Shikonin,a naphthoquinone compound derived from the root of Lithospermum erythrorhizon,has been extensively studied for its antibacterial,antioxidant,and anti-inflammatory properties.Increasing evidence highlights its...Shikonin,a naphthoquinone compound derived from the root of Lithospermum erythrorhizon,has been extensively studied for its antibacterial,antioxidant,and anti-inflammatory properties.Increasing evidence highlights its potential in treating inflammation-related diseases.However,its clinical application is hindered by challenges such as poor water solubility,rapid metabolism in vivo,and other limitations.Recent advancements have demonstrated that encapsulating shikonin within nanocarriers can significantly enhance its water solubility and pharmacokinetic profile.Building on this,this perspective paper outlines the current landscape of inflammation treatment,explores the anti-inflammatory mechanisms of shikonin,reviews the latest progress in shikonin-based nanomaterials for anti-inflammatory applications,and discusses the challenges and future directions for the clinical translation of shikonin nanoformulations.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is cha...Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.展开更多
BACKGROUND Qiweizhigan granule(QWZG)is employed in clinical settings for the treatment of metabolic dysfunctionassociated steatohepatitis(MASH).However,the precise biological mechanisms underlying its therapeutic effe...BACKGROUND Qiweizhigan granule(QWZG)is employed in clinical settings for the treatment of metabolic dysfunctionassociated steatohepatitis(MASH).However,the precise biological mechanisms underlying its therapeutic effects are not yet fully elucidated.AIM To assess the efficacy and the mechanism of QWZG against MASH.METHODS Animal models were established,including normal group,a choline-deficient,L-amino acid-defined high-fat diet(CDAHFD)group,and low/medium/high-dose QWZG groups,as well as a rosiglitazone group.Through comprehensive biochemical,histopathological,RNA sequencing,and bioinformatics analyses,galectin 3(LGALS3)was identified as a critical target of QWZG in the treatment of MASH.The level of LGALS3 was quantitatively assessed and validated using Western blotting,real-time quantitative PCR,and immunofluorescence.The role and function of LGALS3 in inflammation and MASH progression were further investigated through gene knockdown,overexpression,iron assay,and transmission electron microscopy.RESULTS QWZG significantly ameliorated liver pathology by reducing steatosis,inflammation,and fibrosis.RNA sequencing analysis identified 1507 co-expressed differentially expressed genes among the CDAHFD,normal,and QWZG groups.Among these,LGALS3 was identified as one of the most significantly altered differentially expressed genes.Both mRNA and protein levels of LGALS3 were elevated in the CDAHFD group compared to the normal group,whereas treatment with QWZG reduced their levels.Analysis of Human Protein Atlas database indicated that LGALS3 was predominantly expressed in Kupffer cells,and was validated by real-time quantitative PCR and immunofluorescence.Furthermore,the level of LGALS3 was significantly increased in lipopolysaccharide-induced RAW264.7 cells,where its overexpression and recombinant LGALS3 protein both significantly enhanced the expression of interleukin-6,interleukin-1β,and tumor necrosis factor-α.LGALS3 overexpression significantly inhibited glutathione peroxidase 4(GPX4)expression,and exacerbated mitochondrial damage,whereas LGALS3 knockdown markedly increased GPX4 level,and significantly reduced the levels of both total iron and ferrous iron.QWZG treatment significantly reduced the levels of malondialdehyde and ferrous iron,increased the levels of superoxide dismutase and glutathione.In addition,QWZG treatment also significantly enhanced GPX4 expression.Mechanistically,LGALS3 knockdown was associated with reduced expression of tumor necrosis factor receptor-associated factor 6(TRAF6)and NOD-like receptor family pyrin domain containing 3,while its overexpression led to increased levels of these proteins.The TRAF6 inhibitor C25-140 effectively reversed the LGALS3-induced alterations in GPX4 expression and iron accumulation.Furthermore,QWZG treatment significantly decreased the levels of TRAF6 and NOD-like receptor family pyrin domain containing 3.CONCLUSION QWZG ameliorated the progression of MASH by modulating ferroptosis through the LGALS3/TRAF6/GPX4 axis.展开更多
Objective Frailty is becoming increasingly common among aging adults.Frailty transitionis shaped by biological,social,psychological,and environmental factors.This study investigated combined effects of protective fact...Objective Frailty is becoming increasingly common among aging adults.Frailty transitionis shaped by biological,social,psychological,and environmental factors.This study investigated combined effects of protective factors on frailty transition by constructing a Protection Index(PI)to guide targeted interventions.Methods Data were extracted from the 4th Sample Survey of the Aged Population in Urban and Rural China,including baseline(2017)and follow-up(2019)surveys.Frailty was assessed using the Frailty Index(FI),whereas the PI measured protective factors.Frailty transitions over 2 years were analyzed prospectively.Pearson’s correlation examined the relationship between FI and PI,and logistic regression assessed the effects of PI on frailty transitions.Results This study included 9,093 older adults.FI values increased with age and were higher in women,whereas PI values decreased with age and were higher in men.Over 2 years,56.2%of the participants showed a stable frailty status,14.2%improved,and 29.6%worsened.Negative transitions were more common than positive transitions,with transitions occurring most frequently between adjacent states.The PI was moderately negatively correlated with the FI(r=−0.349,P<0.001).A higher PI was associated with a lower risk of negative transitions among robust and prefrail individuals(OR=0.989,0.981,both P<0.05),but showed no significant effect among those with existing frailty.Conclusion Negative frailty transitions were more common with advancing age.Enhancing PI may help prevent negative frailty transitions among robust and pre-frail older adults,underscoring the value of early interventions.展开更多
Understanding the spatial distributions and corresponding variation mechanisms of key soil nutrients in fragile karst ecosystems can assist in promoting sustainable development.However,due to the implementation of eco...Understanding the spatial distributions and corresponding variation mechanisms of key soil nutrients in fragile karst ecosystems can assist in promoting sustainable development.However,due to the implementation of ecological restoration initiatives such as land-use conversions,novel changes in the spatial characteristics of soil nutrients remain unknown.To address this gap,we explored nutrient variations and the drivers of the variation in the 0–15 cm topsoil layer using a regional-scale sampling method in a typical karst area in northwest Guangxi Zhuang Autonomous Region,Southwest China.Descriptive statistics,geostatistics,and spatial analysis were used to assess the soil nutrient variability.The results indicated that soil organic carbon(SOC),total nitrogen(TN),total phosphorus(TP),and total potassium(TK)concentrations showed moderate variations,with coefficients of variance being 0.60,0.60,0.71,and 0.72,respectively.Moreover,they demonstrated positive spatial autocorrelations,with global Moran's indices being 0.68,0.77,0.64,and 0.68,respectively.However,local Moran's index values were low,indicating large spatial variations in soil nutrients.The best-fitting semi-variogram models for SOC,TN,TP,and TK concentrations were spherical,Gaussian,exponential,and exponential,respectively.According to the classification criteria of the Second National Soil Census in China,SOC and TN concentrations were relatively sufficient,with the proportions of rich and very rich levels being up to 90.9 and 96.0%,respectively.TP concentration was in the mediumdeficient level,with the areas of medium and deficient levels accounting for 33.7 and 30.1%of the total,respectively.TK concentration was deficient,with the cumulative area of extremely deficient,very deficient,and deficient levels accounting for 87.6%of the total area.Consequently,the terrestrial ecosystems in the study area were more vulnerable to soil P and K than soil N deficiencies.Furthermore,variance partitioning analysis of the influencing factors showed that,except for the interactions,the single effect of other soil properties accounted more for soil nutrient variations than spatial and environmental variables.These results will aid in the future management of terrestrial ecosystems.展开更多
Flavonoids,abundant in the fruits,are pivotal to their growth,development,and storage.In addition,they have significant beneficial effects on human health.Consequently,research is increasingly concentrating on the reg...Flavonoids,abundant in the fruits,are pivotal to their growth,development,and storage.In addition,they have significant beneficial effects on human health.Consequently,research is increasingly concentrating on the regulatory mechanisms governing flavonoid biosynthesis in fruits.Phytohormones are involved in the regulation of flavonoid biosynthesis.The abscisic acid,ethylene,jasmonic acid,cytokinins,and brassinosteroids promote flavonoid biosynthesis,while auxin negatively regulates flavonoid biosynthesis.Subsequently,transcription factors from the MYB,bHLH,WRKY,NAC,and bZIP families are pivotal in regulating flavonoid biosynthesis.In addition,non-coding RNAs(microRNA and lncRNA)also participate in the regulation of flavonoids biosynthesis.MicroRNAs are generally believed to negatively regulate flavonoid metabolism in fruits,while lncRNAs have the opposite effect.Furthermore,the interactions between plant hormones,transcription factors,and non-coding RNAs in fruit flavonoid biosynthesis were analyzed.Ultimately,a foundational regulatory network for fruit flavonoid biosynthesis was hereby established.展开更多
Rat nerve growth factor and total flavonoids from hawthorn leaf contribute to the recovery of neurological function after spinal cord injury,including traumatic,non-traumatic spinal cord injuries.However,it remains ch...Rat nerve growth factor and total flavonoids from hawthorn leaf contribute to the recovery of neurological function after spinal cord injury,including traumatic,non-traumatic spinal cord injuries.However,it remains challenging to efficiently deliver nerve growth factor and total flavonoids from hawthorn leaf to spinal cord injury sites,ensure their sustained release,and minimize further damage.In the present study,we chose a biocompatible and biodegradable gelatin as the substrate,which was crosslinked with the natural biological crosslinker genipin to form a gelatin-genipin hydrogel carrier for the slow release of nerve growth factor and total flavonoids from hawthorn leaf in spinal cord injury sites.The prepared gelatin-genipin hydrogel had good injectable properties and photothermal effects.Furthermore,when the hydrogel with 2%genipin,200 ng/mL nerve growth factor,and 320μg/mL total flavonoids from hawthorn leaf was combined with near infrared irradiation,there was a slow release of total flavonoids from hawthorn leaf and nerve growth factor,reduced oxidative stress,an improved inflammatory microenvironment,and accelerated angiogenesis and axonal regeneration via inhibition of the nuclear factor kappa-B signaling pathway,thereby promoting recovery from spinal cord injury.Collectively,our results indicate that this new hydrogel may improve the prognosis of spinal cord injury,and may represent a new strategy for treating spinal cord injury.展开更多
Optic nerve injury leads to axonal degeneration and the death of retinal ganglion cells,which ultimately causes vision loss.Notably,current treatments are limited.In the present study,we explored whether neurogenic di...Optic nerve injury leads to axonal degeneration and the death of retinal ganglion cells,which ultimately causes vision loss.Notably,current treatments are limited.In the present study,we explored whether neurogenic differentiation factor 1(NeuroD1 or ND1)overexpression in retinal Müller cells may repair the retina after optic nerve crush in mice.Adult mice were subjected to optic nerve crush followed by intravitreal AAV-7m8-GFAP-GFP-ND1 virus injection.Immunofluorescent staining,multi-electrode array recording,electroretinogram,and visual behavior tests were then performed to examine retinal and optic nerve structure and retinal function at various post-optic nerve crush and virus injection times.Western blot analysis and quantitative reverse transcription polymerase chain reaction were performed to explore the possible mechanisms.Compared with the control virus,specific overexpression of ND1 in Müller cells greatly improved the light responses of retinal ganglion cells and retinal neurons in optic nerve crush-injured mice as early as 1-2 weeks post-virus injection and lasted for up to 4 weeks.Neuronal survival in the ganglion cell layer and synaptic connections in the inner retina were slightly improved at 2 weeks;however,visual behavior,retinal ganglion cell survival,and optic nerve structure were not improved.ND1 transiently enhanced glial cell-derived neurotrophic factor expression in the optic nerve crush-injured retina but hardly inhibited retinal inflammation within 2 weeks.Together,our data indicate that ND1 overexpression in Müller cells improves retinal function in the optic nerve crush-injured retina,and suggest that its neuroprotective effect may be caused by enhanced glial cell-derived neurotrophic factor release.展开更多
Nerve trauma commonly results in chronic neuropathic pain. This is by triggering the release of proinflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability...Nerve trauma commonly results in chronic neuropathic pain. This is by triggering the release of proinflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability. Even without apparent inflammation, injury sites are associated with increased inflammatory markers. This review focuses on how it might be possible to reduce neuropathic pain by reducing inflammation. Physiologically, pain is resolved by a combination of the out-migration of pro-inflammatory cells from the injury site, the down-regulation of the genes underlying the inflammation, up-regulating genes for anti-inflammatory mediators, and reducing nociceptive neuron hyperexcitability. While various techniques reduce chronic neuropathic pain, the best are effective on < 50% of patients, no technique reliably or permanently eliminates neuropathic pain. This is because most techniques are predominantly aimed at reducing pain, not inflammation. In addition, while single factors reduce pain, increasing evidence indicates significant and longer-lasting pain relief requires multiple factors acting simultaneously. Therefore, it is not surprising that extensive data indicate that the application of platelet-rich plasma provides more significant and longer-lasting pain suppression than other techniques, although its analgesia is neither complete nor permanent. However, several case reports indicate that platelet-rich plasma can induce permanent neuropathic pain elimination when the platelet concentration is significantly increased and is applied to longer nerve lengths. This review examines the primary triggers of the development and maintenance of neuropathic pain and techniques that reduce chronic neuropathic pain. The application of plateletrich plasma holds great promise for providing complete and permanent chronic neuropathic pain elimination.展开更多
Ecological factors,such as vegetation roots,can enhance soil shear strength,reduce surface runoff erosion,and improve slope stability.Conversely,heavy rainfall can rapidly saturate unsaturated soil,weakening shear str...Ecological factors,such as vegetation roots,can enhance soil shear strength,reduce surface runoff erosion,and improve slope stability.Conversely,heavy rainfall can rapidly saturate unsaturated soil,weakening shear strength.As such,both ecological and hydrological processes play critical roles in shallow slope failures.In this study,we propose a spatialtemporal landslide hazard model considering ecological and hydrological factors.Specifically,ecological factors are incorporated in convolution neural network as a spatial probability module,and hydrological factors are involved in infinite slope hydrological model as a temporal probability module,finally we integrated the spatial-temporal probabilities using integration module.A case study in the Hengduan Mountain Region demonstrated that the proposed model outperforms traditional models by achieving higher prediction accuracy,with an increase in the landslide hit index,demonstrating the effectiveness of involving ecological and hydrological factors in landslide hazard analysis,offering practical suggestions for landslide risk management.展开更多
Objective:Neuronal ferroptosis has emerged as a promising therapeutic target for ischemic stroke.Tamarixetin,a natural dietary flavonoid,exerts protective effects against ischemic stroke by modulating neuroinflammator...Objective:Neuronal ferroptosis has emerged as a promising therapeutic target for ischemic stroke.Tamarixetin,a natural dietary flavonoid,exerts protective effects against ischemic stroke by modulating neuroinflammatory responses and mitigating oxidative stress.However,its potential role in regulating neuronal ferroptosis remains unclear.Methods:A rat model of middle cerebral artery occlusion and reperfusion and an erastin-treated SH-SY5Y cell model were used for in vivo and in vitro experiments,respectively.The neurological function of the rats was evaluated using a series of behavioral tests,the Garcia scoring system,and 2,3,5-triphenyltetrazolium chloride staining.Neuronal damage was detected via immunofluorescence staining and terminal deoxynucleotidyl transferase(TdT)-mediated deoxyuridine triphosphate(dUTP)nickend labeling.Commercial kits,western blotting,and coimmunoprecipitation were used to analyze neuronal ferroptosis and the activation of the Nuclear factor erythroid-2–related factor 2(Nrf2)signaling pathway.The direct target protein of tamarixetin was examined using the cellular thermal shift assay,drug affinity-responsive target stability assay,surface plasmon resonance,and molecular docking.Cellular Nrf2 was knocked down using small interfering RNA.Results:Tamarixetin mitigated the neurological dysfunctions of middle cerebral artery occlusion and reperfusion(MCAO/R)rats,including motor dysfunction,limb coordination impairment,neurological deficit,cerebral infarction,and reduced neuronal loss.Furthermore,it alleviated neuronal ferroptosis in vivo and in vitro by lowering the levels of iron ions,reactive oxygen species,malondialdehyde,and acyl-CoA synthetase long-chain family member 4 and upregulating the expression of superoxide dismutase,glutathione,glutathione peroxidase 4,heme oxygenase-1,and solute carrier family 7 member 11.Tamarixetin activated the Nrf2 signaling pathway by suppressing Keap1 protein expression,weakening the interaction between Keap1 and Nrf2,upregulating Nrf2 protein expression and nuclear translocation,and promoting antioxidant response element activity.Nrf2 is the direct binding protein of tamarixetin.It specifically interacts with amino acid residues at arginine 72,arginine 515,and lysine 518.The effects of tamarixetin on Nrf2 signaling pathway activation and neuronal ferroptosis inhibition were abrogated in Nrf2 knockdown cells challenged with erastin.Conclusions:Our findings not only identify tamarixetin as a novel ferroptosis inhibitor but also elucidate its mechanism of action via direct binding and Nrf2 pathway activation,providing a promising therapeutic candidate for ischemic stroke.展开更多
Three-dimensional(3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair,with gelatin methacrylate being particularly favored owing to its excellent biocompatibility.However,traditional scaffolds ...Three-dimensional(3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair,with gelatin methacrylate being particularly favored owing to its excellent biocompatibility.However,traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment.Therefore,there is a need to develop smart scaffolds with drug delivery and immune regulation functions.In this study,a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner.The scaffold showed good mechanical properties,biocompatibility,and sustained interferon regulatory factor 4 release.The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5,and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization,thereby facilitating neural regeneration and recovery of spinal cord function.This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis,improve the inflammatory microenvironment after spinal cord injury,and thus provide a new target for promoting neural regeneration.展开更多
Colorectal cancer(CRC)poses a substantial global health challenge.Its pathogenesis involves intricate genetic and signaling pathway aberrations,among which the cellular-mesenchymal epithelial transition factor(c-Met)/...Colorectal cancer(CRC)poses a substantial global health challenge.Its pathogenesis involves intricate genetic and signaling pathway aberrations,among which the cellular-mesenchymal epithelial transition factor(c-Met)/hepatocyte growth factor(HGF)axis functions as a pivotal regulatory hub.Encoded by a proto-oncogene,the transmembrane receptor c-Met is activated by HGF,driving CRC cell proliferation,migration,invasion,and metastasis via critical signal transduction cascades.The c-Met factor overexpression is observed in 30%-70%of CRC tumors.This review elucidates c-Met/HGF-mediated carcinogenesis,emphasizing its crosstalk with epidermal growth factor receptor,vascular endothelial growth factor,and insulin-like growth factor 1 receptor pathways.Notably,c-Met amplification contributes to epidermal growth factor receptor inhibitor resistance,increasing signaling network complexity.MicroRNA-1 and microRNA-137 modulate c-Met expression to suppress CRC progression,while advancements in c-Met-targeted molecular imaging facilitate precise diagnosis and treatment monitoring.Progress in c-Met/HGF-targeted therapies,including small-molecule inhibitors,monoclonal antibodies,and tyrosine kinase inhibitors,shows promise in suppressing tumors and overcoming resistance.Future efforts should focus on optimizing combination therapies,refining patient stratification via imaging,and addressing drug resistance to enable personalized,efficacious CRC treatments leveraging this axis.展开更多
Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of...Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinasesuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinasesuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.展开更多
Ovarian cancer was the eighth most frequently diagnosed cancer among women in 2022.The global age-standardized incidence rate of ovarian cancer decreased from 7.22/100,000 to 6.71/100,000 from 1990 to 2021.However,inc...Ovarian cancer was the eighth most frequently diagnosed cancer among women in 2022.The global age-standardized incidence rate of ovarian cancer decreased from 7.22/100,000 to 6.71/100,000 from 1990 to 2021.However,incidence trends varied across countries.Declining ovarian cancer incidence rates were reported in high-income countries,such as the United States,Austria,the Netherlands,and Norway,while there were increasing incidence rates in Africa and parts of Asia,including Japan and India.The global age-standardized mortality rate of ovarian cancer decreased from 4.73/100,000 to 4.06/100,000 between 1999 and 2021 with varying trends among countries.Moreover,the age-standardized 5-year net ovarian cancer survival rate in most countries remained<50%.Several specific factors related to ovarian cancer risk have been identified,including reproductive factors,use of oral contraceptives,anti-inflammatory diets,endometriosis,pelvic inflammatory disease,obesity,diabetes,and occupational asbestos exposure.No screening or prevention strategy has been proven effective in downstaging or reducing mortality from ovarian cancer in an average-risk population without a family cancer history or pathogenic variants.Indeed,risk-reducing salpingo-oophorectomy remains the gold standard for lowering the risk of ovarian cancer in high-risk individuals with hereditary mutations.This review provides a comprehensive overview of the epidemiology,risk factors,screening,and prevention of ovarian cancer,aiming to offer a global perspective on public health strategies for addressing the disease.展开更多
The HD-ZIP gene family,a group of plant-specific transcription factors,plays pivotal regulatory roles in various aspects of plant growth and development.Accumulating evidence has demonstrated the extensive involvement...The HD-ZIP gene family,a group of plant-specific transcription factors,plays pivotal regulatory roles in various aspects of plant growth and development.Accumulating evidence has demonstrated the extensive involvement of HD-ZIP members in regulating reproductive developmental processes.This review systematically summarizes both the structural characteristics of the four HD-ZIP subfamilies(Ⅰ-Ⅳ)and their distinct regulatory roles in plant reproductive development.Recent studies reveal that a conserved HD-ZIPⅠclade serves as a core regulator of key reproductive processes,ranging from spike development in monocots(e.g.,barley Vrs1 and maize GT1)to sex determination in dicots(e.g.,cucumber CmHB40 and persimmon MeGI).Meanwhile,members of other subfamilies(HD-ZIPⅡ-Ⅳ)contribute significantly to diverse reproductive processes including pistil development,floral organ formation,and anther development,among others.This review provides a comprehensive synthesis of HD-ZIP subfamily functions in reproductive development,integrating current knowledge while highlighting critical research gaps.These insights aim to provide theoretical foundations for functional characterization and potential applications of HDZIP reproductive regulators,while advancing our understanding of transcriptional regulation mechanisms in plant reproductive development.展开更多
Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like be...Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors,and potential therapeutical strategies,remain scarce.In the present study,after long-term exposure to real-world PM2.5 for 15 weeks,male mice displayed depression-like behaviors,which were revealed using the open field and sucrose preference tests.Mechanistically,chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus.Furthermore,PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling.Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication;this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown.Importantly,the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication.Together,our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication,and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.展开更多
Tunnel environments often suffer from GPS denial,uneven illumination,and structural uniformity,which lead to feature degradation,loop closure failure,and long-distance drift in SLAM systems.To solve these problems,thi...Tunnel environments often suffer from GPS denial,uneven illumination,and structural uniformity,which lead to feature degradation,loop closure failure,and long-distance drift in SLAM systems.To solve these problems,this study aims to propose a high-precision SLAM method suitable for tunnel structural health monitoring.Firstly,an ABA-CLAHE image enhancement algorithm is proposed,which adopts cascaded processing of nonlinear brightness adjustment in HSV space and CLAHE local contrast optimization to improve low-light image quality and enhance feature stability.Then,SURF feature matching combined with the RANSAC algorithm is used to ensure feature matching accuracy.Finally,a factor graph model is constructed by integrating IMU pre-integration,laser odometry,visual odometry,and loop closure constraints,and iSAM2 incremental optimization is employed to achieve globally consistent mapping.Municipal tunnel tests show that the loop closure error is reduced to O.096 m and the global reprojection error is l.10 pixels,and the structural continuity of the constructed dense 3D map is significantly improved.This method provides a technical solution with centimeter-level accuracy for tunnel structural health monitoring,which is demonstrating strong practical potential for engineering applications.展开更多
Understanding water chemistry in karst regions is crucial for improving global water resource management and deepening our knowledge of the biogeochemical cycles shaping these sensitive environments.Despite advance-me...Understanding water chemistry in karst regions is crucial for improving global water resource management and deepening our knowledge of the biogeochemical cycles shaping these sensitive environments.Despite advance-ments in karst hydrology,significant gaps remain in long-term trends,underlying processes,and quantitative effects of environmental changes.This is especially true in areas like the Wujiang River(WJ)in China,where human activities such as reservoir construction and land use/cover changes have accelerated hydrochemical changes.We combined recent and historical monitoring data to provide a detailed analysis of the spatial and temporal characteristics,evolution,and controlling factors of major ions in WJ.These findings are important for local water management and contribute to global efforts to manage similar karst systems facing human-induced pressures.Our research shows clear seasonal differences in solute concentrations,with higher levels during the dry season.WJ’s water is rich in calcium,with Ca-HCO3 ion pairs being the most common.Reservoir monitor-ing stations show much higher levels of NO3−and SO42−compared to river-type stations,likely due to longer hydraulic retention time and increased acid deposition.The study confirms the significant role of pH and water temperature in rock weathering processes.Land use/cover changes were identified as the primary drivers of solute variations(46.37%),followed by lithology(13.92%)and temperature(8.35%).Over the past two decades,in-tense carbonate weathering has been observed,especially during wet seasons.Among karstic provinces,Guizhou Province stands out with the highest ion concentrations,indicative of its extensive karst coverage and heightened weathering processes.展开更多
基金supported by the National Natural Science Foundation of China(82373393),Xinjiang Uygur Autonomous Region“Tianchi Yingcai”Project(2023TCYCQNBS02)Xinjiang Uygur Autonomous Region Colleges and Universities Basic Research Operating Expenses Scientific Research Project(XJEDU2022P106).
摘要Shikonin,a naphthoquinone compound derived from the root of Lithospermum erythrorhizon,has been extensively studied for its antibacterial,antioxidant,and anti-inflammatory properties.Increasing evidence highlights its potential in treating inflammation-related diseases.However,its clinical application is hindered by challenges such as poor water solubility,rapid metabolism in vivo,and other limitations.Recent advancements have demonstrated that encapsulating shikonin within nanocarriers can significantly enhance its water solubility and pharmacokinetic profile.Building on this,this perspective paper outlines the current landscape of inflammation treatment,explores the anti-inflammatory mechanisms of shikonin,reviews the latest progress in shikonin-based nanomaterials for anti-inflammatory applications,and discusses the challenges and future directions for the clinical translation of shikonin nanoformulations.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
摘要Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by grants from the Zhejiang Provincial TCM Science and Technology Plan Project,No.2023ZL156(to YH)Ningbo Top Medical and Health Research Program,No.2022020304(to XG)+1 种基金the Natural Science Foundation of Ningbo,No.2023J019(to YH)Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province,No.2022E10026(to YH)。
摘要Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.
基金Supported by National Natural Science Foundation of China,No.82530124Digestive Diseases Committee of the Chinese Association of Traditional Chinese Medicine-The Youth Empowerment Program,No.202557-006State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine,No.LSLSKL20240127.
摘要BACKGROUND Qiweizhigan granule(QWZG)is employed in clinical settings for the treatment of metabolic dysfunctionassociated steatohepatitis(MASH).However,the precise biological mechanisms underlying its therapeutic effects are not yet fully elucidated.AIM To assess the efficacy and the mechanism of QWZG against MASH.METHODS Animal models were established,including normal group,a choline-deficient,L-amino acid-defined high-fat diet(CDAHFD)group,and low/medium/high-dose QWZG groups,as well as a rosiglitazone group.Through comprehensive biochemical,histopathological,RNA sequencing,and bioinformatics analyses,galectin 3(LGALS3)was identified as a critical target of QWZG in the treatment of MASH.The level of LGALS3 was quantitatively assessed and validated using Western blotting,real-time quantitative PCR,and immunofluorescence.The role and function of LGALS3 in inflammation and MASH progression were further investigated through gene knockdown,overexpression,iron assay,and transmission electron microscopy.RESULTS QWZG significantly ameliorated liver pathology by reducing steatosis,inflammation,and fibrosis.RNA sequencing analysis identified 1507 co-expressed differentially expressed genes among the CDAHFD,normal,and QWZG groups.Among these,LGALS3 was identified as one of the most significantly altered differentially expressed genes.Both mRNA and protein levels of LGALS3 were elevated in the CDAHFD group compared to the normal group,whereas treatment with QWZG reduced their levels.Analysis of Human Protein Atlas database indicated that LGALS3 was predominantly expressed in Kupffer cells,and was validated by real-time quantitative PCR and immunofluorescence.Furthermore,the level of LGALS3 was significantly increased in lipopolysaccharide-induced RAW264.7 cells,where its overexpression and recombinant LGALS3 protein both significantly enhanced the expression of interleukin-6,interleukin-1β,and tumor necrosis factor-α.LGALS3 overexpression significantly inhibited glutathione peroxidase 4(GPX4)expression,and exacerbated mitochondrial damage,whereas LGALS3 knockdown markedly increased GPX4 level,and significantly reduced the levels of both total iron and ferrous iron.QWZG treatment significantly reduced the levels of malondialdehyde and ferrous iron,increased the levels of superoxide dismutase and glutathione.In addition,QWZG treatment also significantly enhanced GPX4 expression.Mechanistically,LGALS3 knockdown was associated with reduced expression of tumor necrosis factor receptor-associated factor 6(TRAF6)and NOD-like receptor family pyrin domain containing 3,while its overexpression led to increased levels of these proteins.The TRAF6 inhibitor C25-140 effectively reversed the LGALS3-induced alterations in GPX4 expression and iron accumulation.Furthermore,QWZG treatment significantly decreased the levels of TRAF6 and NOD-like receptor family pyrin domain containing 3.CONCLUSION QWZG ameliorated the progression of MASH by modulating ferroptosis through the LGALS3/TRAF6/GPX4 axis.
基金supported by grants from the National Key R&D Program of China[Grant Nos.2020YFC2003000 and 2020YFC2003001]the National High Level Hospital Clinical Research Funding(BJ-2023-074 and BJ-2023-018)+1 种基金Beijing Municipal Science&Technology Commission“AI+Health Collaborative Innovation Cultivation”Project(Z221100003522015)the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2021-JKCS-024).
摘要Objective Frailty is becoming increasingly common among aging adults.Frailty transitionis shaped by biological,social,psychological,and environmental factors.This study investigated combined effects of protective factors on frailty transition by constructing a Protection Index(PI)to guide targeted interventions.Methods Data were extracted from the 4th Sample Survey of the Aged Population in Urban and Rural China,including baseline(2017)and follow-up(2019)surveys.Frailty was assessed using the Frailty Index(FI),whereas the PI measured protective factors.Frailty transitions over 2 years were analyzed prospectively.Pearson’s correlation examined the relationship between FI and PI,and logistic regression assessed the effects of PI on frailty transitions.Results This study included 9,093 older adults.FI values increased with age and were higher in women,whereas PI values decreased with age and were higher in men.Over 2 years,56.2%of the participants showed a stable frailty status,14.2%improved,and 29.6%worsened.Negative transitions were more common than positive transitions,with transitions occurring most frequently between adjacent states.The PI was moderately negatively correlated with the FI(r=−0.349,P<0.001).A higher PI was associated with a lower risk of negative transitions among robust and prefrail individuals(OR=0.989,0.981,both P<0.05),but showed no significant effect among those with existing frailty.Conclusion Negative frailty transitions were more common with advancing age.Enhancing PI may help prevent negative frailty transitions among robust and pre-frail older adults,underscoring the value of early interventions.
基金supported by the National Natural Science Foundation of China(U2344201 and 42101316)the Natural Science Foundation of Hunan Province,China(2022JJ40866)the Outstanding Youth Project of Education Bureau of Hunan Province,China(20B613)。
摘要Understanding the spatial distributions and corresponding variation mechanisms of key soil nutrients in fragile karst ecosystems can assist in promoting sustainable development.However,due to the implementation of ecological restoration initiatives such as land-use conversions,novel changes in the spatial characteristics of soil nutrients remain unknown.To address this gap,we explored nutrient variations and the drivers of the variation in the 0–15 cm topsoil layer using a regional-scale sampling method in a typical karst area in northwest Guangxi Zhuang Autonomous Region,Southwest China.Descriptive statistics,geostatistics,and spatial analysis were used to assess the soil nutrient variability.The results indicated that soil organic carbon(SOC),total nitrogen(TN),total phosphorus(TP),and total potassium(TK)concentrations showed moderate variations,with coefficients of variance being 0.60,0.60,0.71,and 0.72,respectively.Moreover,they demonstrated positive spatial autocorrelations,with global Moran's indices being 0.68,0.77,0.64,and 0.68,respectively.However,local Moran's index values were low,indicating large spatial variations in soil nutrients.The best-fitting semi-variogram models for SOC,TN,TP,and TK concentrations were spherical,Gaussian,exponential,and exponential,respectively.According to the classification criteria of the Second National Soil Census in China,SOC and TN concentrations were relatively sufficient,with the proportions of rich and very rich levels being up to 90.9 and 96.0%,respectively.TP concentration was in the mediumdeficient level,with the areas of medium and deficient levels accounting for 33.7 and 30.1%of the total,respectively.TK concentration was deficient,with the cumulative area of extremely deficient,very deficient,and deficient levels accounting for 87.6%of the total area.Consequently,the terrestrial ecosystems in the study area were more vulnerable to soil P and K than soil N deficiencies.Furthermore,variance partitioning analysis of the influencing factors showed that,except for the interactions,the single effect of other soil properties accounted more for soil nutrient variations than spatial and environmental variables.These results will aid in the future management of terrestrial ecosystems.
基金supported by the China Agricultural Research System(Grant No.CARS-09)the Central Government Guiding Local Science and Technology Development Project(Grant No.YDZX2023029)the Gansu Planning Projects on Science and Technology(Grant No.23CXNJ0013).
摘要Flavonoids,abundant in the fruits,are pivotal to their growth,development,and storage.In addition,they have significant beneficial effects on human health.Consequently,research is increasingly concentrating on the regulatory mechanisms governing flavonoid biosynthesis in fruits.Phytohormones are involved in the regulation of flavonoid biosynthesis.The abscisic acid,ethylene,jasmonic acid,cytokinins,and brassinosteroids promote flavonoid biosynthesis,while auxin negatively regulates flavonoid biosynthesis.Subsequently,transcription factors from the MYB,bHLH,WRKY,NAC,and bZIP families are pivotal in regulating flavonoid biosynthesis.In addition,non-coding RNAs(microRNA and lncRNA)also participate in the regulation of flavonoids biosynthesis.MicroRNAs are generally believed to negatively regulate flavonoid metabolism in fruits,while lncRNAs have the opposite effect.Furthermore,the interactions between plant hormones,transcription factors,and non-coding RNAs in fruit flavonoid biosynthesis were analyzed.Ultimately,a foundational regulatory network for fruit flavonoid biosynthesis was hereby established.
基金Guangxi Science and Technology Base and Talent Special Project,No.GuiKeAD24010037(to SZ)Guangxi Health Commission Self-Funded Research Project,No.Z-A20241029(to YL).
摘要Rat nerve growth factor and total flavonoids from hawthorn leaf contribute to the recovery of neurological function after spinal cord injury,including traumatic,non-traumatic spinal cord injuries.However,it remains challenging to efficiently deliver nerve growth factor and total flavonoids from hawthorn leaf to spinal cord injury sites,ensure their sustained release,and minimize further damage.In the present study,we chose a biocompatible and biodegradable gelatin as the substrate,which was crosslinked with the natural biological crosslinker genipin to form a gelatin-genipin hydrogel carrier for the slow release of nerve growth factor and total flavonoids from hawthorn leaf in spinal cord injury sites.The prepared gelatin-genipin hydrogel had good injectable properties and photothermal effects.Furthermore,when the hydrogel with 2%genipin,200 ng/mL nerve growth factor,and 320μg/mL total flavonoids from hawthorn leaf was combined with near infrared irradiation,there was a slow release of total flavonoids from hawthorn leaf and nerve growth factor,reduced oxidative stress,an improved inflammatory microenvironment,and accelerated angiogenesis and axonal regeneration via inhibition of the nuclear factor kappa-B signaling pathway,thereby promoting recovery from spinal cord injury.Collectively,our results indicate that this new hydrogel may improve the prognosis of spinal cord injury,and may represent a new strategy for treating spinal cord injury.
基金supported by the Guangdong Grant Key Technologies for Treatment of Brain Disorders,China,No.2018B030332001(to GC)the Natural Science Foundation of Guangdong Province,China,No.2023A1515012397(to YX).
摘要Optic nerve injury leads to axonal degeneration and the death of retinal ganglion cells,which ultimately causes vision loss.Notably,current treatments are limited.In the present study,we explored whether neurogenic differentiation factor 1(NeuroD1 or ND1)overexpression in retinal Müller cells may repair the retina after optic nerve crush in mice.Adult mice were subjected to optic nerve crush followed by intravitreal AAV-7m8-GFAP-GFP-ND1 virus injection.Immunofluorescent staining,multi-electrode array recording,electroretinogram,and visual behavior tests were then performed to examine retinal and optic nerve structure and retinal function at various post-optic nerve crush and virus injection times.Western blot analysis and quantitative reverse transcription polymerase chain reaction were performed to explore the possible mechanisms.Compared with the control virus,specific overexpression of ND1 in Müller cells greatly improved the light responses of retinal ganglion cells and retinal neurons in optic nerve crush-injured mice as early as 1-2 weeks post-virus injection and lasted for up to 4 weeks.Neuronal survival in the ganglion cell layer and synaptic connections in the inner retina were slightly improved at 2 weeks;however,visual behavior,retinal ganglion cell survival,and optic nerve structure were not improved.ND1 transiently enhanced glial cell-derived neurotrophic factor expression in the optic nerve crush-injured retina but hardly inhibited retinal inflammation within 2 weeks.Together,our data indicate that ND1 overexpression in Müller cells improves retinal function in the optic nerve crush-injured retina,and suggest that its neuroprotective effect may be caused by enhanced glial cell-derived neurotrophic factor release.
摘要Nerve trauma commonly results in chronic neuropathic pain. This is by triggering the release of proinflammatory mediators from local and invading cells that induce inflammation and nociceptive neuron hyperexcitability. Even without apparent inflammation, injury sites are associated with increased inflammatory markers. This review focuses on how it might be possible to reduce neuropathic pain by reducing inflammation. Physiologically, pain is resolved by a combination of the out-migration of pro-inflammatory cells from the injury site, the down-regulation of the genes underlying the inflammation, up-regulating genes for anti-inflammatory mediators, and reducing nociceptive neuron hyperexcitability. While various techniques reduce chronic neuropathic pain, the best are effective on < 50% of patients, no technique reliably or permanently eliminates neuropathic pain. This is because most techniques are predominantly aimed at reducing pain, not inflammation. In addition, while single factors reduce pain, increasing evidence indicates significant and longer-lasting pain relief requires multiple factors acting simultaneously. Therefore, it is not surprising that extensive data indicate that the application of platelet-rich plasma provides more significant and longer-lasting pain suppression than other techniques, although its analgesia is neither complete nor permanent. However, several case reports indicate that platelet-rich plasma can induce permanent neuropathic pain elimination when the platelet concentration is significantly increased and is applied to longer nerve lengths. This review examines the primary triggers of the development and maintenance of neuropathic pain and techniques that reduce chronic neuropathic pain. The application of plateletrich plasma holds great promise for providing complete and permanent chronic neuropathic pain elimination.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB1390000,XDA23090301)the National Natural Science Foundation of China(Grants No.42501106,42041006,42177150)+1 种基金the Sichuan Science and Technology Program(2026NSFSC1117)and a grant from State Key Laboratory of Resources and Environmental Information System.This study is a contribution to the Commission 37 on Landslide Nomenclature of the IAEG.
摘要Ecological factors,such as vegetation roots,can enhance soil shear strength,reduce surface runoff erosion,and improve slope stability.Conversely,heavy rainfall can rapidly saturate unsaturated soil,weakening shear strength.As such,both ecological and hydrological processes play critical roles in shallow slope failures.In this study,we propose a spatialtemporal landslide hazard model considering ecological and hydrological factors.Specifically,ecological factors are incorporated in convolution neural network as a spatial probability module,and hydrological factors are involved in infinite slope hydrological model as a temporal probability module,finally we integrated the spatial-temporal probabilities using integration module.A case study in the Hengduan Mountain Region demonstrated that the proposed model outperforms traditional models by achieving higher prediction accuracy,with an increase in the landslide hit index,demonstrating the effectiveness of involving ecological and hydrological factors in landslide hazard analysis,offering practical suggestions for landslide risk management.
基金supported by the National Natural Science Foundation of China(82174076)the Construction Project of Liaoning Provincial Key Laboratory,China(2022JH13/10200026)+2 种基金the Natural Science Foundation of Hebei Province(H2024501002)the Fundamental Research Funds for the Central Universities(N2423006)the 111 Project(B16009).
摘要Objective:Neuronal ferroptosis has emerged as a promising therapeutic target for ischemic stroke.Tamarixetin,a natural dietary flavonoid,exerts protective effects against ischemic stroke by modulating neuroinflammatory responses and mitigating oxidative stress.However,its potential role in regulating neuronal ferroptosis remains unclear.Methods:A rat model of middle cerebral artery occlusion and reperfusion and an erastin-treated SH-SY5Y cell model were used for in vivo and in vitro experiments,respectively.The neurological function of the rats was evaluated using a series of behavioral tests,the Garcia scoring system,and 2,3,5-triphenyltetrazolium chloride staining.Neuronal damage was detected via immunofluorescence staining and terminal deoxynucleotidyl transferase(TdT)-mediated deoxyuridine triphosphate(dUTP)nickend labeling.Commercial kits,western blotting,and coimmunoprecipitation were used to analyze neuronal ferroptosis and the activation of the Nuclear factor erythroid-2–related factor 2(Nrf2)signaling pathway.The direct target protein of tamarixetin was examined using the cellular thermal shift assay,drug affinity-responsive target stability assay,surface plasmon resonance,and molecular docking.Cellular Nrf2 was knocked down using small interfering RNA.Results:Tamarixetin mitigated the neurological dysfunctions of middle cerebral artery occlusion and reperfusion(MCAO/R)rats,including motor dysfunction,limb coordination impairment,neurological deficit,cerebral infarction,and reduced neuronal loss.Furthermore,it alleviated neuronal ferroptosis in vivo and in vitro by lowering the levels of iron ions,reactive oxygen species,malondialdehyde,and acyl-CoA synthetase long-chain family member 4 and upregulating the expression of superoxide dismutase,glutathione,glutathione peroxidase 4,heme oxygenase-1,and solute carrier family 7 member 11.Tamarixetin activated the Nrf2 signaling pathway by suppressing Keap1 protein expression,weakening the interaction between Keap1 and Nrf2,upregulating Nrf2 protein expression and nuclear translocation,and promoting antioxidant response element activity.Nrf2 is the direct binding protein of tamarixetin.It specifically interacts with amino acid residues at arginine 72,arginine 515,and lysine 518.The effects of tamarixetin on Nrf2 signaling pathway activation and neuronal ferroptosis inhibition were abrogated in Nrf2 knockdown cells challenged with erastin.Conclusions:Our findings not only identify tamarixetin as a novel ferroptosis inhibitor but also elucidate its mechanism of action via direct binding and Nrf2 pathway activation,providing a promising therapeutic candidate for ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.81930070(to SF),82002309(to ZS)the Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)a grant from Tianjin Institute of Orthopedic Innovation and Transformation(to SF).
摘要Three-dimensional(3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair,with gelatin methacrylate being particularly favored owing to its excellent biocompatibility.However,traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment.Therefore,there is a need to develop smart scaffolds with drug delivery and immune regulation functions.In this study,a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner.The scaffold showed good mechanical properties,biocompatibility,and sustained interferon regulatory factor 4 release.The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5,and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization,thereby facilitating neural regeneration and recovery of spinal cord function.This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis,improve the inflammatory microenvironment after spinal cord injury,and thus provide a new target for promoting neural regeneration.
摘要Colorectal cancer(CRC)poses a substantial global health challenge.Its pathogenesis involves intricate genetic and signaling pathway aberrations,among which the cellular-mesenchymal epithelial transition factor(c-Met)/hepatocyte growth factor(HGF)axis functions as a pivotal regulatory hub.Encoded by a proto-oncogene,the transmembrane receptor c-Met is activated by HGF,driving CRC cell proliferation,migration,invasion,and metastasis via critical signal transduction cascades.The c-Met factor overexpression is observed in 30%-70%of CRC tumors.This review elucidates c-Met/HGF-mediated carcinogenesis,emphasizing its crosstalk with epidermal growth factor receptor,vascular endothelial growth factor,and insulin-like growth factor 1 receptor pathways.Notably,c-Met amplification contributes to epidermal growth factor receptor inhibitor resistance,increasing signaling network complexity.MicroRNA-1 and microRNA-137 modulate c-Met expression to suppress CRC progression,while advancements in c-Met-targeted molecular imaging facilitate precise diagnosis and treatment monitoring.Progress in c-Met/HGF-targeted therapies,including small-molecule inhibitors,monoclonal antibodies,and tyrosine kinase inhibitors,shows promise in suppressing tumors and overcoming resistance.Future efforts should focus on optimizing combination therapies,refining patient stratification via imaging,and addressing drug resistance to enable personalized,efficacious CRC treatments leveraging this axis.
基金National Natural Science Foundation of China,No.82271440Jiangxi Provincial Health Technology Project,No.202510009(both to LX).
摘要Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinasesuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinasesuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.
基金supported by Beijing Natural Science Foundation(Grant No.Z240004)。
摘要Ovarian cancer was the eighth most frequently diagnosed cancer among women in 2022.The global age-standardized incidence rate of ovarian cancer decreased from 7.22/100,000 to 6.71/100,000 from 1990 to 2021.However,incidence trends varied across countries.Declining ovarian cancer incidence rates were reported in high-income countries,such as the United States,Austria,the Netherlands,and Norway,while there were increasing incidence rates in Africa and parts of Asia,including Japan and India.The global age-standardized mortality rate of ovarian cancer decreased from 4.73/100,000 to 4.06/100,000 between 1999 and 2021 with varying trends among countries.Moreover,the age-standardized 5-year net ovarian cancer survival rate in most countries remained<50%.Several specific factors related to ovarian cancer risk have been identified,including reproductive factors,use of oral contraceptives,anti-inflammatory diets,endometriosis,pelvic inflammatory disease,obesity,diabetes,and occupational asbestos exposure.No screening or prevention strategy has been proven effective in downstaging or reducing mortality from ovarian cancer in an average-risk population without a family cancer history or pathogenic variants.Indeed,risk-reducing salpingo-oophorectomy remains the gold standard for lowering the risk of ovarian cancer in high-risk individuals with hereditary mutations.This review provides a comprehensive overview of the epidemiology,risk factors,screening,and prevention of ovarian cancer,aiming to offer a global perspective on public health strategies for addressing the disease.
基金supported by the National Natural Science Foundation of China(Grant Nos.32402528 and 32372665)。
摘要The HD-ZIP gene family,a group of plant-specific transcription factors,plays pivotal regulatory roles in various aspects of plant growth and development.Accumulating evidence has demonstrated the extensive involvement of HD-ZIP members in regulating reproductive developmental processes.This review systematically summarizes both the structural characteristics of the four HD-ZIP subfamilies(Ⅰ-Ⅳ)and their distinct regulatory roles in plant reproductive development.Recent studies reveal that a conserved HD-ZIPⅠclade serves as a core regulator of key reproductive processes,ranging from spike development in monocots(e.g.,barley Vrs1 and maize GT1)to sex determination in dicots(e.g.,cucumber CmHB40 and persimmon MeGI).Meanwhile,members of other subfamilies(HD-ZIPⅡ-Ⅳ)contribute significantly to diverse reproductive processes including pistil development,floral organ formation,and anther development,among others.This review provides a comprehensive synthesis of HD-ZIP subfamily functions in reproductive development,integrating current knowledge while highlighting critical research gaps.These insights aim to provide theoretical foundations for functional characterization and potential applications of HDZIP reproductive regulators,while advancing our understanding of transcriptional regulation mechanisms in plant reproductive development.
基金National Basic Research Plan Project of China,No.2023YFC3708303the National Natural Science Foundation of China,No.82241084the High-level Talent in Public Health of Beijing,No.Discipline Leaders-03-29(all to XL).
摘要Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors,and potential therapeutical strategies,remain scarce.In the present study,after long-term exposure to real-world PM2.5 for 15 weeks,male mice displayed depression-like behaviors,which were revealed using the open field and sucrose preference tests.Mechanistically,chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus.Furthermore,PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling.Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication;this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown.Importantly,the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication.Together,our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication,and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.
基金funded by the National Key R&D Program of China,grant number 2022YFB2602203the Natural Science Basic Research Program of Shaanxi,grant numbers 2025JC-YBMS-699 and 2024JC-YBQN-0495).
摘要Tunnel environments often suffer from GPS denial,uneven illumination,and structural uniformity,which lead to feature degradation,loop closure failure,and long-distance drift in SLAM systems.To solve these problems,this study aims to propose a high-precision SLAM method suitable for tunnel structural health monitoring.Firstly,an ABA-CLAHE image enhancement algorithm is proposed,which adopts cascaded processing of nonlinear brightness adjustment in HSV space and CLAHE local contrast optimization to improve low-light image quality and enhance feature stability.Then,SURF feature matching combined with the RANSAC algorithm is used to ensure feature matching accuracy.Finally,a factor graph model is constructed by integrating IMU pre-integration,laser odometry,visual odometry,and loop closure constraints,and iSAM2 incremental optimization is employed to achieve globally consistent mapping.Municipal tunnel tests show that the loop closure error is reduced to O.096 m and the global reprojection error is l.10 pixels,and the structural continuity of the constructed dense 3D map is significantly improved.This method provides a technical solution with centimeter-level accuracy for tunnel structural health monitoring,which is demonstrating strong practical potential for engineering applications.
基金supported by Guangdong Basic and Applied Basic Research Foundation(Nos.2023A1515110824 and 2025A1515011839)Shenzhen Science and Technology Program(No.RCBS20231211090638066).
摘要Understanding water chemistry in karst regions is crucial for improving global water resource management and deepening our knowledge of the biogeochemical cycles shaping these sensitive environments.Despite advance-ments in karst hydrology,significant gaps remain in long-term trends,underlying processes,and quantitative effects of environmental changes.This is especially true in areas like the Wujiang River(WJ)in China,where human activities such as reservoir construction and land use/cover changes have accelerated hydrochemical changes.We combined recent and historical monitoring data to provide a detailed analysis of the spatial and temporal characteristics,evolution,and controlling factors of major ions in WJ.These findings are important for local water management and contribute to global efforts to manage similar karst systems facing human-induced pressures.Our research shows clear seasonal differences in solute concentrations,with higher levels during the dry season.WJ’s water is rich in calcium,with Ca-HCO3 ion pairs being the most common.Reservoir monitor-ing stations show much higher levels of NO3−and SO42−compared to river-type stations,likely due to longer hydraulic retention time and increased acid deposition.The study confirms the significant role of pH and water temperature in rock weathering processes.Land use/cover changes were identified as the primary drivers of solute variations(46.37%),followed by lithology(13.92%)and temperature(8.35%).Over the past two decades,in-tense carbonate weathering has been observed,especially during wet seasons.Among karstic provinces,Guizhou Province stands out with the highest ion concentrations,indicative of its extensive karst coverage and heightened weathering processes.