Experimental mice play a critical role in biomedical research.The phenotype and application of different substrains vary due to genetic differentiation and variation.To ensure validity and reliability of results,it is...Experimental mice play a critical role in biomedical research.The phenotype and application of different substrains vary due to genetic differentiation and variation.To ensure validity and reliability of results,it is imperative to adhere to standardized experiments and controls.This paper objectively reviews the origin,differentiation,and phenotypic and genetic differences between the C57BL/6 and BALB/c mouse substrains.Furthermore,an optimal selection strategy is proposed based on the genetic quality control technology to facilitate the precise application of these two mouse substrains.展开更多
The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigati...A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.展开更多
Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume respon...Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.展开更多
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal...TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
[Objective]To explore the protective effect of selenomethionine(Se-Met)on oxidative stress and intestinal barrier damage in mice infected with porcine deltacoronavirus(PDCoV)and the potential regulatory mechanism.[Met...[Objective]To explore the protective effect of selenomethionine(Se-Met)on oxidative stress and intestinal barrier damage in mice infected with porcine deltacoronavirus(PDCoV)and the potential regulatory mechanism.[Methods]Forty female C57 mice were randomly grouped as follows:control,Se-Met(0.3 mg/kg Se),PDCoV,and Se-Met+PDCoV(0.3 mg/kg Se).After being fed with or without Se-Met for 23 days,the mice in the PDCoV group and the Se-Met+PDCoV group were administrated with 300μL suspension of PDCoV HNZK-02-P5 strain(1×10^(6)TCID50)by gavage,while those in the other two groups were administered with the same volume of Dulbecco’s Modified Eagle Medium(DMEM).All the mice were observed daily for clinical signs,food intake,and body weight changes until day 28.At five days post-inoculation(dpi),intestinal tissues were collected and PDCoV titers were determined.Hematoxylin staining and eosin staining were used to monitor pathological changes in intestinal tissues.Oxidative stress-related indicators such as malondialdehyde(MDA),superoxide dismutase(SOD),and glutathione peroxidase(GSH-PX)were investigated.The level of ROS in the jejunum tissue was measured via a 2′,7′-dichlorofluorescein diacetate(DCFH-DA)probe.Immunofluorescence was used to analyze the changes of small intestinal tight junction proteins(ZO-1 and Occludin).The mRNA levels of inflammatory cytokines(TNF-α,IL-1β,IL-6,and IL-10),intestinal tight junction proteins(ZO-1 and Occludin),and the Nrf2 signaling pathway-associated factors(Nrf2,HO-1,and NQO1)were determined by RT-qPCR.Western blotting was employed to assess the protein levels of factors related to the Nrf2 signaling pathway.[Results]The results of body weight,food intake,pathological examination,and viral RNA titers in different intestinal tissues revealed that Se-Met might increase the body weight,decrease viral titers in intestinal tissues,and attenuate PDCoV-induced structural damage of intestinal villi in PDCoV-infected mice.Se-Met attenuated PDCoV-induced inflammation by lowering the mRNA levels of major inflammatory cytokines,such as IL-1β,IL-6,and TNFαin the jejunum.Se-Met ameliorated PDCoV-induced intestinal mucosal barrier damage by up-regulating the mRNA levels of ZO-1 and Occludin in the jejunum.Se-Met ameliorated PDCoV-induced oxidative stress by decreasing the levels of ROS and MDA and increasing the levels of GSH-PX and SOD in the jejunum.Se-Met inhibited PDCoV-induced oxidative stress by activating the Nrf2 signaling pathway.[Conclusion]Se-Met may attenuate the intestinal injury in mice infected with PDCoV by activating the Nrf2 signaling pathway,which provides a theoretical basis for the prevention and treatment of PDCoV infection.展开更多
Objective This study aimed to comprehensively investigate the potential protective effects and underlying mechanisms of taurine against dihydrotestosterone(DHT)-induced androgenetic alopecia(AGA)in male C57BL/6 mice,w...Objective This study aimed to comprehensively investigate the potential protective effects and underlying mechanisms of taurine against dihydrotestosterone(DHT)-induced androgenetic alopecia(AGA)in male C57BL/6 mice,with a focus on hair follicle cycle modulation,cellular proliferation/apoptosis,and key related signaling pathways.Methods Six-week-old female C57BL/6 mice were initially used to assess the hair growth-promoting potential of taurine.After acclimatization,they were randomly assigned to three groups(n=8):control(regular drinking water),taurine(drinking water containing 1%taurine),and minoxidil(topical 2%minoxidil,positive control).For the AGA study,male C57BL/6 mice were randomly divided into five groups(n=8):control(physiological saline),DHT(model group,1 mg/d DHT),DHT+low-dose taurine(1 mg/d DHT+2 mg/d taurine),DHT+high-dose taurine(1 mg/d DHT+10 mg/d taurine),and DHT+minoxidil(positive control,1 mg/d DHT+topical 2%minoxidil).One day before treatment initiation,dorsal hair was shaved with scissors,and residual hair was removed using a depilatory cream.DHT and taurine were administered via daily intraperitoneal injection.Hair regrowth was assessed by photographing the depilated area at regular intervals and quantified using a four-point grading system(0-3).Dorsal skin samples were collected on day 14 for histological analysis(H&E staining),immunofluorescence staining(Ki67 for proliferation,TUNEL for apoptosis),ELISA(DHT quantification),RT-qPCR,and Western blot analysis to evaluate the expression of key genes and proteins(androgen receptor(AR),transforming growth factor(TGF)‑β1,TGF‑β2,Dickkopf-1(DKK1)).Results In female mice,taurine supplementation significantly accelerated hair growth,with effects comparable to minoxidil.This was evidenced by an earlier transition from pink(telogen)to black(anagen)skin and increased hair growth scores.Histological analysis showed that taurine increased hair follicle count and dermal thickness.Immunofluorescence confirmed enhanced keratinocyte proliferation in the hair matrix.In the DHTinduced AGA model,DHT significantly extended the telogen phase,inhibited hair growth,increased skin DHT content,and induced hair follicle miniaturization.Taurine treatment,particularly at the high dose,effectively counteracted these effects:it promoted the telogen-to-anagen transition and improved hair growth scores.Histomorphometric analysis showed that taurine significantly restored DHT-induced reductions in dermal thickness,hair follicle count,hair bulb depth,and follicle size.Taurine treatment also reduced apoptosis and promoted the proliferation of hair follicle cells,as demonstrated by Ki67 and TUNEL assays.Crucially,RT-qPCR and Western blot analyses revealed that DHT significantly up-regulated the expression of AR,TGF‑β1,TGF‑β2,and DKK1 at both mRNA and protein levels in dorsal skin.Taurine administration markedly down-regulated the expression of these pathogenic factors,bringing them closer to the levels observed in the control group.Conclusion Taurine demonstrates significant efficacy in alleviating DHT-induced AGA in male C57BL/6 mice.Its protective effects are mediated through multi-faceted mechanisms.(1)Promoting hair follicle cycle progression:it accelerates the transition from telogen to anagen,counteracting DHT-induced prolongation of the telogen phase.(2)Modulating cellular dynamics:it stimulates the proliferation of hair matrix keratinocytes and reduces DHT-induced apoptosis within hair follicle cells.(3)Suppressing androgen-driven pathogenic pathways:it downregulates the expression of critical molecules in the AGA pathway,including AR,the cytokines TGF-β1 and TGF-β2,and the Wnt pathway inhibitor DKK1.Given its favorable safety profile and multi-targeted action,taurine emerges as a promising novel therapeutic candidate or adjunct for treating AGA.Further investigation into its clinical potential and precise molecular mechanisms is warranted.This study provides a robust preclinical foundation for considering taurine supplementation or topical application in hair loss management strategies.展开更多
Panax notoginseng-steamed chicken(PNSC)is a common medicinal diet in China.In this study,we conducted comprehensive analysis to determine the effect of PNSC on uterine involution in postpartum mice and human umbilical...Panax notoginseng-steamed chicken(PNSC)is a common medicinal diet in China.In this study,we conducted comprehensive analysis to determine the effect of PNSC on uterine involution in postpartum mice and human umbilical vein endothelial cells.The role of the phosphatidylinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(m TOR)pathway in this process was explored.Results showed that PNSC promoted the recovery of endometrial hyperplasia and uterine index in postpartum mice.In vitro and in vivo experiments indicated that PNSC activated PI3K/AKT/m TOR signaling pathway,promoted the proliferation of human umbilical vein endothelial cells(HUVEC),up-regulated the expression of vascular endothelial growth factor(VEGF),and its binding to vascular endothelial growth factor receptor 2(VEGFR2).Moreover,it increased the expression of PCNA,MMP9,and Cyclin D1 in the nucleus.It can also up-regulated the secretion of hormones,such as prolactin(PRL),progesterone(P),as well as the level of VEGF in mice,and down-regulated the secretion of endothelin-1 hormones(ET-1),thereby promoting uterine involution.In conclusion,this study demonstrates that PNSC can regulate angiogenesis to promote uterine involution by activating the PI3K/AKT/mTOR pathway.展开更多
Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safet...Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safety using suitable animal models.In this context,we review the various categories and applications of humanized mice,which have been engrafted with human cells or tissues to mimic the human immune system.These models are extensively utilized in the nonclinical assessment and development of various antibody drugs,acting as a conduit to clinical research.However,several challenges remain,including the limited lifespan of humanized mice,inadequate en-graftment of human cells,and the rudimentary nature of the immune environment in these models.The development of humanized immune system models in mice pre-sents both opportunities and challenges,potentially leading to new insights into the evolution and application of antibody therapeutics.展开更多
BACKGROUND We previously identified miR-10b-5p as a key regulator of gastrointestinal(GI)motility through its essential role in the development and function of interstitial cells of Cajal(ICC),the pacemaker cells of t...BACKGROUND We previously identified miR-10b-5p as a key regulator of gastrointestinal(GI)motility through its essential role in the development and function of interstitial cells of Cajal(ICC),the pacemaker cells of the gut.Loss of miR-10b-5p in ICC im-pairs intestinal motility and contributes to constipation,a common condition in the elderly.Notably,miR-10b-5p is co-expressed with its paralog,miR-10a-5p,in ICC.AIM To investigate the roles of miR-10a-5p and miR-10b-5p in age-associated intestinal dysmotility and assess the therapeutic potential of restoring their expression.METHODS We employed aged mice,mir-10a and mir-10b single and double knockout(KO)models,and human plasma and colon samples across age groups.GI and colonic transit,ICC network integrity,and expression levels of miR-10a/b-5p were eva-luated.Additionally,we tested whether treatment with their microRNA mimics could restore GI motility in aged mice.RESULTS Aged mice exhibited delayed GI and colonic transit,reduced fecal output,and diminished expression of miR-10a-5p and miR-10b-5p,which peaked during late embryonic and early postnatal stages and declined with age.This decline para-lleled ICC network deterioration in the colon.All KO models exhibited impaired motility and ICC loss,with mir-10a KO mice displaying more severe phenotypes than mir-10b KO mice.Double KO mice demonstrated growth retardation and reduced survival,with homozygous mutants living only up to 3 months.Treatment of aged mice with miR-10a-5p and miR-10b-5p mimics encapsu-lated in jetPEI significantly improved GI and colonic motility.Successful delivery to the gut,including the colon,was confirmed.In human samples,both miR-10a/b-5p and KIT expression decreased with age.CONCLUSION miR-10a-5p and miR-10b-5p are essential for ICC maintenance and colonic motility,and their age-related decline contributes to GI dysmotility in both mice and humans.Restoring their levels offers a promising therapeutic stra-tegy for treating age-related constipation and other motility disorders.展开更多
Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Tech...Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.展开更多
Researchers have discovered that mice instinctively exhibit rescue-like behavior towards anesthetized companions-a finding that suggests a biological basis for prosociality.The study,published in PNAS on April 23,2025...Researchers have discovered that mice instinctively exhibit rescue-like behavior towards anesthetized companions-a finding that suggests a biological basis for prosociality.The study,published in PNAS on April 23,2025,was led by Dr.HU Li from the Institute of Psychology of the Chinese Academy of Sciences(IPCAS)and Dr.CHEN Zhoufeng from Washington University School of Medicine and the Shenzhen Medical Academy of Research and Translation.展开更多
Background:Vaccinia virus(VACV)and mpox virus(MPXV)belong to the orthopoxvirus genus and share high genetic similarity,making VACV widely used in the mpox pandemic.CAST/EiJ mice have been widely used for studying orth...Background:Vaccinia virus(VACV)and mpox virus(MPXV)belong to the orthopoxvirus genus and share high genetic similarity,making VACV widely used in the mpox pandemic.CAST/EiJ mice have been widely used for studying orthopoxvirus infection.However,the histopathological features of CAST/EiJ mice with mpox virus(MPXV)and vaccinia virus(VACV)infections have not been fully elucidated.Methods:Four group of CAST/EiJ mice were challenged with low-dose VACV(103 PFU,VACV-L),high-dose VACV(106 PFU,VACV-H),MPXV(106 PFU)or PBS via intraperitoneal route,and the disease signs and body weight were monitored daily.Subsequently,viral loads and titers in the blood and spleen of CAST/EiJ mice were analyzed via qPCR and TCID 50 assay.Finally,the spleen samples were analyzed for histopathological,immunohistochemical and RNA-seq.Results:Herein,we found that VACV-L and MPXV caused splenomegaly via the intraperitoneal route,whereas VACV-H caused rapid lethality with limited splenomegaly.Transcriptome analysis from spleen revealed significant differences in gene expression between VACV-L and VACV-H groups,but the differentially expressed genes induced by splenomegaly between VACV-L and MPXV groups were highly similar.Furthermore,pathway enrichment analysis demonstrated that the VACV-L,VACV-H,and MPXV groups were all associated with the calcium,MAPK,and PI3K-Akt signaling pathway.Compared to the lethal infection observed in VACV-H group,the splenomegaly in the VACV-L and MPXV groups was characterized by extramedullary hematopoiesis and increased macrophages infiltration in the red pulp.Transcriptome analysis of the spleen demonstrated that the Wnt,tumor necrosis factor(TNF),and transforming growth factorβ(TGF-β)signaling pathways may promote splenomegaly by modulating granulocyte infiltration and inflammatory responses.Compared to VACV-L group,the limited splenomegaly but lethality in VACV-H-infected mice might be associated with extensive splenic necrosis,diffuse congestion,and hemorrhage in the red pulp,as well as changes in the cGMP-PKG,Ras signaling,and Fc gamma Rmediated phagocytosis pathways.Conclusions:Our findings systematically compared the pathogenicity of VACV and MPXV in CAST/EiJ mice,incorporating splenic transcriptome analysis to provide insights into the potential molecular mechanism behind orthopoxvirus-induced splenomegaly in CAST/EiJ mice.展开更多
Germ-free mice exhibit profound immunological immaturity.Despite recent studies emphasizing the role of specific bacterium-derived metabolites in immune cell development and differentiation,the mechanisms linking micr...Germ-free mice exhibit profound immunological immaturity.Despite recent studies emphasizing the role of specific bacterium-derived metabolites in immune cell development and differentiation,the mechanisms linking microbiota absence to systemic immune deficits remain incompletely defined.Here,droplet-based single-cell RNA sequencing of bone marrow and peripheral blood from both germ-free and specific pathogen-free mice was performed,identifying 25 transcriptionally distinct cell types.Neutrophil apoptosis was elevated in germ-free mice,potentially due to the absence of niacin dehydrogenase,a metabolite primarily produced by Pseudomonas.In addition,germ-free mice exhibited increased excretion of 5’-methylthioadenosine,enhanced ERK activation driven by reactive oxygen species,and disruption of bone marrow stromal antigen 2 signaling.Monocytes and CD8^(+)T cells from germ-free mice showed diminished responses to interferon-β and interferon-γ,consistent with heightened viral susceptibility.These findings establish a microbiota-dependent regulatory pathway linking immunodeficiency to microbial absence in germ-free mice,confirmed through complementary validation techniques.展开更多
The Japanese encephalitis virus(JEV)causes Japanese encephalitis(JE),a severe disease that primarily affects children and induces significant central nervous system complications.With the widespread adoption of vaccin...The Japanese encephalitis virus(JEV)causes Japanese encephalitis(JE),a severe disease that primarily affects children and induces significant central nervous system complications.With the widespread adoption of vaccination in children,the incidence among older individuals has increased substantially.Despite this epidemiological shift,research on JEV infection in the elderly remains limited.We established JEV infection models using both aged and young mice to explore age-related differences in pathology and underlying mechanisms.Brain tissue samples were analyzed for pathological changes and viral tropism in major cell types.To further characterize immune response variations,we conducted transcriptomic sequencing on the brain tissues following JEV infection.Aged mice exhibited lower mortality,delayed disease progression,and milder brain pathology compared to young mice after JEV infection.Viral titers and infection rates of major brain cell types were similar in both groups.Transcriptomic analysis revealed diminished immune activation and weaker inflammatory responses in aged mice.Additionally,microglial activation and CD8^(+) T cell function were significantly reduced.Interestingly,JEV infection induced the selective recruitment of B cells in the brains of aged mice.These B cells may modulate the effects of CD8^(+) T cells in the disease process.Compared to young mice,aged mice showed enhanced resistance to JEV progression and reduced brain pathology.This resistance was associated with a weakened immune response in the aged brain,rather than differences in viral infection.The specific recruitment of B cells in the brains of aged mice may play a crucial role in limiting disease progression.展开更多
Background:Cannabidiol(CBD)has numerous therapeutic properties,and is used to treat neurological conditions,such as neuroinflammation.However,the optimal dose of CBD to penetrate the brain requires further investigati...Background:Cannabidiol(CBD)has numerous therapeutic properties,and is used to treat neurological conditions,such as neuroinflammation.However,the optimal dose of CBD to penetrate the brain requires further investigation.The primary aim of this study was to use a mouse model and the intrabuccal route for CBD administration to determine the optimal dose at which CBD can penetrate the brain.The secondary aim was to determine whether sex is a confounding factor.Methods:Thirty adult Kramnik mice,divided equally into three groups,were ad-ministered CBD oil intrabuccally at three doses-10,20,and 30 mg/kg,euthanized 6 h later,and whole brain,urine,and blood samples were collected.Liquid chro-matography with tandem mass spectrometry was used to analyze the collected samples.Results:CBD and its three metabolites—7-carboxy cannabidiol(7-COOH-CBD),7-hydroxy cannabidiol(7-OH-CBD)and 6-hydroxy cannabidiol(6-OH-CBD),were identified and quantified in all samples.The 10 and 20 mg/kg doses of CBD produced similar results in the brain,but the group given the 10 mg/kg dose had the least vari-ation.The 30 mg/kg dose yielded the highest abundance of CBD and its metabolites in all samples,but also the greatest variation.Sex only became a confounding factor at 30 mg/kg.Conclusions:This study shows that the intrabuccal route of CBD administration is reliable and the 10 mg/kg dose of CBD is recommended in mice because there were good CBD metabolite concentrations in all samples,with the least variation among the doses,and sex was not a confounder at 10 mg/kg.展开更多
Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology i...Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.展开更多
基金National Key R&D Program of China,Grant/Award Number:2021YFF0703200Key Technology Fund of the National Institutes for Food and Drug Control,Grant/Award Number:GJJS-2022-1-5。
文摘Experimental mice play a critical role in biomedical research.The phenotype and application of different substrains vary due to genetic differentiation and variation.To ensure validity and reliability of results,it is imperative to adhere to standardized experiments and controls.This paper objectively reviews the origin,differentiation,and phenotypic and genetic differences between the C57BL/6 and BALB/c mouse substrains.Furthermore,an optimal selection strategy is proposed based on the genetic quality control technology to facilitate the precise application of these two mouse substrains.
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China,No.82001155(to LL)the Natural Science Foundation of Zhejiang Province,No.LY23H090004(to LL)+5 种基金the Natural Science Foundation of Ningbo,No.2023J068(to LL)the Fundamental Research Funds for the Provincial Universities of Zhejiang Province,No.SJLY2023008(to LL)the College Students'Scientific and Technological Innovation Project(Xin Miao Talent Plan)of Zhejiang Province,No.2022R405A045(to CC)the Student ResearchInnovation Program(SRIP)of Ningbo University,Nos.20235RIP1919(to CZ),2023SRIP1938(to YZ)the K.C.Wong Magna Fund in Ningbo University。
文摘A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.
基金supported by the National Natural Science Foundation of China,No.31930068National Key Research and Development Program of China,Nos.2018YFA0107302 and 2021YFA1101203(all to HX).
文摘Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.
基金supported by the Koeln Fortune Program/Faculty of Medicine,University of Cologne,the Alzheimer Forschung Initiative e.V.(grant#22039,to HZ)open-access funding from the DFG/GRC issued to the University of CologneAlzheimer Forschung Initiative e.V.for Open Access Publishing(a publication grant#P2401,to MAAK)。
文摘TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
文摘[Objective]To explore the protective effect of selenomethionine(Se-Met)on oxidative stress and intestinal barrier damage in mice infected with porcine deltacoronavirus(PDCoV)and the potential regulatory mechanism.[Methods]Forty female C57 mice were randomly grouped as follows:control,Se-Met(0.3 mg/kg Se),PDCoV,and Se-Met+PDCoV(0.3 mg/kg Se).After being fed with or without Se-Met for 23 days,the mice in the PDCoV group and the Se-Met+PDCoV group were administrated with 300μL suspension of PDCoV HNZK-02-P5 strain(1×10^(6)TCID50)by gavage,while those in the other two groups were administered with the same volume of Dulbecco’s Modified Eagle Medium(DMEM).All the mice were observed daily for clinical signs,food intake,and body weight changes until day 28.At five days post-inoculation(dpi),intestinal tissues were collected and PDCoV titers were determined.Hematoxylin staining and eosin staining were used to monitor pathological changes in intestinal tissues.Oxidative stress-related indicators such as malondialdehyde(MDA),superoxide dismutase(SOD),and glutathione peroxidase(GSH-PX)were investigated.The level of ROS in the jejunum tissue was measured via a 2′,7′-dichlorofluorescein diacetate(DCFH-DA)probe.Immunofluorescence was used to analyze the changes of small intestinal tight junction proteins(ZO-1 and Occludin).The mRNA levels of inflammatory cytokines(TNF-α,IL-1β,IL-6,and IL-10),intestinal tight junction proteins(ZO-1 and Occludin),and the Nrf2 signaling pathway-associated factors(Nrf2,HO-1,and NQO1)were determined by RT-qPCR.Western blotting was employed to assess the protein levels of factors related to the Nrf2 signaling pathway.[Results]The results of body weight,food intake,pathological examination,and viral RNA titers in different intestinal tissues revealed that Se-Met might increase the body weight,decrease viral titers in intestinal tissues,and attenuate PDCoV-induced structural damage of intestinal villi in PDCoV-infected mice.Se-Met attenuated PDCoV-induced inflammation by lowering the mRNA levels of major inflammatory cytokines,such as IL-1β,IL-6,and TNFαin the jejunum.Se-Met ameliorated PDCoV-induced intestinal mucosal barrier damage by up-regulating the mRNA levels of ZO-1 and Occludin in the jejunum.Se-Met ameliorated PDCoV-induced oxidative stress by decreasing the levels of ROS and MDA and increasing the levels of GSH-PX and SOD in the jejunum.Se-Met inhibited PDCoV-induced oxidative stress by activating the Nrf2 signaling pathway.[Conclusion]Se-Met may attenuate the intestinal injury in mice infected with PDCoV by activating the Nrf2 signaling pathway,which provides a theoretical basis for the prevention and treatment of PDCoV infection.
基金supported by grants from The National Natural Science Foundation of China(31772690)the Natural Science Foundation of Shanxi Province(201701D121106)PhD Research Startup Foundation of Changzhi Medical College(BS202308)。
文摘Objective This study aimed to comprehensively investigate the potential protective effects and underlying mechanisms of taurine against dihydrotestosterone(DHT)-induced androgenetic alopecia(AGA)in male C57BL/6 mice,with a focus on hair follicle cycle modulation,cellular proliferation/apoptosis,and key related signaling pathways.Methods Six-week-old female C57BL/6 mice were initially used to assess the hair growth-promoting potential of taurine.After acclimatization,they were randomly assigned to three groups(n=8):control(regular drinking water),taurine(drinking water containing 1%taurine),and minoxidil(topical 2%minoxidil,positive control).For the AGA study,male C57BL/6 mice were randomly divided into five groups(n=8):control(physiological saline),DHT(model group,1 mg/d DHT),DHT+low-dose taurine(1 mg/d DHT+2 mg/d taurine),DHT+high-dose taurine(1 mg/d DHT+10 mg/d taurine),and DHT+minoxidil(positive control,1 mg/d DHT+topical 2%minoxidil).One day before treatment initiation,dorsal hair was shaved with scissors,and residual hair was removed using a depilatory cream.DHT and taurine were administered via daily intraperitoneal injection.Hair regrowth was assessed by photographing the depilated area at regular intervals and quantified using a four-point grading system(0-3).Dorsal skin samples were collected on day 14 for histological analysis(H&E staining),immunofluorescence staining(Ki67 for proliferation,TUNEL for apoptosis),ELISA(DHT quantification),RT-qPCR,and Western blot analysis to evaluate the expression of key genes and proteins(androgen receptor(AR),transforming growth factor(TGF)‑β1,TGF‑β2,Dickkopf-1(DKK1)).Results In female mice,taurine supplementation significantly accelerated hair growth,with effects comparable to minoxidil.This was evidenced by an earlier transition from pink(telogen)to black(anagen)skin and increased hair growth scores.Histological analysis showed that taurine increased hair follicle count and dermal thickness.Immunofluorescence confirmed enhanced keratinocyte proliferation in the hair matrix.In the DHTinduced AGA model,DHT significantly extended the telogen phase,inhibited hair growth,increased skin DHT content,and induced hair follicle miniaturization.Taurine treatment,particularly at the high dose,effectively counteracted these effects:it promoted the telogen-to-anagen transition and improved hair growth scores.Histomorphometric analysis showed that taurine significantly restored DHT-induced reductions in dermal thickness,hair follicle count,hair bulb depth,and follicle size.Taurine treatment also reduced apoptosis and promoted the proliferation of hair follicle cells,as demonstrated by Ki67 and TUNEL assays.Crucially,RT-qPCR and Western blot analyses revealed that DHT significantly up-regulated the expression of AR,TGF‑β1,TGF‑β2,and DKK1 at both mRNA and protein levels in dorsal skin.Taurine administration markedly down-regulated the expression of these pathogenic factors,bringing them closer to the levels observed in the control group.Conclusion Taurine demonstrates significant efficacy in alleviating DHT-induced AGA in male C57BL/6 mice.Its protective effects are mediated through multi-faceted mechanisms.(1)Promoting hair follicle cycle progression:it accelerates the transition from telogen to anagen,counteracting DHT-induced prolongation of the telogen phase.(2)Modulating cellular dynamics:it stimulates the proliferation of hair matrix keratinocytes and reduces DHT-induced apoptosis within hair follicle cells.(3)Suppressing androgen-driven pathogenic pathways:it downregulates the expression of critical molecules in the AGA pathway,including AR,the cytokines TGF-β1 and TGF-β2,and the Wnt pathway inhibitor DKK1.Given its favorable safety profile and multi-targeted action,taurine emerges as a promising novel therapeutic candidate or adjunct for treating AGA.Further investigation into its clinical potential and precise molecular mechanisms is warranted.This study provides a robust preclinical foundation for considering taurine supplementation or topical application in hair loss management strategies.
基金supported by National Key Research and Development Plan(2023YFC3503802)Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(C12021B013)+1 种基金Yunnan Major Scientific and Technological Projects(202202AG050021)the National Key Research and Development Program(2021YFD1000201)。
文摘Panax notoginseng-steamed chicken(PNSC)is a common medicinal diet in China.In this study,we conducted comprehensive analysis to determine the effect of PNSC on uterine involution in postpartum mice and human umbilical vein endothelial cells.The role of the phosphatidylinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(m TOR)pathway in this process was explored.Results showed that PNSC promoted the recovery of endometrial hyperplasia and uterine index in postpartum mice.In vitro and in vivo experiments indicated that PNSC activated PI3K/AKT/m TOR signaling pathway,promoted the proliferation of human umbilical vein endothelial cells(HUVEC),up-regulated the expression of vascular endothelial growth factor(VEGF),and its binding to vascular endothelial growth factor receptor 2(VEGFR2).Moreover,it increased the expression of PCNA,MMP9,and Cyclin D1 in the nucleus.It can also up-regulated the secretion of hormones,such as prolactin(PRL),progesterone(P),as well as the level of VEGF in mice,and down-regulated the secretion of endothelin-1 hormones(ET-1),thereby promoting uterine involution.In conclusion,this study demonstrates that PNSC can regulate angiogenesis to promote uterine involution by activating the PI3K/AKT/mTOR pathway.
基金supported by the Independent Research and Development Projects Foundation of Shanghai InnoStar Bio-Techology Co.,Ltd.(H23ZZYF01 and H24ZZYF01).
文摘Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safety using suitable animal models.In this context,we review the various categories and applications of humanized mice,which have been engrafted with human cells or tissues to mimic the human immune system.These models are extensively utilized in the nonclinical assessment and development of various antibody drugs,acting as a conduit to clinical research.However,several challenges remain,including the limited lifespan of humanized mice,inadequate en-graftment of human cells,and the rudimentary nature of the immune environment in these models.The development of humanized immune system models in mice pre-sents both opportunities and challenges,potentially leading to new insights into the evolution and application of antibody therapeutics.
基金Supported by National Institutes of Health Grants,No.R01DK103055(to Ro S)RosVivo Therapeutics,No.AWD-01-00003158(to Ro S)the National Research Foundation of Korea Grant Funded by the Korean Government(MSIT),No.NRF-2021R1C1C2006743(to Kim MS)and No.NRF-2021R1A2C1095311(to Lee MY).
文摘BACKGROUND We previously identified miR-10b-5p as a key regulator of gastrointestinal(GI)motility through its essential role in the development and function of interstitial cells of Cajal(ICC),the pacemaker cells of the gut.Loss of miR-10b-5p in ICC im-pairs intestinal motility and contributes to constipation,a common condition in the elderly.Notably,miR-10b-5p is co-expressed with its paralog,miR-10a-5p,in ICC.AIM To investigate the roles of miR-10a-5p and miR-10b-5p in age-associated intestinal dysmotility and assess the therapeutic potential of restoring their expression.METHODS We employed aged mice,mir-10a and mir-10b single and double knockout(KO)models,and human plasma and colon samples across age groups.GI and colonic transit,ICC network integrity,and expression levels of miR-10a/b-5p were eva-luated.Additionally,we tested whether treatment with their microRNA mimics could restore GI motility in aged mice.RESULTS Aged mice exhibited delayed GI and colonic transit,reduced fecal output,and diminished expression of miR-10a-5p and miR-10b-5p,which peaked during late embryonic and early postnatal stages and declined with age.This decline para-lleled ICC network deterioration in the colon.All KO models exhibited impaired motility and ICC loss,with mir-10a KO mice displaying more severe phenotypes than mir-10b KO mice.Double KO mice demonstrated growth retardation and reduced survival,with homozygous mutants living only up to 3 months.Treatment of aged mice with miR-10a-5p and miR-10b-5p mimics encapsu-lated in jetPEI significantly improved GI and colonic motility.Successful delivery to the gut,including the colon,was confirmed.In human samples,both miR-10a/b-5p and KIT expression decreased with age.CONCLUSION miR-10a-5p and miR-10b-5p are essential for ICC maintenance and colonic motility,and their age-related decline contributes to GI dysmotility in both mice and humans.Restoring their levels offers a promising therapeutic stra-tegy for treating age-related constipation and other motility disorders.
文摘Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.
文摘Researchers have discovered that mice instinctively exhibit rescue-like behavior towards anesthetized companions-a finding that suggests a biological basis for prosociality.The study,published in PNAS on April 23,2025,was led by Dr.HU Li from the Institute of Psychology of the Chinese Academy of Sciences(IPCAS)and Dr.CHEN Zhoufeng from Washington University School of Medicine and the Shenzhen Medical Academy of Research and Translation.
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2023-I2M-2-001National Key Research and Development Project of China,Grant/Award Number:2022YFC2304100 and 2023YFC2309000+1 种基金National Natural Science Foundation of China,Grant/Award Number:82241068 and 82222041Beijing Natural Science Foundation,Grant/Award Number:Z220018。
文摘Background:Vaccinia virus(VACV)and mpox virus(MPXV)belong to the orthopoxvirus genus and share high genetic similarity,making VACV widely used in the mpox pandemic.CAST/EiJ mice have been widely used for studying orthopoxvirus infection.However,the histopathological features of CAST/EiJ mice with mpox virus(MPXV)and vaccinia virus(VACV)infections have not been fully elucidated.Methods:Four group of CAST/EiJ mice were challenged with low-dose VACV(103 PFU,VACV-L),high-dose VACV(106 PFU,VACV-H),MPXV(106 PFU)or PBS via intraperitoneal route,and the disease signs and body weight were monitored daily.Subsequently,viral loads and titers in the blood and spleen of CAST/EiJ mice were analyzed via qPCR and TCID 50 assay.Finally,the spleen samples were analyzed for histopathological,immunohistochemical and RNA-seq.Results:Herein,we found that VACV-L and MPXV caused splenomegaly via the intraperitoneal route,whereas VACV-H caused rapid lethality with limited splenomegaly.Transcriptome analysis from spleen revealed significant differences in gene expression between VACV-L and VACV-H groups,but the differentially expressed genes induced by splenomegaly between VACV-L and MPXV groups were highly similar.Furthermore,pathway enrichment analysis demonstrated that the VACV-L,VACV-H,and MPXV groups were all associated with the calcium,MAPK,and PI3K-Akt signaling pathway.Compared to the lethal infection observed in VACV-H group,the splenomegaly in the VACV-L and MPXV groups was characterized by extramedullary hematopoiesis and increased macrophages infiltration in the red pulp.Transcriptome analysis of the spleen demonstrated that the Wnt,tumor necrosis factor(TNF),and transforming growth factorβ(TGF-β)signaling pathways may promote splenomegaly by modulating granulocyte infiltration and inflammatory responses.Compared to VACV-L group,the limited splenomegaly but lethality in VACV-H-infected mice might be associated with extensive splenic necrosis,diffuse congestion,and hemorrhage in the red pulp,as well as changes in the cGMP-PKG,Ras signaling,and Fc gamma Rmediated phagocytosis pathways.Conclusions:Our findings systematically compared the pathogenicity of VACV and MPXV in CAST/EiJ mice,incorporating splenic transcriptome analysis to provide insights into the potential molecular mechanism behind orthopoxvirus-induced splenomegaly in CAST/EiJ mice.
基金supported by the Science Technology and Innovation Commission of Shenzhen Municipality,China(SGCX20190919142801722)。
文摘Germ-free mice exhibit profound immunological immaturity.Despite recent studies emphasizing the role of specific bacterium-derived metabolites in immune cell development and differentiation,the mechanisms linking microbiota absence to systemic immune deficits remain incompletely defined.Here,droplet-based single-cell RNA sequencing of bone marrow and peripheral blood from both germ-free and specific pathogen-free mice was performed,identifying 25 transcriptionally distinct cell types.Neutrophil apoptosis was elevated in germ-free mice,potentially due to the absence of niacin dehydrogenase,a metabolite primarily produced by Pseudomonas.In addition,germ-free mice exhibited increased excretion of 5’-methylthioadenosine,enhanced ERK activation driven by reactive oxygen species,and disruption of bone marrow stromal antigen 2 signaling.Monocytes and CD8^(+)T cells from germ-free mice showed diminished responses to interferon-β and interferon-γ,consistent with heightened viral susceptibility.These findings establish a microbiota-dependent regulatory pathway linking immunodeficiency to microbial absence in germ-free mice,confirmed through complementary validation techniques.
基金the National Natural Science Foundation of China(82172266to P.G.W.)Natural Science Foundation of Beijing(7232002 to N.G.).
文摘The Japanese encephalitis virus(JEV)causes Japanese encephalitis(JE),a severe disease that primarily affects children and induces significant central nervous system complications.With the widespread adoption of vaccination in children,the incidence among older individuals has increased substantially.Despite this epidemiological shift,research on JEV infection in the elderly remains limited.We established JEV infection models using both aged and young mice to explore age-related differences in pathology and underlying mechanisms.Brain tissue samples were analyzed for pathological changes and viral tropism in major cell types.To further characterize immune response variations,we conducted transcriptomic sequencing on the brain tissues following JEV infection.Aged mice exhibited lower mortality,delayed disease progression,and milder brain pathology compared to young mice after JEV infection.Viral titers and infection rates of major brain cell types were similar in both groups.Transcriptomic analysis revealed diminished immune activation and weaker inflammatory responses in aged mice.Additionally,microglial activation and CD8^(+) T cell function were significantly reduced.Interestingly,JEV infection induced the selective recruitment of B cells in the brains of aged mice.These B cells may modulate the effects of CD8^(+) T cells in the disease process.Compared to young mice,aged mice showed enhanced resistance to JEV progression and reduced brain pathology.This resistance was associated with a weakened immune response in the aged brain,rather than differences in viral infection.The specific recruitment of B cells in the brains of aged mice may play a crucial role in limiting disease progression.
基金National Research Fund of South Africa(grant number:137792).
文摘Background:Cannabidiol(CBD)has numerous therapeutic properties,and is used to treat neurological conditions,such as neuroinflammation.However,the optimal dose of CBD to penetrate the brain requires further investigation.The primary aim of this study was to use a mouse model and the intrabuccal route for CBD administration to determine the optimal dose at which CBD can penetrate the brain.The secondary aim was to determine whether sex is a confounding factor.Methods:Thirty adult Kramnik mice,divided equally into three groups,were ad-ministered CBD oil intrabuccally at three doses-10,20,and 30 mg/kg,euthanized 6 h later,and whole brain,urine,and blood samples were collected.Liquid chro-matography with tandem mass spectrometry was used to analyze the collected samples.Results:CBD and its three metabolites—7-carboxy cannabidiol(7-COOH-CBD),7-hydroxy cannabidiol(7-OH-CBD)and 6-hydroxy cannabidiol(6-OH-CBD),were identified and quantified in all samples.The 10 and 20 mg/kg doses of CBD produced similar results in the brain,but the group given the 10 mg/kg dose had the least vari-ation.The 30 mg/kg dose yielded the highest abundance of CBD and its metabolites in all samples,but also the greatest variation.Sex only became a confounding factor at 30 mg/kg.Conclusions:This study shows that the intrabuccal route of CBD administration is reliable and the 10 mg/kg dose of CBD is recommended in mice because there were good CBD metabolite concentrations in all samples,with the least variation among the doses,and sex was not a confounder at 10 mg/kg.
基金funded by grants from the National Natural Science Foundation of China(grant numbers 82170912 and 82370910)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(No.YSP202404).
文摘Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
