Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury ...Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.展开更多
Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension a...Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension and cerebral small vessel disease remains unclear.Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease.Chronic hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and stroke.Hypertension is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of hypertension.This review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive ability.We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.展开更多
BACKGROUND For patients with acute paraplegia caused by spinal giant cell tumor(GCT)who require emergency decompressive surgery,there is still a lack of relevant reports on surgical options.This study is the first to ...BACKGROUND For patients with acute paraplegia caused by spinal giant cell tumor(GCT)who require emergency decompressive surgery,there is still a lack of relevant reports on surgical options.This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy(TES).Despite tumor recurrence,three-level TES was repeated after denosumab therapy.CASE SUMMARY A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor.After emergency TES,the patient's spinal cord function recovered,and permanent paralysis was avoided.The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT.Unfortunately,the tumor recurred 9 months after the first surgery.After 12 months of denosumab therapy,the tumor size was reduced,and tumor calcification.To prevent recurrent tumor progression and provide a possible cure,a three-level TES was performed again.The patient returned to an active lifestyle 1 month after the second surgery,and no recurrence of GCT was found at the last follow-up.CONCLUSION This patient with acute paraplegia underwent TES twice,including once in an emergency,and achieved good therapeutic results.TES in emergency surgery is feasible and safe when conditions permit;however,it may increase the risk of tumor recurrence.展开更多
Background The presence of mental health conditions is pervasive in patients who experienced acute myocardial infarction(AMI),significantly disrupting their recovery.Providing timely and easily accessible psychologica...Background The presence of mental health conditions is pervasive in patients who experienced acute myocardial infarction(AMI),significantly disrupting their recovery.Providing timely and easily accessible psychological interventions using virtual reality-based cognitive-behavioural therapy(VR-CBT)could potentially improve both acute and long-term symptoms affecting their mental health.Aims We aim to examine the effectiveness of VR-CBT on anxiety symptoms in patients with AMI who were admitted to the intensive care unit(ICU)during the acute stage of their illness.Methods In this single-blind randomised clinical trial,participants with anxiety symptoms who were admitted to the ICU due to AMI were continuously recruited from December 2022 to February 2023.Patients who were Han Chinese aged 18-75 years were randomly assigned(1:1)via block randomisation to either the VR-CBT group to receive VR-CBT in addition to standard mental health support,or the control group to receive standard mental health support only.VR-CBT consisted of four modules and was delivered at the bedside over a 1-week period.Assessments were done at baseline,immediately after treatment and at 3-month follow-up.The intention-to-treat analysis began in June 2023.The primary outcome measure was the changes in anxiety symptoms as assessed by the Hamilton Anxiety Rating Scale(HAM-A).Results Among 148 randomised participants,70 were assigned to the VR-CBT group and 78 to the control group.The 1-week VR-CBT intervention plus standard mental health support significantly reduced the anxiety symptoms compared with standard mental health support alone in terms of HAM-A scores at both post intervention(Cohen’s d=−1.27(95%confidence interval(CI):−1.64 to−0.90,p<0.001)and 3-month follow-up(Cohen’s d=−0.37(95%CI:−0.72 to−0.01,p=0.024).Of the 70 participants who received VR-CBT,62(88.6%)completed the entire intervention.Cybersickness was the main reported adverse event(n=5).Conclusions Our results indicate that VR-CBT can significantly reduce post-AMI anxiety at the acute stage of the illness;the improvement was maintained at the 3-month follow-up.Trial registration number The trial was registered at www.chictr.org.cn with the identifier:ChiCTR2200066435.展开更多
Hepatoblastoma is the most frequent liver malignancy in children.HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture.Intriguingly,we observed that the addition of calciu...Hepatoblastoma is the most frequent liver malignancy in children.HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture.Intriguingly,we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells.The calcium signal is in connection with a series of processes critical in the tumorigenesis.Here,we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells.Mechanistically,calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase(FAK),protein kinase B,and p38 mitogen-activated protein kinase.The inhibitor of FAK or Ca2+/calmodulin-dependent kinaseⅡ(CaMKⅡ)reversed the Ca2+-induced effects on HepG2 cells,including cell proliferation and migration,epithelial-mesenchymal transition protein expression levels,and phosphorylation levels of FAK and protein kinase B.Moreover,calcium ions decreased HepG2 cells'sensitivity to cisplatin.Furthermore,we found that the expression levels of FAK and CaMKⅡwere increased in hepatoblastoma.The group with high expression levels of FAK and CaMKⅡexhibited significantly lower ImmunoScore as well as CD8+T and NK cells.The expression of CaMKⅡwas positively correlated with that of PDCD1 and LAG3.Correspondingly,the expression of FAK was negatively correlated with that of TNFSF9,TNFRSF4,and TNFRSF18.Collectively,extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡand enhances cisplatin resistance.FAK and CaMKⅡshape immune cell infiltration and responses in tumor microenvironments,thereby serving as potential targets for hepatoblastoma.展开更多
In the present study, we hypothesized that 5-hydroxymethyl-2-furfural could attenuate ischemic brain damage by reducing oxidative injury. Thus, mice were subjected to bilateral common carotid artery occlusion to estab...In the present study, we hypothesized that 5-hydroxymethyl-2-furfural could attenuate ischemic brain damage by reducing oxidative injury. Thus, mice were subjected to bilateral common carotid artery occlusion to establish a model of permanent forebrain ischemia. The mice were intraperitoneally injected with 5-hydroxymethyl-2-furfura130 minutes before ischemia or 5 minutes after ischemia. The survival time of mice injected with 5-hydroxymethyl-2-furfural was longer compared with untreated mice. The mice subjected to ischemia for 30 minutes and reperfusion for 5 minutes were intraperitoneally injected with 5-hydroxymethyl-2-furfural 5 minutes prior to reperfusion, which increased superoxide dismutase content and reduced malondialdehyde content, similar to the effects of Edaravone, a hydroxyl radical scavenger used for the treatment of stroke. These findings indicate that intraperitoneal injection of 5-hydroxymethyl-2-furfural can prolong the survival of mice with permanent forebrain ischemia. This outcome may be mediated by its antioxidative effects.展开更多
AIM:To identify factors contributing to visual improvement after treatment of macular edema(ME)secondary to branch retinal vein occlusion(BRVO),and to assess the interaction between laser therapy and intravitreal rani...AIM:To identify factors contributing to visual improvement after treatment of macular edema(ME)secondary to branch retinal vein occlusion(BRVO),and to assess the interaction between laser therapy and intravitreal ranibizumab(IVR).METHODS:We retrospectively reviewed the medical records of patients who had been treated for BRVO-related ME at our hospital.Records were traceable for at least 12 mo,and evaluated factors included age,sex,medical history,smoking history,treatment methods,foveal hemorrhage,and change in visual acuity.Treatments included laser therapy,IVR,sub-Tenon’s capsule injection of triamcinolone(STTA),a combination,or no intervention.Multivariate logistic regression analysis and interaction terms were used to assess the clinical efficacy of the treatments,and odds ratios(OR)and 95%confidence intervals(CI)were calculated.RESULTS:Seventy-three patients(34 men,39 women;73 eyes)with a mean age of 69.4±12.1 y were included.Patients who underwent IVR monotherapy,laser monotherapy,and STTA+laser had significantly higher best corrected visual acuity at 12 mo compared to baseline(P<0.001,<0.001,and 0.019,respectively).Logistic regression analysis without interaction terms found that IVR was a significant visual acuity recovery factor(adjusted OR:3.89,95%CI:1.25-12.1,P=0.019).Adjusted OR using an interaction model by logistic regression was 16.6(95%CI:2.54-108.47,P=0.003)with IVR treatment,and 8.25(95%CI:1.34-50.57,P=0.023)with laser treatment.No interaction was observed(adjusted OR:0.07,95%CI:0.01-0.75,P=0.029).CONCLUSION:IVR contributes to improvements in visual acuity at 12 mo in ME secondary to BRVO.No interaction is observed between laser therapy and IVR treatments.展开更多
OBJECTIVE In order to investigate whether cornel iridoid glycoside(CIG),the main component extracted from Cornus officinalis,can treat demyelinating diseases of the central nervous system(CNS)such as multiple sclerosi...OBJECTIVE In order to investigate whether cornel iridoid glycoside(CIG),the main component extracted from Cornus officinalis,can treat demyelinating diseases of the central nervous system(CNS)such as multiple sclerosis(MS).METHODS CIG(30,60 and 120mg·kg-1)or vehicle was intragastrically administered once daily to rats,starting immediately after purified myelin basic protein(MBP)68-86 peptides immunization until day 20 post immunization(p.i.).Histopathological staining,enzyme-linked immunosorbent assay,biochemical methods and Western blotting approaches were used to evaluate the disease incidence and severity,neuroinflammatory and neurotrophic response in the CNS.RESULTS Neurological deficit and proportion of incidence seen in EAE rats were significantly reduced by CIG treatment in a dose-dependent manner.Histopathological staining showed that CIG treatment alleviated demyelination and inflammatory infiltration,increased the number of oligodendrocytes,enhanced the expression of brain-derived neurotrophic factor(BDNF).Production of proinflammatory molecules such as interleukin-1β(IL-1β),tumour necrosis factor-αand interferon-γwere also inhibited by CIG administration.CIG could ameliorate phosphorylation of STAT1,STAT3 and JAK1 as well as IL-6/IL-6 Rexpression,which involved in immune response and inflammation.CONCLUSION Our results demonstrated that CIG may ameliorate EAE rats through down-regulation of JAK/STAT signaling pathway.This study gave new insight into the novel regulatory mechanism of CIG and highlight novel therapeutic targets and a potential therapeutic agent for the treatment of MS.展开更多
OBJECTIVE To observe effects of tetrahydroxystilbene glucoside(TSG)on behavior,content of dopamine and its metabolites in striatum of Parkinson′s disease(PD)model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrop...OBJECTIVE To observe effects of tetrahydroxystilbene glucoside(TSG)on behavior,content of dopamine and its metabolites in striatum of Parkinson′s disease(PD)model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)injection.METHODS Mice were randomly divided into control group,model group,TSG low dose(60mg·kg-1)and high dose(120mg·kg-1)groups.The behavior changes of mice were observed by pole test,rotarod test and spontaneous movement test.The tyrosine hydroxylase(TH)positive cells were detected by immunohistochemical method.The content of dopamine(DA)and its metabolites in striatum were determined by HPLC-ECD.RESULTS MPTP model mice showed behavior deficit.The number of TH positive neurons in substantia nigra,the content of dopamine and its metabolites in striatum in model mice decreased significantly compared with control group.TSG ameliorated mice behavior,increased the number of TH positive neurons in the substantia nigra about 18.8%,and elevated the content of dopamine in striatum about 34.5% compared with model mice.CONCLUSION TSG protected dopaminergic neurons against MPTP-induced damage,and may become a candidate drug for prevention and treatment of Parkinson′s disease.展开更多
Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely ...Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells.Upon in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging.In particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular senescence.This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.展开更多
Background of database.Organ degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative disease...Background of database.Organ degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative diseases,including cardiovascular diseases,neurodegenerative diseases,and osteoarthritis,etc.(Aging Biomarker et al.,2023;Becker et al.,2018;Cai et al.,2022).展开更多
Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differenti...Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive.Here,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response mechanisms.Through comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular regeneration.We found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic processes.Altogether,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.展开更多
The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of infertility.However,the molecular basis of ovarian aging in higher vertebrates remains poorly underst...The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of infertility.However,the molecular basis of ovarian aging in higher vertebrates remains poorly understood.Herein,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries.From a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian aging.Further,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ovary.Moreover,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal outward.Our study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.展开更多
N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 h...N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.展开更多
Acute kidney injury(AKI)can lead to loss of kidney function and a substantial increase in mortality.The burst of reactive oxygen species(ROS)plays a key role in the pathological progression of AKI.Mitochondrial-target...Acute kidney injury(AKI)can lead to loss of kidney function and a substantial increase in mortality.The burst of reactive oxygen species(ROS)plays a key role in the pathological progression of AKI.Mitochondrial-targeted antioxidant therapy is very promising because mitochondria are the main source of ROS in AKI.Antioxidant nanodrugs with actively targeted mitochondria have achieved encouraging success in many oxidative stress-induced diseases.However,most strategies to actively target mitochondria make the size of nanodrugs too large to pass through the glomerular system to reach the renal tubules,the main damage site of AKI.Here,an ultra-small Tungsten-based nanodots(TWNDs)with strong ROS scavenging can be very effective for treatment of AKI.TWNDs can reach the tubular site after crossing the glomerular barrier,and enter the mitochondria of the renal tubule without resorting to complex active targeting strategies.To our knowledge,this is the first time that ultra-small negatively charged nanodots can be used to passively target mitochondrial therapy for AKI.Through in-depth study of the therapeutic mechanism,such passive mitochondria-targeted TWNDs are highly effective in protecting mitochondria by reducing mitochondrial ROS and increasing mitophagy.In addition,TWNDs can also reduce the infiltration of inflammatory cells.This work provides a new way to passively target mitochondria for AKI,and give inspiration for the treatment of many major diseases closely related to mitochondria,such as myocardial infarction and cerebral infarction.展开更多
Dear Editor,Cells enter senescence,or irreversible growth arrest,when exposed to stressors such as DNA damage,epigenetic alterations and chronic inflammation(Zhao and Chen,2022).In aging and aging-related diseases,sen...Dear Editor,Cells enter senescence,or irreversible growth arrest,when exposed to stressors such as DNA damage,epigenetic alterations and chronic inflammation(Zhao and Chen,2022).In aging and aging-related diseases,senescent cells are known to accumulate across tissues and organs(Sun et al.,2022;Lopez-Otin et al.,2023).展开更多
Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of ...Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.展开更多
The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.H...The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for spermatogenesis.Collectively,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.展开更多
Parkinson's disease(PD)is the second most common neurodegenerative disease,affecting around 1.0%of the population over 65 years of age[1].In China,there are estimated to be more than 3 million PD patients,with eac...Parkinson's disease(PD)is the second most common neurodegenerative disease,affecting around 1.0%of the population over 65 years of age[1].In China,there are estimated to be more than 3 million PD patients,with each year about 100,000 PD patients being newly diagnosed.Along with China stepping into an aging society,it was estimated that in 2030,there would be around 5 million PD patients in China alone,which would create huge socioeconomic burdens on patients and their families.展开更多
Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses o...Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging.A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types,indicating a higher susceptibility of skeletal muscle fiber to aging.We found a downregulation of Foxo3 in aged primate skeletal muscle,and identi-fied FOxo3 as a hub transcription factor maintaining skeletal muscle homeostasis.Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model,we revealed that silence of Foxo3 accelerates human myotube senescence,whereas genetic activation of endogenous FOxO3 alleviates human myotube aging.Altogether,based on a combination of monkey skeletal muscle and human myotube aging research models,we unraveled the pivotal role of the FOxO3 in safeguarding primate skeletal muscle from aging,providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-relateddisorders.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071376(to ZC)and 82001471(to CJ)the Natural Science Foundation of Shanghai,No.20ZR1410500(to ZC).
文摘Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.
基金supported by the National Natural Science Foundation of China,Nos.82274611 (to LZ),82104419 (to DM)Capital Science and Technology Leading Talent Training Project,No.Z1 91100006119017 (to LZ)+3 种基金Beijing Hospitals Authority Ascent Plan,No.DFL20190803 (to LZ)Cultivation Fund of Hospital Management Center in Beijing,No.PZ2022006 (to DM)R&D Program of Beijing Municipal Education Commission,No.KM202210025017 (to DM)Beijing Gold-Bridge Project,No.ZZ20145 (to DM)。
文摘Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension and cerebral small vessel disease remains unclear.Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease.Chronic hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and stroke.Hypertension is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of hypertension.This review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive ability.We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.
基金Supported by The Shanghai Municipal Health Commission Clinical Research Project,No.202140140.
文摘BACKGROUND For patients with acute paraplegia caused by spinal giant cell tumor(GCT)who require emergency decompressive surgery,there is still a lack of relevant reports on surgical options.This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy(TES).Despite tumor recurrence,three-level TES was repeated after denosumab therapy.CASE SUMMARY A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor.After emergency TES,the patient's spinal cord function recovered,and permanent paralysis was avoided.The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT.Unfortunately,the tumor recurred 9 months after the first surgery.After 12 months of denosumab therapy,the tumor size was reduced,and tumor calcification.To prevent recurrent tumor progression and provide a possible cure,a three-level TES was performed again.The patient returned to an active lifestyle 1 month after the second surgery,and no recurrence of GCT was found at the last follow-up.CONCLUSION This patient with acute paraplegia underwent TES twice,including once in an emergency,and achieved good therapeutic results.TES in emergency surgery is feasible and safe when conditions permit;however,it may increase the risk of tumor recurrence.
基金The study was supported by the Transverse Project of Zhongshan Hospital and Hangzhou Xinjing Science and Technology(XH,H2022-009)National Key Research and Development Program of China(XH,2023YFC2506200)Shanghai Clinical Research Center for Interventional Medicine(JBG,19MC1910300).
文摘Background The presence of mental health conditions is pervasive in patients who experienced acute myocardial infarction(AMI),significantly disrupting their recovery.Providing timely and easily accessible psychological interventions using virtual reality-based cognitive-behavioural therapy(VR-CBT)could potentially improve both acute and long-term symptoms affecting their mental health.Aims We aim to examine the effectiveness of VR-CBT on anxiety symptoms in patients with AMI who were admitted to the intensive care unit(ICU)during the acute stage of their illness.Methods In this single-blind randomised clinical trial,participants with anxiety symptoms who were admitted to the ICU due to AMI were continuously recruited from December 2022 to February 2023.Patients who were Han Chinese aged 18-75 years were randomly assigned(1:1)via block randomisation to either the VR-CBT group to receive VR-CBT in addition to standard mental health support,or the control group to receive standard mental health support only.VR-CBT consisted of four modules and was delivered at the bedside over a 1-week period.Assessments were done at baseline,immediately after treatment and at 3-month follow-up.The intention-to-treat analysis began in June 2023.The primary outcome measure was the changes in anxiety symptoms as assessed by the Hamilton Anxiety Rating Scale(HAM-A).Results Among 148 randomised participants,70 were assigned to the VR-CBT group and 78 to the control group.The 1-week VR-CBT intervention plus standard mental health support significantly reduced the anxiety symptoms compared with standard mental health support alone in terms of HAM-A scores at both post intervention(Cohen’s d=−1.27(95%confidence interval(CI):−1.64 to−0.90,p<0.001)and 3-month follow-up(Cohen’s d=−0.37(95%CI:−0.72 to−0.01,p=0.024).Of the 70 participants who received VR-CBT,62(88.6%)completed the entire intervention.Cybersickness was the main reported adverse event(n=5).Conclusions Our results indicate that VR-CBT can significantly reduce post-AMI anxiety at the acute stage of the illness;the improvement was maintained at the 3-month follow-up.Trial registration number The trial was registered at www.chictr.org.cn with the identifier:ChiCTR2200066435.
基金funded by the Jiangsu Medical Scientific Research Project of Jiangsu Health Commission(to Q.Y.)the 789 Outstanding Talent Program of SAHNMU(Grant No.789ZYRC 202070102 to Q.Y.)+1 种基金the Guangzhou Key Medical Discipline Construction Project(to Q.Y.)the National Natural Science Foundation of China(Grant Nos.81870409 and 81671543 to Q.Y.).
文摘Hepatoblastoma is the most frequent liver malignancy in children.HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture.Intriguingly,we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells.The calcium signal is in connection with a series of processes critical in the tumorigenesis.Here,we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells.Mechanistically,calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase(FAK),protein kinase B,and p38 mitogen-activated protein kinase.The inhibitor of FAK or Ca2+/calmodulin-dependent kinaseⅡ(CaMKⅡ)reversed the Ca2+-induced effects on HepG2 cells,including cell proliferation and migration,epithelial-mesenchymal transition protein expression levels,and phosphorylation levels of FAK and protein kinase B.Moreover,calcium ions decreased HepG2 cells'sensitivity to cisplatin.Furthermore,we found that the expression levels of FAK and CaMKⅡwere increased in hepatoblastoma.The group with high expression levels of FAK and CaMKⅡexhibited significantly lower ImmunoScore as well as CD8+T and NK cells.The expression of CaMKⅡwas positively correlated with that of PDCD1 and LAG3.Correspondingly,the expression of FAK was negatively correlated with that of TNFSF9,TNFRSF4,and TNFRSF18.Collectively,extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡand enhances cisplatin resistance.FAK and CaMKⅡshape immune cell infiltration and responses in tumor microenvironments,thereby serving as potential targets for hepatoblastoma.
基金supported by the National Basic Research Program of China (973 Program),No.2003CB517104the National Natural Science Foundation of China,No.30973513+3 种基金Beijing Municipal Science and Technology Program,No.D0206001043191the Natural Science Foundation of Beijing,No.7112061Beijing Key Foundation of Traditional Chinese Medicine,No.KJTS2011-04Beijing Health and Technical Personal of High-Level Plan,No.2009-3-66
文摘In the present study, we hypothesized that 5-hydroxymethyl-2-furfural could attenuate ischemic brain damage by reducing oxidative injury. Thus, mice were subjected to bilateral common carotid artery occlusion to establish a model of permanent forebrain ischemia. The mice were intraperitoneally injected with 5-hydroxymethyl-2-furfura130 minutes before ischemia or 5 minutes after ischemia. The survival time of mice injected with 5-hydroxymethyl-2-furfural was longer compared with untreated mice. The mice subjected to ischemia for 30 minutes and reperfusion for 5 minutes were intraperitoneally injected with 5-hydroxymethyl-2-furfural 5 minutes prior to reperfusion, which increased superoxide dismutase content and reduced malondialdehyde content, similar to the effects of Edaravone, a hydroxyl radical scavenger used for the treatment of stroke. These findings indicate that intraperitoneal injection of 5-hydroxymethyl-2-furfural can prolong the survival of mice with permanent forebrain ischemia. This outcome may be mediated by its antioxidative effects.
文摘AIM:To identify factors contributing to visual improvement after treatment of macular edema(ME)secondary to branch retinal vein occlusion(BRVO),and to assess the interaction between laser therapy and intravitreal ranibizumab(IVR).METHODS:We retrospectively reviewed the medical records of patients who had been treated for BRVO-related ME at our hospital.Records were traceable for at least 12 mo,and evaluated factors included age,sex,medical history,smoking history,treatment methods,foveal hemorrhage,and change in visual acuity.Treatments included laser therapy,IVR,sub-Tenon’s capsule injection of triamcinolone(STTA),a combination,or no intervention.Multivariate logistic regression analysis and interaction terms were used to assess the clinical efficacy of the treatments,and odds ratios(OR)and 95%confidence intervals(CI)were calculated.RESULTS:Seventy-three patients(34 men,39 women;73 eyes)with a mean age of 69.4±12.1 y were included.Patients who underwent IVR monotherapy,laser monotherapy,and STTA+laser had significantly higher best corrected visual acuity at 12 mo compared to baseline(P<0.001,<0.001,and 0.019,respectively).Logistic regression analysis without interaction terms found that IVR was a significant visual acuity recovery factor(adjusted OR:3.89,95%CI:1.25-12.1,P=0.019).Adjusted OR using an interaction model by logistic regression was 16.6(95%CI:2.54-108.47,P=0.003)with IVR treatment,and 8.25(95%CI:1.34-50.57,P=0.023)with laser treatment.No interaction was observed(adjusted OR:0.07,95%CI:0.01-0.75,P=0.029).CONCLUSION:IVR contributes to improvements in visual acuity at 12 mo in ME secondary to BRVO.No interaction is observed between laser therapy and IVR treatments.
基金The project supported by National Natural Science Foundation of China(81341088,81001656)Beijing Nova Star Program in Science and Technology(Z12111000250000)
文摘OBJECTIVE In order to investigate whether cornel iridoid glycoside(CIG),the main component extracted from Cornus officinalis,can treat demyelinating diseases of the central nervous system(CNS)such as multiple sclerosis(MS).METHODS CIG(30,60 and 120mg·kg-1)or vehicle was intragastrically administered once daily to rats,starting immediately after purified myelin basic protein(MBP)68-86 peptides immunization until day 20 post immunization(p.i.).Histopathological staining,enzyme-linked immunosorbent assay,biochemical methods and Western blotting approaches were used to evaluate the disease incidence and severity,neuroinflammatory and neurotrophic response in the CNS.RESULTS Neurological deficit and proportion of incidence seen in EAE rats were significantly reduced by CIG treatment in a dose-dependent manner.Histopathological staining showed that CIG treatment alleviated demyelination and inflammatory infiltration,increased the number of oligodendrocytes,enhanced the expression of brain-derived neurotrophic factor(BDNF).Production of proinflammatory molecules such as interleukin-1β(IL-1β),tumour necrosis factor-αand interferon-γwere also inhibited by CIG administration.CIG could ameliorate phosphorylation of STAT1,STAT3 and JAK1 as well as IL-6/IL-6 Rexpression,which involved in immune response and inflammation.CONCLUSION Our results demonstrated that CIG may ameliorate EAE rats through down-regulation of JAK/STAT signaling pathway.This study gave new insight into the novel regulatory mechanism of CIG and highlight novel therapeutic targets and a potential therapeutic agent for the treatment of MS.
基金The project supported by National Natural Science Foundation of China(81273498)the Capital Health Research and Development Foundation(2011-1001-04)
文摘OBJECTIVE To observe effects of tetrahydroxystilbene glucoside(TSG)on behavior,content of dopamine and its metabolites in striatum of Parkinson′s disease(PD)model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)injection.METHODS Mice were randomly divided into control group,model group,TSG low dose(60mg·kg-1)and high dose(120mg·kg-1)groups.The behavior changes of mice were observed by pole test,rotarod test and spontaneous movement test.The tyrosine hydroxylase(TH)positive cells were detected by immunohistochemical method.The content of dopamine(DA)and its metabolites in striatum were determined by HPLC-ECD.RESULTS MPTP model mice showed behavior deficit.The number of TH positive neurons in substantia nigra,the content of dopamine and its metabolites in striatum in model mice decreased significantly compared with control group.TSG ameliorated mice behavior,increased the number of TH positive neurons in the substantia nigra about 18.8%,and elevated the content of dopamine in striatum about 34.5% compared with model mice.CONCLUSION TSG protected dopaminergic neurons against MPTP-induced damage,and may become a candidate drug for prevention and treatment of Parkinson′s disease.
基金supported by the National Key Research and Development Program of China (Grant Nos.2022YFA1103700,2020YFA0804000,2020YFA0112200,2021YFF1201000,2022YFA1103800,2021YFA1101401,the STI2030-Major Projects-2021ZD0202400)the National Natural Science Foundation of China (Grant Nos.92049116,81921006,82125011,92149301,92168201,91949209,92049304,32121001,82192863,82122024,82071588,32000500,82271600)+9 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16000000)CAS Project for Young Scientists in Basic Research (YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation (Z190019)the Pilot Project for Public Welfare Development and Reform of Beijing-affiliated Medical Research Institutes (No.11000022T000000461062)Youth Innovation Promotion Association of CAS (E1CAZW0401,2023092,2022083)Young Elite Scientists Sponsorship Program by CAST (YESS20200012,YESS20210002)the Informatization Plan of Chinese Academy of Sciences (CAS-WX2021SF-0301,CAS-WX2022SDC-XK14,CAS-WX2021SF-0101)New Cormerstone Science Foundation through the XPLORER PRIZE (2021-1045)Excellent Young Talents Program of Capital Medical University (No.12300927)Excellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher Team (BPHR202203105).
文摘Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells.Upon in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging.In particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular senescence.This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.
基金This work was supported by the National Key Research and Development Program of China(2020YFA0112200,2020YFA0804000,2022YFA1103700,the STI2030-Major Projects-2021ZD0202400,2021YFF1201000)the National Natural Science Foundation of China(81921006,82125011,92149301)+9 种基金the Informatization Plan of Chinese Academy of Sciences(CAS-WX2022SDC-XK14,CASWX2021SF-0301,CAS-WX2021SF-0101)the National Natural Science Foundation of China(92168201,91949209,92049304,82271600,82322025,32000500,92049116,32121001,82192863,82122024,82071588)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z230011)New Cornerstone Science Foundation through the XPLORER PRIZE(2021-1045)Young Elite Scientists Sponsorship Program by CAST(2021QNRC001)Youth Innovation Promotion Association of CAS(2022083,E1CAZW0401)Excellent Young Talents Program of Capital Medical University(12300927)The Project for Technology Development of Beijing-affiliated Medical Research Institutes(11000023T000002036310)Excellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher Team(BPHR202203105).
文摘Background of database.Organ degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative diseases,including cardiovascular diseases,neurodegenerative diseases,and osteoarthritis,etc.(Aging Biomarker et al.,2023;Becker et al.,2018;Cai et al.,2022).
基金supported by the National Key Research and Development Program of China (Nos.2020YFA0804000,2022YFA1103700,2020YFA0112200,2021YFF1201005,the ST12030-Major Projects-2021ZD0202400,2021YFA1101401)the National Natural Science Foundation of China (Nos.81921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,and 82201714)+10 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences (No.XDA1000000)CAS Project for Young Scientists in Basic Research (No.YSBR-076 and YSBR-012)the Program of the Beijing Natural Science Foundation (No.Z190019)The Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes (No.110000227000000461062)the Excellent Young Talents Program of Capital Medical University (12300927)the Excellent Young Talents Training Program for the Construction of Beiing Municipal University Teacher Team (BPHR202203105)Youth Innovation Promotion Association of CAS (No.E1CAZW0401)Young Elite Scientists Sponsorship Program by CAST (No.YESS20200012)the Informatization Plan of Chinese Academy of Sciences (Nos.CAS-WX2021SF-0301,CAS-WX2022SDC-XK14,and CAS-WX2021SF-0101)The Fellowship of China Postdoctoral Science Foundation (2022M712216)the Tencent Foundation (2021-1045).
文摘Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive.Here,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response mechanisms.Through comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular regeneration.We found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic processes.Altogether,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.82122024,92149301,82125011,81921006)the National Key Research and Development Program of China(2022YFA1103700,2020YFA0804000,2020YFA0112200,2021YFF1201000,the STI2030-Major Projects-2021ZD0202400)+11 种基金the National Natural Science Foundation of China(Grant Nos.92168201,82225019,91949209,92049304,82071588,82322025,32000500,82271600,92049116,32121001,82192863,82201714)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine,Ferring Pharmaceuticals and the Chinese Academy of Sciences(FIRMC180305)the Program of the Beijing Natural Science Foundation(Z230011)the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CAS-WX2022SDC-XK14,CAS-WX2021SF-0101)New Cornerstone Science Foundation through the XPLORER PRIZE(2021-1045)Youth Innovation Promotion Association of CAS(2022083,E1CAZW0401)Excellent Young Talents Program of Capital Medical University(12300927)the Project for Technology Development of Beijing-affiliated Medical Research Institutes(11000023T000002036310)Excellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher Team(BPHR202203105)Young Elite Scientists Sponsorship Program by CAST(2021QNRC001)The Fellowship of China Postdoctoral Science Foundation(2022M712216).
文摘The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of infertility.However,the molecular basis of ovarian aging in higher vertebrates remains poorly understood.Herein,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries.From a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian aging.Further,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ovary.Moreover,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal outward.Our study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.
基金supported by the National Natural Science Foundation of China(82230067,82061148013,91842105,81821001)Shanghai Science and Technology Committee(20JC1417400,201409005500)+3 种基金the National Key Research and Development Program of China(2018YFA0508000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030101)the CAS Project for Young Scientists in Basic Research(YSBR-074)the Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment(2021B1212040004).
文摘N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.
基金National Natural Science Foundation of China(No.81974508,21974134)Hunan Science Fund for Distinguished Young Scholar of China(No.2021JJ10067)+3 种基金Innovation-Driven Project of Central South University(No.202045005)Hunan Provincial Natural Science Foundation of China(No.2021JJ31066)Key Research Project of Ningxia Hui Autonomous Region in 2021 of China(Major Project)(No.2021BEG01001)Key Program of Ningxia Hui Autonomous Region Natural Science Foundation of China(No.2022JJ21059).
文摘Acute kidney injury(AKI)can lead to loss of kidney function and a substantial increase in mortality.The burst of reactive oxygen species(ROS)plays a key role in the pathological progression of AKI.Mitochondrial-targeted antioxidant therapy is very promising because mitochondria are the main source of ROS in AKI.Antioxidant nanodrugs with actively targeted mitochondria have achieved encouraging success in many oxidative stress-induced diseases.However,most strategies to actively target mitochondria make the size of nanodrugs too large to pass through the glomerular system to reach the renal tubules,the main damage site of AKI.Here,an ultra-small Tungsten-based nanodots(TWNDs)with strong ROS scavenging can be very effective for treatment of AKI.TWNDs can reach the tubular site after crossing the glomerular barrier,and enter the mitochondria of the renal tubule without resorting to complex active targeting strategies.To our knowledge,this is the first time that ultra-small negatively charged nanodots can be used to passively target mitochondrial therapy for AKI.Through in-depth study of the therapeutic mechanism,such passive mitochondria-targeted TWNDs are highly effective in protecting mitochondria by reducing mitochondrial ROS and increasing mitophagy.In addition,TWNDs can also reduce the infiltration of inflammatory cells.This work provides a new way to passively target mitochondria for AKI,and give inspiration for the treatment of many major diseases closely related to mitochondria,such as myocardial infarction and cerebral infarction.
基金supported by the National Key Research and Development Program of China (2020YFA0804000)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16000000)+9 种基金the National Natural Science Foundation of China (81921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82271600,82192863,32000500,82122024,82071588,32000510)the National Key Research and Development Program of China (2018YFC2000100,2018YFA0107203,2020YFA0112200,2021YFF1201005,the STI2030-Major Projects-2021ZD0202400,2022YFA1103700)CAS Project for Young Scientists in Basic Research (YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation (Z190019)K.C.Wong Education Foundation (GJTD-2019-06,GJTD-2019-08)The Pilot Project for Public Welfare Development and Reform of Beijingaffiliated Medical Research Institutes (11000022T000000461062)Youth Innovation Promotion Association of CAS (E1CAzW0401,2022083)Young Elite Scientists Sponsorship Program by CAST (YESS20200012,YESS20210002)the Informatization Plan of Chinese Academy of Sciences (CAS-WX2021SF-0301,CASWX2022SDC-XK14,CAS-WX2021SF-0101)the Tencent Foundation (2021-1045).
文摘Dear Editor,Cells enter senescence,or irreversible growth arrest,when exposed to stressors such as DNA damage,epigenetic alterations and chronic inflammation(Zhao and Chen,2022).In aging and aging-related diseases,senescent cells are known to accumulate across tissues and organs(Sun et al.,2022;Lopez-Otin et al.,2023).
基金supported by the National Key Research and Development Program of China(2018YFC2000100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000)+9 种基金the National Natural Science Foundation of China(8190143281921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,81861168034,81922027,81870228,32100937,31900524,82201727)the National Key Research and Development Program of China(2020YFA0804000,2020YFA0113400,2020YFA0112200,2018YFA0107203,the STI2030-Major Projects-2021ZD0202400,2021YFF1201005,2022YFA1103700,2022YFA1103800)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z190019,JQ20031)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Young Elite Scientists Sponsorship Program by CAST(YESS20200012)Youth Innovation Promotion Association of CAS(EiCAZW0401)the Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(11000022T000000461062)the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CASWX2022SDC-XK14)CAS Special Research Assistant(SRA)Program,and the Tencent Foundation(2021-1045).
文摘Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.
基金supported by the National Key Research-and Development Program of China(2022YFA1103700)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA160000c0)+9 种基金the National Key Research and Development Program of China(2020YFAOB04000,2020YFA0112200,2021YFF1201005,2022YFA1103B00),the STI2030-Major Projects(20212D0202400)the National Natural Science Foundation af China(Grant Nos 81921006,82125011,92149301,9216820191949209,92049304,92049116,32121001,82192863,82122024.82071588,32000500,31900523,82201714,82271600,82201727)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z190019)China Postdoctoral Science Foundation(2022M712216)кC.Wong Education Foundation(GJTD-2019-06 GTD-2019-08)the lot Proje for Publie Welfare Development and Reform of Beijing-affiliated Medical Restarch Institutes(11000022T000000461062)Young Elte Scientists Sponsorship Progran by CAST YESS20000012,YES520210002)Yout Innovation Promotion Association of CAS(E1CAZWO-401,2022083)the Tencent Foundation(2021-1045)the Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CAS-WX2021SF-0101,CAS-WX2022SDC-XK14)Strategic Collaborative Research Program of the Ferring Institute of ReproductiveMedicine,Grant No.FIRMC180305。
文摘The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for spermatogenesis.Collectively,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.
基金supported by the Beijing Municipal Science&Technology Commission(Z221100007422016 and Z221100002722007)the National Natural Science Foundation of China(82171250 and 82030037)+3 种基金the STI2030-Major Projects(2021ZD0201801)the Translational and Application Project of Brain-inspired and Network Neuroscience on Brain Disorders,Beijing Municipal Health Commission(11000023T000002036286)the Beijing Talents Foundation(2017000021223TD03)the Beijing Municipal Health Commission Fund(PXM2020_026283_000005)。
文摘Parkinson's disease(PD)is the second most common neurodegenerative disease,affecting around 1.0%of the population over 65 years of age[1].In China,there are estimated to be more than 3 million PD patients,with each year about 100,000 PD patients being newly diagnosed.Along with China stepping into an aging society,it was estimated that in 2030,there would be around 5 million PD patients in China alone,which would create huge socioeconomic burdens on patients and their families.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16000000)the National Natural Science Foundation of China(Nos.82071588,81921006,82125011,92149301,92168201,92049116,32121001,82192863,91949209,92049304,82122024,82001477,31900523,81861168034,32000500,82271600,82201714)+10 种基金the National Key Research and Development Program of China(Nos.2018YFC2000100,2020YFA0804000,2018YFA0107203,2020YFA0112200,2021YFF1201005,2021ZD0202401,2018YFC2000400,2020YFA0113400,2021YFE0111800,2022YFA1103700)the Program of the Beijing Natural Science Foundation(No.Z190019)K.C.Wong Education Foundation(Nos.GJTD-2019-06,GJTD-2019-08)Beijing Medical Research(2021-8)the Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(No.11000022T000000461062)Young Elite Scientists Sponsorship Program by CAST(Nos.YESS20200012,YESS20210002)CAS Project for Young Scientists in Basic Research(No.YSBR-076,YSBR-012,YSBR-036)Youth Innovation Promotion Association of CAS(Nos.E1CAZW0401,2020085,2022083)the Informatization Plan of Chinese Academy of Sciences(Nos.CAS-WX2022SDC-XK14,CASWX2021SF-0301,CAS-WX2021SF-0101)the Tencent Foundation(No.2021-1045),CAMS Innovation Fund for Medical Sciences(No.2021-12M-1-050)the Fellowship of China Postdoctoral Science Foundation(2022M712216).
文摘Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging.A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types,indicating a higher susceptibility of skeletal muscle fiber to aging.We found a downregulation of Foxo3 in aged primate skeletal muscle,and identi-fied FOxo3 as a hub transcription factor maintaining skeletal muscle homeostasis.Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model,we revealed that silence of Foxo3 accelerates human myotube senescence,whereas genetic activation of endogenous FOxO3 alleviates human myotube aging.Altogether,based on a combination of monkey skeletal muscle and human myotube aging research models,we unraveled the pivotal role of the FOxO3 in safeguarding primate skeletal muscle from aging,providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-relateddisorders.