Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within...Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.展开更多
When mammals are exposed to cold,their metabolism undergoes substantial changes.The liver plays a central role in maintaining energy homeostasis by shifting from glucose metabolism to lipid catabolism.A recent study b...When mammals are exposed to cold,their metabolism undergoes substantial changes.The liver plays a central role in maintaining energy homeostasis by shifting from glucose metabolism to lipid catabolism.A recent study by Davidson et al.^([1]),published in Cell Metabolism,highlights a novel mechanism involving lysosomal lipid remodeling during cold adaptation.Specifically,the study reveals that cold exposure elevates hepatic levels of Bis(Monoacylglycerol)Phosphate(BMP)lipids,which are regulated by Transcription Factor EB(TFEB)and Phospholipase A2 group XV(PLA2G15).展开更多
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases,metabolic disorders,inflammatory conditions,and other related diseases,closely influencing their o...The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases,metabolic disorders,inflammatory conditions,and other related diseases,closely influencing their onset and progression.Therefore,restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management.In this review,we will introduce the lysosomal biogenesis,structure,and function,as well as the biological process of the autophagy-lysosome system.Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed,emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment.Finally,we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system,and summarize different strategies and methods for achieving this goal.This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.展开更多
Small interfering RNAs(siRNA)provide a novel and highly specific therapy due to their ability to effectively silence target genes,to date six siRNA therapeutics are approved for clinical use.Even so,some critical chal...Small interfering RNAs(siRNA)provide a novel and highly specific therapy due to their ability to effectively silence target genes,to date six siRNA therapeutics are approved for clinical use.Even so,some critical challenges remain to overcome in the therapeutic application of siRNAs,with delivery issues at the forefront.Among them,endo/lysosomal barrier is one of the important but often-neglected limitations hindering the delivery of siRNA therapeutics.In this review,we summarize the promising strategies that facilitate siRNAs overcoming endo/lysosomal barriers based on the cellular uptake and intracellular transport pathways,including promoting escape once endocytosis into the endo/lysosomes and bypassing lysosomes via endosome-Golgi-endoplasmic reticulum(ER)pathway or nonendocytosis pathway,and discuss the principal considerations and the future directions of promoting endo/lysosomal escape in the development of therapeutic siRNAs.展开更多
Lysosomal acid lipase-deficiency(LAL-D)is a rare and systemic condition,secondary to lipase A gene mutations,responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues.It is a very ...Lysosomal acid lipase-deficiency(LAL-D)is a rare and systemic condition,secondary to lipase A gene mutations,responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues.It is a very heterogeneous disease in terms of the age of onset,severity,and the type of clinical and radiological manifestations.Dyslipidemia,hepatomegaly,and hepatosteatosis with increased levels of transaminases are the most common features.In association with liver dysfunction and evolution to cirrhosis,there is an increased risk of premature atherosclerosis and cardiovascular disorders,secondary to a generalized alteration of lipid profile and lipoprotein dysfunction associated with LAL-D.Therefore,we provide an update on the frequently under-recognized LAL-D,focusing on the late-onset form:Cholesteryl ester storage disease.展开更多
Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the target...Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes;however,the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability,cytosolic delivery and subsequent therapeutic efficacy.In this case,the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo/lysosomal escape,which relies on the development of safe and efficient nanodelivery systems.A deeper mechanistic understanding in the endo/lysosomal escape will guide the development of more efficient nano-delivery systems.In this review,we summarize various mechanisms by which nanoparticles escape from the endo/lysosome,and showcase the recent progress in dissecting the endo/lysosomal approaches based on nano-delivery systems.Emphasis will lie on the properties of nanoparticles that govern the endo/lysosomal escape pathway as well as the latest promising applications in vaccine delivery and genetic engineering field.展开更多
Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into mul...Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.展开更多
Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-tar...Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes,creating a deprotonated environment.This environment allows drugs to bypass protonation issues in lysosomes,thereby reversing drug resistance and improving therapeutic efficacy.As a proof of concept,a quaternary ammonium salt-based pH indicator was developed,berberrubine(BRB),enhancing the action of the anticancer drug hydroxycamptothecin(HCPT)in resistant cells.BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity,enabling HCPT to bypass protonation constraints.This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells,providing an innovative approach to address drug resistance and advancing therapeutic technologies.展开更多
Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma(COAD),yet the prognostic significance and therapeutic potential of lysosome-related genes(LRGs)remain underexplored.In this study,we...Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma(COAD),yet the prognostic significance and therapeutic potential of lysosome-related genes(LRGs)remain underexplored.In this study,we construct a 6-LRG-based prognostic risk stratification model(DPP7,ADAM8,CD1B,LRP2,ATP6V1C2,and PLAAT3)by integrating LASSO and Cox regression analyses.Stratifying patients based on median risk scores,we demonstrate that high-risk patients exhibit significantly worse clinical outcomes across the TCGA cohort and five independent GEO datasets.Furthermore,this panel outperforms 136 previously published models in terms of predictive accuracy for 1-,3-,and 5-year survival rates.Validation multiplex immunofluorescence using an in-house tissue microarray cohort confirms that the 6-LRG signature serves as an independent prognostic factor.Additionally,high-risk patients exhibit distinct immunosuppressive tumor microenvironment and aggressive malignancy characteristics.Functional depletion of DPP7 significantly inhibits tumor cell proliferation,migration,and metastasis in both in vitro and in vivo settings.Moreover,DPP7 silencing attenuates epithelialemesenchymal transition,as evidenced by the upregulation of E-cadherin and downregulation of N-cadherin,Vimentin,and Snail.In conclusion,this study establishes an LRG-based model for COAD prognostic prediction and nominates DPP7 as a promising therapeutic target for COAD treatment.展开更多
Objective:To evaluate the efficacy of boswellic acid against monosodium urate crystal-induced inflammation in mice.Methods:The mice were divided into four experimental groups.GroupⅠserved as control;mice in groupⅡwe...Objective:To evaluate the efficacy of boswellic acid against monosodium urate crystal-induced inflammation in mice.Methods:The mice were divided into four experimental groups.GroupⅠserved as control;mice in groupⅡwere injected with monosodium urate crystal;groupⅢconsisted of monosodium urate crystal-induced mice who were treated with boswellic acid(30mg/kg/b.w.);groupⅣcomprised monosodium urate crystal-induced mice who were treated with indomethacin(3mg/kg/b.w.).Paw volume and levels/activities of lysosomal enzymes,lipid peroxidation,anti-oxidant status and inflammatory mediator TNF-αwere determined in control and monosodium urate crystal-induced mice.In addition,the levels ofβ-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes(PMNL)in vitro.Results:The activities of lysosomal enzymes,lipid peroxidation,and tumour necrosis factor-αlevels and paw volume were increased significantly in monosodium urate crystal-induced mice,whereas the activities of antioxidant status were in turn decreased.However,these changes were modulated to near normal levels upon boswellic acid administration.In vitro,boswellic acid reduced the level ofβ-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated PMNL in concentration dependent manner when compared with control cells.Conclusions:The results obtained in this study further strengthen the anti-inflammatory/antiarthritic effect of boswellic acid,which was already well established by several investigators.展开更多
AIM To investigate the capability of salvianolic acid B(Sal B) to protect hepatocytes from hydrogen peroxide(H_2O_2)/carbon tetrachloride(CCl_4)-induced lysosomal membrane permeabilization. METHODS Cell Counting Kit-8...AIM To investigate the capability of salvianolic acid B(Sal B) to protect hepatocytes from hydrogen peroxide(H_2O_2)/carbon tetrachloride(CCl_4)-induced lysosomal membrane permeabilization. METHODS Cell Counting Kit-8 assay was used to measure cell viability. Apoptosis and death were assayed through flow cytometry. Brd U incorporation was used to detect cell proliferation. Serum alanine aminotransferase activity and liver malondialdehyde(MDA) content were measured. Liver histopathological changes were evaluated using hematoxylin-eosin staining. Lysosomal membrane permeability was detected with Lyso Tracker Green-labeled probes and acridine orange staining. The levels of protein carbonyl content(PCC), cathepsins(Cat)B/D, and lysosome-associated membrane protein 1(LAMP1) were evaluated through western blotting. Cytosol Cat B activity analysis was performed with chemiluminescence detection. The m RNA level ofLAMP1 was evaluated through quantitative real-time polymerase chain reaction. RESULTS Results indicated that H_2O_2 induced cell injury/death. Sal B attenuated H_2O_2-induced cell apoptosis and death, restored the inhibition of proliferation, decreased the amount of PCC, and stabilized the lysosome membrane by increasing the LAMP1 protein level and antagonizing Cat B/D leakage into the cytosol. CCl_4 also triggered hepatocyte death. Furthermore, Sal B effectively rescued hepatocytes by increasing LAMP1 expression and by reducing lysosomal enzyme translocation to the cytosol.CONCLUSION Sal B protected mouse embryonic hepatocytes from H_2O_2/CCl_4-induced injury/death by stabilizing the lysosomal membrane.展开更多
Lysosomal acid lipase(LAL)plays a key role in intracellular lipid metabolism.Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage,as observed in two recessive autosomal genetic disea...Lysosomal acid lipase(LAL)plays a key role in intracellular lipid metabolism.Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage,as observed in two recessive autosomal genetic diseases,Wolman disease and Cholesterol ester storage disease.Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency.By contrast,few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene.In the last few years,a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease(NAFLD),suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease.Patients with NAFLD show a significant,progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis.Among cirrhosis of different etiologies,those with cryptogenic cirrhosis show the most significant reductions of LAL activity.These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD.Moreover,the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.展开更多
Lysosomal storage disorders(LSD)are a rare group of genetic disorders.The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage[Gaucher disease(GD)and Niemann-Pick disease]and lysosomal a...Lysosomal storage disorders(LSD)are a rare group of genetic disorders.The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage[Gaucher disease(GD)and Niemann-Pick disease]and lysosomal acid lipase deficiency[cholesteryl ester storage disease and Wolman disease(WD)].These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension.Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders.Dyslipidemia causes micronodular cirrhosis in lipid storage disorders.These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults.GD,Niemann-Pick type C,and WD also cause neonatal cholestasis and infantile liver failure.Genotype and liver phenotype correlation is variable in these conditions.Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease.The diagnosis of all LSD is based on enzymatic activity,tissue histology,and genetic testing.Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome.Those that progress invariably require liver transplantation with variable outcomes.The prognosis of Niemann-Pick type C and WD is universally poor.Enzyme replacement therapy has a promising role in cholesteryl ester storage disease.This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.展开更多
Autophagy plays a vital role in maintaining the balance of normal physiological state of living cells.In this paper,a polarity-specific two-phot on fluorescent probe Lyso-NA based on naphthalimide was synthesized for ...Autophagy plays a vital role in maintaining the balance of normal physiological state of living cells.In this paper,a polarity-specific two-phot on fluorescent probe Lyso-NA based on naphthalimide was synthesized for the purpose of monitoring autophagy during biological research.The results of photophysical properties and theoretical calculation con firmed that different polarities of solvents mainly effected fluorescent intensities of probe.Fluoresce nt intensity,quantum yield and fluorescence lifetime of probe kept a good linear relationship with polarity respectively.In addition,due to its low toxicity and selective accumulation in lysosomes,Lyso-NA is suitable for detecting changes in lysosomal polarity of living cells.Compare with the imaging results of plasmid transfection,a better performed realtime long-term fluoresce nt visualization of autophagy in living cells was achieved.Probe Lyso-NA can work as an efficient and cost effective imaging tool for visualizing autophagy in living cells.展开更多
The normal operation of lysosome, mitochondria, Golgi apparatus and endoplasmic reticulum plays a significant role in maintaining cell homeostasis. Reflecting the state and function of lysosomes, viscosity is a pivota...The normal operation of lysosome, mitochondria, Golgi apparatus and endoplasmic reticulum plays a significant role in maintaining cell homeostasis. Reflecting the state and function of lysosomes, viscosity is a pivotal parameter to assess the stability of microenvironment. Herein, based on TICT mechanism,a new NIR pH-dependent fluorescent probe DCIC with push-pull electronic moiety was synthesized to identify the lysosomes viscosity. In viscous media, DCIC was highly sensitive to viscosity, fluorescence intensity increased by 180 times as viscosity increased from 1.0 cp to 438.4 cp. In addition, DCIC have high localization ability for lysosome, mitochondria, Golgi apparatus, and endoplasmic reticulum and can monitor lysosomal viscosity fluctuations with laser confocal microscopy.展开更多
AIM： To establish whether there are fundamental differences in the biochemistries of adenocarcinomas of the gastroesophageal junction （GEJ） and the squamous cell carcinomas of the lower third of the esophagus （LTE...AIM： To establish whether there are fundamental differences in the biochemistries of adenocarcinomas of the gastroesophageal junction （GEJ） and the squamous cell carcinomas of the lower third of the esophagus （LTE）. METHODS： Between February 1, 1997 and February 1, 2000, we obtained tissue samples at the moment of resection from 54 patients for biochemical analysis. The full set of data could be comprehensively analyzed in 47 of 54 patients＇ samples （81%）. Of these, 29 were adenocarcinomas of the GEJ Siewert type Ⅰ （n = 8）, type Ⅱ （n = 12）, type Ⅲ （n = 9）, and 18 presented as squamous cell carcinomas of the LTE. We evaluated the mean values of 11-lysosomal enzyme and 1-cytosol protease activities of the tumorous and surrounding mucosae as well as their relative activities, measured as the ratio of activity in tumor and normal tissues from the same patient. These data were further analyzed to establish the correlation with tumor localization, TNM stage （lymph-node involvement）, histological type （papillary, signet-ring cell, tubular）, state of differentiation （good, moderate, poor）, and survival （≤24 or ≥24 mo）. RESULTS： In adenocarcinomas, the activity of α-mannosidase （AMAN）, cathepsin B （CB） and dipeptidyl-peptidase Ⅰ （DPP Ⅰ） increased significantly as compared to the normal gastric mucosa. In squamous cell carcinomas of the esophagus, we also found a significant difference in the activity of cathepsin L and tripeptidyl-peptidase Ⅰ in addition to these three. There was a statistical correlation of AMAN, CB, and DPP Ⅰ activity between the level of differentiation of adenocarcinomas of the GEJ and lymph node involvement,because tumors with no lymph node metastases histologically confirmed as well-differentiated, showed a significantly lower activity. The differences in CB and DPP Ⅰ activity correlated well with the differences in survival rates, since the CB and DPP Ⅰ values of those who died within 24 mo following surgical intervention were significantly higher than of those who survived for 2 years or more. CONCLUSION： Adenocarcinomas of the GEJ form a homogenous group from a tumor-biochemical aspect, and differ from the biochemical characteristics of squamous cell carcinomas of the LTE on many points. When adenocarcinomas of the GEJs are examined at the preoperative phase, the ratio of the performed AMAN, CB, and DPP Ⅰ enzymatic activity of the tissue sample from the tumor and adjacent intact mucosa within 2 cm of the tumor may have a prognostic value even in the preoperative examination period, and may indicate that ranking of these patients into the neo-adjuvant treatment group should be considered.展开更多
Benzo[4,5]imidazo[1,2-a]pyrimidine-based derivatives play crucial roles in medicines,pesticides,tracers and photoelectric materials.However,their synthesis approach still needs to be optimized,and their fluorescent pr...Benzo[4,5]imidazo[1,2-a]pyrimidine-based derivatives play crucial roles in medicines,pesticides,tracers and photoelectric materials.However,their synthesis approach still needs to be optimized,and their fluorescent properties in intracellular microenvironment are unclear.Here,a Cu(II)-catalyzed cascade coupling cyclization reaction was successfully developed to synthesize benzo[4,5]imidazo[1,2-a]pyrimidine scaffold with mild reaction conditions,broad substrate scopes and high yields.After a system study,we found that compound 4aa displayed an optimal viscosity-specific response with remarkable fluorescence enhancement(102-fold)for glycerol at 490 nm.Particularly,4aa possessed excellent structure-inherent targeting(SIT)capability for lysosome(P=0.95)with high p H stability and large Stokes shift.Importantly,4aa was validated for its effectiveness in diagnosing lysosomal storage disorders(LSD)in living cells.The 4aa also showed its potential to map the micro-viscosity and its metabolism process in zebrafish.This work not only affords an efficient protocol to fabricate benzo[4,5]imidazo[1,2-a]pyrimidine derivatives,reveals this skeleton has excellent SIT features for lysosome,but also manifests that 4aa can serve as a practical tool to monitor lysosomal viscosity and diagnose LSD.展开更多
Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials,playing a pivotal role in maintaining cellular homeostasis.Their acidic environment,maintained by numerous ...Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials,playing a pivotal role in maintaining cellular homeostasis.Their acidic environment,maintained by numerous hydrolytic enzymes,facilitates substrate degradation.Dysfunction in lysosomal processes can lead to abnormal substrate degradation,significantly impacting cellular homeostasis.High energy-demanding cells,such as post-mitotic neurons,are especially vulnerable to these changes,often resulting in neurological diseases.Autophagy,a conserved catabolic process,requires extensive lysosomal utilization.It plays a key role in removing unnecessary intracellular components,ensuring cellular homeostasis,and promoting cell survival during stress conditions such as starvation,infection,or cellular damage.展开更多
Euphopepluanones F−K(1−4),four new jatrophane type diterpenoids were isolated from the seeds of Euphorbia peplus,along with eight known diterpenoids(5−12).Their structures were established on the basis of extensive sp...Euphopepluanones F−K(1−4),four new jatrophane type diterpenoids were isolated from the seeds of Euphorbia peplus,along with eight known diterpenoids(5−12).Their structures were established on the basis of extensive spectroscopic analysis and X-ray crystallographic experiments.The new compounds 1−4 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining.Compound 2 significantly induced lysosomal biogenesis.In addi-tion,compound 2 could increase the number of LC3 dots,indicating that it could activate the lysosomal-autophagy pathway.展开更多
基金supported by the Natural Science Foundation of Shanghai,No.22ZR147750Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission,No.23Y11906600Shanghai Changzheng Hospital Innovative Clinical Research Project,No.2020YLCYJ-Y02(all to YY).
文摘Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.
文摘When mammals are exposed to cold,their metabolism undergoes substantial changes.The liver plays a central role in maintaining energy homeostasis by shifting from glucose metabolism to lipid catabolism.A recent study by Davidson et al.^([1]),published in Cell Metabolism,highlights a novel mechanism involving lysosomal lipid remodeling during cold adaptation.Specifically,the study reveals that cold exposure elevates hepatic levels of Bis(Monoacylglycerol)Phosphate(BMP)lipids,which are regulated by Transcription Factor EB(TFEB)and Phospholipase A2 group XV(PLA2G15).
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金supported by the Taishan Scholars Program of Shandong Province(No.tsqn202103112)the Shandong Provincial Natural Science Foundation(No.ZR2021QB202)+2 种基金the Development Plan of Youth Innovation Team in Colleges and Universities of Shandong Province(No.2021KJ052)the Shandong-Chongqing Science and Technology Cooperation Project for Technological Innovation and Application Development(No.CSTB2023TIAD-LDX0015)the Supporting Fund for Leading Talents above Provincial Level in Yantai,China.
文摘The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases,metabolic disorders,inflammatory conditions,and other related diseases,closely influencing their onset and progression.Therefore,restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management.In this review,we will introduce the lysosomal biogenesis,structure,and function,as well as the biological process of the autophagy-lysosome system.Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed,emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment.Finally,we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system,and summarize different strategies and methods for achieving this goal.This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.
基金supported by National Natural Science Foundation of China(No.82173769)the National Key R&D Program of China(No.2021YFE0106900)+1 种基金Applied Basic Research Multiinvestment Foundation of Tianjin(No.21JCYBJC01540)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(No.2023ZD019)。
文摘Small interfering RNAs(siRNA)provide a novel and highly specific therapy due to their ability to effectively silence target genes,to date six siRNA therapeutics are approved for clinical use.Even so,some critical challenges remain to overcome in the therapeutic application of siRNAs,with delivery issues at the forefront.Among them,endo/lysosomal barrier is one of the important but often-neglected limitations hindering the delivery of siRNA therapeutics.In this review,we summarize the promising strategies that facilitate siRNAs overcoming endo/lysosomal barriers based on the cellular uptake and intracellular transport pathways,including promoting escape once endocytosis into the endo/lysosomes and bypassing lysosomes via endosome-Golgi-endoplasmic reticulum(ER)pathway or nonendocytosis pathway,and discuss the principal considerations and the future directions of promoting endo/lysosomal escape in the development of therapeutic siRNAs.
文摘Lysosomal acid lipase-deficiency(LAL-D)is a rare and systemic condition,secondary to lipase A gene mutations,responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues.It is a very heterogeneous disease in terms of the age of onset,severity,and the type of clinical and radiological manifestations.Dyslipidemia,hepatomegaly,and hepatosteatosis with increased levels of transaminases are the most common features.In association with liver dysfunction and evolution to cirrhosis,there is an increased risk of premature atherosclerosis and cardiovascular disorders,secondary to a generalized alteration of lipid profile and lipoprotein dysfunction associated with LAL-D.Therefore,we provide an update on the frequently under-recognized LAL-D,focusing on the late-onset form:Cholesteryl ester storage disease.
基金support from the Postdoctoral Fellowship Scheme of The Chinese University of Hong Kong,the Postdoctoral Fellowship Program of CPSF(GZC20241828)The China Postdoctoral Science Foundation(2024M763416).
文摘Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes;however,the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability,cytosolic delivery and subsequent therapeutic efficacy.In this case,the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo/lysosomal escape,which relies on the development of safe and efficient nanodelivery systems.A deeper mechanistic understanding in the endo/lysosomal escape will guide the development of more efficient nano-delivery systems.In this review,we summarize various mechanisms by which nanoparticles escape from the endo/lysosome,and showcase the recent progress in dissecting the endo/lysosomal approaches based on nano-delivery systems.Emphasis will lie on the properties of nanoparticles that govern the endo/lysosomal escape pathway as well as the latest promising applications in vaccine delivery and genetic engineering field.
基金funded by the National Natural Science Foundation of China(81902815,81802786)the Natural Science Foundation of Shandong Province(ZR2023MH011,ZR2019BH044,ZR2018BH025).
文摘Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.
基金supported by Young Elite Scientists Sponsorship Program by China Association for Science and Technology(No.CACM-2023-QNRC1–02)Shandong Province Key R&D Program(Major Technological Innovation Project)(No.2021CXGC010501)+6 种基金National Natural Science Foundation of China(No.22107059)Natural Science Foundation of Shandong Province(No.ZR2021QH057)Program for Youth Innovation Technology in Colleges and Universities of Shandong Province of China(No.2021KJ035)Taishan Scholars Program(No.TSQN202211221)Shandong Science Fund for Excellent Young Scholars(No.ZR2022YQ66)Funded by Shandong Postdoctoral Science Foundation(No.SDCX-ZG-202400084)the National Administration of Traditional Chinese Medicine Young Qihuang Scholar Project。
文摘Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes,creating a deprotonated environment.This environment allows drugs to bypass protonation issues in lysosomes,thereby reversing drug resistance and improving therapeutic efficacy.As a proof of concept,a quaternary ammonium salt-based pH indicator was developed,berberrubine(BRB),enhancing the action of the anticancer drug hydroxycamptothecin(HCPT)in resistant cells.BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity,enabling HCPT to bypass protonation constraints.This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells,providing an innovative approach to address drug resistance and advancing therapeutic technologies.
基金supported by the Natural Science Foundation of Shandong Province(ZR2021MH110,ZR2020MH257,ZR2020MH323)the National Natural Science Foundation of China(82172339 and 82272410)+1 种基金Major Scientific and Technological Innovation Project of Shandong Province(2021CXGC010603 and 2021CXGC011105)Taishan Scholar Program of Shandong Province(tstp20221156 and tsqn202306346).
文摘Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma(COAD),yet the prognostic significance and therapeutic potential of lysosome-related genes(LRGs)remain underexplored.In this study,we construct a 6-LRG-based prognostic risk stratification model(DPP7,ADAM8,CD1B,LRP2,ATP6V1C2,and PLAAT3)by integrating LASSO and Cox regression analyses.Stratifying patients based on median risk scores,we demonstrate that high-risk patients exhibit significantly worse clinical outcomes across the TCGA cohort and five independent GEO datasets.Furthermore,this panel outperforms 136 previously published models in terms of predictive accuracy for 1-,3-,and 5-year survival rates.Validation multiplex immunofluorescence using an in-house tissue microarray cohort confirms that the 6-LRG signature serves as an independent prognostic factor.Additionally,high-risk patients exhibit distinct immunosuppressive tumor microenvironment and aggressive malignancy characteristics.Functional depletion of DPP7 significantly inhibits tumor cell proliferation,migration,and metastasis in both in vitro and in vivo settings.Moreover,DPP7 silencing attenuates epithelialemesenchymal transition,as evidenced by the upregulation of E-cadherin and downregulation of N-cadherin,Vimentin,and Snail.In conclusion,this study establishes an LRG-based model for COAD prognostic prediction and nominates DPP7 as a promising therapeutic target for COAD treatment.
文摘Objective:To evaluate the efficacy of boswellic acid against monosodium urate crystal-induced inflammation in mice.Methods:The mice were divided into four experimental groups.GroupⅠserved as control;mice in groupⅡwere injected with monosodium urate crystal;groupⅢconsisted of monosodium urate crystal-induced mice who were treated with boswellic acid(30mg/kg/b.w.);groupⅣcomprised monosodium urate crystal-induced mice who were treated with indomethacin(3mg/kg/b.w.).Paw volume and levels/activities of lysosomal enzymes,lipid peroxidation,anti-oxidant status and inflammatory mediator TNF-αwere determined in control and monosodium urate crystal-induced mice.In addition,the levels ofβ-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes(PMNL)in vitro.Results:The activities of lysosomal enzymes,lipid peroxidation,and tumour necrosis factor-αlevels and paw volume were increased significantly in monosodium urate crystal-induced mice,whereas the activities of antioxidant status were in turn decreased.However,these changes were modulated to near normal levels upon boswellic acid administration.In vitro,boswellic acid reduced the level ofβ-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated PMNL in concentration dependent manner when compared with control cells.Conclusions:The results obtained in this study further strengthen the anti-inflammatory/antiarthritic effect of boswellic acid,which was already well established by several investigators.
基金Supported by National Natural Science Funds of China,No.81503367the Budget Research Project of Shanghai Education Commission,No.2014YSN03 and No.2014YSN22
文摘AIM To investigate the capability of salvianolic acid B(Sal B) to protect hepatocytes from hydrogen peroxide(H_2O_2)/carbon tetrachloride(CCl_4)-induced lysosomal membrane permeabilization. METHODS Cell Counting Kit-8 assay was used to measure cell viability. Apoptosis and death were assayed through flow cytometry. Brd U incorporation was used to detect cell proliferation. Serum alanine aminotransferase activity and liver malondialdehyde(MDA) content were measured. Liver histopathological changes were evaluated using hematoxylin-eosin staining. Lysosomal membrane permeability was detected with Lyso Tracker Green-labeled probes and acridine orange staining. The levels of protein carbonyl content(PCC), cathepsins(Cat)B/D, and lysosome-associated membrane protein 1(LAMP1) were evaluated through western blotting. Cytosol Cat B activity analysis was performed with chemiluminescence detection. The m RNA level ofLAMP1 was evaluated through quantitative real-time polymerase chain reaction. RESULTS Results indicated that H_2O_2 induced cell injury/death. Sal B attenuated H_2O_2-induced cell apoptosis and death, restored the inhibition of proliferation, decreased the amount of PCC, and stabilized the lysosome membrane by increasing the LAMP1 protein level and antagonizing Cat B/D leakage into the cytosol. CCl_4 also triggered hepatocyte death. Furthermore, Sal B effectively rescued hepatocytes by increasing LAMP1 expression and by reducing lysosomal enzyme translocation to the cytosol.CONCLUSION Sal B protected mouse embryonic hepatocytes from H_2O_2/CCl_4-induced injury/death by stabilizing the lysosomal membrane.
文摘Lysosomal acid lipase(LAL)plays a key role in intracellular lipid metabolism.Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage,as observed in two recessive autosomal genetic diseases,Wolman disease and Cholesterol ester storage disease.Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency.By contrast,few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene.In the last few years,a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease(NAFLD),suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease.Patients with NAFLD show a significant,progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis.Among cirrhosis of different etiologies,those with cryptogenic cirrhosis show the most significant reductions of LAL activity.These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD.Moreover,the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.
文摘Lysosomal storage disorders(LSD)are a rare group of genetic disorders.The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage[Gaucher disease(GD)and Niemann-Pick disease]and lysosomal acid lipase deficiency[cholesteryl ester storage disease and Wolman disease(WD)].These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension.Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders.Dyslipidemia causes micronodular cirrhosis in lipid storage disorders.These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults.GD,Niemann-Pick type C,and WD also cause neonatal cholestasis and infantile liver failure.Genotype and liver phenotype correlation is variable in these conditions.Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease.The diagnosis of all LSD is based on enzymatic activity,tissue histology,and genetic testing.Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome.Those that progress invariably require liver transplantation with variable outcomes.The prognosis of Niemann-Pick type C and WD is universally poor.Enzyme replacement therapy has a promising role in cholesteryl ester storage disease.This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.
基金This work was supported by the National Natural Science Foundation of China(Nos.22077001,21778001 and 21672001)the Natural Science Foundation of Anhui Province(No.2008085J08)+2 种基金the Natural Science Foundation of Education Department of Anhui Province(No.KJ2019A0010)Joint Open Fund of Jiangsu Collaborative Innovation Center for Ecological Building Material and Environmental Protection Equipments,Key Laboratory for Advanced Technology in Environmental Protection of Jiangsu Province(No.JH201803)the Open fund for Discipline Construction in Institute of Physical Science and In formation Technology of Anhui University.
文摘Autophagy plays a vital role in maintaining the balance of normal physiological state of living cells.In this paper,a polarity-specific two-phot on fluorescent probe Lyso-NA based on naphthalimide was synthesized for the purpose of monitoring autophagy during biological research.The results of photophysical properties and theoretical calculation con firmed that different polarities of solvents mainly effected fluorescent intensities of probe.Fluoresce nt intensity,quantum yield and fluorescence lifetime of probe kept a good linear relationship with polarity respectively.In addition,due to its low toxicity and selective accumulation in lysosomes,Lyso-NA is suitable for detecting changes in lysosomal polarity of living cells.Compare with the imaging results of plasmid transfection,a better performed realtime long-term fluoresce nt visualization of autophagy in living cells was achieved.Probe Lyso-NA can work as an efficient and cost effective imaging tool for visualizing autophagy in living cells.
基金financial supports from Scientific and Technological Key Project in Henan Province(No.22170015)National Natural Science Foundation of China(No.U1704161)+1 种基金Zhengzhou University(No.32211807)Henan Provincial Science and Technology Research Project(No.JC21253010)。
文摘The normal operation of lysosome, mitochondria, Golgi apparatus and endoplasmic reticulum plays a significant role in maintaining cell homeostasis. Reflecting the state and function of lysosomes, viscosity is a pivotal parameter to assess the stability of microenvironment. Herein, based on TICT mechanism,a new NIR pH-dependent fluorescent probe DCIC with push-pull electronic moiety was synthesized to identify the lysosomes viscosity. In viscous media, DCIC was highly sensitive to viscosity, fluorescence intensity increased by 180 times as viscosity increased from 1.0 cp to 438.4 cp. In addition, DCIC have high localization ability for lysosome, mitochondria, Golgi apparatus, and endoplasmic reticulum and can monitor lysosomal viscosity fluctuations with laser confocal microscopy.
文摘AIM： To establish whether there are fundamental differences in the biochemistries of adenocarcinomas of the gastroesophageal junction （GEJ） and the squamous cell carcinomas of the lower third of the esophagus （LTE）. METHODS： Between February 1, 1997 and February 1, 2000, we obtained tissue samples at the moment of resection from 54 patients for biochemical analysis. The full set of data could be comprehensively analyzed in 47 of 54 patients＇ samples （81%）. Of these, 29 were adenocarcinomas of the GEJ Siewert type Ⅰ （n = 8）, type Ⅱ （n = 12）, type Ⅲ （n = 9）, and 18 presented as squamous cell carcinomas of the LTE. We evaluated the mean values of 11-lysosomal enzyme and 1-cytosol protease activities of the tumorous and surrounding mucosae as well as their relative activities, measured as the ratio of activity in tumor and normal tissues from the same patient. These data were further analyzed to establish the correlation with tumor localization, TNM stage （lymph-node involvement）, histological type （papillary, signet-ring cell, tubular）, state of differentiation （good, moderate, poor）, and survival （≤24 or ≥24 mo）. RESULTS： In adenocarcinomas, the activity of α-mannosidase （AMAN）, cathepsin B （CB） and dipeptidyl-peptidase Ⅰ （DPP Ⅰ） increased significantly as compared to the normal gastric mucosa. In squamous cell carcinomas of the esophagus, we also found a significant difference in the activity of cathepsin L and tripeptidyl-peptidase Ⅰ in addition to these three. There was a statistical correlation of AMAN, CB, and DPP Ⅰ activity between the level of differentiation of adenocarcinomas of the GEJ and lymph node involvement,because tumors with no lymph node metastases histologically confirmed as well-differentiated, showed a significantly lower activity. The differences in CB and DPP Ⅰ activity correlated well with the differences in survival rates, since the CB and DPP Ⅰ values of those who died within 24 mo following surgical intervention were significantly higher than of those who survived for 2 years or more. CONCLUSION： Adenocarcinomas of the GEJ form a homogenous group from a tumor-biochemical aspect, and differ from the biochemical characteristics of squamous cell carcinomas of the LTE on many points. When adenocarcinomas of the GEJs are examined at the preoperative phase, the ratio of the performed AMAN, CB, and DPP Ⅰ enzymatic activity of the tissue sample from the tumor and adjacent intact mucosa within 2 cm of the tumor may have a prognostic value even in the preoperative examination period, and may indicate that ranking of these patients into the neo-adjuvant treatment group should be considered.
基金supported by the National Natural Science Foundation of China(Nos.22077099,22171223 and 22307102)the Innovation Capability Support Program of Shaanxi(Nos.2023-CXTD-75 and 2022KJXX-32)+5 种基金the Technology Innovation Leading Program of Shaanxi(Nos.2023KXJ-209 and 2024QCY-KXJ-142)the Key Research and Development Program of Shaanxi(No.2024GHZDXM-22)the Natural Science Basic Research Program of Shaanxi(Nos.2023-JC-YB-141 and 2022JQ-151)Young Talent Fund of Association for Science and Technology in Shaanxi,China(No.SWYY202206)the Shaanxi Fundamental Science Research Project for Chemistry&Biology(Nos.22JHZ010 and 22JHQ080)the Yan’an City Science and Technology Project(No.2022SLZDCY-002)。
文摘Benzo[4,5]imidazo[1,2-a]pyrimidine-based derivatives play crucial roles in medicines,pesticides,tracers and photoelectric materials.However,their synthesis approach still needs to be optimized,and their fluorescent properties in intracellular microenvironment are unclear.Here,a Cu(II)-catalyzed cascade coupling cyclization reaction was successfully developed to synthesize benzo[4,5]imidazo[1,2-a]pyrimidine scaffold with mild reaction conditions,broad substrate scopes and high yields.After a system study,we found that compound 4aa displayed an optimal viscosity-specific response with remarkable fluorescence enhancement(102-fold)for glycerol at 490 nm.Particularly,4aa possessed excellent structure-inherent targeting(SIT)capability for lysosome(P=0.95)with high p H stability and large Stokes shift.Importantly,4aa was validated for its effectiveness in diagnosing lysosomal storage disorders(LSD)in living cells.The 4aa also showed its potential to map the micro-viscosity and its metabolism process in zebrafish.This work not only affords an efficient protocol to fabricate benzo[4,5]imidazo[1,2-a]pyrimidine derivatives,reveals this skeleton has excellent SIT features for lysosome,but also manifests that 4aa can serve as a practical tool to monitor lysosomal viscosity and diagnose LSD.
文摘Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials,playing a pivotal role in maintaining cellular homeostasis.Their acidic environment,maintained by numerous hydrolytic enzymes,facilitates substrate degradation.Dysfunction in lysosomal processes can lead to abnormal substrate degradation,significantly impacting cellular homeostasis.High energy-demanding cells,such as post-mitotic neurons,are especially vulnerable to these changes,often resulting in neurological diseases.Autophagy,a conserved catabolic process,requires extensive lysosomal utilization.It plays a key role in removing unnecessary intracellular components,ensuring cellular homeostasis,and promoting cell survival during stress conditions such as starvation,infection,or cellular damage.
基金This research was supported by the National Natural Science Foundation of China under Grant(Numbers 21432010,31872666,82073740)National Key R&D Program of China under Grant(Number 2018YFA0900600)+2 种基金Technological leading talent project of Yunnan(2015HA020)Special Fund for Talent Introduction of Kunming Institute of Botany,CAS(to Xin Fang)and Key R&D Program of Yunnan under Grant(2019ZF011-2).
文摘Euphopepluanones F−K(1−4),four new jatrophane type diterpenoids were isolated from the seeds of Euphorbia peplus,along with eight known diterpenoids(5−12).Their structures were established on the basis of extensive spectroscopic analysis and X-ray crystallographic experiments.The new compounds 1−4 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining.Compound 2 significantly induced lysosomal biogenesis.In addi-tion,compound 2 could increase the number of LC3 dots,indicating that it could activate the lysosomal-autophagy pathway.
