Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a...Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.展开更多
Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macro...Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macrophages have been poorly understood and largely overlooked. However, a recent study reported that border-associated macrophages participate in stroke-induced inflammation, although many details and the underlying mechanisms remain unclear. In this study, we performed a comprehensive single-cell analysis of mouse border-associated macrophages using sequencing data obtained from the Gene Expression Omnibus(GEO) database(GSE174574 and GSE225948). Differentially expressed genes were identified, and enrichment analysis was performed to identify the transcription profile of border-associated macrophages. CellChat analysis was conducted to determine the cell communication network of border-associated macrophages. Transcription factors were predicted using the ‘pySCENIC' tool. We found that, in response to hypoxia, borderassociated macrophages underwent dynamic transcriptional changes and participated in the regulation of inflammatory-related pathways. Notably, the tumor necrosis factor pathway was activated by border-associated macrophages following ischemic stroke. The pySCENIC analysis indicated that the activity of signal transducer and activator of transcription 3(Stat3) was obviously upregulated in stroke, suggesting that Stat3 inhibition may be a promising strategy for treating border-associated macrophages-induced neuroinflammation. Finally, we constructed an animal model to investigate the effects of border-associated macrophages depletion following a stroke. Treatment with liposomes containing clodronate significantly reduced infarct volume in the animals and improved neurological scores compared with untreated animals. Taken together, our results demonstrate comprehensive changes in border-associated macrophages following a stroke, providing a theoretical basis for targeting border-associated macrophages-induced neuroinflammation in stroke treatment.展开更多
Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet th...Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet the underlying complex neural circuitry mechanisms remain unclear.The spinal trigeminal nucleus caudalis(Sp5C)serves as the primary central hub for orofacial nociceptive input,receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus.Therefore,we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis.In this study,we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin(NTG).Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry,we found a marked periorbital and plantar mechanical allodynia in CM mice,accompanied by increased glutamatergic neuronal activity in Sp5C.Chemogenetic manipulation of Sp5C glutamatergic neurons(Sp5CV^(glut2))bidirectionally modulated migraine-like behaviors and induced pain-related affective states,as evidenced by conditioned place preference/aversion(CPP/CPA)paradigms.Anterograde viral tracing revealed dense projections from Sp5C^(Vglut2)to the subthalamic nucleus(STN),which was activated in CM mice.Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice.Altogether,we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM.Our findings provide novel mechanistic insights into the central mechanisms underlying CM,establishing potential theoretical foundations for clinical diagnosis and therapeutic development.展开更多
Dear Editor,Psoriasis,a chronic inflammatory cutaneous condition,is characterized by the development of red plaques with silvery scales,significantly affecting patients'quality of life and mental health[1].This co...Dear Editor,Psoriasis,a chronic inflammatory cutaneous condition,is characterized by the development of red plaques with silvery scales,significantly affecting patients'quality of life and mental health[1].This condition is thought to affect approximately 2%of the Western population,with diagnosis peaking in early adulthood[2].Vitamin D,a fat-soluble vitamin,is essential for phospho-calcium metabolism,calcium homeostasis,and bone health.展开更多
Neuromuscular electrical stimulation(NMES)is a well-established therapeutic approach for chronic wounds.Conventionally,NMES involves direct electrode contact with wounds or adjacent healthy skin;however,it is limited ...Neuromuscular electrical stimulation(NMES)is a well-established therapeutic approach for chronic wounds.Conventionally,NMES involves direct electrode contact with wounds or adjacent healthy skin;however,it is limited by the need for wound exposure and by increased pain.Our preliminary study demonstrated the innovative application of remote NMES(rNMES)to the skeletal muscle of the distal calf,which showed the potential to accelerate wound healing in remote areas.rNMES was effective in human clinical trials in our previous work,although the underlying mechanisms remain unclear.As rNMES is often used to stimulate muscle contraction in long-term bedridden patients,we analyzed data from the Gene Expression Omnibus(GEO)database and found that exercise promotes midkine(MDK)expression in muscle.MDK is a small secreted heparin-binding protein that interacts with multiple cell surface receptors to promote growth.In the present study,we found that MDK significantly enhanced macrophage efferocytosis in a low-density lipoprotein receptor-related protein 1(LRP1)-dependent manner.Our findings demonstrate that rNMES upregulates MDK expression in skeletal muscles through the AMPK-ERK axis,facilitating its delivery to wounds through the circulatory system and promoting LRP1-mediated efferocytosis of apoptotic cells,thereby expediting wound healing.展开更多
Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indice...Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9%)and 0.759(with an accuracy of 65.3%),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3%).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.展开更多
Articular cartilage maintains joint homeostasis by adapting to mechanical loading,but both insufficient and excessive loading can impair cartilage integrity.Whether mechanical activity should be restricted in early os...Articular cartilage maintains joint homeostasis by adapting to mechanical loading,but both insufficient and excessive loading can impair cartilage integrity.Whether mechanical activity should be restricted in early osteoarthritis(OA),particularly among exercise enthusiasts,remains controversial.Here,we established in vitro and in vivo models of prolonged moderate mechanical loading(7.5%strain,1 Hz)and analyzed human cartilage from weight-bearing and non-weight-bearing regions using RNA sequencing.Prolonged exposure(≥12 h)significantly increased chondrocyte apoptosis(2.3-fold),reduced expression of the chondrogenic transcription factor SOX9 and the matrix markers COL2A1,and elevated nerve growth factor(NGF)expression(1.8-fold),accompanied by enrichment of neural sensitization and inflammatory pathways.Immunofluorescence staining revealed NGF accumulation in mechanically stressed cartilage.Unlike high-intensity stress,which led to immediate apoptosis,moderate loading induced a delayed pro-apoptotic response after 12 h.These findings indicate that prolonged moderate mechanical loading may promote chondrocyte apoptosis through an NGFmediated inflammatory microenvironment and provide mechanistic evidence suggesting that patients with early OA may benefit from limiting high-impact or prolonged moderate-intensity exercise sessions to prevent cartilage damage and guide rehabilitation.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
Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remai...Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remain elusive.Repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising non-invasive intervention;however,its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding.A recent landmark study published in Brain Stimulation by Chen et al.addressed these challenges by combining a high-dose intermittent theta-burst stimulation(iTBS)protocol with concurrent transcranial magnetic stimulation-electroencephalography(TMS-EEG).This commentary provides an in-depth analysis of their findings,highlighting the restoration of cerebello-cortical inhibition(CBI)as a key therapeutic mechanism.Furthermore,we discuss the broader implications of this work,proposing that future translational research should integrate accelerated iTBS(aiTBS)paradigms,cortical response measurements(CRM),and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.展开更多
Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.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
Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of ...Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of life and restrict therapeutic outcomes.Addressing this pressing issue,this review presents a thorough and systematic analysis of innovative and emerging strategies designed to minimize the toxicity induced by treatment,while maintaining or even enhancing antitumor efficacy.The focus is on six promising therapeutic approaches:combination therapies utilizing natural bioactive products,molecularly targeted therapies,immunotherapies,nanotechnology-mediated drug delivery systems,adjunct traditional Chinese medicine interventions,and low-dose spatiotemporally concerted regimens.Each approach employs unique mechanisms—such as enhanced targeting precision,immune system activation,tumor microenvironment reprogramming,and multi-component synergistic effects—to mitigate damage to normal tissues and reduce systemic adverse reactions.Despite promising preclinical and clinical advancements,several challenges persist,including drug resistance,high economic costs,a lack of reliable predictive biomarkers,and complexities in clinical translation and regulatory approval.Looking ahead,the incorporation of artificial intelligence,multi-omics profiling,and novel biomimetic nanotechnologies offers unprecedented opportunities for developing highly personalized,low-toxicity treatment frameworks.This review highlights a fundamental shift in oncology towards precision medicine that balances efficacy with safety,demonstrating the transformative potential of these strategies in shaping the future of cancer therapy and enhancing patient care globally.展开更多
Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists...Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists on methamphetamine(MAP)reinforcement,motivation,and relapse remain uncertain.In this study,we evaluated the effects of Ro 64-6198,a selective NOP agonist,on MAP reinforcement,motivation,and relapse in rats.Rats underwent a fixed-ratio 1(FR1)training to establish stable MAP intravenous self-administration(0.05 mg/kg/infusion)for 12 days,and the motivation for MAP was quantified using a progressive-ratio(PR)schedule,while the relapse was assessed through cue-and MAP-primed reinstatement after abstinence.Western blot analysis was employed to measure the relative expression of phosphorylated CREB,ERK,and Akt in the nucleus accumbens(NAc)following drug priming.Acute treatment of Ro 64-6198(1 mg/kg)significantly reduced the motivated behavior for MAP under PR testing(P<0.05 vs.vehicle).Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues,respectively(P<0.05),whereas only the higher dose(1 mg/kg)could attenuate MAP primed drug-seeking(P<0.05).These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc.Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors,positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.展开更多
Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted t...Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.展开更多
Objective Peripheral nerve injury leads to various degrees of functional defects.Nerve guidance conduits are considered as a new promising scaffold for peripheral nerve repair.However,conventional single-material nerv...Objective Peripheral nerve injury leads to various degrees of functional defects.Nerve guidance conduits are considered as a new promising scaffold for peripheral nerve repair.However,conventional single-material nerve conduits have shown limited efficacy in protecting cells from posttraumatic inflammation.This study aims to develop a single-process PLGA-based nerve conduit loaded with melatonin to enhance the biological performance of pure PLGA materials by suppressing oxidative stress and inflammatory responses.Methods The PLGA conduit is prepared with dry-jet wet spinning methods.The melatonin is integrated into PLGA conduits directly with the single-step process.Scanning electrical microscope observation,FTIR test,degradation test and drug releasing test were performed to characterize the morphology and physical properties of the nerve conduits.Schwann cells were cultured to test the biocompatibility of the prepared nerve conduits.Oxidative stress was applied on Schwann cell using hydrogen peroxide.Then the protecting effects of the nerve conduits were tested on the hydrogen peroxide-treated cells.SD rat sciatic model was applied to test the conduit in vivo.Results The melatonin is successfully integrated into the nerve conduit with the dry-jet wet spinning method.Cell adhesion and proliferation test of the Schwann cell indicated that the nerve conduits exhibit excellent biocompatibility.While the mitochondrial morphology observation and JC-1 potential detection also showed protecting effects on Mitochondria.The q-PCR analysis showed nerve conduits reduced cellular oxidative stress and inflammatory responses while enhancing cellular proliferation.A marked enhancement on SD rat sciatic nerve regeneration was also observed on melatonin loaded conduits.Conclusions By integrating melatonin into PLGA using the dryjet wet-spinning technique,the conduit is endowed with multiple functional advantages,including antiinflammatory,antioxidant,and neuroprotective properties.This approach is expected to create a favorable microenvironment for nerve tissue regeneration and provide a new perspective for the treatment of peripheral nerve injuries.展开更多
Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apopt...Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.展开更多
A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an or...A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an orally administered nanogene delivery system.Designed to achieve in situ,efficient delivery of chimeric antigen receptor(CAR)genes to tumor sites,this approach offers a novel strategy for CAR-macrophage(CAR-M)based immunotherapy.Its key highlights are as follows.展开更多
BACKGROUND:Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders,manifested as abnormal hyperplasia of breast tissue.In recent years,traditional Chinese medicine compounds and probi...BACKGROUND:Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders,manifested as abnormal hyperplasia of breast tissue.In recent years,traditional Chinese medicine compounds and probiotics have shown good potential in regulating the endocrine system and improving the intestinal microecology,providing new ideas for the treatment of breast hyperplasia.OBJECTIVE:To explore the effects and mechanisms of traditional Chinese medicine compounds and fermented probiotic compounds on breast hyperplasia in mice,providing new theoretical and experimental bases for the clinical treatment and prevention of breast hyperplasia.METHODS:(1)Network pharmacology tools were used to predict the anti-breast-hyperplasia activity of Herba Gueldenstaedtiae(Euphorbia humifusa),as well as its potential targets and signaling pathways.The databases included:TCMSP,OMIM,GeneCards database,UniProt website,Venny2.1.0 website,Metascape,HERB website,and STRING database,all of which are open-access databases.Network pharmacology can predict and screen key information such as the targets corresponding to the active ingredients of traditional Chinese medicine,disease targets,and action pathways through network analysis and computer-system analysis.Therefore,it has been increasingly widely used in the research of traditional Chinese medicine.(2)A breast hyperplasia model was induced in mice by injecting estrogen and progesterone.Mice in the normal blank group were injected intraperitoneally with normal saline every day.Mice in the model group and drugadministration groups were injected intraperitoneally with estradiol benzoate injection at a concentration of 0.5 mg/kg every day for 25 days.From the 26th day,the injection of estradiol benzoate injection was stopped.Mice in the normal blank group were injected intramuscularly with normal saline every day,and mice in the model group and drug-administration groups were injected intramuscularly with progesterone injection at a concentration of 5 mg/kg for 5 days.After the model was established,each group was given drugs respectively.The normal blank group and the model group were gavaged with 0.2 mL/d of normal saline;the positive blank group(Xiaozheng Pill group)was gavaged with an aqueous solution of Xiaozheng Pill at 0.9 mg/g;the low-,medium-and high-dose groups of Compound Herba Gueldenstaedtiae were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively;the low-,medium-and high-dose groups of traditional Chinese medicine-bacteria fermentation were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively.The administration was continuous for 30 days.RESULTS AND CONCLUSION:(1)The results of network pharmacology research showed that the Compound Herba Gueldenstaedtiae(Euphorbia humifusa)contained 46 active ingredients,which were related to 1213 potential targets.After comparison with 588 known breast-hyperplasia targets,it was speculated that 50 of these targets might be related to the direct effect of the compound on breast hyperplasia.(2)After drug intervention,there was no significant change in the high-dose group of Compound Herba Gueldenstaedtiae compared with the normal blank group.The liver indicators of the other intervention groups all significantly decreased(P<0.05).(3)In terms of kidney and uterine indicators,the medium-dose group of Compound Herba Gueldenstaedtiae decreased significantly compared with the normal blank group(P<0.05).In terms of the uterine index,the model group increased significantly compared with the normal blank group(P<0.01).(4)After 1-month drug treatment,the number of lobules and acini in the breast tissue of the Xiaozheng Pill group,the low,medium,and high-dose group of Compound Herba Gueldenstaedtiae,the low,medium,and highdose groups of traditional Chinese medicine-bacteria fermentation decreased,and the duct openings narrowed.With the increase of drug dose,diffuse hyperplasia of breast tissue was significantly improved.(5)The ELISA results showed that compared with the model group,the estrogen level was lower in the medium-dose group of traditional Chinese medicine-bacteria fermentation after the intervention(P<0.05).In addition,the follicle-stimulating hormone level in the low-dose group of Compound Herba Gueldenstaedtiae was lower than that of the model group(P<0.05).(6)The intervention in the mouse model led to changes in the abundance of short chain fatty acids and intestinal flora in all groups.To conclude,the Compound Herba Gueldenstaedtiae and its probiotic fermentation products significantly improved mammary gland hyperplasia in mice by regulating hormone levels,improving the structure of the gut microbiota,and increasing the content of shortchain fatty acids,providing new ideas and potential sources of drugs for the treatment of breast hyperplasia.展开更多
Cyclopropenones have been extensively utilized in catalytic ring-opening and ring-expansion reactions for the synthesis of unsaturated carbonyl compounds.The first rhodium-catalyzed ring-opening reaction of aryl-/alky...Cyclopropenones have been extensively utilized in catalytic ring-opening and ring-expansion reactions for the synthesis of unsaturated carbonyl compounds.The first rhodium-catalyzed ring-opening reaction of aryl-/alkyl-substituted cyclopropenones is accomplished,successfully affording acyloin derivatives.This transformation represents a novel reaction pattern involving cyclopropenones.The resulting acyloin products constitute important building blocks in organic synthesis and serve as fundamental structural frameworks in numerous natural products.展开更多
基金supported by the National Natural Science Foundation of China,82471345(to LC)the Key Research and Development Program for Social Development by the Jiangsu Provincial Department of Science and Technology.No.BE2022668(to LC).
文摘Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.
基金supported by Qingdao Key Medical and Health Discipline ProjectThe Intramural Research Program of the Affiliated Hospital of Qingdao University,No. 4910Qingdao West Coast New Area Science and Technology Project,No. 2020-55 (all to SW)。
文摘Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macrophages have been poorly understood and largely overlooked. However, a recent study reported that border-associated macrophages participate in stroke-induced inflammation, although many details and the underlying mechanisms remain unclear. In this study, we performed a comprehensive single-cell analysis of mouse border-associated macrophages using sequencing data obtained from the Gene Expression Omnibus(GEO) database(GSE174574 and GSE225948). Differentially expressed genes were identified, and enrichment analysis was performed to identify the transcription profile of border-associated macrophages. CellChat analysis was conducted to determine the cell communication network of border-associated macrophages. Transcription factors were predicted using the ‘pySCENIC' tool. We found that, in response to hypoxia, borderassociated macrophages underwent dynamic transcriptional changes and participated in the regulation of inflammatory-related pathways. Notably, the tumor necrosis factor pathway was activated by border-associated macrophages following ischemic stroke. The pySCENIC analysis indicated that the activity of signal transducer and activator of transcription 3(Stat3) was obviously upregulated in stroke, suggesting that Stat3 inhibition may be a promising strategy for treating border-associated macrophages-induced neuroinflammation. Finally, we constructed an animal model to investigate the effects of border-associated macrophages depletion following a stroke. Treatment with liposomes containing clodronate significantly reduced infarct volume in the animals and improved neurological scores compared with untreated animals. Taken together, our results demonstrate comprehensive changes in border-associated macrophages following a stroke, providing a theoretical basis for targeting border-associated macrophages-induced neuroinflammation in stroke treatment.
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China(No.32571336 and 32271048)Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(No.2025IHM01100)。
文摘Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet the underlying complex neural circuitry mechanisms remain unclear.The spinal trigeminal nucleus caudalis(Sp5C)serves as the primary central hub for orofacial nociceptive input,receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus.Therefore,we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis.In this study,we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin(NTG).Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry,we found a marked periorbital and plantar mechanical allodynia in CM mice,accompanied by increased glutamatergic neuronal activity in Sp5C.Chemogenetic manipulation of Sp5C glutamatergic neurons(Sp5CV^(glut2))bidirectionally modulated migraine-like behaviors and induced pain-related affective states,as evidenced by conditioned place preference/aversion(CPP/CPA)paradigms.Anterograde viral tracing revealed dense projections from Sp5C^(Vglut2)to the subthalamic nucleus(STN),which was activated in CM mice.Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice.Altogether,we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM.Our findings provide novel mechanistic insights into the central mechanisms underlying CM,establishing potential theoretical foundations for clinical diagnosis and therapeutic development.
基金supported by the National Natural Science Foundation of China(Grant Nos.82573974 and 82373475)to Z.Y.
文摘Dear Editor,Psoriasis,a chronic inflammatory cutaneous condition,is characterized by the development of red plaques with silvery scales,significantly affecting patients'quality of life and mental health[1].This condition is thought to affect approximately 2%of the Western population,with diagnosis peaking in early adulthood[2].Vitamin D,a fat-soluble vitamin,is essential for phospho-calcium metabolism,calcium homeostasis,and bone health.
基金supported by the National Natural Science Foundation of China(Grant No.82271252 to W.L.,No.8217091029 to T.W.and No.82204542 to L.H.)the Key Medical Research Projects of Jiangsu Health and Health Commission(Grant No.K2023066 to L.Z.)the Taishan Industrial Talent Project(Grant No.2020-371722-73-03-097290 to W.L.).
文摘Neuromuscular electrical stimulation(NMES)is a well-established therapeutic approach for chronic wounds.Conventionally,NMES involves direct electrode contact with wounds or adjacent healthy skin;however,it is limited by the need for wound exposure and by increased pain.Our preliminary study demonstrated the innovative application of remote NMES(rNMES)to the skeletal muscle of the distal calf,which showed the potential to accelerate wound healing in remote areas.rNMES was effective in human clinical trials in our previous work,although the underlying mechanisms remain unclear.As rNMES is often used to stimulate muscle contraction in long-term bedridden patients,we analyzed data from the Gene Expression Omnibus(GEO)database and found that exercise promotes midkine(MDK)expression in muscle.MDK is a small secreted heparin-binding protein that interacts with multiple cell surface receptors to promote growth.In the present study,we found that MDK significantly enhanced macrophage efferocytosis in a low-density lipoprotein receptor-related protein 1(LRP1)-dependent manner.Our findings demonstrate that rNMES upregulates MDK expression in skeletal muscles through the AMPK-ERK axis,facilitating its delivery to wounds through the circulatory system and promoting LRP1-mediated efferocytosis of apoptotic cells,thereby expediting wound healing.
基金supported by the National Natural Science Foundation of China,No.82071909(to GF)the Natural Science Foundation of Liaoning Province,No.2023-MS-07(to HL)。
文摘Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9%)and 0.759(with an accuracy of 65.3%),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3%).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.
基金supported by the Zhejiang Medical and Health Innovation Talent Support Project(Grant No.2021RC128 to S.S.)Zhejiang Medicine and Health Science and Technology Project(2025KY1540 to J.J.L.)+3 种基金Zhejiang Province Health Science and Technology Project(2024KY409 and 2021KY1086 to J.Y.L.)Huzhou Science and Technology Planning Project(2020GY10 to W.L.,2022GZ65 to J.Y.L.)Huzhou Basic and Clinical Translation of Orthopedics Key Laboratory(Grant No.HZGKSYS01Y to S.S.)South Taihu Lake Outstanding Young Health Talents Cultivation Program(Grant No.rsk2023001 to S.S.).
文摘Articular cartilage maintains joint homeostasis by adapting to mechanical loading,but both insufficient and excessive loading can impair cartilage integrity.Whether mechanical activity should be restricted in early osteoarthritis(OA),particularly among exercise enthusiasts,remains controversial.Here,we established in vitro and in vivo models of prolonged moderate mechanical loading(7.5%strain,1 Hz)and analyzed human cartilage from weight-bearing and non-weight-bearing regions using RNA sequencing.Prolonged exposure(≥12 h)significantly increased chondrocyte apoptosis(2.3-fold),reduced expression of the chondrogenic transcription factor SOX9 and the matrix markers COL2A1,and elevated nerve growth factor(NGF)expression(1.8-fold),accompanied by enrichment of neural sensitization and inflammatory pathways.Immunofluorescence staining revealed NGF accumulation in mechanically stressed cartilage.Unlike high-intensity stress,which led to immediate apoptosis,moderate loading induced a delayed pro-apoptotic response after 12 h.These findings indicate that prolonged moderate mechanical loading may promote chondrocyte apoptosis through an NGFmediated inflammatory microenvironment and provide mechanistic evidence suggesting that patients with early OA may benefit from limiting high-impact or prolonged moderate-intensity exercise sessions to prevent cartilage damage and guide rehabilitation.
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)。
文摘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 Open Research Fund of the Zhejiang Key Laboratory of Precision Psychiatry(2025A2)the Natural Science Foundation of Zhejiang Province(LY23C090002)。
文摘Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remain elusive.Repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising non-invasive intervention;however,its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding.A recent landmark study published in Brain Stimulation by Chen et al.addressed these challenges by combining a high-dose intermittent theta-burst stimulation(iTBS)protocol with concurrent transcranial magnetic stimulation-electroencephalography(TMS-EEG).This commentary provides an in-depth analysis of their findings,highlighting the restoration of cerebello-cortical inhibition(CBI)as a key therapeutic mechanism.Furthermore,we discuss the broader implications of this work,proposing that future translational research should integrate accelerated iTBS(aiTBS)paradigms,cortical response measurements(CRM),and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
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)。
文摘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.
文摘Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of life and restrict therapeutic outcomes.Addressing this pressing issue,this review presents a thorough and systematic analysis of innovative and emerging strategies designed to minimize the toxicity induced by treatment,while maintaining or even enhancing antitumor efficacy.The focus is on six promising therapeutic approaches:combination therapies utilizing natural bioactive products,molecularly targeted therapies,immunotherapies,nanotechnology-mediated drug delivery systems,adjunct traditional Chinese medicine interventions,and low-dose spatiotemporally concerted regimens.Each approach employs unique mechanisms—such as enhanced targeting precision,immune system activation,tumor microenvironment reprogramming,and multi-component synergistic effects—to mitigate damage to normal tissues and reduce systemic adverse reactions.Despite promising preclinical and clinical advancements,several challenges persist,including drug resistance,high economic costs,a lack of reliable predictive biomarkers,and complexities in clinical translation and regulatory approval.Looking ahead,the incorporation of artificial intelligence,multi-omics profiling,and novel biomimetic nanotechnologies offers unprecedented opportunities for developing highly personalized,low-toxicity treatment frameworks.This review highlights a fundamental shift in oncology towards precision medicine that balances efficacy with safety,demonstrating the transformative potential of these strategies in shaping the future of cancer therapy and enhancing patient care globally.
基金supported by Ningbo Top Medical and Health Research Program(No.2022030410)National Key Research and Development Program of China(No.2022YFC3300905,2023YFC3304202).
文摘Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists on methamphetamine(MAP)reinforcement,motivation,and relapse remain uncertain.In this study,we evaluated the effects of Ro 64-6198,a selective NOP agonist,on MAP reinforcement,motivation,and relapse in rats.Rats underwent a fixed-ratio 1(FR1)training to establish stable MAP intravenous self-administration(0.05 mg/kg/infusion)for 12 days,and the motivation for MAP was quantified using a progressive-ratio(PR)schedule,while the relapse was assessed through cue-and MAP-primed reinstatement after abstinence.Western blot analysis was employed to measure the relative expression of phosphorylated CREB,ERK,and Akt in the nucleus accumbens(NAc)following drug priming.Acute treatment of Ro 64-6198(1 mg/kg)significantly reduced the motivated behavior for MAP under PR testing(P<0.05 vs.vehicle).Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues,respectively(P<0.05),whereas only the higher dose(1 mg/kg)could attenuate MAP primed drug-seeking(P<0.05).These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc.Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors,positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.
基金supported by the National Natural Science Foundation of China,Nos.32271389,31900987(both to PY)the Natural Science Foundation of Jiangsu Province,No.BK20230608(to JJ)。
文摘Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.
文摘Objective Peripheral nerve injury leads to various degrees of functional defects.Nerve guidance conduits are considered as a new promising scaffold for peripheral nerve repair.However,conventional single-material nerve conduits have shown limited efficacy in protecting cells from posttraumatic inflammation.This study aims to develop a single-process PLGA-based nerve conduit loaded with melatonin to enhance the biological performance of pure PLGA materials by suppressing oxidative stress and inflammatory responses.Methods The PLGA conduit is prepared with dry-jet wet spinning methods.The melatonin is integrated into PLGA conduits directly with the single-step process.Scanning electrical microscope observation,FTIR test,degradation test and drug releasing test were performed to characterize the morphology and physical properties of the nerve conduits.Schwann cells were cultured to test the biocompatibility of the prepared nerve conduits.Oxidative stress was applied on Schwann cell using hydrogen peroxide.Then the protecting effects of the nerve conduits were tested on the hydrogen peroxide-treated cells.SD rat sciatic model was applied to test the conduit in vivo.Results The melatonin is successfully integrated into the nerve conduit with the dry-jet wet spinning method.Cell adhesion and proliferation test of the Schwann cell indicated that the nerve conduits exhibit excellent biocompatibility.While the mitochondrial morphology observation and JC-1 potential detection also showed protecting effects on Mitochondria.The q-PCR analysis showed nerve conduits reduced cellular oxidative stress and inflammatory responses while enhancing cellular proliferation.A marked enhancement on SD rat sciatic nerve regeneration was also observed on melatonin loaded conduits.Conclusions By integrating melatonin into PLGA using the dryjet wet-spinning technique,the conduit is endowed with multiple functional advantages,including antiinflammatory,antioxidant,and neuroprotective properties.This approach is expected to create a favorable microenvironment for nerve tissue regeneration and provide a new perspective for the treatment of peripheral nerve injuries.
基金supported by the National Natural Science Foundation of China,Nos.32271043(to ZW)and 82171047(to YM)the both Science and Technology Major Project of Shanghai,No.2018SHZDZX01 and ZJLabShanghai Center for Brain Science and Brain-Inspired Technology(to ZW)。
文摘Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.
文摘A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an orally administered nanogene delivery system.Designed to achieve in situ,efficient delivery of chimeric antigen receptor(CAR)genes to tumor sites,this approach offers a novel strategy for CAR-macrophage(CAR-M)based immunotherapy.Its key highlights are as follows.
文摘BACKGROUND:Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders,manifested as abnormal hyperplasia of breast tissue.In recent years,traditional Chinese medicine compounds and probiotics have shown good potential in regulating the endocrine system and improving the intestinal microecology,providing new ideas for the treatment of breast hyperplasia.OBJECTIVE:To explore the effects and mechanisms of traditional Chinese medicine compounds and fermented probiotic compounds on breast hyperplasia in mice,providing new theoretical and experimental bases for the clinical treatment and prevention of breast hyperplasia.METHODS:(1)Network pharmacology tools were used to predict the anti-breast-hyperplasia activity of Herba Gueldenstaedtiae(Euphorbia humifusa),as well as its potential targets and signaling pathways.The databases included:TCMSP,OMIM,GeneCards database,UniProt website,Venny2.1.0 website,Metascape,HERB website,and STRING database,all of which are open-access databases.Network pharmacology can predict and screen key information such as the targets corresponding to the active ingredients of traditional Chinese medicine,disease targets,and action pathways through network analysis and computer-system analysis.Therefore,it has been increasingly widely used in the research of traditional Chinese medicine.(2)A breast hyperplasia model was induced in mice by injecting estrogen and progesterone.Mice in the normal blank group were injected intraperitoneally with normal saline every day.Mice in the model group and drugadministration groups were injected intraperitoneally with estradiol benzoate injection at a concentration of 0.5 mg/kg every day for 25 days.From the 26th day,the injection of estradiol benzoate injection was stopped.Mice in the normal blank group were injected intramuscularly with normal saline every day,and mice in the model group and drug-administration groups were injected intramuscularly with progesterone injection at a concentration of 5 mg/kg for 5 days.After the model was established,each group was given drugs respectively.The normal blank group and the model group were gavaged with 0.2 mL/d of normal saline;the positive blank group(Xiaozheng Pill group)was gavaged with an aqueous solution of Xiaozheng Pill at 0.9 mg/g;the low-,medium-and high-dose groups of Compound Herba Gueldenstaedtiae were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively;the low-,medium-and high-dose groups of traditional Chinese medicine-bacteria fermentation were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively.The administration was continuous for 30 days.RESULTS AND CONCLUSION:(1)The results of network pharmacology research showed that the Compound Herba Gueldenstaedtiae(Euphorbia humifusa)contained 46 active ingredients,which were related to 1213 potential targets.After comparison with 588 known breast-hyperplasia targets,it was speculated that 50 of these targets might be related to the direct effect of the compound on breast hyperplasia.(2)After drug intervention,there was no significant change in the high-dose group of Compound Herba Gueldenstaedtiae compared with the normal blank group.The liver indicators of the other intervention groups all significantly decreased(P<0.05).(3)In terms of kidney and uterine indicators,the medium-dose group of Compound Herba Gueldenstaedtiae decreased significantly compared with the normal blank group(P<0.05).In terms of the uterine index,the model group increased significantly compared with the normal blank group(P<0.01).(4)After 1-month drug treatment,the number of lobules and acini in the breast tissue of the Xiaozheng Pill group,the low,medium,and high-dose group of Compound Herba Gueldenstaedtiae,the low,medium,and highdose groups of traditional Chinese medicine-bacteria fermentation decreased,and the duct openings narrowed.With the increase of drug dose,diffuse hyperplasia of breast tissue was significantly improved.(5)The ELISA results showed that compared with the model group,the estrogen level was lower in the medium-dose group of traditional Chinese medicine-bacteria fermentation after the intervention(P<0.05).In addition,the follicle-stimulating hormone level in the low-dose group of Compound Herba Gueldenstaedtiae was lower than that of the model group(P<0.05).(6)The intervention in the mouse model led to changes in the abundance of short chain fatty acids and intestinal flora in all groups.To conclude,the Compound Herba Gueldenstaedtiae and its probiotic fermentation products significantly improved mammary gland hyperplasia in mice by regulating hormone levels,improving the structure of the gut microbiota,and increasing the content of shortchain fatty acids,providing new ideas and potential sources of drugs for the treatment of breast hyperplasia.
基金Project supported by the National Natural Science Foundation of China(Nos.22071242,21871260)。
文摘Cyclopropenones have been extensively utilized in catalytic ring-opening and ring-expansion reactions for the synthesis of unsaturated carbonyl compounds.The first rhodium-catalyzed ring-opening reaction of aryl-/alkyl-substituted cyclopropenones is accomplished,successfully affording acyloin derivatives.This transformation represents a novel reaction pattern involving cyclopropenones.The resulting acyloin products constitute important building blocks in organic synthesis and serve as fundamental structural frameworks in numerous natural products.
