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo.Conversely,solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H_(2)O_(2)-induced ferroptosis of 661W cells.These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.
基金supported by the Army Laboratory Animal Foundation of China,No.SYDW[2020]22(to TC)the Shaanxi Provincial Key R&D Plan General Project of China,No.2022SF-236(to YM)the National Natural Science Foundation of China,No.82202070(to TC)。
文摘A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
基金supported by the Michael Michelson Gift FundNIA grants R01AG073349 (M.V.R.), R01AG044034 (R.F.L.), and R01AG078609 (J.C.)
文摘Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain.While the etiological factors for disc degeneration vary,age is still one of the most important risk factors.Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health,however its role in the intervertebral disc health remains unexplored.We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc(AcanCreERT2;Sirt6fl/fl).Histological studies showed a degenerative phenotype in knockout mice compared to Sirt6fl/fl control mice at 12 months,which became pronounced at 24 months.RNA-Seq analysis of NP and AF tissues,in vitro quantitative histone analysis,and RNA-seq with ATAC-seq multiomic studies revealed that SIRT6-loss resulted in changes in acetylation and methylation status of specific Histone 3 lysine residues and affected DNA accessibility and transcriptomic landscape.A decrease in autophagy and an increase in DNA damage were also noted in Sirt6-deficient cells.Further mechanistic insights revealed that loss of SIRT6 increased senescence and SASP burden in the disc characterized by increased p21,p19,γH2AX,IL-6,IL-1β,and TGF-βabundance.Taken together,our study highlights the contribution of SIRT6 in modulating DNA damage,autophagy,and cell senescence and its importance in maintaining disc health during aging,thereby underscoring it as a potential therapeutic target to treat intervertebral disc degeneration.
基金supported by National Natural Science Foundation of China(82272549,82472505,and 82472498)National key Research and Development plan,Ministry of Science and Technology of the People’s Republic of China(2022YFC2407203)+2 种基金the Young Health Talents of Shanghai Municipal Health Commission,China(2022YQ011)China Medical Education Association(3030537245)The Youth Talent Project of Huashan Hospital(30302164006).
文摘Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.
基金supported by the National Natural Science Foundation of China (NSFC) (No.82172497)
文摘Intervertebral disc degeneration(IDD)is a progressive and dynamic process in which the senescence-associated secretory phenotype(SASP)of nucleus pulposus cells(NPC)plays a significant role.While impaired chaperone-mediated autophagy(CMA)has been associated with inflammation and cellular senescence,its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood.Through LAMP2A knockout in NPC,we identified a significant upregulation of DYRK1A,a core mediator of premature senescence in Down syndrome.Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC.Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition,elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation,initiating transcriptional activation of cell cycle arrest.Intriguingly,CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC,thereby augmenting their survival fitness.Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis,mediated by decreased glutamine flux via GLUL degradation.Therefore,CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis.This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits,providing novel therapeutic insights for IDD and other age-related pathologies.
基金Supported by National Natural Science Foundation of China(No.82371033)Tianjin Health Bureau Fund(No.ZC20030)+4 种基金Tianjin Eye Hospital Fund Project(No.YKYB1911)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-016A)Nankai University Institute of Optometry Science Research Open Fund(No.YKPY2208)Tianjin Eye Hospital Science and Technology Fund(No.NKSGY202405)Xianyang Science and Technology Plan Project(No.L2022ZDYFSF038).
文摘AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized genome-wide association study(GWAS)summary statistics derived from the IEU OpenGWAS repositories.The investigation focused on 11 oxidative stress markers and AMD phenotypes,encompassing both wet and dry subtypes.The MR methodology incorporated inverse-variance weighted(IVW)calculations,MR-Egger statistical regression,weighted median approximation,and weighted mode assessments to estimate causative relationships.Sensitivity evaluations were conducted to verify result robustness and identify potential pleiotropy.RESULTS:Genetically predicted elevated catalase(CAT)concentrations demonstrated significant associations with heightened risks of overall AMD(IVW OR=1.084,95%CI:1.021-1.151,P=0.008)and wet AMD phenotype(IVW OR=1.113,95%CI:1.047-1.247,P=0.007).Higher genetically predicted albumin concentrations corresponded with reduced AMD risk(IVW OR=0.827,95%CI:0.715-0.957,P=0.013)but increased wet AMD risk(IVW OR=1.229,95%CI:1.036-1.458,P=0.018).Reverse MR analysis revealed that genetically predicted dry AMD exhibited significant association with reduced albumin levels(IVW OR=0.987,95%CI:0.979-0.996,P=0.004),while wet AMD corresponded with decreased total bilirubin(TBIL)and paraoxonase(PON)activity.CONCLUSION:The results offer strong support for a causal link between markers of oxidative stress and the development of AMD,indicating that oxidative processes play a role in driving the disease progression.
基金supported by the National Natural Science Foundation of China,No.82171080Nanjing Medical Science and Technology Development Project,No.YKK23264Postgraduate Research&Practice Innovation Program of Jiangsu Province,Nos.JX10414151,JX10414152(all to KL)。
文摘Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are consequently lacking.The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host.The intestinal microbiome undergoes dynamic changes owing to age,diet,genetics,and other factors.Such dysregulation of the intestinal flora can disrupt the microecological balance,resulting in immunological and metabolic dysfunction in the host,and affecting the development of many diseases.In recent decades,significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract,including the brain.Indeed,several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.Similarly,the role of the“gut-eye axis”has been confirmed to play a role in the pathogenesis of many ocular disorders.Moreover,age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies.As such,the intestinal flora may play an important role in age-related macular degeneration.Given the above context,the present review aims to clarify the gut-brain and gut-eye connections,assess the effect of intestinal flora and metabolites on age-related macular degeneration,and identify potential diagnostic markers and therapeutic strategies.Currently,direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited,while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration.Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions,while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.
基金supported by the National Natural Science Foundation of China,Nos.81800919(to YX),82171140(to PW)the International Cooperation and Exchange of the National Natural Science Foundation of China,Nos.82020108008(to HS),81720108010(to SY).
文摘Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
基金National Natural Science Foundation of China(U24A20670,82372419,82072435)Tianjin Science and Technology Plan Project“Unveiling and Directing”Major Project(21ZXJBSY00130)Beijing-Tianjin-Hebei Basic Research Cooperation Project(J230020)。
文摘Intervertebral disc degeneration is a degenerative disease where inflammation and immune responses play significant roles.Macrophages,as key immune cells,critically regulate inflammation through polarization into different phenotypes.In recent years,the role of macrophages in inflammation-related degenerative diseases,such as intervertebral disc degeneration,has been increasingly recognized.Macrophages construct the inflammatory microenvironment of the intervertebral disc and are involved in regulating intervertebral disc cell activities,extracellular matrix metabolism,intervertebral disc vascularization,and innervation,profoundly influencing the progression of disc degeneration.To gain a deeper understanding of the inflammatory microenvironment of intervertebral disc degeneration,this review will summarize the role of macrophages in the pathological process of intervertebral disc degeneration,analyze the regulatory mechanisms involving macrophages,and review therapeutic strategies targeting macrophage modulation for the treatment of intervertebral disc degeneration.These insights will be valuable for the treatment and research directions of intervertebral disc degeneration.
基金jointly General Research Fund(17121619)of the Research Grant Council of Hong KongGuangdong Basic and Applied Basic Research Foundation(2024A1515010104 and 2023A1515220095)Scientific Research Foundation of Peking University Shenzhen Hospital(KYQD202100X)。
文摘Fibrotic remodeling of nucleus pulposus(NP)leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration,leading to low back pain incidence and disability.Emergence of fibroblastic cells in disc degeneration has been reported,yet their nature and origin remain elusive.In this study,we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens.We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype,characterized by CD45 and collagen I dual positivity,and expression of myofibroblast markerα-smooth muscle actin.Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells-and immunocytes-clusters,expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β.In injury-induced mouse disc degeneration model,fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype.Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs,and prevent disc height loss and histomorphological abnormalities.Marker analysis supports that disc degeneration progression is dependent on a function of CD45^(+)COL1A1^(+)andαSMA^(+)cells.Our findings reveal that myeloid-derived fibrocytes play a pivotal role in NP fibrosis and may therefore be a target for modifying disc degeneration and promoting its repair.
基金funded by the National Natural Science Foundation of China(Grant No.32201896)the Zhejiang Province Key Research and Development Plan Project,China(Grant No.2022C02034)the National Modern Agricultural Industrial Technology System Construction Project,China(Grant No.CARS-01-21).
文摘Rice yield is heavily reliant on the number of spikelets per panicle,a factor determined by the processes of spikelet differentiation and degeneration.In rice cultivars with large panicles,spikelet degeneration negates the advantages of large panicle and constrains yield potential.Environmental stress-induced metabolic disorders in plants aggravate spikelet degeneration,with the sensitive period for this process commencing approximately 15‒20 d before panicle heading.Notable positional variations occur within the panicle,with significantly higher spikelet degeneration rates at the basal than at the upper positions.An imbalance of carbon and nitrogen metabolism represents the primary physiological basis for aggravated spikelet degeneration under abiotic stress.Impaired carbon and nitrogen metabolism leads to disordered energy metabolism and disrupted respiratory electron transport,which accelerates the apoptosis of young spikelets through excessive reactive oxygen species accumulation.Sucrose serves as the main carbohydrate source for spikelet development,demonstrating an apical dominance pattern that favors spikelet formation.However,under abiotic stress,the inhibition of sucrose decomposition,rather than sucrose transport impairment,predominantly contributes to aggravated spikelet degeneration at the basal panicle positions.Brassinolide and auxin have a significant relationship with spikelet formation,potentially mediating apical dominance.Specifically,brassinolide enhances sucrose accumulation and utilization,thereby alleviating spikelet degeneration.At present,the mechanisms underlying rice spikelet degeneration have not been fully revealed,and the joint effects of hormones,carbohydrates,and carbon and nitrogen metabolism on this process require further investigation.To reduce the spikelet degeneration,the strategic application of water and fertilizer to establish a stable rice population can enhance the rice plants’resilience to abiotic stress.An effective approach to reducing spikelet degeneration is to increase the dry matter occupancy of each spikelet during the panicle initiation period.
