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动物模型与实验医学（英文）
中国实验动物学会、中国医学科学院医学实验动物研究所
动物模型与实验医学（英文）

中国实验动物学会、中国医学科学院医学实验动物研究所

季刊

2096-5451

动物模型与实验医学（英文）/Journal Animal Models and Experimental MedicineCSCD北大核心
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    A comprehensive view on the fisetin impact on colorectal cancer in animal models:Focusing on cellular and molecular mechanisms

    Mohammad Yasin ZamanianNiloofar TaheriMontather F.RamadanYasser Fakri Mustafa...
    591-605页
    查看更多>>摘要：Flavonoids,including fisetin,have been linked to a reduced risk of colorectal cancer(CRC)and have potential therapeutic applications for the condition.Fisetin,a natural flavonoid found in various fruits and vegetables,has shown promise in managing CRC due to its diverse biological activities.It has been found to influence key cell signaling pathways related to inflammation,angiogenesis,apoptosis,and transcription factors.The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms.It impacts the p53 pathway,leading to increased levels of p53 and decreased levels of murine double minute 2,contributing to apoptosis induction.Fisetin also triggers the release of important components in the apoptotic process,such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pl and cytochrome c.Furthermore,fisetin inhibits the cyclooxygenase-2 and wingless-related integration site(Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways,reducing Wnt target gene expression and hindering colony formation.It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4,reducing retinoblastoma protein phosphorylation,decreasing cyclin E levels,and increasing p21 levels,ulti-mately influencing E2 promoter binding factor 1 and cell division cycle 2(CDC2)protein levels.Additionally,fisetin exhibits various effects on CRC cells,including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase,promoting the phosphorylation of extracellular signal-regulated kinase 1/2,and disrupting the repair process of DNA double-strand breaks.Moreover,fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α(PIK3CA)-mutant CRC,resulting in a reduction in phos-phatidylinositol-3 kinase(PI3K)expression,Ak strain transforming phosphorylation,mTOR activity,and downstream target proteins in CRC cells with a PIK3CA mutation.These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.
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    The activation of adenosine monophosphate-activated protein kinase inhibits the migration of tongue squamous cell carcinoma cells by targeting Claudin-1 via epithelial-mesenchymal transition

    Xin-Yue ZhouQiu-Ming LiuZhuang LiXia-Yang Liu...
    606-616页
    查看更多>>摘要：Background:The role of Claudin-1 in tongue squamous cell carcinoma(TSCC)metas-tasis needs further clarification,particularly its impact on cell migration.Herein,our study aims to investigate the role of Claudin-1 in TSCC cell migration and its underly-ing mechanisms.Methods:36 TSCC tissue samples underwent immunohistochemical staining for Claudin-1.Western blotting and immunofluorescence analyses were conducted to evaluate Claudin-1 expression and distribution in TSCC cells.Claudin-1 knockdown cell lines were established using short hairpin RNA transfection.Migration effects were assessed through wound healing assays.Furthermore,the expression of EMT-associated molecules was measured via western blotting.Results:Claudin-1 expression decreased as TSCC malignancy increased.Adenosine monophosphate-activated protein kinase(AMPK)activation led to increased Claudin-1 expression and membrane translocation,inhibiting TSCC cell migration and epithelial-mesenchymal transition(EMT).Conversely,Claudin-1 knockdown reversed these inhibitory effects on migration and EMT caused by AMPK activation.Conclusions:Our results indicated that AMPK activation suppresses TSCC cell migra-tion by targeting Claudin-1 and EMT pathways.
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    Single-cell analysis of tumor microenvironment and cell adhesion reveals that interleukin-1 beta promotes cancer cell proliferation in breast cancer

    Wenyan WangGehong DongZiguo YangShaoxiang Li...
    617-625页
    查看更多>>摘要：Background:Triple-negative breast cancer(TNBC),which is so called because of the lack of estrogen receptors(ER),progesterone receptors(PR),and human epidermal growth factor receptor 2(HER2)receptors on the cancer cells,accounts for 10％-15％of all breast cancers.The heterogeneity of the tumor microenvironment is high.However,the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood.Methods:We analyzed single-cell RNA sequencing data from five HER2 positive,12 ER positive/PR positive,and nine TNBC samples.The potential targets were validated by immunohistochemistry.Results:Plasma cells were enriched in TNBC samples,which was consistent with validation using data from The Cancer Genome Atlas.Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion mol-ecule 2-integrin-aLb2 complex,and then release interleukin 1 beta(IL1B),as verified by immunohistochemistry,ultimately promoting tumor growth.Conclusion:Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.
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    Aurora B facilitates cholangiocarcinoma progression by stabilizing c-Myc

    Ke LiuXuxuan ZhouFei HuangLihao Liu...
    626-640页
    查看更多>>摘要：Background:Cholangiocarcinoma(CCA),a malignancy that arises from biliary epithe-lial cells,has a dismal prognosis,and few targeted therapies are available.Aurora B,a key mitotic regulator,has been reported to be involved in the progression of various tumors,yet its role in CCA is still unclarified.Methods:Human CCA tissues and murine spontaneous CCA models were used to assess Aurora B expression in CCA.A loss-of-function model was constructed in CCA cells to determine the role of Aurora B in CCA progression.Subcutaneous and liver orthotopic xenograft models were used to assess the therapeutic potential of Aurora B inhibitors in CCA.Results:In murine spontaneous CCA models,Aurora B was significantly upregu-lated.Elevated Aurora B expression was also observed in 62.3％of human speci-mens in our validation cohort(143 CCA specimens),and high Aurora B expression was positively correlated with pathological parameters of tumors and poor sur-vival.Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide(HDO)or an Aurora B kinase inhibitor(AZD1152)significantly suppressed CCA progres-sion via G2/M arrest induction.An interaction between Aurora B and c-Myc was found in CCA cells.Targeting Aurora B significantly reduced this interaction and accelerated the proteasomal degradation of c-Myc,suggesting that Aurora B pro-moted the malignant properties of CCA by stabilizing c-Myc.Furthermore,sequen-tial application of AZD1152 or Aurora B HDO drastically improved the efficacy of gemcitabine in CCA.Conclusions:Aurora B plays an essential role in CCA progression by modulating c-Myc stability and represents a new target for treatment and chemosensitization in CCA.
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    Role of short-chain fatty acids in host physiology

    Mingyue LiuYubo LuGuoyu XueLe Han...
    641-652页
    查看更多>>摘要：Short-chain fatty acids(SCFAs)are major metabolites produced by the gut microbiota through the fermentation of dietary fiber,and they have garnered significant attention due to their close association with host health.As important mediators between the gut microbiota and the host,SCFAs serve as energy substrates for intestinal epithelial cells and maintain homeostasis in host immune and energy metabolism by influencing host epigenetics,activating G protein-coupled receptors,and inhibiting pathogenic microbial infections.This review provides a comprehensive summary of SCFAs synthesis and metabolism and offering an overview of the latest research progress on their roles in protecting gut health,enhancing energy metabolism,mitigating diseases such as cancer,obesity,and diabetes,modulating the gut-brain axis and gut-lung axis,and promoting bone health.
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    Pharmacological effects of bioactive agents in earthworm extract:A comprehensive review

    Zihan ZhuXinyi DengWenqing XieHengzhen Li...
    653-672页
    查看更多>>摘要：This review compiles information from the literature on the chemical composition,pharmacological effects,and molecular mechanisms of earthworm extract(EE)and suggests possibilities for clinical translation of EE.We also consider future trends and concerns in this domain.We summarize the bioactive components of EE,including G-90,lysenin,lumbrokinase,antimicrobial peptides,earthworm serine protease(ESP),and polyphenols,and detail the antitumor,antithrombotic,antiviral,antibacterial,anti-inflammatory,analgesic,antioxidant,wound-healing,antifibrotic,and hypoglyce-mic activities and mechanisms of action of EE based on existing in vitro and in vivo studies.We further propose the potential of EE for clinical translation in anticancer and lipid-modifying therapies,and its promise as source of a novel agent for wound healing and resistance to antibiotic tolerance.The earthworm enzyme lumbrokinase embodies highly effective anticoagulant and thrombolytic properties and has the ad-vantage of not causing bleeding phenomena due to hyperfibrinolysis.Its antifibrotic properties can reduce the excessive accumulation of extracellular matrix.The glycoli-poprotein extract G-90 can effectively scavenge reactive oxygen groups and protect cellular tissues from oxidative damage.Earthworms have evolved a well-developed defense mechanism to fight against microbial infections,and the bioactive agents in EE have shown good antibacterial,fungal,and viral properties in in vitro and in vivo experiments and can alleviate inflammatory responses caused by infections,effec-tively reducing pain.Recent studies have also highlighted the role of EE in lowering blood glucose.EE shows high medicinal value and is expected to be a source of many bioactive compounds.
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    Applications and advancements in animal models for antiviral research on mosquito-borne arboviruses

    Megan Caifeng TangKa Heng WongAdzzie Shazleen AzmanRafidah Lani...
    673-684页
    查看更多>>摘要：Vector-borne diseases caused by arthropod-borne viruses(arboviruses)are a con-siderable challenge to public health globally.Mosquito-borne arboviruses,such as Chikungunya,Dengue,and Zika viruses,cause a range of human illnesses and may be fatal.Currently,efforts to control these diseases still face challenges due to growing vector resistance towards insecticides,urbanization,and limited effective antiviral treatments and vaccines.Animal models are crucial in antiviral research on mosquito-borne arboviruses,playing a role in understanding disease mechanisms,vaccine development,and toxicity testing,but the application of animal models still faces the challenges of ethical considerations and animal-to-human translational suc-cess.Genetically engineered mouse models,hamster models and non-human primate(NHP)are currently used in arbovirus research,but new models such as tree shrews and novel humanized mice are emerging.In the context of Malaysian research,the use of long-tailed macaques as potential NHP models for arbovirus research is possible;however,it faces the ethical dilemma of using an endangered species for scientific purposes.Overall,animal models play a crucial role in advancing infectious disease research,but a balance between medical research and species conservation must be upheld.
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    Adipose-derived mesenchymal stem cell-incorporated PLLA porous microspheres for cartilage regeneration

    Chang GaoWenlong YuanDongcheng WangXin Zhang...
    685-695页
    查看更多>>摘要：Background:In facial plastic surgery,patients with nasal deformity are often treated by rib cartilage transplantation.In recent years,cartilage tissue engineering has developed as an alternative to complex surgery for patients with minor nasal defects via injection of nasal filler material.In this study,we prepared an injectable nasal filler material containing poly-L-lactic acid(PLLA)porous microspheres(PMs),hyaluronic acid(HA)and adipose-derived mesenchymal stem cells(ADMSCs).Methods:We seeded ADMSCs into as-prepared PLLA PMs using our newly invented centrifugation perfusion technique.Then,HA was mixed with ADMSC-incorporated PLLA PMs to form a hydrophilic and injectable cell delivery system(ADMSC-incorporated PMH).Results:We evaluated the biocompatibility of PMH in vitro and in vivo.PMH has good injectability and provides a favorable environment for the proliferation and chondrogenic differentiation of ADMSCs.In vivo experiments,we observed that PMH has good biocompatibility and cartilage regeneration ability.Conclusion:In this study,a injectable cell delivery system was successfully constructed.We believe that PMH has potential application in cartilage tissue engineering,especially in nasal cartilage regeneration.
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    LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD-fed mice

    Xingxian GuoJiangxia PuZiqi TangCan Jia...
    696-706页
    查看更多>>摘要：Background:LDL receptor-related protein-1(LRP1)is a cell-surface receptor that functions in diverse physiological pathways.We previously demonstrated that hepatocyte-specific LRP1 deficiency(hLRP1KO)promotes diet-induced insulin re-sistance and increases hepatic gluconeogenesis in mice.However,it remains unclear whether LRP1 regulates hepatic glycogenesis.Methods:Insulin signaling,glycogenic gene expression,and glycogen content were assessed in mice and HepG2 cells.The pcDNA 3.1 plasmid and adeno-associated virus serotype 8 vector(AAV8)were used to overexpress the truncated β-chain(βΔ)of LRP1 both in vitro and in vivo.Results:On a normal chow diet,hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content.Moreover,LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose-and time-dependent manner.Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3β,increased levels of phosphorylated glycogen synthase(GYS),and dimin-ished glycogen synthesis in insulin-stimulated HepG2 cells,which was restored by exogenous expression of the βΔ-chain.By contrast,AAV8-mediated hepatic βΔ-chain overexpression significantly improved the insulin signaling pathway,thus activating glycogenesis and enhancing glycogen storage in the livers of high-fat diet(HFD)-fed mice.Conclusion:Our data revealed that LRP1,especially its β-chain,facilitates hepatic glycogenesis by improving the insulin signaling pathway,suggesting a new therapeutic strategy for hepatic insulin resistance-related diseases.
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    The ever-changing microenvironment of Staphylococcus aureus in cutaneous infections

    Zhenru ZhouJing TianShi LiLiyue Fei...
    707-716页
    查看更多>>摘要：Background:Staphylococcus aureus is responsible for the majority of skin and soft tissue infections,which are often diagnosed at a late stage,thereby impacting treatment efficacy.Our study was designed to reveal the physiological changes at different stages of infection by S.aureus through the combined analysis of variations in the skin microenvironment,providing insights for the diagnosis and treatment of S.aureus infections.Methods:We established a murine model of skin and soft tissue infection with S.aureus as the infectious agent to investigate the differences in the microenvironment at different stages of infection.By combining analysis of the host immune status and histological observations,we elucidate the progression of S.aureus infection in mice.Results:The results indicate that the infection process in mice can be divided into at least two stages:early infection(1-3 days post-infection)and late infection(5-7days post-infection).During the early stage of infection,notable symptoms such as erythema and abundant exudate at the infection site were observed.Histological examination revealed infiltration of numerous neutrophils and bacterial clusters,accompanied by elevated levels of cytokines(IL-6,IL-10).There was a decrease in microbial alpha diversity within the microenvironment(Shannon,Faith's PD,Chao1,Observed species,Simpson,Pielou's E).In contrast,during the late stage of infection,a reduction or even absence of exudate was observed at the infected site,accompanied by the formation of scabs.Additionally,there was evidence of fibroblast proliferation and neovascularization.The levels of cytokines and microbial composition gradually returned to a healthy state.Conclusion:This study reveals synchrony between microbial composition and histological/immunological changes during S.aureus-induced SSTIs.
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