BACKGROUND:Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders,manifested as abnormal hyperplasia of breast tissue.In recent years,traditional Chinese medicine compounds and probi...BACKGROUND:Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders,manifested as abnormal hyperplasia of breast tissue.In recent years,traditional Chinese medicine compounds and probiotics have shown good potential in regulating the endocrine system and improving the intestinal microecology,providing new ideas for the treatment of breast hyperplasia.OBJECTIVE:To explore the effects and mechanisms of traditional Chinese medicine compounds and fermented probiotic compounds on breast hyperplasia in mice,providing new theoretical and experimental bases for the clinical treatment and prevention of breast hyperplasia.METHODS:(1)Network pharmacology tools were used to predict the anti-breast-hyperplasia activity of Herba Gueldenstaedtiae(Euphorbia humifusa),as well as its potential targets and signaling pathways.The databases included:TCMSP,OMIM,GeneCards database,UniProt website,Venny2.1.0 website,Metascape,HERB website,and STRING database,all of which are open-access databases.Network pharmacology can predict and screen key information such as the targets corresponding to the active ingredients of traditional Chinese medicine,disease targets,and action pathways through network analysis and computer-system analysis.Therefore,it has been increasingly widely used in the research of traditional Chinese medicine.(2)A breast hyperplasia model was induced in mice by injecting estrogen and progesterone.Mice in the normal blank group were injected intraperitoneally with normal saline every day.Mice in the model group and drugadministration groups were injected intraperitoneally with estradiol benzoate injection at a concentration of 0.5 mg/kg every day for 25 days.From the 26th day,the injection of estradiol benzoate injection was stopped.Mice in the normal blank group were injected intramuscularly with normal saline every day,and mice in the model group and drug-administration groups were injected intramuscularly with progesterone injection at a concentration of 5 mg/kg for 5 days.After the model was established,each group was given drugs respectively.The normal blank group and the model group were gavaged with 0.2 mL/d of normal saline;the positive blank group(Xiaozheng Pill group)was gavaged with an aqueous solution of Xiaozheng Pill at 0.9 mg/g;the low-,medium-and high-dose groups of Compound Herba Gueldenstaedtiae were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively;the low-,medium-and high-dose groups of traditional Chinese medicine-bacteria fermentation were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively.The administration was continuous for 30 days.RESULTS AND CONCLUSION:(1)The results of network pharmacology research showed that the Compound Herba Gueldenstaedtiae(Euphorbia humifusa)contained 46 active ingredients,which were related to 1213 potential targets.After comparison with 588 known breast-hyperplasia targets,it was speculated that 50 of these targets might be related to the direct effect of the compound on breast hyperplasia.(2)After drug intervention,there was no significant change in the high-dose group of Compound Herba Gueldenstaedtiae compared with the normal blank group.The liver indicators of the other intervention groups all significantly decreased(P<0.05).(3)In terms of kidney and uterine indicators,the medium-dose group of Compound Herba Gueldenstaedtiae decreased significantly compared with the normal blank group(P<0.05).In terms of the uterine index,the model group increased significantly compared with the normal blank group(P<0.01).(4)After 1-month drug treatment,the number of lobules and acini in the breast tissue of the Xiaozheng Pill group,the low,medium,and high-dose group of Compound Herba Gueldenstaedtiae,the low,medium,and highdose groups of traditional Chinese medicine-bacteria fermentation decreased,and the duct openings narrowed.With the increase of drug dose,diffuse hyperplasia of breast tissue was significantly improved.(5)The ELISA results showed that compared with the model group,the estrogen level was lower in the medium-dose group of traditional Chinese medicine-bacteria fermentation after the intervention(P<0.05).In addition,the follicle-stimulating hormone level in the low-dose group of Compound Herba Gueldenstaedtiae was lower than that of the model group(P<0.05).(6)The intervention in the mouse model led to changes in the abundance of short chain fatty acids and intestinal flora in all groups.To conclude,the Compound Herba Gueldenstaedtiae and its probiotic fermentation products significantly improved mammary gland hyperplasia in mice by regulating hormone levels,improving the structure of the gut microbiota,and increasing the content of shortchain fatty acids,providing new ideas and potential sources of drugs for the treatment of breast hyperplasia.展开更多
Objective:To study the potential of Pituranthos chloranthus essential oil(PC)as a chemoprotective agent.Methods:In the in vitro study,cell proliferation were determined in CT26,SW620,and SW480 cells.Cells were exposed...Objective:To study the potential of Pituranthos chloranthus essential oil(PC)as a chemoprotective agent.Methods:In the in vitro study,cell proliferation were determined in CT26,SW620,and SW480 cells.Cells were exposed to in creasing concentrations of PC(0,6.25,12.5,25,50,100,and 200μg/mL).Combination index was calculated by applying the Chou-Talalay method,apoptopsis was analyzed by annexin V/propidium iodide staining,reactive oxygen species accumulation,and theΔψm drop were also assessed.In the in vivo study,mice were divided into 5 groups:the normal control group,the CT26 tumor-bearing group,the CT26 tumor-bearing mice+PC group,the CT26 tumor-bearing mice+cisplatin group,and the CT26 tumor-bearing mice+cisplatin+PC group.Organ coefficients and tumor volume were calculated.Alanine aminotransferase,aspartate aminotransferase,creatinine,and tumor necrosis factor-αlevels were assessed.Results:Cisplatin with PC induced a synergistic effect,allowing for reduced cisplatin dose while maintaining the same therapeutic efficacy.PC-cisplatin combinations inhibited cell viability by significantly inducing apoptosis,increasing reactive oxygen species accumulation and reducing mitochondrial membrane potential.Co-treatment with cisplatin and PC restored organ coefficients,reduced tumor volume,and alleviated nephrotoxicity in CT26 tumor-bearing mice by restoring kidney function markers and ameliorating kidney inflammation status.Conclusions:PC shows a chemoprotective potential by enhancing the antitumor effect of cisplatin while alleviating its side effects.展开更多
Objective:To investigate the effect of Catalpa ovata fruit extract(COFE)on muscle growth and exercise performance in C2C12 myoblasts and mice.Me t h o d s:Cel l viabi l i ty was determined through a 3-(4,5-dimethylthi...Objective:To investigate the effect of Catalpa ovata fruit extract(COFE)on muscle growth and exercise performance in C2C12 myoblasts and mice.Me t h o d s:Cel l viabi l i ty was determined through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Myogenic differentiation was observed using Giemsa staining.COFE was administered to mice orally at 50 and 200 mg/kg for 10 weeks.Muscular strength was evaluated using the whole-limb grip strength assay.The expression levels of myogenesis-and energy metabolism-related proteins in vitro and in vivo were determined using Western blotting.Results:COFE significantly improved myoblast-to-myotube differentiation in C2C12 myoblasts.It also increased the expression of myogenesis determination protein 1 and myogenin compared with the control group.Moreover,the expression levels of glucose transporter type 4(Glut4)and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha(PGC-1α)were significantly elevated in the presence of COFE in C2C12 myoblasts.COFE also markedly increased phosphorylation of AMP-activated protein kinase,which regulates Glut4 and PGC-1αexpression levels in C2C12 myoblasts.Mice treated with COFE showed improved grip strength.Myogenesis-and energy metabolism-related protein levels in muscle tissue were significantly increased in COFE-administered mice.Conclusions:COFE treatment improves exercise performance by controlling myogenesis and energy metabolism in skeletal muscle.COFE has the potential to be used as an effective natural agent for enhancing muscular strength.展开更多
Parkinson’s disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson’s disease indu...Parkinson’s disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.However,the effect of GLP-1 on intrinsic synuclein malfunction remains unclear.In this study,we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms.Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death,reduced pathological aggregation ofα-synuclein,and decreased movement disorders in SncaA53T transgenic mice.Furthermore,Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation,reduced cerebral activation of microglia and astrocytes,and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra.Additionally,Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide,lipopolysaccharide binding protein,interleukin-1β,and interleukin-6.Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice.Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis.Collectively,our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson’s disease.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
Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzhei...Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.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
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
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
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
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
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
Background:P regnancy affects learning and memory in women.Thus,to investigate the effects of pregnancy,the authors examined the brain electrophysiology of pregnant mice.Methods:U sing the whole-c ell patch-c lamp tec...Background:P regnancy affects learning and memory in women.Thus,to investigate the effects of pregnancy,the authors examined the brain electrophysiology of pregnant mice.Methods:U sing the whole-c ell patch-c lamp technique on isolated brain slices,we detected and compared the electrophysiological changes in the hippocampal CA1(HIP CA1)region,medial prefrontal cortex(mPFC),and basolateral amygdala(BLA)among 15 pregnant and 15 nonpregnant mice.Results:In pregnant mice,there was a trend toward an increase in the frequency of miniature excitatory postsynaptic currents(mEPSCs)(p=0.092)and a trend toward a decrease in the amplitude of miniature inhibitory postsynaptic currents(mIPSC)(p=0.071)in the HIP CA1.In the BLA,both the amplitudes of mEPSCs and mIPSCs were significantly reduced(p=0.004 and 0.042,respectively).In the mPFC,the amplitudes of mEPSCs and hyperpolarization-a ctivated currents(Ih),as well as the frequencies of mIPSCs,were higher compared to nonpregnant mice(p=0.035,0.009,and 0.038,respectively).Conclusions:I n pregnant mice,the electrophysiological change in neurons in the mPFC and BLA might contribute to the cognitive and emotional changes during pregnancy.A trend toward electrophysiological change in the HIP CA1 revealed that the mechanism of cognitive change during pregnancy might differ from that of other conditions.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
抓挠“痒痒包”到底是好是坏?这个看似简单的动作背后竟有科学奥秘!Don’t scratch that mosquito(蚊子)bite!Maybe you’ve heard this advice before-and found it hard to follow.So you may already know that scratching can feel ...抓挠“痒痒包”到底是好是坏?这个看似简单的动作背后竟有科学奥秘!Don’t scratch that mosquito(蚊子)bite!Maybe you’ve heard this advice before-and found it hard to follow.So you may already know that scratching can feel good at the time,but may not help in the long run.A study in mice finds that scratching can have both positive and negative effects.展开更多
文摘BACKGROUND:Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders,manifested as abnormal hyperplasia of breast tissue.In recent years,traditional Chinese medicine compounds and probiotics have shown good potential in regulating the endocrine system and improving the intestinal microecology,providing new ideas for the treatment of breast hyperplasia.OBJECTIVE:To explore the effects and mechanisms of traditional Chinese medicine compounds and fermented probiotic compounds on breast hyperplasia in mice,providing new theoretical and experimental bases for the clinical treatment and prevention of breast hyperplasia.METHODS:(1)Network pharmacology tools were used to predict the anti-breast-hyperplasia activity of Herba Gueldenstaedtiae(Euphorbia humifusa),as well as its potential targets and signaling pathways.The databases included:TCMSP,OMIM,GeneCards database,UniProt website,Venny2.1.0 website,Metascape,HERB website,and STRING database,all of which are open-access databases.Network pharmacology can predict and screen key information such as the targets corresponding to the active ingredients of traditional Chinese medicine,disease targets,and action pathways through network analysis and computer-system analysis.Therefore,it has been increasingly widely used in the research of traditional Chinese medicine.(2)A breast hyperplasia model was induced in mice by injecting estrogen and progesterone.Mice in the normal blank group were injected intraperitoneally with normal saline every day.Mice in the model group and drugadministration groups were injected intraperitoneally with estradiol benzoate injection at a concentration of 0.5 mg/kg every day for 25 days.From the 26th day,the injection of estradiol benzoate injection was stopped.Mice in the normal blank group were injected intramuscularly with normal saline every day,and mice in the model group and drug-administration groups were injected intramuscularly with progesterone injection at a concentration of 5 mg/kg for 5 days.After the model was established,each group was given drugs respectively.The normal blank group and the model group were gavaged with 0.2 mL/d of normal saline;the positive blank group(Xiaozheng Pill group)was gavaged with an aqueous solution of Xiaozheng Pill at 0.9 mg/g;the low-,medium-and high-dose groups of Compound Herba Gueldenstaedtiae were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively;the low-,medium-and high-dose groups of traditional Chinese medicine-bacteria fermentation were gavaged with an aqueous solution of the compound medicine at 0.75,1.5,and 3.0 mg/(g·d)respectively.The administration was continuous for 30 days.RESULTS AND CONCLUSION:(1)The results of network pharmacology research showed that the Compound Herba Gueldenstaedtiae(Euphorbia humifusa)contained 46 active ingredients,which were related to 1213 potential targets.After comparison with 588 known breast-hyperplasia targets,it was speculated that 50 of these targets might be related to the direct effect of the compound on breast hyperplasia.(2)After drug intervention,there was no significant change in the high-dose group of Compound Herba Gueldenstaedtiae compared with the normal blank group.The liver indicators of the other intervention groups all significantly decreased(P<0.05).(3)In terms of kidney and uterine indicators,the medium-dose group of Compound Herba Gueldenstaedtiae decreased significantly compared with the normal blank group(P<0.05).In terms of the uterine index,the model group increased significantly compared with the normal blank group(P<0.01).(4)After 1-month drug treatment,the number of lobules and acini in the breast tissue of the Xiaozheng Pill group,the low,medium,and high-dose group of Compound Herba Gueldenstaedtiae,the low,medium,and highdose groups of traditional Chinese medicine-bacteria fermentation decreased,and the duct openings narrowed.With the increase of drug dose,diffuse hyperplasia of breast tissue was significantly improved.(5)The ELISA results showed that compared with the model group,the estrogen level was lower in the medium-dose group of traditional Chinese medicine-bacteria fermentation after the intervention(P<0.05).In addition,the follicle-stimulating hormone level in the low-dose group of Compound Herba Gueldenstaedtiae was lower than that of the model group(P<0.05).(6)The intervention in the mouse model led to changes in the abundance of short chain fatty acids and intestinal flora in all groups.To conclude,the Compound Herba Gueldenstaedtiae and its probiotic fermentation products significantly improved mammary gland hyperplasia in mice by regulating hormone levels,improving the structure of the gut microbiota,and increasing the content of shortchain fatty acids,providing new ideas and potential sources of drugs for the treatment of breast hyperplasia.
基金funded by The Tunisian Ministry of Research and Higher Education.
文摘Objective:To study the potential of Pituranthos chloranthus essential oil(PC)as a chemoprotective agent.Methods:In the in vitro study,cell proliferation were determined in CT26,SW620,and SW480 cells.Cells were exposed to in creasing concentrations of PC(0,6.25,12.5,25,50,100,and 200μg/mL).Combination index was calculated by applying the Chou-Talalay method,apoptopsis was analyzed by annexin V/propidium iodide staining,reactive oxygen species accumulation,and theΔψm drop were also assessed.In the in vivo study,mice were divided into 5 groups:the normal control group,the CT26 tumor-bearing group,the CT26 tumor-bearing mice+PC group,the CT26 tumor-bearing mice+cisplatin group,and the CT26 tumor-bearing mice+cisplatin+PC group.Organ coefficients and tumor volume were calculated.Alanine aminotransferase,aspartate aminotransferase,creatinine,and tumor necrosis factor-αlevels were assessed.Results:Cisplatin with PC induced a synergistic effect,allowing for reduced cisplatin dose while maintaining the same therapeutic efficacy.PC-cisplatin combinations inhibited cell viability by significantly inducing apoptosis,increasing reactive oxygen species accumulation and reducing mitochondrial membrane potential.Co-treatment with cisplatin and PC restored organ coefficients,reduced tumor volume,and alleviated nephrotoxicity in CT26 tumor-bearing mice by restoring kidney function markers and ameliorating kidney inflammation status.Conclusions:PC shows a chemoprotective potential by enhancing the antitumor effect of cisplatin while alleviating its side effects.
基金supported by Project to Make Multi-Ministerial National Biological Research Resources More Advanced Program,Korea Environment Industry&Technology Institute,and funded by Korea Ministry of Environment(grant number RS-2023-00230403).
文摘Objective:To investigate the effect of Catalpa ovata fruit extract(COFE)on muscle growth and exercise performance in C2C12 myoblasts and mice.Me t h o d s:Cel l viabi l i ty was determined through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Myogenic differentiation was observed using Giemsa staining.COFE was administered to mice orally at 50 and 200 mg/kg for 10 weeks.Muscular strength was evaluated using the whole-limb grip strength assay.The expression levels of myogenesis-and energy metabolism-related proteins in vitro and in vivo were determined using Western blotting.Results:COFE significantly improved myoblast-to-myotube differentiation in C2C12 myoblasts.It also increased the expression of myogenesis determination protein 1 and myogenin compared with the control group.Moreover,the expression levels of glucose transporter type 4(Glut4)and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha(PGC-1α)were significantly elevated in the presence of COFE in C2C12 myoblasts.COFE also markedly increased phosphorylation of AMP-activated protein kinase,which regulates Glut4 and PGC-1αexpression levels in C2C12 myoblasts.Mice treated with COFE showed improved grip strength.Myogenesis-and energy metabolism-related protein levels in muscle tissue were significantly increased in COFE-administered mice.Conclusions:COFE treatment improves exercise performance by controlling myogenesis and energy metabolism in skeletal muscle.COFE has the potential to be used as an effective natural agent for enhancing muscular strength.
基金supported by grants from the Jiangxi Provincial Natural Science Foundation,No.20242BAB26134(to XF)the National Natural Science Foundation of China,Nos.82060638(to TC),82060222(to XF),82460237(to XF)+1 种基金the Major Disciplines of Academic and Technical Leaders Project of Jiangxi Province,Nos.20194BCJ22032(to TC),20213BCJL22049(to XF)Science and Technology Plan of Jiangxi Health Planning Committee,No.202210390(to XF).
文摘Parkinson’s disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.However,the effect of GLP-1 on intrinsic synuclein malfunction remains unclear.In this study,we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms.Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death,reduced pathological aggregation ofα-synuclein,and decreased movement disorders in SncaA53T transgenic mice.Furthermore,Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation,reduced cerebral activation of microglia and astrocytes,and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra.Additionally,Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide,lipopolysaccharide binding protein,interleukin-1β,and interleukin-6.Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice.Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis.Collectively,our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson’s disease.
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financially supported by the National Natural Science Foundation of China,No.823 74552 (to WP)the Science and Technology Innovation Program of Hunan Province,No.2022RC1220 (to WP)+1 种基金the Natural Science Foundation of Hunan Province of China,Nos.2020JJ4803 (to WP),2022JJ40723 (to MY)the Scientific Research Launch Project for New Employees of the Second Xiangya Hospital of Central South University (to MY)
文摘Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.
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 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 the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金supported by 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Guangdong Province Medical Research Fund,Grant/Award Number:A2021108。
文摘Background:P regnancy affects learning and memory in women.Thus,to investigate the effects of pregnancy,the authors examined the brain electrophysiology of pregnant mice.Methods:U sing the whole-c ell patch-c lamp technique on isolated brain slices,we detected and compared the electrophysiological changes in the hippocampal CA1(HIP CA1)region,medial prefrontal cortex(mPFC),and basolateral amygdala(BLA)among 15 pregnant and 15 nonpregnant mice.Results:In pregnant mice,there was a trend toward an increase in the frequency of miniature excitatory postsynaptic currents(mEPSCs)(p=0.092)and a trend toward a decrease in the amplitude of miniature inhibitory postsynaptic currents(mIPSC)(p=0.071)in the HIP CA1.In the BLA,both the amplitudes of mEPSCs and mIPSCs were significantly reduced(p=0.004 and 0.042,respectively).In the mPFC,the amplitudes of mEPSCs and hyperpolarization-a ctivated currents(Ih),as well as the frequencies of mIPSCs,were higher compared to nonpregnant mice(p=0.035,0.009,and 0.038,respectively).Conclusions:I n pregnant mice,the electrophysiological change in neurons in the mPFC and BLA might contribute to the cognitive and emotional changes during pregnancy.A trend toward electrophysiological change in the HIP CA1 revealed that the mechanism of cognitive change during pregnancy might differ from that of other conditions.
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.
文摘抓挠“痒痒包”到底是好是坏?这个看似简单的动作背后竟有科学奥秘!Don’t scratch that mosquito(蚊子)bite!Maybe you’ve heard this advice before-and found it hard to follow.So you may already know that scratching can feel good at the time,but may not help in the long run.A study in mice finds that scratching can have both positive and negative effects.
