1|INTRODUCTION For decades,experimental animal models have been powerful tools for biomedical research and have supported most of the physiological or medical achievements recognized by Nobel Prizes,including the rese...1|INTRODUCTION For decades,experimental animal models have been powerful tools for biomedical research and have supported most of the physiological or medical achievements recognized by Nobel Prizes,including the research that won this year's Physiology or Medicine Prize.On 4th October 2021,the Nobel Prize in Physiology or Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian"for their discoveries of receptors for temperature and touch."1 Their discoveries have profoundly changed our view of how we sense the world around us2.展开更多
Although hypertension is a frequently seen chronic condition across the world,its exact cause remains unclear.Animal models are beneficial for clarifying the pathogenic mechanism of hypertension and examining new trea...Although hypertension is a frequently seen chronic condition across the world,its exact cause remains unclear.Animal models are beneficial for clarifying the pathogenic mechanism of hypertension and examining new treatments.An optimal animal model for studies on hypertension must well mimic human-like hemodynamics and pathophysiological structural modification,showing human disease features and complications timely or even ahead of time.A review of the most frequently used hypertensive animal models available,including small and large animals,induced and genetic models,would provide an insight into the appropriate targets to be addressed in the development of different hypertensive animal models.Another focus of the review are the processes of target-organs injury caused by high blood pressure,which mainly influences human health.展开更多
Alzheimer's disease(AD)is a neurodegenerative disorder.The pathology of AD is characterized by extracellular amyloid beta(Aβ)plaques,neurofibrillary tangles com-posed of hyperphosphorylated tau,neuronal death,syn...Alzheimer's disease(AD)is a neurodegenerative disorder.The pathology of AD is characterized by extracellular amyloid beta(Aβ)plaques,neurofibrillary tangles com-posed of hyperphosphorylated tau,neuronal death,synapse loss,and brain atrophy.Many therapies have been tested to improve or at least effectively modify the course of AD.Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease.Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction,although certain weak-nesses or limitations need to be overcome.This review recapitulates rodent models for AD,the therapeutic efficacy of stem cells,influencing factors,and the underlying mechanisms behind these changes.Stem cell therapy provides perspective and chal-lenges for its clinical application in the future.展开更多
Background:The continuing emergence of influenza virus has highlighted the value of public databases and related bioinformatic analysis tools in investigating transcriptomic change caused by different influenza virus ...Background:The continuing emergence of influenza virus has highlighted the value of public databases and related bioinformatic analysis tools in investigating transcriptomic change caused by different influenza virus infections in human and animal models.Methods:We collected a large amount of transcriptome research data related to influenza virus-i nfected human and animal models in public databases(GEO and ArrayExpress),and extracted and integrated array and metadata.The gene expression matrix was generated through strictly quality control,balance,standardization,batch correction,and gene annotation.We then analyzed gene expression in different species,virus,cells/tissues or after antibody/vaccine treatment and imported sample metadata and gene expression datasets into the database.Results:Overall,maintaining careful processing and quality control,we collected 8064 samples from 103 independent datasets,and constructed a comparative transcriptomics database of influenza virus named the Flu-CED database(Influenza comparative expression database,https://flu.com-med.org.cn/).Using integrated and processed transcriptomic data,we established a user-friendly website for realizing the integration,online retrieval,visualization,and exploration of gene expression of influenza virus infection in different species and the biological functions involved in differential genes.Flu-CED can quickly query single and multi-gene expression profiles,combining different experimental conditions for comparative transcriptome analysis,identifying differentially expressed genes(DEGs)between comparison groups,and conveniently finding DEGs.Conclusion:Flu-CED provides data resources and tools for analyzing gene expression in human and animal models infected with influenza virus that can deepen our understanding of the mechanisms underlying disease occurrence and development,and enable prediction of key genes or therapeutic targets that can be used for medical research.展开更多
Myelodysplastic syndrome(MDS)is a malignant tumor of the hematological system characterized by long-term,progressive refractory hemocytopenia.In addition,the risk of leukemia is high,and once it develops,the course of...Myelodysplastic syndrome(MDS)is a malignant tumor of the hematological system characterized by long-term,progressive refractory hemocytopenia.In addition,the risk of leukemia is high,and once it develops,the course of acute leukemia is short with poor curative effect.Animal models are powerful tools for studying human diseases and are highly effective preclinical platforms.Animal models of MDS can accurately show genetic aberrations and hematopoietic clone phenotypes with similar cellular features(such as impaired differentiation and increased apoptosis),and symptoms can be used to assess existing treatments.Animal models are also helpful for understanding the pathogenesis of MDS and its relationship with acute leukemia,which helps with the identification of candidate genes related to the MDS phenotype.This review summarizes the current status of animal models used to research myelodysplastic syndrome(MDS).展开更多
Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhib...Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.展开更多
Background:Liver diseases are a major contributor to both morbidity and mortality.Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal.The use of floxed ra...Background:Liver diseases are a major contributor to both morbidity and mortality.Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal.The use of floxed rat resource has rapidly increased,but the liver-specific Cre rat lines for studying liver diseases and interested genes are limited,especially in a spatially and temporally restricted manner.Methods:RNA sequencing and real-time polymerase chain reaction(PCR)were used to screen and confirm the presence of liver-specific genes.Apoa4-Cre rats and Cyp2c11-Cre rats were produced by CRISPR/Cas9 knockin.Rosa26-imCherry rats were employed to hybridize with the Cre rats to obtain the Apoa4-Cre/Rosa26-imCherry and Cyp2c11-Cre/Rosa26-imCherry rats.The temporal and spatial patterns of Cre expression were determined by the observation of red fluorescence on tis-sue sections.Hematoxylin-eosin stain was used to evaluate the liver histopathologic changes.The blood biochemical analysis of several liver enzymes and liver lipid profile was performed to evaluate the liver function of Cre rats.Results:Apoa4 and Cyp2c11 were identified as two liver-specific genes.Apoa4-Cre and Cyp2c11-Cre rats were produced and hybridized with Rosa26-imCherry rats.The red fluorescence indicated that the Cre recombinases were specially expressed in the juvenile and adult liver and not in other organs of two hybridized rats.All the blood biochemical parameters except low-density lipoprotein(LDL)did not change signifi-cantly in the Cre rats.No histological alterations were detected in the livers of the Cre rats.Conclusions:Liver-specific Apoa4-Cre and Cyp2c11-Cre rats have been established successfully and could be used to study gene knockout,specifically in juvenile and adult liver.展开更多
Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce dr...Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce drug resistance or recurrence.Patientderived xenograft(PDX)models are widely used to simulate tumor progression and drug responses,serving as translational tools for precision medicine.This study aimed to establish drug-resistant OSCC PDX models.Human OSCC tissues were transplanted into immunodeficient mice and passaged(P1–P2).At P2(tumor volume:40–80 mm^(3)),mice received cisplatin(1 mg/kg,three times/week)with cetuximab(1 mg/kg,weekly),GSK690693(10 mg/kg,five times/week),or rapamycin(4 mg/kg,five times/week).PDX tissues from groups with less-therapeutic response(manifested as larger tumor volumes)were serially passaged to assess treatment efficacy.Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin–eosin(HE)and immunohistochemical staining after one additional passage and retreatment.Results demonstrated that successive passaging accelerates tumor growth.First-generation treatments showed universal sensitivity.At P2,cisplatin–cetuximab and rapamycin groups remained sensitive,whereas GSK690693 efficacy declined.Continued passaging of GSK690693-treated tumors confirmed resistance,as evidenced by exhibiting enhanced malignant characteristics at histological level.The GSK690693-resistant model was established first,whereas resistant models of other treatment groups were established according to similar protocols.These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution,enabling the development of drug-resistant OSCC models.This study can offer methodological insights for precision therapy of OSCC.展开更多
Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agen...Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).Results:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits.Neuropathology revealed brain atrophy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formaldehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of sporadic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.展开更多
Background:Alzheimer's disease(AD)represents the most prevalent neurodegenerative disorder,with mitochondrial dysfunction being observed in both AD patients and mouse models.Nonetheless,further investigation is re...Background:Alzheimer's disease(AD)represents the most prevalent neurodegenerative disorder,with mitochondrial dysfunction being observed in both AD patients and mouse models.Nonetheless,further investigation is required to elucidate the pathogenic genes associated with AD and to develop early diagnostic methodologies centered on mitochondrial function.Methods:In this study,the dataset GSE132903 was retrieved from the GEO database,encompassing both non-demented(ND)control and AD samples.Through the combination of differential expression gene analysis,weighted gene co-expression network analysis,and intersection with mitochondrial database gene sets,four hub genes associated with AD were identified.These four hub genes were subsequently validated in APP/PS1 and 5xFAD mouse models using molecular biology techniques.Results:The hub genes identified through bioinformatics analysis include SYNJ2BP,VDAC1,NUBPL,and COX19.Within the GSE132903 dataset,the expression levels of SYNJ2BP,NUBPL,and COX19 were significantly elevated in the AD group compared to the non-demented(ND)group,whereas VDAC1 expression was reduced in the AD group relative to the ND group.Furthermore,in the hippocampus of APP/PS1 and 5xFAD mouse models,the expression patterns of SYNJ2BP and NUBPL were consistent with the bioinformatics analysis results.Conclusion:Hub genes identified here through bioinformatics and molecular biology may help early diagnosis of AD patients and may also help build new AD models to explore its pathogenesis.展开更多
Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 10<sup>14</sup> organisms dispersed on approximately 1000 different species. Today, diagnost...Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 10<sup>14</sup> organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation.展开更多
Background: Alzheimer's disease(AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis o...Background: Alzheimer's disease(AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APP^(swe)/PS1^(ΔE9) mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.Methods: Evodiamine and its derivatives were effectively synthesized by EDCImediated condensation at room temperature. These target compounds contained 1 thio-and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H_2O_2-induced cell loss in SH-SY5 Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APP^(swe)/PS1^(ΔE9) mice.Results: In this study, a series of oxo-and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APP^(swe)/PS1^(ΔE9) mice.Conclusion: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.展开更多
Background: With the aim of establishing the most comprehensive database of laboratory animal strains, the "laboratory animal strain resources database"(LasDB)was constructed as a searchable online database ...Background: With the aim of establishing the most comprehensive database of laboratory animal strains, the "laboratory animal strain resources database"(LasDB)was constructed as a searchable online database of all laboratory animal strains,stocks and mutant embryonic stem-cell lines available worldwide, including inbred,outbred, mutant and genetically engineered strains.Methods: MySQL database software was used to construct the LasDB, offering an easy-to-use interface.Results: To date, LasDB has a collection covering data for 21 596 mouse strains,2062 rat strains, 13 monkey strains, 2 hamster strains, 5 dog strains, 5 rabbit strains and more than 50 other laboratory animal strains. LasDB will be continually improved with regular updates of new laboratory animal strains from all over the world.Conclusion: To the best of our knowledge, this is the first database that attempts to systematically integrate all available laboratory animal strain data with the aim of supporting open usage and full resource sharing.展开更多
Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.N...Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prog-nosis in several types of tumors.Methods:We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells.We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer.The development of colorectal tumors were investigated using post-necropsy quantification,immunohistochemistry,and enzyme-linked immunosorbent assay(ELISA).Results:Compared with wild-type(WT)control mice,NSD2^(fl/fl)-Vil1-Cre mice exhib-ited significantly decreased tumor numbers,histopathological changes,and cytokine expression in colorectal tumors.Conclusions:Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.展开更多
Background:Breast cancer is the most common cancer in women,and in advanced stages,it often metastasizes to the brain.However,research on the biological mechanisms of breast cancer brain metastasis and potential thera...Background:Breast cancer is the most common cancer in women,and in advanced stages,it often metastasizes to the brain.However,research on the biological mechanisms of breast cancer brain metastasis and potential therapeutic targets are limited.Methods:Differential gene expression analysis(DEGs)for the datasets GSE43837 and GSE125989 from the GEO database was performed using online analysis tools such as GEO2R and Sangerbox.Further investigation related to SULF1 was conducted using online databases such as Kaplan-Meier Plotter and cBioPortal.Thus,expression levels,variations,associations with HER2,biological processes,and pathways involv-ing SULF1 could be analyzed using UALCAN,cBioPortal,GEPIA2,and LinkedOmics databases.Moreover,the sensitivity of SULF1 to existing drugs was explored using drug databases such as RNAactDrug and CADSP.Results:High expression of SULF1 was associated with poor prognosis in advanced breast cancer brain metastasis and was positively correlated with the expression of HER2.In the metastatic breast cancer population,SULF1 ranked top among the 16 DEGs with the highest mutation rate,reaching 11%,primarily due to amplification.KEGG and GSEA analyses revealed that the genes co-expressed with SULF1 were positively enriched in the‘ECM-receptor interaction’gene set and negatively enriched in the‘Ribosome’gene set.Currently,docetaxel and vinorelbine can act as treatment options if the expression of SULF1 is high.Conclusions:This study,through bioinformatics analysis,unveiled SULF1 as a poten-tial target for treating breast cancer brain metastasis(BM).展开更多
Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has no...Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has not been explored yet.This study aimed to investigate KIF13B’s role and underlying mechanism in MAFLD and proposes it as a potential pharmacological target.Methods:We assessed KIF13B expression in MAFLD patients and rodent models.The roles of Kif13b in lipid metabolism and MAFLD were investigated using whole-body Kif13b knockout mice,hepatocyte-specific Kif13b-deficient mice and hamsters exposed to different diets.The underlying mechanisms by which Kif13bgoverned hepatic lipid homeostasis and MAFLD progression were explored in vitro.Finally,the Kif13b’s impact on atherosclerotic development was studied in the context of MAFLD.Results:KIF13B expression was reduced in patients and murine models with MAFLD.Rodents with global or liver-specific knockout of the Kif13b gene exhibit spontaneous hepatic steatosis,which is further exacerbated by different overnutrition diets.Overexpression of human KIF13B by lentivirus effectively prevented metabolic dysfunction-associated steatohepatitis(MASH)in methionine-choline-deficient diet(MCD)-fed mice.Furthermore,Kif13b deficiency accelerates atherosclerosis in the context of MAFLD.Mechanistically,Kif13b depletion increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation.Further screening reveals that Kif13b interacts with AMP-activated catalytic subunit alpha 1(AMPKα1)to regulate the phosphorylation of AMPKα1,governing mitochondrial homeostasis and suppressing sterol regulatory element binding protein 1(Srebp1)-mediated denovo lipogenesis in the liver.Conclusion:This work establishes a causal relationship between KIF13B deficiency and MAFLD,emphasizing KIF13B as a potential therapeutic target for treating MAFLD.展开更多
Background:Alzheimer's disease(AD)and lung cancer are leading causes of mortality among the older population.Epidemiological evidence suggests an antagonistic relationship between them,whereby patients with AD exh...Background:Alzheimer's disease(AD)and lung cancer are leading causes of mortality among the older population.Epidemiological evidence suggests an antagonistic relationship between them,whereby patients with AD exhibit a reduced risk of developing cancer and vice versa.However,the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.Methods:To this end,we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane.We visualized and quantified surface lung tumor colonies,assessed pathological parameters associated with lung cancer and AD using histopathological analysis,and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.Results:Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type(WT)group.The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress.Moreover,greater CD8^(+)T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8^(+)T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.Conclusion:This study identified essential mechanisms through which AD suppresses lung tumorigenesis,thereby providing targets for potential therapeutic interventions in these diseases.展开更多
Background:C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons.However,its function is still not clear.We established C1ql3-deficient rats to investigate the role of C...Background:C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons.However,its function is still not clear.We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain.Methods:C1ql3 knockout(KO)rats were generated using CRISPR/Cas9.C1ql3 KO was determined by polymerase chain reaction(PCR),DNA sequencing,and western blot-ting.Microglia morphology and cytokine expression with or without lipopolysaccha-ride(LPS)stimulus were analyzed using immunohistochemistry and real-time PCR.The brain structure changes in KO rats were examined using magnetic resonance imaging.Neuronal architecture alteration was analyzed by performing Golgi staining.Behavior was evaluated using the open field test,Morris water maze test,and Y maze test.Results:C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia,whereas C1ql3 KO did not in-fluence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10.C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation.The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats.C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density.C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory.Conclusions:C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation,resulting in hyperactive behavior and impaired short memory in rats,which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.展开更多
Background:Globally,breast cancer constitutes the predominant malignancy in women.Abnormal regulation of epigenetic factors plays a key role in the development of tumors.Anti-apoptosis is a characteristic of tumor cel...Background:Globally,breast cancer constitutes the predominant malignancy in women.Abnormal regulation of epigenetic factors plays a key role in the development of tumors.Anti-apoptosis is a characteristic of tumor cells.Therefore,exploring and identifying relevant epigenetic factors that regulate the apoptosis of tumor cells is the foundation for clarifying the pathogenesis of tumors and achieving precision antitumor therapy.Method:This study focused on exploring the epigenetic mechanism of FOXK1 in the development of estrogen receptor-positive(ER^(+))breast cancer.We used overexpressing FLAG-FOXK1 MCF-7 cells to perform silver staining mass spectrometry analysis and conducted Co-IP experiments to verify the interactions.ChIP-seq was conducted on MCF-7 cells to examine FOXK1's binding across the genome and its transcriptional target sites.To validate the ChIP-seq results,qChIP,western blotting,and quantitative polymerase chain reaction(qPCR)were performed.Through TUNEL assay,cell counting assay,colony formation assay,and the mouse xenograft models,the effect of FOXK1 on breast cancer progression was detected.Finally,by analyzing online databases,the correlation between FOXK1 and the survival of breast cancer patients was examined.Results:FOXK1 interacts with the REST/CoREST transcriptional corepression complex to transcriptionally inhibit target genes representing the apoptotic pathway.Abnormally high expression of FOXK1 prevents the apoptosis of ER+breast cancer cells in vitro and promotes ER+breast tumor progression in vivo.Furthermore,the expression of FOXK1 is negatively correlated with the survival of ER+breast cancer patients.Conclusion:FOXK1 promotes ER+breast carcinogenesis through anti-apoptosis and acts as a potential target for ER+breast cancer treatment.展开更多
Colorectal cancer is the third most common malignant tumor globally.The current clinical therapeutic outcome is often jeopardized by the complex pathological process that is highly heterogenous among individual patien...Colorectal cancer is the third most common malignant tumor globally.The current clinical therapeutic outcome is often jeopardized by the complex pathological process that is highly heterogenous among individual patients.It becomes increasingly critical for successful treatments to have diverse valid therapeutic options in clinic,which urgently demands efficient preclinical animal model to develop new drug and screen effective and safe clinical interventions.Patient-derived xenograft(PDX)mouse models,created by implanting fresh tumor tissue into immunodeficient or humanized mice,serve as a crucial resource in translational cancer research.These models closely replicate the tissue,cellular,and genetic characteristics of the original tumors,supporting their use in precision medicine,drug discovery,biomarker research,and studies of drug resistance.However,repeated transplantation can introduce genomic instability,molecular shifts,and phenotype variability.This article explores the development,advantages,limitations,and future directions of PDX models in preclinical cancer research.展开更多
基金Young Elite Scientists Sponsorship Program by CAST(YESS:2019QNRC001)National Natural Science Foundation of China Grant(31970510,81941012)+1 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)grant(2021-1-I2M-034)SAFEA:Introduction of Overseas Talents in Cultural and Educational Sector(G20190001626).
文摘1|INTRODUCTION For decades,experimental animal models have been powerful tools for biomedical research and have supported most of the physiological or medical achievements recognized by Nobel Prizes,including the research that won this year's Physiology or Medicine Prize.On 4th October 2021,the Nobel Prize in Physiology or Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian"for their discoveries of receptors for temperature and touch."1 Their discoveries have profoundly changed our view of how we sense the world around us2.
基金National Natural Science Foundation of China,Grant/Award Number:82270289Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CAMS),Grant/Award Number:2021-I2M-1-035the National key research and development program,Grant/Award Number:2022YFF0710600。
文摘Although hypertension is a frequently seen chronic condition across the world,its exact cause remains unclear.Animal models are beneficial for clarifying the pathogenic mechanism of hypertension and examining new treatments.An optimal animal model for studies on hypertension must well mimic human-like hemodynamics and pathophysiological structural modification,showing human disease features and complications timely or even ahead of time.A review of the most frequently used hypertensive animal models available,including small and large animals,induced and genetic models,would provide an insight into the appropriate targets to be addressed in the development of different hypertensive animal models.Another focus of the review are the processes of target-organs injury caused by high blood pressure,which mainly influences human health.
基金National Natural Science Foundation of China Grant(81941012)CAMS initiative for Innovative Medicine of China(2021-I2 M-1-034)National Key Research and Development Project(2017YFA0105200).
文摘Alzheimer's disease(AD)is a neurodegenerative disorder.The pathology of AD is characterized by extracellular amyloid beta(Aβ)plaques,neurofibrillary tangles com-posed of hyperphosphorylated tau,neuronal death,synapse loss,and brain atrophy.Many therapies have been tested to improve or at least effectively modify the course of AD.Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease.Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction,although certain weak-nesses or limitations need to be overcome.This review recapitulates rodent models for AD,the therapeutic efficacy of stem cells,influencing factors,and the underlying mechanisms behind these changes.Stem cell therapy provides perspective and chal-lenges for its clinical application in the future.
基金Chinese Academy of Medical Sciences Initiative for Innovative MedicineGrant/Award Number:2021-I2M-1-035+3 种基金Beijing Municipal Natural Science FoundationGrant/Award Number:M21027National Key Research and Development Program of ChinaGrant/Award Number:2021YFF0702800。
文摘Background:The continuing emergence of influenza virus has highlighted the value of public databases and related bioinformatic analysis tools in investigating transcriptomic change caused by different influenza virus infections in human and animal models.Methods:We collected a large amount of transcriptome research data related to influenza virus-i nfected human and animal models in public databases(GEO and ArrayExpress),and extracted and integrated array and metadata.The gene expression matrix was generated through strictly quality control,balance,standardization,batch correction,and gene annotation.We then analyzed gene expression in different species,virus,cells/tissues or after antibody/vaccine treatment and imported sample metadata and gene expression datasets into the database.Results:Overall,maintaining careful processing and quality control,we collected 8064 samples from 103 independent datasets,and constructed a comparative transcriptomics database of influenza virus named the Flu-CED database(Influenza comparative expression database,https://flu.com-med.org.cn/).Using integrated and processed transcriptomic data,we established a user-friendly website for realizing the integration,online retrieval,visualization,and exploration of gene expression of influenza virus infection in different species and the biological functions involved in differential genes.Flu-CED can quickly query single and multi-gene expression profiles,combining different experimental conditions for comparative transcriptome analysis,identifying differentially expressed genes(DEGs)between comparison groups,and conveniently finding DEGs.Conclusion:Flu-CED provides data resources and tools for analyzing gene expression in human and animal models infected with influenza virus that can deepen our understanding of the mechanisms underlying disease occurrence and development,and enable prediction of key genes or therapeutic targets that can be used for medical research.
基金National Science and Technology Major Project,Grant/Award Number:2017ZX10304402。
文摘Myelodysplastic syndrome(MDS)is a malignant tumor of the hematological system characterized by long-term,progressive refractory hemocytopenia.In addition,the risk of leukemia is high,and once it develops,the course of acute leukemia is short with poor curative effect.Animal models are powerful tools for studying human diseases and are highly effective preclinical platforms.Animal models of MDS can accurately show genetic aberrations and hematopoietic clone phenotypes with similar cellular features(such as impaired differentiation and increased apoptosis),and symptoms can be used to assess existing treatments.Animal models are also helpful for understanding the pathogenesis of MDS and its relationship with acute leukemia,which helps with the identification of candidate genes related to the MDS phenotype.This review summarizes the current status of animal models used to research myelodysplastic syndrome(MDS).
文摘Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.
基金CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2021-I2M-1-035National Natural Science Foundation of China,Grant/Award Number:31970508。
文摘Background:Liver diseases are a major contributor to both morbidity and mortality.Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal.The use of floxed rat resource has rapidly increased,but the liver-specific Cre rat lines for studying liver diseases and interested genes are limited,especially in a spatially and temporally restricted manner.Methods:RNA sequencing and real-time polymerase chain reaction(PCR)were used to screen and confirm the presence of liver-specific genes.Apoa4-Cre rats and Cyp2c11-Cre rats were produced by CRISPR/Cas9 knockin.Rosa26-imCherry rats were employed to hybridize with the Cre rats to obtain the Apoa4-Cre/Rosa26-imCherry and Cyp2c11-Cre/Rosa26-imCherry rats.The temporal and spatial patterns of Cre expression were determined by the observation of red fluorescence on tis-sue sections.Hematoxylin-eosin stain was used to evaluate the liver histopathologic changes.The blood biochemical analysis of several liver enzymes and liver lipid profile was performed to evaluate the liver function of Cre rats.Results:Apoa4 and Cyp2c11 were identified as two liver-specific genes.Apoa4-Cre and Cyp2c11-Cre rats were produced and hybridized with Rosa26-imCherry rats.The red fluorescence indicated that the Cre recombinases were specially expressed in the juvenile and adult liver and not in other organs of two hybridized rats.All the blood biochemical parameters except low-density lipoprotein(LDL)did not change signifi-cantly in the Cre rats.No histological alterations were detected in the livers of the Cre rats.Conclusions:Liver-specific Apoa4-Cre and Cyp2c11-Cre rats have been established successfully and could be used to study gene knockout,specifically in juvenile and adult liver.
基金National Natural Science Foundation of China,Grant/Award Number:82173399Young Elite Scientists Sponsorship Program by CAST,Grant/Award Number:2022QNRC001+2 种基金Beijing Natural Science Foundation,Grant/Award Number:7252096Beijing Natural Science Foundation-Haidian Original Innovation Joint Fund Project,Grant/Award Number:L222145CAMS&Comparative Medicine Center,PUMC (IACUC approval number:QC24002)
文摘Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce drug resistance or recurrence.Patientderived xenograft(PDX)models are widely used to simulate tumor progression and drug responses,serving as translational tools for precision medicine.This study aimed to establish drug-resistant OSCC PDX models.Human OSCC tissues were transplanted into immunodeficient mice and passaged(P1–P2).At P2(tumor volume:40–80 mm^(3)),mice received cisplatin(1 mg/kg,three times/week)with cetuximab(1 mg/kg,weekly),GSK690693(10 mg/kg,five times/week),or rapamycin(4 mg/kg,five times/week).PDX tissues from groups with less-therapeutic response(manifested as larger tumor volumes)were serially passaged to assess treatment efficacy.Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin–eosin(HE)and immunohistochemical staining after one additional passage and retreatment.Results demonstrated that successive passaging accelerates tumor growth.First-generation treatments showed universal sensitivity.At P2,cisplatin–cetuximab and rapamycin groups remained sensitive,whereas GSK690693 efficacy declined.Continued passaging of GSK690693-treated tumors confirmed resistance,as evidenced by exhibiting enhanced malignant characteristics at histological level.The GSK690693-resistant model was established first,whereas resistant models of other treatment groups were established according to similar protocols.These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution,enabling the development of drug-resistant OSCC models.This study can offer methodological insights for precision therapy of OSCC.
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-034Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01+1 种基金PUMC Innovation Fund for Graduate Students,Grant/Award Number:2017-1001-07National Natural Science Foundation of China,Grant/Award Number:82161138027。
文摘Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).Results:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits.Neuropathology revealed brain atrophy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formaldehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of sporadic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.
基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01 and 2023-PT330-01Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-034National Natural Science Foundation of China,Grant/Award Number:82161138027。
文摘Background:Alzheimer's disease(AD)represents the most prevalent neurodegenerative disorder,with mitochondrial dysfunction being observed in both AD patients and mouse models.Nonetheless,further investigation is required to elucidate the pathogenic genes associated with AD and to develop early diagnostic methodologies centered on mitochondrial function.Methods:In this study,the dataset GSE132903 was retrieved from the GEO database,encompassing both non-demented(ND)control and AD samples.Through the combination of differential expression gene analysis,weighted gene co-expression network analysis,and intersection with mitochondrial database gene sets,four hub genes associated with AD were identified.These four hub genes were subsequently validated in APP/PS1 and 5xFAD mouse models using molecular biology techniques.Results:The hub genes identified through bioinformatics analysis include SYNJ2BP,VDAC1,NUBPL,and COX19.Within the GSE132903 dataset,the expression levels of SYNJ2BP,NUBPL,and COX19 were significantly elevated in the AD group compared to the non-demented(ND)group,whereas VDAC1 expression was reduced in the AD group relative to the ND group.Furthermore,in the hippocampus of APP/PS1 and 5xFAD mouse models,the expression patterns of SYNJ2BP and NUBPL were consistent with the bioinformatics analysis results.Conclusion:Hub genes identified here through bioinformatics and molecular biology may help early diagnosis of AD patients and may also help build new AD models to explore its pathogenesis.
文摘Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 10<sup>14</sup> organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation.
基金National Natural Science Foundation of China,Grant/Award Number 31970508Drug Innovation Major Project,Grant/Award Number 2018ZX09711-001-005Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences,Grant/Award Number CAMS-I2M and 2016-I2M-1-004。
文摘Background: Alzheimer's disease(AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APP^(swe)/PS1^(ΔE9) mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.Methods: Evodiamine and its derivatives were effectively synthesized by EDCImediated condensation at room temperature. These target compounds contained 1 thio-and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H_2O_2-induced cell loss in SH-SY5 Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APP^(swe)/PS1^(ΔE9) mice.Results: In this study, a series of oxo-and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APP^(swe)/PS1^(ΔE9) mice.Conclusion: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.
基金the Central Research Institutes Basic Operating Grants,Grant/Award Number:DWS201512CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2016-I2M-2-006-03National Major Scientific and Technological Special Project for Key Infectious Diseases,Grant/Award Number:2017ZX10304402-001
文摘Background: With the aim of establishing the most comprehensive database of laboratory animal strains, the "laboratory animal strain resources database"(LasDB)was constructed as a searchable online database of all laboratory animal strains,stocks and mutant embryonic stem-cell lines available worldwide, including inbred,outbred, mutant and genetically engineered strains.Methods: MySQL database software was used to construct the LasDB, offering an easy-to-use interface.Results: To date, LasDB has a collection covering data for 21 596 mouse strains,2062 rat strains, 13 monkey strains, 2 hamster strains, 5 dog strains, 5 rabbit strains and more than 50 other laboratory animal strains. LasDB will be continually improved with regular updates of new laboratory animal strains from all over the world.Conclusion: To the best of our knowledge, this is the first database that attempts to systematically integrate all available laboratory animal strain data with the aim of supporting open usage and full resource sharing.
基金supported by the National Key Research and Development Program of China (2022YFF0710705)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-0 13)+2 种基金funding support from the Special Research Fund for Central UniversitiesPeking Union Medical College (3332022182)the 111 Project (B20095)
文摘Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prog-nosis in several types of tumors.Methods:We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells.We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer.The development of colorectal tumors were investigated using post-necropsy quantification,immunohistochemistry,and enzyme-linked immunosorbent assay(ELISA).Results:Compared with wild-type(WT)control mice,NSD2^(fl/fl)-Vil1-Cre mice exhib-ited significantly decreased tumor numbers,histopathological changes,and cytokine expression in colorectal tumors.Conclusions:Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.
基金Peking Union Medical College,Grant/Award Number:3332022182。
文摘Background:Breast cancer is the most common cancer in women,and in advanced stages,it often metastasizes to the brain.However,research on the biological mechanisms of breast cancer brain metastasis and potential therapeutic targets are limited.Methods:Differential gene expression analysis(DEGs)for the datasets GSE43837 and GSE125989 from the GEO database was performed using online analysis tools such as GEO2R and Sangerbox.Further investigation related to SULF1 was conducted using online databases such as Kaplan-Meier Plotter and cBioPortal.Thus,expression levels,variations,associations with HER2,biological processes,and pathways involv-ing SULF1 could be analyzed using UALCAN,cBioPortal,GEPIA2,and LinkedOmics databases.Moreover,the sensitivity of SULF1 to existing drugs was explored using drug databases such as RNAactDrug and CADSP.Results:High expression of SULF1 was associated with poor prognosis in advanced breast cancer brain metastasis and was positively correlated with the expression of HER2.In the metastatic breast cancer population,SULF1 ranked top among the 16 DEGs with the highest mutation rate,reaching 11%,primarily due to amplification.KEGG and GSEA analyses revealed that the genes co-expressed with SULF1 were positively enriched in the‘ECM-receptor interaction’gene set and negatively enriched in the‘Ribosome’gene set.Currently,docetaxel and vinorelbine can act as treatment options if the expression of SULF1 is high.Conclusions:This study,through bioinformatics analysis,unveiled SULF1 as a poten-tial target for treating breast cancer brain metastasis(BM).
基金supported by the National Natural Science Foundation of China(82270479,82070460)the Beijing Natural Science Foundation(7242084 to Xun-De Xian)the National Key Research and Development Program of China from the Ministry of Science and Technology(2021YFF0702802 to Yu-Hui Wang).
文摘Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has not been explored yet.This study aimed to investigate KIF13B’s role and underlying mechanism in MAFLD and proposes it as a potential pharmacological target.Methods:We assessed KIF13B expression in MAFLD patients and rodent models.The roles of Kif13b in lipid metabolism and MAFLD were investigated using whole-body Kif13b knockout mice,hepatocyte-specific Kif13b-deficient mice and hamsters exposed to different diets.The underlying mechanisms by which Kif13bgoverned hepatic lipid homeostasis and MAFLD progression were explored in vitro.Finally,the Kif13b’s impact on atherosclerotic development was studied in the context of MAFLD.Results:KIF13B expression was reduced in patients and murine models with MAFLD.Rodents with global or liver-specific knockout of the Kif13b gene exhibit spontaneous hepatic steatosis,which is further exacerbated by different overnutrition diets.Overexpression of human KIF13B by lentivirus effectively prevented metabolic dysfunction-associated steatohepatitis(MASH)in methionine-choline-deficient diet(MCD)-fed mice.Furthermore,Kif13b deficiency accelerates atherosclerosis in the context of MAFLD.Mechanistically,Kif13b depletion increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation.Further screening reveals that Kif13b interacts with AMP-activated catalytic subunit alpha 1(AMPKα1)to regulate the phosphorylation of AMPKα1,governing mitochondrial homeostasis and suppressing sterol regulatory element binding protein 1(Srebp1)-mediated denovo lipogenesis in the liver.Conclusion:This work establishes a causal relationship between KIF13B deficiency and MAFLD,emphasizing KIF13B as a potential therapeutic target for treating MAFLD.
基金CAMS Innovation Fund for Medical Science,Grant/Award Number:2021-I2M-1-034The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01。
文摘Background:Alzheimer's disease(AD)and lung cancer are leading causes of mortality among the older population.Epidemiological evidence suggests an antagonistic relationship between them,whereby patients with AD exhibit a reduced risk of developing cancer and vice versa.However,the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.Methods:To this end,we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane.We visualized and quantified surface lung tumor colonies,assessed pathological parameters associated with lung cancer and AD using histopathological analysis,and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.Results:Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type(WT)group.The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress.Moreover,greater CD8^(+)T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8^(+)T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.Conclusion:This study identified essential mechanisms through which AD suppresses lung tumorigenesis,thereby providing targets for potential therapeutic interventions in these diseases.
基金The present work was supported by the National Natural Science Foundation(31970508)the National Key Research and Development Program of China(2022YFF0710702).
文摘Background:C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons.However,its function is still not clear.We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain.Methods:C1ql3 knockout(KO)rats were generated using CRISPR/Cas9.C1ql3 KO was determined by polymerase chain reaction(PCR),DNA sequencing,and western blot-ting.Microglia morphology and cytokine expression with or without lipopolysaccha-ride(LPS)stimulus were analyzed using immunohistochemistry and real-time PCR.The brain structure changes in KO rats were examined using magnetic resonance imaging.Neuronal architecture alteration was analyzed by performing Golgi staining.Behavior was evaluated using the open field test,Morris water maze test,and Y maze test.Results:C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia,whereas C1ql3 KO did not in-fluence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10.C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation.The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats.C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density.C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory.Conclusions:C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation,resulting in hyperactive behavior and impaired short memory in rats,which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.
基金Beijing High-Level Innovation and Entrepreneurship Talent Support Plan,Grant/Award Number:G04070024National Natural Science Foundation of China,Grant/Award Number:82073122。
文摘Background:Globally,breast cancer constitutes the predominant malignancy in women.Abnormal regulation of epigenetic factors plays a key role in the development of tumors.Anti-apoptosis is a characteristic of tumor cells.Therefore,exploring and identifying relevant epigenetic factors that regulate the apoptosis of tumor cells is the foundation for clarifying the pathogenesis of tumors and achieving precision antitumor therapy.Method:This study focused on exploring the epigenetic mechanism of FOXK1 in the development of estrogen receptor-positive(ER^(+))breast cancer.We used overexpressing FLAG-FOXK1 MCF-7 cells to perform silver staining mass spectrometry analysis and conducted Co-IP experiments to verify the interactions.ChIP-seq was conducted on MCF-7 cells to examine FOXK1's binding across the genome and its transcriptional target sites.To validate the ChIP-seq results,qChIP,western blotting,and quantitative polymerase chain reaction(qPCR)were performed.Through TUNEL assay,cell counting assay,colony formation assay,and the mouse xenograft models,the effect of FOXK1 on breast cancer progression was detected.Finally,by analyzing online databases,the correlation between FOXK1 and the survival of breast cancer patients was examined.Results:FOXK1 interacts with the REST/CoREST transcriptional corepression complex to transcriptionally inhibit target genes representing the apoptotic pathway.Abnormally high expression of FOXK1 prevents the apoptosis of ER+breast cancer cells in vitro and promotes ER+breast tumor progression in vivo.Furthermore,the expression of FOXK1 is negatively correlated with the survival of ER+breast cancer patients.Conclusion:FOXK1 promotes ER+breast carcinogenesis through anti-apoptosis and acts as a potential target for ER+breast cancer treatment.
基金supported by the National Natural Science Foundation of China(No.82303782)Beijing Natural Science Foundation(No.7252096)+1 种基金the Young Elite Scientists Sponsorship Program by CAST(No.2022QNRC001)the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2023-PT180-01).
文摘Colorectal cancer is the third most common malignant tumor globally.The current clinical therapeutic outcome is often jeopardized by the complex pathological process that is highly heterogenous among individual patients.It becomes increasingly critical for successful treatments to have diverse valid therapeutic options in clinic,which urgently demands efficient preclinical animal model to develop new drug and screen effective and safe clinical interventions.Patient-derived xenograft(PDX)mouse models,created by implanting fresh tumor tissue into immunodeficient or humanized mice,serve as a crucial resource in translational cancer research.These models closely replicate the tissue,cellular,and genetic characteristics of the original tumors,supporting their use in precision medicine,drug discovery,biomarker research,and studies of drug resistance.However,repeated transplantation can introduce genomic instability,molecular shifts,and phenotype variability.This article explores the development,advantages,limitations,and future directions of PDX models in preclinical cancer research.
