Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.Ho...Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.展开更多
Concern about the biological hazards involved in microbiological research, especially research involving laboratory animals, has increased in recent years. Working in an animal biosafety level 2 facility （ABSL-2）, c...Concern about the biological hazards involved in microbiological research, especially research involving laboratory animals, has increased in recent years. Working in an animal biosafety level 2 facility （ABSL-2）, commonly used for research on infectious diseases, poses various biological hazards. Here, the regulations and standards related to laboratory biosafety in China are introduced, the potential biological hazards present in ABSL-2 facilities are analyzed, and a series of strategies to control the hazards are presented.展开更多
Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society bec...Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society because of the ethical issue. This paper takes Wenzhou Medical University as an example to give a brief introduction to the ethical review about laboratory animals in the university so as to further draw attention and concerns from the public about the ethical issue of laboratory animals. We successively introduce its scientific projects, nurturing environment and ethical review of laboratory animals.展开更多
The supply and demand of laboratory animals for teaching in colleges and universities has its own internal characteristics.To grasp the supply and demand characteristics of laboratory animals for teaching is of vital ...The supply and demand of laboratory animals for teaching in colleges and universities has its own internal characteristics.To grasp the supply and demand characteristics of laboratory animals for teaching is of vital importance to the planning,supply and use of teaching animals,the realization of teaching objectives and the completion of teaching tasks.Based on the supply of teaching experimental animals and the work of animal experimental teaching in our university in recent years,this paper expounds the inherent characteristics and practice of supply and demand of teaching experimental animals.展开更多
The rodent running-wheel recording apparatus is a reliable approach for studying cir-cadian rhythm.This study demonstrated how to construct a simple and intelligent running-wheel recording system.The running wheel was...The rodent running-wheel recording apparatus is a reliable approach for studying cir-cadian rhythm.This study demonstrated how to construct a simple and intelligent running-wheel recording system.The running wheel was attached to the cage's base,whereas the Hall sensor was attached to the cage's cover.Then,the RJ25 adaptor relayed the running signal to the main control board.Finally,the main control board was connected to the USB port of the computer with the USB connection.Data were collected using the online-accessible,self-created software Magturning.Through Magturning,generated data were saved and exported in real time.Afterward,the device was validated by collecting data on the locomotor activities of mice under dif-ferent light conditions.In conclusion,this new device can record circadian activity of rodents.Our device is appropriate for interdisciplinary investigations related to biological clock research.展开更多
Timothy (Phleum pretense L.) pastures of 3 Total mixed ration (TMR) centers in Hokkaido were selected, the first cutting grasses were continuously collected from the same pastures on different harvest days over 4 year...Timothy (Phleum pretense L.) pastures of 3 Total mixed ration (TMR) centers in Hokkaido were selected, the first cutting grasses were continuously collected from the same pastures on different harvest days over 4 years (2011-2014), and changes in the water soluble carbohydrates (WSC) content were analyzed to investigate the relationship with weather conditions. The harvest days in the 4-year period were June 17-22, June 24-26, June 27-30, and July 2-5, and grasses on these dates were designated as the harvest date groups. The weather data during the cutting period in each year were utilized. The WSC content tended to change yearly and it was significantly lower in the 4 groups (67.3 - 82.1 g/kg DM) in 2011 than in the groups (101.5 - 130.3 g/kg DM) in 2013 excluding the June 24-26 group (P < 0.05, P < 0.01). The WSC content tended to increase as the harvest date progressed in 2011-2013 and it significantly increased even though the harvest date was delayed only in 2013 (P < 0.01). It was suggested that differences in the WSC content among the years were related to the weather condition and dry matter yield of the grass.展开更多
Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is...Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.展开更多
Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrog...Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.展开更多
Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for ...Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients.The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy.Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC.However,inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy(PTT).This study modified gold nanodots(AuNDs)with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT.The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuN Ds.The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC.Moreover,owing to its stable long-term fluorescence and high X-ray attenuation coefficient,the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC,rendering it useful for early tumor detection and accurate delineation of surgical margins.In conclusion,Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.展开更多
Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregati...Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregation,and alleviates scopolamine-induced cognitive impairment,similar to the phase Ⅲ clinical drug resveratrol.In this study,we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology.Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment,promoted fibrillar amyloid-β clearance from the hippocampus and cortex,suppressed oxidative stress,and inhibited activation of microglia and astrocytes.D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression.Notably,we demonstrated that exogenous fibrillar amyloid-βintroduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain,and this increase was blocked by D30.Considering the role of D30 in clearing amyloid-β,inhibiting neuroinflammation,protecting synapses,and improving cognition,this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.展开更多
Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnormalities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)hav...Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnormalities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)have identified numerous risk genes for CJD,the mechanisms underlying these risk loci remain poorly understood.This study aims to elucidate novel genetically prioritized candidate proteins associated with CJD in the human brain through an integrative analytical pipeline.Utilizing datasets from Protein Quantitative Trait Loci(pQTL)(NpQTL1=152,NpQTL2=376),expression QTL(eQTL)(N=452),and the CJD GWAS(NCJD=4110,NControls=13569),we implemented a systematic analytical pipeline.This pipeline included Proteome-Wide Association Study(PWAS),Mendelian randomization(MR),Bayesian colocalization,and Transcriptome-Wide Association Study(TWAS)to identify novel genetically prioritized candidate proteins implicated in CJD pathogenesis within the brain.Through PWAS,we identified that the altered abundance of six brain proteins was significantly associated with CJD.Two genes,STX6 and PDIA4,were established as lead causal genes for CJD,supported by robust evidence(False Discovery Rate<0.05 in MR analysis;PP4/(PP3+PP4)≥0.75 in Bayesian colocalization).Specifically,elevated levels of STX6 and PDIA4 were associated with an increased risk of CJD.Additionally,TWAS demonstrated that STX6 and PDIA4 were associated with CJD at the transcriptional level.展开更多
Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and ...Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive.Here,we show that the mechanical protein Polysyctin-1(PC1,Pkd1)regulates CTSK lineage tendon-derived mesenchymal stem cell(TDMSC)fate and ECM organization,thus affecting HO progression.First,we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model.Moreover,we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation.Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis,fibrogenesis and ECM organization,and consequently attenuate HO progression.These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of pro...Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.展开更多
Background:Lung adenocarcinoma,the most prevalent lung cancer subtype,is increasingly diagnosed in non-smokers and females.The cell cycle regulator CDC20(Cell Division Cycle 20),a crucial activator of the Anaphase-Pro...Background:Lung adenocarcinoma,the most prevalent lung cancer subtype,is increasingly diagnosed in non-smokers and females.The cell cycle regulator CDC20(Cell Division Cycle 20),a crucial activator of the Anaphase-Promoting Complex/Cyclosome(APC/C),is frequently overexpressed in various cancers,including lung adenocarcinoma,and is implicated in tumorigenesis.Preclinical studies indicate that inhibiting the CDC20-APC/C signaling axis can enhance chemotherapy-induced apoptosis.Analysis of The Cancer Genome Atlas(TCGA)data confirms that elevated CDC20 expression in lung adenocarcinoma is significantly associated with poorer patient prognosis and correlates with immune cell infiltration.These collective findings highlight CDC20 as a promising prognostic biomarker and a potential novel therapeutic target for lung adenocarcinoma.Methods:We collected 539 patients with LUAD and 59 normal controls of clinical data from the Cancer Genome Atlas(TCGA)for bioinformatics analysis to investigate the role of CDC20 in LUAD and address the above questions.We evaluated the association between CDC20 expression and clinicopathological features using the Kruskal Wallis test and multivariate logistic regression.Prognostic values were assessed using Cox regression and Kaplan-Meier survival analyses.We further used single-sample gene set enrichment analysis(ssGSEA)to explore correlations between CDC20 expression and immune infiltration levels.Results:CDC20 expression in LUAD tissues was significantly higher than that in normal controls(p<0.001)and showed high diagnostic accuracy(AUC[area under the curve]=0.979).Kaplan-Meier analysis revealed that high CDC20 expression predicted poorer overall survival(OS;HR=1.47,95%CI:1.10–1.97,p=0.009),although no significant association emerged with progression-free interval(p=0.172).ssGSEA indicated a strong positive correlation between CDC20 and T helper 2 cell infiltration(R=0.764,p<0.001),but negative correlations with mast cells(R=−0.469,p<0.001)and eosinophils(R=−0.343,p<0.001).Functional enrichment analyses(Gene ontology/Kyoto Encyclopedia of Genes and Genomes[GO/KEGG])of CDC20-associated genes provided additional mechanistic insights.Conclusions:The significantly elevated expression of CDC20 in LUAD tissues,coupled with its high diagnostic accuracy(AUC=0.979),underscores its potential utility in differentiating LUAD from normal tissue.More importantly,the strong association between high CDC20 expression and poorer overall survival(OS)establishes its independent prognostic value for predicting adverse patient outcomes.Beyond its correlation with clinical parameters,our findings illuminate potential mechanisms underlying CDC20's oncogenic role.The distinct positive correlation with T helper 2(Th2)cell infiltration and negative correlations with mast cells and eosinophils suggest that CDC20 may actively shape an immunosuppressive tumor microenvironment,potentially facilitating tumor immune evasion and progression.Functional enrichment analyses of CDC20-coexpressed genes further support its involvement in key oncogenic pathways,including cell cycle regulation and mitotic processes.Collectively,this study not only validates CDC20 as a valuable prognostic factor but also provides novel mechanistic insights linking its overexpression to altered immune landscapes in LUAD.展开更多
A decomposable and sono-enzyme co-triggered nanoparticle(p TCP-CR NP)with“AND gate”logic was synthesized,combining a meso–carboxyl-porphyrin-based sonosensitizer(5,10,15,20-tetrakis(carboxyl)porphyrin,TCP)and a thi...A decomposable and sono-enzyme co-triggered nanoparticle(p TCP-CR NP)with“AND gate”logic was synthesized,combining a meso–carboxyl-porphyrin-based sonosensitizer(5,10,15,20-tetrakis(carboxyl)porphyrin,TCP)and a thiophenyl-croconium(2,5-bis[(2-(2-(2-hydroxyethoxy)ethoxy)ethyl-4-carboxylate-piperidylamino)thiophenyl]-croconium,CR)via ester groups.TCP releases carbon monoxide(CO)under ultrasound(US)irradiation,offering both sonodynamic and gas therapy.CR decomposes into stronger reactive oxygen species(ROS)compared to oxygen-based radicals.The F?rster resonance energy transfer(FRET)effect between TCP and CR inhibits ROS and CO generation until triggered by tumor cell overexpressed carboxylesterase(CEs).p TCP-CR NPs“AND gate”logic ensures activation only in the presence of both CEs and US,targeting tumor cells while safety in normal tissues.The ROS and CO generation abilities,as well as the releasing of SO_(4)^(·-)have been systemically examined.p TCP-CR can be thoroughly decomposed into low-toxic molecules post the treatment,showing the safety with negligible phototoxic reactions.In vivo anti-cancer therapy has been evaluated using mice bearing hepatocellular carcinoma.展开更多
Background : Cancer-associated cardiac cachexia(CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed. Methods : This study established CAC...Background : Cancer-associated cardiac cachexia(CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed. Methods : This study established CACC models in C57BL/6J and BALB/c mice using orthotopic, intra-abdominal, and hematogenous metastatic tumor induction. Multimodal cardiac assessments, including echocardiography, transmission electron microscopy for myocardial ultrastructural and mitochondrial analysis, and ex vivo cardiomyocyte contractility assays, were systematically applied. Results : Metastatic burden triggered CACC characterized by cardiac mass reduction, epicardial fat depletion, interstitial fibrosis, and electrocardiographic abnormalities. Histopathological analysis revealed cardiomyocyte atrophy, myofibrillar disarray, mitochondrial dysfunction, and ubiquitin-mediated Myh6 degradation via Mu RF-1, accompanied by compensatory Myh7 upregulation. These findings mechanistically link tumor-induced cachexia to cardiac dysfunction through contractile protein remodeling. Conclusion : This work establishes a preclinical framework for targeting ubiquitin pathways to mitigate the morbidity of cancer-related cardiopathy. Our integrated approach delineates a hierarchical progression from subcellular dysfunction to macroscopic cardiac deterioration.展开更多
Macrophages derived from the human THP-1 cell line have been widely used as substitutes for primary macrophages in various macrophage-related studies.However,difficulties still exist in establishing THP-I macrophage m...Macrophages derived from the human THP-1 cell line have been widely used as substitutes for primary macrophages in various macrophage-related studies.However,difficulties still exist in establishing THP-I macrophage models.This research presents techniques for generating different phenotypes of activated macrophages derived from THP-1 cells by introducing specific stimuli and provides some potential markers to confirm each type of activated macrophage.It is hoped to provide novel and useful methods for scientific research and to help researchers explore this field more intuitively and effectively.展开更多
OBJECTIVE:To explore the mechanism of action of Tiaogeng decoction(调更汤,TG)in alleviating oxidative stress damage in the hippocampus of a mouse model of cognitive impairment.METHODS:Amyloid precursor protein/preseni...OBJECTIVE:To explore the mechanism of action of Tiaogeng decoction(调更汤,TG)in alleviating oxidative stress damage in the hippocampus of a mouse model of cognitive impairment.METHODS:Amyloid precursor protein/presenilin-1(APP/PS1)transgenic female mice were randomly divided into model,estradiol valerate,low-,medium-,and high-dose TG groups,female C57 mice were used as the control group(n=12/group).After 12 weeks of treatment,the behavior of mice was tested with the Morris water maze,and brain tissue samples were collected,and changes in hippocampal neurons were observed using electron microscopy.The deposition of beta-amyloid protein(Aβ)amyloid plaques in the hippocampus was determined by light microscopy.Aβ1-42 protein levels were detected through immunofluorescence.Oxidative stress indicators in the hippocampus were detected by enzyme linked immunosorbent assay.The expressions of nuclear factor-erythroid 2-related factor 2(Nrf2),c-Jun N-terminal kinase(JNK),phospho-JNK(p-JNK),B-cell lymphoma-2(Bcl-2),caspase-9,and cleaved caspase-9 were detected by Western blot.Hippocampal cell apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated nick end Labeling.RESULTS:TG improved the cognitive function of APP/PS1 mice,as judged by improvements in several indices from the Morris water maze test.TG increased Nrf2,superoxide dismutase,and heme oxygenase-1 protein expression and reduced malondialdelyde and reactive oxygen species expression.TG also inhibited the expression of JNK proteins,upregulated the expression of Bcl-2,and downregulated the expression of caspase-9,reducing cell apoptosis.TG decreased the percentage of the hippocampal cornu ammonis 1 area positive for Aβ1-42,reducing mitochondrial damage caused by oxidative stress and Aβprotein deposition.CONCLUSIONS:TG may improve memory ability while reducing oxidative stress and apoptosis.It also reduces Aβprotein deposition in the hippocampus,protecting the central nervous system and improving memory function.TG may reduce the risk of AD.展开更多
Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice...Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice enter puberty only 4–5 days earlier than normal mice),the related research is limited.Methods:Therefore,the MKRN3-modified rabbit was developed using CRISPR(clus-tered regularly interspaced short palindromic repeats)gene editing technology.The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.Results:The first estrus of MKRN3-modified female rabbits was observed~27 days earlier than that of wild-type female rabbits,with a typical CPP phenotype.This study found increased gonadotropin releasing hormone(GnRH)and decreased gonadotropin inhibiting hormone(GnIH)in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation.Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation,it found some differentially expressed genes and potential pathways through transcriptome sequencing.Conclusions:This study established a novel CPP model:paternal MKRN3 gene-modified rabbit.It is hoped that the establishment of this model will help researchers better understand,treat,and prevent CPP in the future.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(226-2022-00035)the National Natural Science Foundation of China(81600986).
文摘Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.
基金supported by the National Science and Technology Major Projects of Infectious Disease(2012ZX10004-404)
文摘Concern about the biological hazards involved in microbiological research, especially research involving laboratory animals, has increased in recent years. Working in an animal biosafety level 2 facility （ABSL-2）, commonly used for research on infectious diseases, poses various biological hazards. Here, the regulations and standards related to laboratory biosafety in China are introduced, the potential biological hazards present in ABSL-2 facilities are analyzed, and a series of strategies to control the hazards are presented.
基金supported by fund of science and technology project of Wenzhou(Y20140601)
文摘Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society because of the ethical issue. This paper takes Wenzhou Medical University as an example to give a brief introduction to the ethical review about laboratory animals in the university so as to further draw attention and concerns from the public about the ethical issue of laboratory animals. We successively introduce its scientific projects, nurturing environment and ethical review of laboratory animals.
文摘The supply and demand of laboratory animals for teaching in colleges and universities has its own internal characteristics.To grasp the supply and demand characteristics of laboratory animals for teaching is of vital importance to the planning,supply and use of teaching animals,the realization of teaching objectives and the completion of teaching tasks.Based on the supply of teaching experimental animals and the work of animal experimental teaching in our university in recent years,this paper expounds the inherent characteristics and practice of supply and demand of teaching experimental animals.
基金Startup Fund for scientific research,Fujian Medical University,Grant/Award Number:2020QH1039Joint Funds for the Innovation of Science and Technology,Fujian Province,Grant/Award Number:2020Y9114 and 2020Y9119。
文摘The rodent running-wheel recording apparatus is a reliable approach for studying cir-cadian rhythm.This study demonstrated how to construct a simple and intelligent running-wheel recording system.The running wheel was attached to the cage's base,whereas the Hall sensor was attached to the cage's cover.Then,the RJ25 adaptor relayed the running signal to the main control board.Finally,the main control board was connected to the USB port of the computer with the USB connection.Data were collected using the online-accessible,self-created software Magturning.Through Magturning,generated data were saved and exported in real time.Afterward,the device was validated by collecting data on the locomotor activities of mice under dif-ferent light conditions.In conclusion,this new device can record circadian activity of rodents.Our device is appropriate for interdisciplinary investigations related to biological clock research.
文摘Timothy (Phleum pretense L.) pastures of 3 Total mixed ration (TMR) centers in Hokkaido were selected, the first cutting grasses were continuously collected from the same pastures on different harvest days over 4 years (2011-2014), and changes in the water soluble carbohydrates (WSC) content were analyzed to investigate the relationship with weather conditions. The harvest days in the 4-year period were June 17-22, June 24-26, June 27-30, and July 2-5, and grasses on these dates were designated as the harvest date groups. The weather data during the cutting period in each year were utilized. The WSC content tended to change yearly and it was significantly lower in the 4 groups (67.3 - 82.1 g/kg DM) in 2011 than in the groups (101.5 - 130.3 g/kg DM) in 2013 excluding the June 24-26 group (P < 0.05, P < 0.01). The WSC content tended to increase as the harvest date progressed in 2011-2013 and it significantly increased even though the harvest date was delayed only in 2013 (P < 0.01). It was suggested that differences in the WSC content among the years were related to the weather condition and dry matter yield of the grass.
基金supported by the Notional Natural Science Foundation of Chino,No.82160690Colloborotive Innovation Center of Chinese Ministry of Education,No.2020-39Science and Technology Foundation of Guizhou Province,No.ZK[2021]-014(all to FZ)。
文摘Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.
基金supported by the National Research Foundation of Korea (NRF)funded by the Ministry of Science,ICT&Future Planning (2022R1A2C2006229,2022R1A6A3A01086868)Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)funded by the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea (RS-2024-00345328)KIST Institutional Grant (2E32851)。
文摘Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.
基金supported by the Science and Technology Projects of Jilin Provincial Department of Science and Technology(Grant/Award Numbers:20240305037YY)National Key Research and Development Program of China(2021YFC2400603)+1 种基金the Joint Funds of the National Natural Science Foundation of China(Grant No.U23A20269)the Jilin University young teachers and students cross-disciplinary training project(Grant No.2023-JCXK-08,2024-JCXK-07)。
文摘Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients.The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy.Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC.However,inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy(PTT).This study modified gold nanodots(AuNDs)with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT.The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuN Ds.The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC.Moreover,owing to its stable long-term fluorescence and high X-ray attenuation coefficient,the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC,rendering it useful for early tumor detection and accurate delineation of surgical margins.In conclusion,Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.
基金supported by the Research Foundation for Talented Scholars of Fujian Medical University,No.XRCZX2018014(to DZ)Startup Fund for Scientific Research,Fujian Medical University,No.2019QH1017(to CW)the Natural Science Foundation of Fujian Province,China,Nos.2021J01693(to DZ),2021J02032(to ZCY)。
文摘Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregation,and alleviates scopolamine-induced cognitive impairment,similar to the phase Ⅲ clinical drug resveratrol.In this study,we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology.Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment,promoted fibrillar amyloid-β clearance from the hippocampus and cortex,suppressed oxidative stress,and inhibited activation of microglia and astrocytes.D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression.Notably,we demonstrated that exogenous fibrillar amyloid-βintroduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain,and this increase was blocked by D30.Considering the role of D30 in clearing amyloid-β,inhibiting neuroinflammation,protecting synapses,and improving cognition,this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.
文摘Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnormalities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)have identified numerous risk genes for CJD,the mechanisms underlying these risk loci remain poorly understood.This study aims to elucidate novel genetically prioritized candidate proteins associated with CJD in the human brain through an integrative analytical pipeline.Utilizing datasets from Protein Quantitative Trait Loci(pQTL)(NpQTL1=152,NpQTL2=376),expression QTL(eQTL)(N=452),and the CJD GWAS(NCJD=4110,NControls=13569),we implemented a systematic analytical pipeline.This pipeline included Proteome-Wide Association Study(PWAS),Mendelian randomization(MR),Bayesian colocalization,and Transcriptome-Wide Association Study(TWAS)to identify novel genetically prioritized candidate proteins implicated in CJD pathogenesis within the brain.Through PWAS,we identified that the altered abundance of six brain proteins was significantly associated with CJD.Two genes,STX6 and PDIA4,were established as lead causal genes for CJD,supported by robust evidence(False Discovery Rate<0.05 in MR analysis;PP4/(PP3+PP4)≥0.75 in Bayesian colocalization).Specifically,elevated levels of STX6 and PDIA4 were associated with an increased risk of CJD.Additionally,TWAS demonstrated that STX6 and PDIA4 were associated with CJD at the transcriptional level.
基金National Natural Science Foundation of China(Grant Nos.82261160397,82272560)Central South University Research Programme of Advanced Interdisciplinary Studies(2023QYJC011)+4 种基金National Natural Science Foundation of China(Grant Nos.82472521,81922017)Hunan Provincial Science and Technology Department(2023JJ30896)Key Research and Development Program of Hunan Province(2022SK2023)Science and Technology Innovation Program of Hunan Province(2023RC1027)Major Basic Research Projects in Hunan Province(No.2024JC0004)。
文摘Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive.Here,we show that the mechanical protein Polysyctin-1(PC1,Pkd1)regulates CTSK lineage tendon-derived mesenchymal stem cell(TDMSC)fate and ECM organization,thus affecting HO progression.First,we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model.Moreover,we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation.Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis,fibrogenesis and ECM organization,and consequently attenuate HO progression.These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
基金supported by the Natural Science Foundation of Guangdong Province(No.2024A1515010605,2022A1515140034)Discipline Construction Project of Guangdong Medical University(No.4SG24007G,4SG22302P)+1 种基金Medical Scientific Research Fund of Guangdong Province(No.B2024193)Dongguan Social Development and Scientific Technology Project,China(No.20231800936562).
文摘Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.
基金funded by the Liaoning Province Science and Technology Plan Joint Project (No.2023JH2/101700140)
文摘Background:Lung adenocarcinoma,the most prevalent lung cancer subtype,is increasingly diagnosed in non-smokers and females.The cell cycle regulator CDC20(Cell Division Cycle 20),a crucial activator of the Anaphase-Promoting Complex/Cyclosome(APC/C),is frequently overexpressed in various cancers,including lung adenocarcinoma,and is implicated in tumorigenesis.Preclinical studies indicate that inhibiting the CDC20-APC/C signaling axis can enhance chemotherapy-induced apoptosis.Analysis of The Cancer Genome Atlas(TCGA)data confirms that elevated CDC20 expression in lung adenocarcinoma is significantly associated with poorer patient prognosis and correlates with immune cell infiltration.These collective findings highlight CDC20 as a promising prognostic biomarker and a potential novel therapeutic target for lung adenocarcinoma.Methods:We collected 539 patients with LUAD and 59 normal controls of clinical data from the Cancer Genome Atlas(TCGA)for bioinformatics analysis to investigate the role of CDC20 in LUAD and address the above questions.We evaluated the association between CDC20 expression and clinicopathological features using the Kruskal Wallis test and multivariate logistic regression.Prognostic values were assessed using Cox regression and Kaplan-Meier survival analyses.We further used single-sample gene set enrichment analysis(ssGSEA)to explore correlations between CDC20 expression and immune infiltration levels.Results:CDC20 expression in LUAD tissues was significantly higher than that in normal controls(p<0.001)and showed high diagnostic accuracy(AUC[area under the curve]=0.979).Kaplan-Meier analysis revealed that high CDC20 expression predicted poorer overall survival(OS;HR=1.47,95%CI:1.10–1.97,p=0.009),although no significant association emerged with progression-free interval(p=0.172).ssGSEA indicated a strong positive correlation between CDC20 and T helper 2 cell infiltration(R=0.764,p<0.001),but negative correlations with mast cells(R=−0.469,p<0.001)and eosinophils(R=−0.343,p<0.001).Functional enrichment analyses(Gene ontology/Kyoto Encyclopedia of Genes and Genomes[GO/KEGG])of CDC20-associated genes provided additional mechanistic insights.Conclusions:The significantly elevated expression of CDC20 in LUAD tissues,coupled with its high diagnostic accuracy(AUC=0.979),underscores its potential utility in differentiating LUAD from normal tissue.More importantly,the strong association between high CDC20 expression and poorer overall survival(OS)establishes its independent prognostic value for predicting adverse patient outcomes.Beyond its correlation with clinical parameters,our findings illuminate potential mechanisms underlying CDC20's oncogenic role.The distinct positive correlation with T helper 2(Th2)cell infiltration and negative correlations with mast cells and eosinophils suggest that CDC20 may actively shape an immunosuppressive tumor microenvironment,potentially facilitating tumor immune evasion and progression.Functional enrichment analyses of CDC20-coexpressed genes further support its involvement in key oncogenic pathways,including cell cycle regulation and mitotic processes.Collectively,this study not only validates CDC20 as a valuable prognostic factor but also provides novel mechanistic insights linking its overexpression to altered immune landscapes in LUAD.
基金supported by grants from the National Natural Science Foundation of China(No.22375027)the Natural Science Foundation of Jiangsu Province(Nos.BK20221265,BK20211100)+1 种基金the Fundamental Research Funds for the Central Universities(No.DUT23YG133)the Research Funds from Liaoning Cancer Hospital(No.2024ZLKF-35)。
文摘A decomposable and sono-enzyme co-triggered nanoparticle(p TCP-CR NP)with“AND gate”logic was synthesized,combining a meso–carboxyl-porphyrin-based sonosensitizer(5,10,15,20-tetrakis(carboxyl)porphyrin,TCP)and a thiophenyl-croconium(2,5-bis[(2-(2-(2-hydroxyethoxy)ethoxy)ethyl-4-carboxylate-piperidylamino)thiophenyl]-croconium,CR)via ester groups.TCP releases carbon monoxide(CO)under ultrasound(US)irradiation,offering both sonodynamic and gas therapy.CR decomposes into stronger reactive oxygen species(ROS)compared to oxygen-based radicals.The F?rster resonance energy transfer(FRET)effect between TCP and CR inhibits ROS and CO generation until triggered by tumor cell overexpressed carboxylesterase(CEs).p TCP-CR NPs“AND gate”logic ensures activation only in the presence of both CEs and US,targeting tumor cells while safety in normal tissues.The ROS and CO generation abilities,as well as the releasing of SO_(4)^(·-)have been systemically examined.p TCP-CR can be thoroughly decomposed into low-toxic molecules post the treatment,showing the safety with negligible phototoxic reactions.In vivo anti-cancer therapy has been evaluated using mice bearing hepatocellular carcinoma.
基金National Natural Science Foundation of China,Grant/Award Number:81970219, 82170261, 82200289 and 82370283National Key Research and Development Program of China,Grant/Award Number:2023YFF0724900。
文摘Background : Cancer-associated cardiac cachexia(CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed. Methods : This study established CACC models in C57BL/6J and BALB/c mice using orthotopic, intra-abdominal, and hematogenous metastatic tumor induction. Multimodal cardiac assessments, including echocardiography, transmission electron microscopy for myocardial ultrastructural and mitochondrial analysis, and ex vivo cardiomyocyte contractility assays, were systematically applied. Results : Metastatic burden triggered CACC characterized by cardiac mass reduction, epicardial fat depletion, interstitial fibrosis, and electrocardiographic abnormalities. Histopathological analysis revealed cardiomyocyte atrophy, myofibrillar disarray, mitochondrial dysfunction, and ubiquitin-mediated Myh6 degradation via Mu RF-1, accompanied by compensatory Myh7 upregulation. These findings mechanistically link tumor-induced cachexia to cardiac dysfunction through contractile protein remodeling. Conclusion : This work establishes a preclinical framework for targeting ubiquitin pathways to mitigate the morbidity of cancer-related cardiopathy. Our integrated approach delineates a hierarchical progression from subcellular dysfunction to macroscopic cardiac deterioration.
基金supported by the Shaanxi University of Chinese Medicine-National Natural Science Foundation Cultivation Project(No.2023GP16)the Shaanxi Key Laboratory of Research on TCM Physical Constitution and Diseases Prevention and Treatment(No.KF202311)the Graduate Student Innovative Practical Ability Improvement Project(No.CXSJ202302),China.
文摘Macrophages derived from the human THP-1 cell line have been widely used as substitutes for primary macrophages in various macrophage-related studies.However,difficulties still exist in establishing THP-I macrophage models.This research presents techniques for generating different phenotypes of activated macrophages derived from THP-1 cells by introducing specific stimuli and provides some potential markers to confirm each type of activated macrophage.It is hoped to provide novel and useful methods for scientific research and to help researchers explore this field more intuitively and effectively.
基金Supported by Natural Science Foundation-funded Project:Mechanism of Tiaogeng Decoction improving Cognitive Function via Regulating Nuclear Factor-erythroid 2-related Factor 2/c-Jun N-terminal kinase/Aβ Oxidative Stress Network in Hippocampus Neurons (No. 81874482)
文摘OBJECTIVE:To explore the mechanism of action of Tiaogeng decoction(调更汤,TG)in alleviating oxidative stress damage in the hippocampus of a mouse model of cognitive impairment.METHODS:Amyloid precursor protein/presenilin-1(APP/PS1)transgenic female mice were randomly divided into model,estradiol valerate,low-,medium-,and high-dose TG groups,female C57 mice were used as the control group(n=12/group).After 12 weeks of treatment,the behavior of mice was tested with the Morris water maze,and brain tissue samples were collected,and changes in hippocampal neurons were observed using electron microscopy.The deposition of beta-amyloid protein(Aβ)amyloid plaques in the hippocampus was determined by light microscopy.Aβ1-42 protein levels were detected through immunofluorescence.Oxidative stress indicators in the hippocampus were detected by enzyme linked immunosorbent assay.The expressions of nuclear factor-erythroid 2-related factor 2(Nrf2),c-Jun N-terminal kinase(JNK),phospho-JNK(p-JNK),B-cell lymphoma-2(Bcl-2),caspase-9,and cleaved caspase-9 were detected by Western blot.Hippocampal cell apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated nick end Labeling.RESULTS:TG improved the cognitive function of APP/PS1 mice,as judged by improvements in several indices from the Morris water maze test.TG increased Nrf2,superoxide dismutase,and heme oxygenase-1 protein expression and reduced malondialdelyde and reactive oxygen species expression.TG also inhibited the expression of JNK proteins,upregulated the expression of Bcl-2,and downregulated the expression of caspase-9,reducing cell apoptosis.TG decreased the percentage of the hippocampal cornu ammonis 1 area positive for Aβ1-42,reducing mitochondrial damage caused by oxidative stress and Aβprotein deposition.CONCLUSIONS:TG may improve memory ability while reducing oxidative stress and apoptosis.It also reduces Aβprotein deposition in the hippocampus,protecting the central nervous system and improving memory function.TG may reduce the risk of AD.
基金National Natural Science Foundation of China,Grant/Award Number:82101937Guangdong Medical Science and Technology Research Fund Project,China,Grant/Award Number:B2024069Guangzhou Science and Technology Plan Project,China,Grant/Award Number:2024A04J4923 and SL2023A04J02229。
文摘Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice enter puberty only 4–5 days earlier than normal mice),the related research is limited.Methods:Therefore,the MKRN3-modified rabbit was developed using CRISPR(clus-tered regularly interspaced short palindromic repeats)gene editing technology.The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.Results:The first estrus of MKRN3-modified female rabbits was observed~27 days earlier than that of wild-type female rabbits,with a typical CPP phenotype.This study found increased gonadotropin releasing hormone(GnRH)and decreased gonadotropin inhibiting hormone(GnIH)in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation.Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation,it found some differentially expressed genes and potential pathways through transcriptome sequencing.Conclusions:This study established a novel CPP model:paternal MKRN3 gene-modified rabbit.It is hoped that the establishment of this model will help researchers better understand,treat,and prevent CPP in the future.
