SOX4 is highly expressed in gastric cancer(GC)and is associated with tumor grade,metastasis and prognosis,however the mechanism is not clear.We report herein that SOX4 was upregulated and overexpression of SOX4 was as...SOX4 is highly expressed in gastric cancer(GC)and is associated with tumor grade,metastasis and prognosis,however the mechanism is not clear.We report herein that SOX4 was upregulated and overexpression of SOX4 was associated with increased expression of the markers of Epithelialemesenchymal transition(EMT)and stemness in clinic patient samples.In vitro,overexpression of SOX4 promoted the invasion as showed by Transwell assay and stemness of GC cells as assessed by sphere formation assay,which was suppressed by silencing SOX4 with shRNA.Further studies showed that SOX4 up-regulated the expression of EMT transcription factors Twist1,snail1 and zeb1 and stemness transcription factors SOX2 and OCT4,and promoted the nuclear translocation of β-catenin.Moreover,we revealed that TGF-β treatment significantly up-regulated the expression of SOX4 and silencing SOX4 reversed TGF-β induced invasion and sphere formation ability of GC cells.Finally,we showed that SOX4 promoted the lung metastasis and tumor formation ability of gastric cancer cells in nude mice.Our results suggest that SOX4 is a target TGF-β signaling and mediates TGF-β-induced EMT and stem cell characteristics of GC cells,revealing a novel role of TGF-β/SOX4 axis in the regulation of malignant behavior of GC.展开更多
AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)...AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.展开更多
Epithelial-mesenchymal transition(EMT)plays an irreplaceable role in the development of silicosis.However,molecular mechanisms of EMT induced by silica exposure still remain to be addressed.Herein,metabolic profiles o...Epithelial-mesenchymal transition(EMT)plays an irreplaceable role in the development of silicosis.However,molecular mechanisms of EMT induced by silica exposure still remain to be addressed.Herein,metabolic profiles of human alveolar type II epithelial cells(A549 cells)exposed directly to silica were characterized using non-targeted metabolomic approaches.A total of 84 differential metabolites(DMs)were identified in silica-treated A549 cells undergoing EMT,which were mainly enriched in metabolisms of amino acids(e.g.,glutamate,alanine,aspartate),purine metabolism,glycolysis,etc.The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica.Remarkably,glutamine catabolism was significantly promoted in the silica-treated A549 cells,and the levels of related metabolites(e.g.,succinate)and enzymes(e.g.,α-ketoglutarate(α-KG)dehydrogenase)were substantially up-regulated,with a preference toα-KG pathway.Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail(zinc finger transcription factor).Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.展开更多
The dark blue pigment(DBP)is a health ingredient from Vaccinium bracteatum Thunb.leaves used as a functional food supplement.However,the details of transepithelial absorption on the intestinal epithelial cells are bar...The dark blue pigment(DBP)is a health ingredient from Vaccinium bracteatum Thunb.leaves used as a functional food supplement.However,the details of transepithelial absorption on the intestinal epithelial cells are barely understood.This study aimed to clarify the absorption properties of DBP in the Caco-2 cell monolayer model and evaluate the effect on the endo-metabolism and barrier function of Caco-2 cells.The results showed that the DBP did not show the dose-dependent toxic effect to Caco-2 cells between 0.25 and 1.5 mg/mL,which did not cause disorder in the normal cell metabolism and absorption activity.The Caco-2 cell monolayer model could absorb DBP by passive and active transport,and the absorptive pattern was dosedependent when the concentration was more than 0.25 mg/mL.During DBP absorption,an increase in m RNA and protein expressions of glucose transporters demonstrated that the glucose transporters were the potential transporter of DBP.But the glucose transport amounts were significantly lowered after 30 min of DBP treatment,indicating that DBP owned the inhibitory effect on glucose transportation.Furthermore,DBP also owned protective effects on the barrier function of intestinal epithelial cells.展开更多
Background Using yeast culture as additives in ruminant feed prevents rumen microbial dysbiosis,enhances performance,and regulates rumen pH.The yeast culture used in this study was developed in-house,and has been show...Background Using yeast culture as additives in ruminant feed prevents rumen microbial dysbiosis,enhances performance,and regulates rumen pH.The yeast culture used in this study was developed in-house,and has been shown to promote rumen epithelial growth in several sheep trials.Changes in protein expression associated with the promotion of rumen epithelial development following the addition of yeast culture,along with the associated molecular mechanisms,remain unknown.We used 2045-day-old weaned lambs to investigate the specific proteins and molecular mechanisms involved in these processes.Half of the lambs were fed yeast culture,and the other half were used as controls.Results Yeast culture enhanced growth performance,facilitated rumen fermentation,and promoted rumen papilla development in weaned lambs.Proteomics data identified 4,831 proteins in the rumen epithelial tissue of lambs,comprising 87 upregulated and 425 downregulated proteins.Administration of yeast culture activated multiple molecular functions within rumen epithelial cells,including oxidative phosphorylation,glutathione metabolism,apoptosis,cell cycle,and vitamin digestion and absorption.The expression of proteins associated with cell cycle regulation increased,whereas those associated with apoptosis decreased.Administration of yeast culture also reduced the duration of the G0/G1 phase of rumen epithelial cells and accelerated the cell cycle.Furthermore,yeast culture showed increased cyclin D1,cyclin-dependent kinase(CDK)2,CDK4,CDK6,and cyclin E1 expressions and decreased cytochrome C(Cyto-c),Bcl-2-related X protein(Bax),cleaved caspase 3(C-caspase 3),caspase 3,and cleaved caspase 7(C-caspase 7)protein expressions.Yeast culture upregulated the insulin-like growth factor-1 receptor(IGF-1R)and insulin-like growth factor-binding protein 5(IGFBP-5)mRNA expressions in rumen epithelial cells.Conclusions Yeast culture facilitates rumen epithelial development by regulating the cell cycle and IGF-1 signaling and reducing the expression of proteins associated with apoptosis in rumen epithelial cells.The findings of this study provide novel insights into the molecular mechanisms through which yeast culture promotes rumen epithelial development in weaned lambs.展开更多
Background Clostridium perfringens is a pathogen that secretes multiple toxins,impacting humans and animals.It can cause intestinal diseases such as necrotic enteritis.Although tannins inhibit C.perfringens proliferat...Background Clostridium perfringens is a pathogen that secretes multiple toxins,impacting humans and animals.It can cause intestinal diseases such as necrotic enteritis.Although tannins inhibit C.perfringens proliferation,the precise underlying mechanisms are unclear.Objective This study integrated transcriptomics and metabolomics to systematically investigate the mechanism by which tannins,specifically pentagalloylglucose(PGG)and tannic acid(TA),inhibit C.perfringens and potential pathways to alleviate infection in vivo.Results Ion concentration measurements,flow cytometric analysis,and transmission electron microscopy revealed that PGG and TA damaged the cell membrane structure of C.perfringens,triggering cytoplasmic content leakage.Additionally,PGG and TA significantly affected C.perfringens at the transcriptional and metabolic levels.Bioinformatics analysis revealed that PGG and TA induced amino acid restriction,disrupted energy metabolism,and impeded the ability of C.perfringens to sense and respond to the external environment.In an in vitro C.perfringens-infected intestinal cell model,PGG and TA boundαtoxin,significantly reduced the mRNA expression of inflammatory factors,and improved intestinal barrier function and cell viability.Compared to PGG,TA exhibited stronger inhibitory activity against C.perfringens and binding toαtoxin.In vivo,PGG and TA alleviated C.perfringens-induced weight loss in mice,improved intestinal villi morphology,and reduced intestinal inflammation and tight junction gene dysregulation.Conclusion These findings indicate that tannins inhibit C.perfringens,improve gut tissue integrity and reduce inflammation,demonstrating their multi-target effects of resisting intestinal diseases caused by harmful bacteria.This offers new insights for plant polyphenol-based strategies against necrotic enteritis.展开更多
The cornea is a transparent tissue that serves as the main refractive element of the eye ball.Limbal epithelial stem cells(LESCs),residing in the basal epithelial layer of the Palisades of Vogt located in the corneal ...The cornea is a transparent tissue that serves as the main refractive element of the eye ball.Limbal epithelial stem cells(LESCs),residing in the basal epithelial layer of the Palisades of Vogt located in the corneal limbus between cornea and scleral,are believed to be crucial for the continuous turnover of the corneal epithelium.The proliferation,migration,and differentiation of the LESCs are modulated by unique physical and chemical futures contained within the microenvironment known as the limbal niche.This niche,composed of nerve terminals,cells,extracellular matrix,vasculature,and signaling molecules,is the home for processes such as proliferation,migration and differentiation.Corneal nerve terminals possess special anatomical structures in the limbal region and basal epithelial cells,and they demonstrate pivotal biological effects in the regulation of the LESC function and corneal epithelium homeostasis.Biological molecules such as neuropeptides,neurotransmitters,and neurotrophic factors play a crucial role in modulating the LESCs phenotype responsible for corneal epithelium homeostasis.This paper will review recent studies on how these nerve derived molecules function in this process and provide clear orientations for future research.展开更多
Adenoid cystic carcinoma of the lacrimal gland(LGACC)is the most common type of malignant epithelial tumor of the lacrimal gland,which is characterized by a high recurrence rate,perineural invasion,and a propensity to...Adenoid cystic carcinoma of the lacrimal gland(LGACC)is the most common type of malignant epithelial tumor of the lacrimal gland,which is characterized by a high recurrence rate,perineural invasion,and a propensity to metastasize to distant sites.Due to its unclear pathogenesis,LGACC has a poor prognosis and a high mortality rate.In recent years,a range of radiotherapy and chemotherapy have been clinically applied,leading to a shift in the treatment approach for LGACC.This article discussed the advances being made in the treatment of LGACC and provides readers with an overview of the impact of LGACC treatment modalities on patient survival and prognostic levels.展开更多
Background Mastitis caused by Staphylococcus aureus(S.aureus)is one of the most intractable problems for the dairy industry,causing significantly reduced milk yields and early slaughter of cows worldwide.MicroRNAs(miR...Background Mastitis caused by Staphylococcus aureus(S.aureus)is one of the most intractable problems for the dairy industry,causing significantly reduced milk yields and early slaughter of cows worldwide.MicroRNAs(miRNAs)can post-transcriptionally regulate gene expression and studies in recent years have shown the importance of miRNA-associated gene regulation in S.aureus-induced mastitis.Results In this study,to investigate the role of miR-223 in mastitis,we performed experiments to overexpress and suppress miR-223 in an immortalized bovine mammary epithelial cell line(MAC-T)infected with S.aureus.Overexpression of miR-223 in MAC-T cells repressed cell apoptosis and necrosis induced by S.aureus infection,whereas suppression of miR-223 had the opposite effect.Transcriptome expression profiling with weighted gene co-expression network analysis(WGCNA)and gene set variation analysis(GSVA)showed that miR-223 affects apoptosis and inflammation-related pathways.Furthermore,differentially expressed(DE)genes were evaluated,and genes exhibiting contrasting expression trends in the miR-223 overexpressed and suppressed groups were assessed as potential target genes of miR-223.Potential target genes,including CDC25B,PTPRF,DCTN1,and DPP9,were observed to be associated with apoptosis and necroptosis.Finally,through integrative analysis of genome-wide association study(GWAS)data and the animal quantitative trait loci(QTL)database,we determined that target genes of miR-223 were significantly enriched in single-nucleotide polymorphisms(SNP)and QTLs related to somatic cell count(SCC)and mastitis.Conclusion In summary,miR-223 has an inhibitory effect on S.aureus-induced cell apoptosis and necrosis by regulating PTPRF,DCTN1,and DPP9.These genes were significantly enriched in QTL regions associated with bovine mastitis resistance,underscoring their relevance in genetic regulation of disease resilience.Our findings provide critical genetic markers for enhancing mastitis resistance,particularly S.aureus-induced mastitis,through selective breeding.This work offers valuable insights for developing cattle with improved resistance to mastitis via targeted genetic selection.展开更多
Background Ferroptosis is characterized by increased production of reactive oxygen species(ROS)and membrane lipid peroxidation that can exacerbate inflammatory damage.Extracellular vesicles(EVs)isolated from bovine mi...Background Ferroptosis is characterized by increased production of reactive oxygen species(ROS)and membrane lipid peroxidation that can exacerbate inflammatory damage.Extracellular vesicles(EVs)isolated from bovine milk have many biological functions,including antioxidant properties.However,the role of EVs on Klebsiella pneumoniaeinduced ferroptosis and oxidative stress in bovine mammary epithelial cells(bMECs)and murine mammary tissue is unclear.In this study,EVs were isolated from bovine colostrum,mature milk and clinical mastitis milk(defined as C-EVs,M-EVs and CM-EVs,respectively)and assessed by transmission electron microscopy,Western blot and transcriptome sequencing.Effects of EVs on K.pneumoniae-induced ferroptosis and oxidative stress in bMECs were evaluated with immunofluorescence and Western blot.Results In bMECs,infection with K.pneumoniae induced oxidative stress,decreasing protein expression of Nrf2,Keap1 and HO-1 plus SOD activity,and increasing ROS concentrations.However,protein expression of GPX4,ACSL4 and S100A4 in bMECs,all factors that regulate ferroptosis,was downregulated by K.pneumoniae.Furthermore,this bacterium compromised tight junctions in murine mammary tissue,with low expression of ZO-1 and Occludin,whereas protein expression of Nrf2 and GPX4 was also decreased in mammary tissue.Adding C-EVs,M-EVs or CMEVs reduced oxidative stress and ferroptosis in K.pneumoniae-infected bMECs in vitro and murine mammary tissues in vivo.Conclusion In conclusion,all 3 sources of milk-derived EVs alleviated oxidative stress and ferroptosis in K.pneumoniae-infected bMECs and mammary tissues.展开更多
The oviduct epithelium is the initial maternal contact site for embryos after fertilization,offering the microenviron-ment before implantation.This early gestation period is particularly sensitive to stress,which can ...The oviduct epithelium is the initial maternal contact site for embryos after fertilization,offering the microenviron-ment before implantation.This early gestation period is particularly sensitive to stress,which can cause reduced fertil-ity and reproductive disorders in mammals.Nevertheless,the local impact of elevated stress hormones on the ovi-duct epithelium has received limited attention to date,except for a few reports on polyovulatory species like mice and pigs.In this study,we focused on the effects of chronic maternal stress on cattle,given its association with infertil-ity issues in this monoovulatory species.Bovine oviduct epithelial cells(BOEC)differentiated at the air–liquid interface(ALI)were stimulated with 250 nmol/L cortisol for 1 or 3 weeks.Subsequently,they were assessed for morphology,bioelectrical properties,and gene expression related to oviduct function,glucocorticoid pathway,cortisol metabo-lism,inflammation,and apoptosis.Results revealed adverse effects of cortisol on epithelium structure,featured by deciliation,vacuole formation,and multilayering.Additionally,cortisol exposure led to an increase in transepithelial potential difference,downregulated mRNA expression of the major glucocorticoid receptor(NR3C1),upregulated the expression of cortisol-responsive genes(FKBP5,TSC22D3),and significant downregulation of oviductal glycopro-tein 1(OVGP1)and steroid receptors PGR and ESR1.The systematic comparison to a similar experiment previously performed by us in porcine oviduct epithelial cells,indicated that bovine cultures were more susceptible to elevated cortisol levels than porcine.The distinct responses between both species are likely linked to their divergence in the cortisol-induced expression changes of HSD11B2,an enzyme controlling the cellular capacity to metabolise cortisol.These findings provide insights into the species-specific reactions and reproductive consequences triggered by maternal stress.展开更多
Pigeons and certain other avian species produce a milklike secretion in their crop sacs to nourish offspring,yet the detailed processes involved are not fully elucidated.This study investigated the crop sacs of 225-da...Pigeons and certain other avian species produce a milklike secretion in their crop sacs to nourish offspring,yet the detailed processes involved are not fully elucidated.This study investigated the crop sacs of 225-day-old unpaired non-lactating male pigeons(MN)and males initiating lactation on the first day after incubation(ML).Using RNA sequencing,ribosomeprofiling,andsingle-cell transcriptome sequencing(scRNA-seq),we identified a significant up-regulation of genes associated with ribosome assembly and protein synthesis in ML compared to MN.Results from scRNA-seq analysis identified 12distinct cell types and 22 clusters,with secretory epithelial cells(SECs)exhibiting marked expression of plasma cell markers,including IGLL1 and MZB1.RNA fluorescence in situ hybridization(RNA FISH)and IgY quantification confirmed the critical role of SECs in producing endogenous IgY during lactation.We propose that fibroblast-derived BAFF signals activate SECs,mimicking B cell transformation and enhancing protein production through the unfolded protein response(UPR).These findings shed light on the cellular dynamics of pigeon milk production and contribute to a broader understanding of avian biology.展开更多
Dear Editor,Historically,dipeptidyl peptidase 4(DPP4),found in alveolar regions,has been recognized as the primary receptor for several merbecoviruses like MERS-CoV(Meyerholz et al.,2016).However,angiotensin-convertin...Dear Editor,Historically,dipeptidyl peptidase 4(DPP4),found in alveolar regions,has been recognized as the primary receptor for several merbecoviruses like MERS-CoV(Meyerholz et al.,2016).However,angiotensin-converting enzyme 2(ACE2),highly expressed in the motile cilia of human airway epithelial cells(Sungnak et al.,2020),has been identified as the functional receptor for sarbecoviruses(e.g.,SARS-CoV-2,SARS-CoV)and setracoviruses(e.g.,HCoV-NL63).Recent studies have shown that some bat-circulating MERS-related coronaviruses(MERSr-CoVs),such as MOW15-22,PnNL2018B and HKU5,can use ACE2 to enter cells(Ma et al.,2025;Park et al.,2025).Even more worrying is that one novel bat-infecting merbecovirus HKU5-CoV lineage 2(BtHKU5-CoV-2)has been reported to use human ACE2 as a cell entry receptor(Chen et al.,2025).These ACE2-utilizing merbecoviruses expand the diversity,geographic distribution,and transmission potential of coronaviruses,posing a significant threat of spillover to humans.If an ACE2-utilizing MERSr-CoV acquire the high lethality of MERS-CoV and the high transmissibility of SARS-CoV-2 using ACE2 as a receptor,it could trigger a global pandemic with catastrophic consequences for humanity.Therefore,it is essential to evaluate serological cross-reactivity in sera from SARS-CoV-2-infected individuals against ACE2-using MERSr-CoVs,and urgent to develop preventive vaccines and pan-coronavirus antivirals confront the potential threat(Jiang and Wu,2025).展开更多
Background:EMP2 is a tumor-associated membrane protein belonging to the GAS-3/PMP22 gene family.EMP2 expression demonstrates significant tissue specificity and heterogeneity in various human tissues and tumor tissues,...Background:EMP2 is a tumor-associated membrane protein belonging to the GAS-3/PMP22 gene family.EMP2 expression demonstrates significant tissue specificity and heterogeneity in various human tissues and tumor tissues,where it may play a role in either promoting or inhibiting tumor growth.This study aimed to investigate the expression level,biological functions,and molecular mechanisms of EMP2 in liver cancer.Methods:we analyzed the mRNA expression levels of EMPs family genes in hepatocellular carcinoma(HCC)tissues and normal liver tissues based on the TCGA database and immunohistochemical analysis of tissue microarrays.Subsequently,we constructed HCC cell lines with either knockdown or overexpression of EMP2 to examine the biological functions and molecular mechanisms of EMP2 in tumorigenesis in vivo and in vitro.Results:Bioinformatic and immunohistochemical analysis of tissue microarrays have confirmed the significant upregulation of EMP2 in HCC tissues.In vitro and in vivo studies have shown that downregulation of EMP2 results in a moderate reduction in the proliferation and invasive capacity of HCC cells.Conversely,overexpression of EMP2 enhances the invasive capacity of HCC cells and induces autophagy.Initial investigations into the molecular mechanisms underlying EMP2-mediated enhancement of HCC cell invasion have revealed the dual regulation of EMP2-induced autophagy and the integrin pathway,which synergistically influence the invasive and metastatic potential of HCC cells.Conclusion:EMP2 holds promise as a diagnostic marker for HCC metastasis and a potential target for targeted therapy.展开更多
Background:Oral cancer remains a significant global health challenge,as it has high morbidity and mortality rates.Current treatments show limited efficacy and have severe side effects,prompting searches for new therap...Background:Oral cancer remains a significant global health challenge,as it has high morbidity and mortality rates.Current treatments show limited efficacy and have severe side effects,prompting searches for new therapeutic agents.SH003,a traditional herbal formulation comprising Astragalus membranaceus,Angelica gigas,and Trichosanthes kirilowii,has demonstrated potential anticancer properties in previous studies.However,its specific efficacy against oral cancer and the role of its key components,particularly Cucurbitacin D,remain underexplored.Methods:The cytotoxic effects of SH003 and its major components—i.e.,Cucurbitacin D,Decursin,Formononetin,and Nodakenin—were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide(MTT),Trypan Blue exclusion,and Lactate Dehydrogenase(LDH)release assays.Cell migration was analyzed via wound healing assays,and apoptosis induction was assessed using cell cycle analysis and caspase activation assays.Epithelial-tomesenchymal transition(EMT)marker expression(E-cadherin and N-cadherin)was measured using Western blotting and Quantitative reverse transcription PCR(qRT-PCR).Results:SH003 significantly reduced cell viability in a dosedependent manner,with YD-8 and YD-9 cells showing greater sensitivity than YD-38 cells.Of the individual compounds,Cucurbitacin D was identified as a key active agent,as it exhibited potent inhibition of cell migration and significant modulation of EMT markers,including the upregulation of E-cadherin and downregulation of N-cadherin.These effects were most pronounced in YD-9 cells.Conclusions:Taken together,these findings suggest that Cucurbitacin D plays a crucial role mediating the anticancer activity of SH003,particularly via the reversal of EMT and the reduction of migratory and invasive potential of oral cancer cells.This study provides valuable insight into the mechanistic basis of SH003,highlighting its potential as a therapeutic agent against oral cancer.Further research,including in vivo studies and clinical trials,is needed to elucidate its precise mechanisms and potential applications against other cancer types.展开更多
Domoic acid(DA),a biotoxin,is produced by several species of marine dinoflagellate and diatom during harmful algal bloom events.DA is a neurotoxin,in humans and non-human primates,oral exposure to DA results in gastro...Domoic acid(DA),a biotoxin,is produced by several species of marine dinoflagellate and diatom during harmful algal bloom events.DA is a neurotoxin,in humans and non-human primates,oral exposure to DA results in gastrointestinal effects,while DA at higher doses leads to neurological symptoms,seizures and memory deficiency.Exposure of humans to DA occurs mainly through consumption of contaminated seafoods containing an accumulation of the toxin.Previously,it was unclear if DA can have toxic effects on the retina.We assessed the toxicity of DA in human retinal cells(ARPE-19)and in zebrafish embryos.DA significantly lowered ARPE-19 cell viability dose-dependently,and decreased anti-oxidative capacity,increased inflammation,and promoted cell death,possibly through modulating the NRF2 and NF-κB signalling pathways.Zebrafish embryos exposed to DA for 4 days from 1 day post fertilization(dpf)had an increase in mortality and a decrease in both hatching and heartbeat rate and exhibited morphological abnormalities.DA treatment also significantly downregulated expression of antioxidant genes and upregulated expression of inflammation mediators,as well as causing photoreceptor death in zebrafish embryos.The results demonstrate that consuming seafood containing DA will have potential toxic effects in human retinas.展开更多
Smoking is a well-established risk factor for periodontitis,yet the precise mechanisms by which smoking contributes to periodontal disease remain poorly understood.Recent advances in spatial transcriptomics have enabl...Smoking is a well-established risk factor for periodontitis,yet the precise mechanisms by which smoking contributes to periodontal disease remain poorly understood.Recent advances in spatial transcriptomics have enabled a deeper exploration of the periodontal tissue microenvironment at single-cell resolution,offering new opportunities to investigate these mechanisms.In this study,we utilized Visium HD single-cell spatial transcriptomics to profile gingival tissues from 12 individuals,including those with periodontitis,those with smoking-associated periodontitis,and healthy controls.Our analysis revealed that smoking disrupts the epithelial barrier integrity,induces fibroblast alterations,and dysregulates fibroblast–epithelial cell communication,thereby exacerbating periodontitis.The spatial analysis showed that endothelial cells and macrophages are in close proximity and interact,which further promotes the progression of smoking-induced periodontal disease.Importantly,we found that targeting the endothelial CXCL12 signalling pathway in smoking-associated periodontitis reduced the proinflammatory macrophage phenotype,alleviated epithelial inflammation,and reduced alveolar bone resorption.These findings provide novel insights into the pathogenesis of smoking-associated periodontitis and highlight the potential of targeting the endothelial–macrophage interaction as a therapeutic strategy.Furthermore,this study establishes an essential information resource for investigating the effects of smoking on periodontitis,providing a foundation for future research and therapeutic development for this prevalent and debilitating disease.展开更多
AIM:To investigate the effect of skullcapflavone II(SCF-II)on the epithelial-mesenchymal transition(EMT)induced by transforming growth factor beta(TGF-β)in human corneal epithelial cells(HCECs),as well as to identify...AIM:To investigate the effect of skullcapflavone II(SCF-II)on the epithelial-mesenchymal transition(EMT)induced by transforming growth factor beta(TGF-β)in human corneal epithelial cells(HCECs),as well as to identify the signaling pathways that may be involved.METHODS:HCECs were cultured in vitro.At a SCFII(5,10μmol/L)dose,cell viability was analysed with a cell counting kit-8(CCK-8)assay,and cell migration was monitored with wound healing and Transwell migration assays.There were 4 groups:SCF-II,TGF-β,SCF-II+TGF-βand Control.Western blotting and immunofluorescence were performed to show the expression of EMT markers and the translocation of nuclear factor kappa-B(NF-κB)into the nucleus in the 4 groups.RESULTS:Treatment with SCF-II decreased HCEC viability in a dose-dependent manner.A concentration below 10μmol/L did not present obvious cell toxicity,and survival rates were more than 70%at 48h.Treatment with SCF-II(5 and 10μmol/L)significantly impeded migration in wound healing and Transwell migration assays(P<0.05),and EMT markers and NF-κB translocation into the nucleus were inhibited.After both TGF-βand SCF-II treatment,the migration of TGF-β-treated HCECs were suppressed by SCF-II(P<0.05).The expression levels of the mesenchymal markers N-cadherin(P<0.05),α-smooth muscle actin(α-SMA;P<0.05)and NF-κB(P<0.05)in both TGF-β-and SCF-II-treated HCECs were lower than those in the HCECs treated with TGF-βalone and higher than those in HCECs treated with SCF-II alone.Immunofluorescence showed that the entry of NF-κB into the nucleus in both TGF-β-and SCF-IItreated HCECs was less than that in the TGF-β-treated HCECs.CONCLUSION:SCF-II inhibit TGF-β-induced EMT in HCECs by potentially regulating the NF-κB signalling pathway.Thus,SCF-II represents a candidate putative therapeutic agent in corneal fibrotic diseases.展开更多
Dear Editor,A microsporidial infection of the cornea predominantly manifests in two forms,the more common epithelial keratoconjunctivitis(MKC),and the less common stromal keratitis(MSK)^([1]).MKC typically presents as...Dear Editor,A microsporidial infection of the cornea predominantly manifests in two forms,the more common epithelial keratoconjunctivitis(MKC),and the less common stromal keratitis(MSK)^([1]).MKC typically presents as multifocal,coarse,punctate,raised,corneal epithelial lesions,with a characteristic“stuck-on”appearance.This form is usually selfresolving,either with or without leaving any residual scar^([2-3]).In contrast,MSK is generally infective,runs a chronic indolent course,and presents as suppurative,mid-stromal,multifocal corneal infiltrates^([4]).展开更多
BACKGROUND Diabetic nephropathy(DN)is a leading cause of chronic kidney disease and endstage renal disease,and is a significant global healthcare burden.Although proximal tubular epithelial cells(PTECs)and podocytes a...BACKGROUND Diabetic nephropathy(DN)is a leading cause of chronic kidney disease and endstage renal disease,and is a significant global healthcare burden.Although proximal tubular epithelial cells(PTECs)and podocytes are involved in DN progression,the specific molecular interactions between these cells are not well understood.AIM To elucidate the role of interleukin-6(IL-6)/Rab5 signaling in mediating crosstalk between PTECs and podocytes,and to evaluate the protective effects of nicotinamide mononucleotide(NMN)against DN progression.METHODS We utilized in vitro and in vivo models to investigate the pathogenesis of DN.In vitro,human PTECs and murine podocytes were cultured under high-glucose conditions,and IL-6 neutralizing antibodies or NMN treatments were applied.Podocyte injury was assessed by measurements of nephrin endocytosis,Rab5 activity,cytoskeletal organization,cell adhesion,and cell-spreading assays.In vivo,DN was induced in mice using streptozotocin,and mice then received NMN,insulin,or both treatments over an 8-week period.Renal tissues were analyzed histologically,ultrastructurally,and immunochemically,and urinary albumin excretion was measured to assess renal function.Statistical analyses were conducted using one-way ANOVA and Tukey's test.RESULTS High-glucose conditions induced the epithelial-mesenchymal transition(EMT)in PTECs,increased IL-6 secretion,and activated Rab5 signaling in podocytes,leading to increased nephrin endocytosis and podocyte injury.Blocking IL-6 significantly attenuated these effects.NMN treatment of diabetic mice markedly reduced podocyte injury,glomerular hypertrophy,foot-process effacement,and urinary albumin excretion.Mechanistically,NMN suppressed the EMT and IL-6 secretion by PTECs,inhibited Rab5 activation in podocytes,and prevented nephrin endocytosis,thereby preserving the cytoskeletal integrity and function of podocytes.CONCLUSION Our findings reveal a novel pathogenic mechanism of DN in which IL-6 released from glucose-stressed PTECs activates Rab5 signaling in podocytes,followed by nephrin endocytosis and structural injury of podocytes.Importantly,NMN treatment effectively disrupted this pathological pathway of intercellular communication,and provided significant protection against DN progression.These results suggest that NMN supplementation and targeting the IL-6/Rab5 signaling axis has promise as a therapeutic strategy for managing DN.展开更多
基金This study was supported by National Key Clinical Specialties Construction Program of China(No.[2012]649).
文摘SOX4 is highly expressed in gastric cancer(GC)and is associated with tumor grade,metastasis and prognosis,however the mechanism is not clear.We report herein that SOX4 was upregulated and overexpression of SOX4 was associated with increased expression of the markers of Epithelialemesenchymal transition(EMT)and stemness in clinic patient samples.In vitro,overexpression of SOX4 promoted the invasion as showed by Transwell assay and stemness of GC cells as assessed by sphere formation assay,which was suppressed by silencing SOX4 with shRNA.Further studies showed that SOX4 up-regulated the expression of EMT transcription factors Twist1,snail1 and zeb1 and stemness transcription factors SOX2 and OCT4,and promoted the nuclear translocation of β-catenin.Moreover,we revealed that TGF-β treatment significantly up-regulated the expression of SOX4 and silencing SOX4 reversed TGF-β induced invasion and sphere formation ability of GC cells.Finally,we showed that SOX4 promoted the lung metastasis and tumor formation ability of gastric cancer cells in nude mice.Our results suggest that SOX4 is a target TGF-β signaling and mediates TGF-β-induced EMT and stem cell characteristics of GC cells,revealing a novel role of TGF-β/SOX4 axis in the regulation of malignant behavior of GC.
文摘AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.
基金supported by the National Natural Science Foundation of China(Nos.22206207,22127810,and 22276224)the Natural Science Foundation of Guangdong Province(Nos.2021A1515011546 and 2023A1515010085)the Science and Technology Planning Project of Guangzhou(No.202102080005)。
文摘Epithelial-mesenchymal transition(EMT)plays an irreplaceable role in the development of silicosis.However,molecular mechanisms of EMT induced by silica exposure still remain to be addressed.Herein,metabolic profiles of human alveolar type II epithelial cells(A549 cells)exposed directly to silica were characterized using non-targeted metabolomic approaches.A total of 84 differential metabolites(DMs)were identified in silica-treated A549 cells undergoing EMT,which were mainly enriched in metabolisms of amino acids(e.g.,glutamate,alanine,aspartate),purine metabolism,glycolysis,etc.The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica.Remarkably,glutamine catabolism was significantly promoted in the silica-treated A549 cells,and the levels of related metabolites(e.g.,succinate)and enzymes(e.g.,α-ketoglutarate(α-KG)dehydrogenase)were substantially up-regulated,with a preference toα-KG pathway.Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail(zinc finger transcription factor).Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.
基金supported by the China Postdoctoral Science Foundation(2021M701462)the National Natural Science Foundation of China(32072254)+2 种基金the Postdoctoral Research Funding Program of Jiangsu Province(2021K097A)the Fundamental Research Funds for the Central Universities(JUSRP121106)the“Qing Lan Project”of Jiangsu Province。
文摘The dark blue pigment(DBP)is a health ingredient from Vaccinium bracteatum Thunb.leaves used as a functional food supplement.However,the details of transepithelial absorption on the intestinal epithelial cells are barely understood.This study aimed to clarify the absorption properties of DBP in the Caco-2 cell monolayer model and evaluate the effect on the endo-metabolism and barrier function of Caco-2 cells.The results showed that the DBP did not show the dose-dependent toxic effect to Caco-2 cells between 0.25 and 1.5 mg/mL,which did not cause disorder in the normal cell metabolism and absorption activity.The Caco-2 cell monolayer model could absorb DBP by passive and active transport,and the absorptive pattern was dosedependent when the concentration was more than 0.25 mg/mL.During DBP absorption,an increase in m RNA and protein expressions of glucose transporters demonstrated that the glucose transporters were the potential transporter of DBP.But the glucose transport amounts were significantly lowered after 30 min of DBP treatment,indicating that DBP owned the inhibitory effect on glucose transportation.Furthermore,DBP also owned protective effects on the barrier function of intestinal epithelial cells.
基金supported by the National Key Research and Development Program of China(2023YFE0100400)Science and Technology Project of Inner Mongolia Autonomous Region(2020GG0036)+2 种基金Basic Scientific Research Business Project of Universities directly under the Inner Mongolia Autonomous Region(BR22-11-17)National Center of Technology Innovation for Dairy(2023-JSGG-5)the Special Project for Improving the Research Ability of Young Teachers of Inner Mongolia Agricultural University(BR220133).
文摘Background Using yeast culture as additives in ruminant feed prevents rumen microbial dysbiosis,enhances performance,and regulates rumen pH.The yeast culture used in this study was developed in-house,and has been shown to promote rumen epithelial growth in several sheep trials.Changes in protein expression associated with the promotion of rumen epithelial development following the addition of yeast culture,along with the associated molecular mechanisms,remain unknown.We used 2045-day-old weaned lambs to investigate the specific proteins and molecular mechanisms involved in these processes.Half of the lambs were fed yeast culture,and the other half were used as controls.Results Yeast culture enhanced growth performance,facilitated rumen fermentation,and promoted rumen papilla development in weaned lambs.Proteomics data identified 4,831 proteins in the rumen epithelial tissue of lambs,comprising 87 upregulated and 425 downregulated proteins.Administration of yeast culture activated multiple molecular functions within rumen epithelial cells,including oxidative phosphorylation,glutathione metabolism,apoptosis,cell cycle,and vitamin digestion and absorption.The expression of proteins associated with cell cycle regulation increased,whereas those associated with apoptosis decreased.Administration of yeast culture also reduced the duration of the G0/G1 phase of rumen epithelial cells and accelerated the cell cycle.Furthermore,yeast culture showed increased cyclin D1,cyclin-dependent kinase(CDK)2,CDK4,CDK6,and cyclin E1 expressions and decreased cytochrome C(Cyto-c),Bcl-2-related X protein(Bax),cleaved caspase 3(C-caspase 3),caspase 3,and cleaved caspase 7(C-caspase 7)protein expressions.Yeast culture upregulated the insulin-like growth factor-1 receptor(IGF-1R)and insulin-like growth factor-binding protein 5(IGFBP-5)mRNA expressions in rumen epithelial cells.Conclusions Yeast culture facilitates rumen epithelial development by regulating the cell cycle and IGF-1 signaling and reducing the expression of proteins associated with apoptosis in rumen epithelial cells.The findings of this study provide novel insights into the molecular mechanisms through which yeast culture promotes rumen epithelial development in weaned lambs.
基金The China Agriculture Research System Program(Project No.CARS-41-G04)Shenyang Governmental Science and Technology Program(Project No.22316-2-02)supported this work.
文摘Background Clostridium perfringens is a pathogen that secretes multiple toxins,impacting humans and animals.It can cause intestinal diseases such as necrotic enteritis.Although tannins inhibit C.perfringens proliferation,the precise underlying mechanisms are unclear.Objective This study integrated transcriptomics and metabolomics to systematically investigate the mechanism by which tannins,specifically pentagalloylglucose(PGG)and tannic acid(TA),inhibit C.perfringens and potential pathways to alleviate infection in vivo.Results Ion concentration measurements,flow cytometric analysis,and transmission electron microscopy revealed that PGG and TA damaged the cell membrane structure of C.perfringens,triggering cytoplasmic content leakage.Additionally,PGG and TA significantly affected C.perfringens at the transcriptional and metabolic levels.Bioinformatics analysis revealed that PGG and TA induced amino acid restriction,disrupted energy metabolism,and impeded the ability of C.perfringens to sense and respond to the external environment.In an in vitro C.perfringens-infected intestinal cell model,PGG and TA boundαtoxin,significantly reduced the mRNA expression of inflammatory factors,and improved intestinal barrier function and cell viability.Compared to PGG,TA exhibited stronger inhibitory activity against C.perfringens and binding toαtoxin.In vivo,PGG and TA alleviated C.perfringens-induced weight loss in mice,improved intestinal villi morphology,and reduced intestinal inflammation and tight junction gene dysregulation.Conclusion These findings indicate that tannins inhibit C.perfringens,improve gut tissue integrity and reduce inflammation,demonstrating their multi-target effects of resisting intestinal diseases caused by harmful bacteria.This offers new insights for plant polyphenol-based strategies against necrotic enteritis.
文摘The cornea is a transparent tissue that serves as the main refractive element of the eye ball.Limbal epithelial stem cells(LESCs),residing in the basal epithelial layer of the Palisades of Vogt located in the corneal limbus between cornea and scleral,are believed to be crucial for the continuous turnover of the corneal epithelium.The proliferation,migration,and differentiation of the LESCs are modulated by unique physical and chemical futures contained within the microenvironment known as the limbal niche.This niche,composed of nerve terminals,cells,extracellular matrix,vasculature,and signaling molecules,is the home for processes such as proliferation,migration and differentiation.Corneal nerve terminals possess special anatomical structures in the limbal region and basal epithelial cells,and they demonstrate pivotal biological effects in the regulation of the LESC function and corneal epithelium homeostasis.Biological molecules such as neuropeptides,neurotransmitters,and neurotrophic factors play a crucial role in modulating the LESCs phenotype responsible for corneal epithelium homeostasis.This paper will review recent studies on how these nerve derived molecules function in this process and provide clear orientations for future research.
基金Supported by National Key R&D Program of China(No.2023YFC2410203)Beijing Hospitals Authority Clinical medicine Development of Special Funding Support(No.ZLRK202503).
文摘Adenoid cystic carcinoma of the lacrimal gland(LGACC)is the most common type of malignant epithelial tumor of the lacrimal gland,which is characterized by a high recurrence rate,perineural invasion,and a propensity to metastasize to distant sites.Due to its unclear pathogenesis,LGACC has a poor prognosis and a high mortality rate.In recent years,a range of radiotherapy and chemotherapy have been clinically applied,leading to a shift in the treatment approach for LGACC.This article discussed the advances being made in the treatment of LGACC and provides readers with an overview of the impact of LGACC treatment modalities on patient survival and prognostic levels.
基金supported by the National Key Research and Development Program of China(Grant No.2023YFF1000902,2021YFD1200903)the National Science Foundation for Young Scientists of China(Grant No.32302706)the Beijing Dairy Industry Innovation Team(Grant No.BAIC06).
文摘Background Mastitis caused by Staphylococcus aureus(S.aureus)is one of the most intractable problems for the dairy industry,causing significantly reduced milk yields and early slaughter of cows worldwide.MicroRNAs(miRNAs)can post-transcriptionally regulate gene expression and studies in recent years have shown the importance of miRNA-associated gene regulation in S.aureus-induced mastitis.Results In this study,to investigate the role of miR-223 in mastitis,we performed experiments to overexpress and suppress miR-223 in an immortalized bovine mammary epithelial cell line(MAC-T)infected with S.aureus.Overexpression of miR-223 in MAC-T cells repressed cell apoptosis and necrosis induced by S.aureus infection,whereas suppression of miR-223 had the opposite effect.Transcriptome expression profiling with weighted gene co-expression network analysis(WGCNA)and gene set variation analysis(GSVA)showed that miR-223 affects apoptosis and inflammation-related pathways.Furthermore,differentially expressed(DE)genes were evaluated,and genes exhibiting contrasting expression trends in the miR-223 overexpressed and suppressed groups were assessed as potential target genes of miR-223.Potential target genes,including CDC25B,PTPRF,DCTN1,and DPP9,were observed to be associated with apoptosis and necroptosis.Finally,through integrative analysis of genome-wide association study(GWAS)data and the animal quantitative trait loci(QTL)database,we determined that target genes of miR-223 were significantly enriched in single-nucleotide polymorphisms(SNP)and QTLs related to somatic cell count(SCC)and mastitis.Conclusion In summary,miR-223 has an inhibitory effect on S.aureus-induced cell apoptosis and necrosis by regulating PTPRF,DCTN1,and DPP9.These genes were significantly enriched in QTL regions associated with bovine mastitis resistance,underscoring their relevance in genetic regulation of disease resilience.Our findings provide critical genetic markers for enhancing mastitis resistance,particularly S.aureus-induced mastitis,through selective breeding.This work offers valuable insights for developing cattle with improved resistance to mastitis via targeted genetic selection.
基金supported by the National Natural Science Foundation of China(32273082 and U21A20262).
文摘Background Ferroptosis is characterized by increased production of reactive oxygen species(ROS)and membrane lipid peroxidation that can exacerbate inflammatory damage.Extracellular vesicles(EVs)isolated from bovine milk have many biological functions,including antioxidant properties.However,the role of EVs on Klebsiella pneumoniaeinduced ferroptosis and oxidative stress in bovine mammary epithelial cells(bMECs)and murine mammary tissue is unclear.In this study,EVs were isolated from bovine colostrum,mature milk and clinical mastitis milk(defined as C-EVs,M-EVs and CM-EVs,respectively)and assessed by transmission electron microscopy,Western blot and transcriptome sequencing.Effects of EVs on K.pneumoniae-induced ferroptosis and oxidative stress in bMECs were evaluated with immunofluorescence and Western blot.Results In bMECs,infection with K.pneumoniae induced oxidative stress,decreasing protein expression of Nrf2,Keap1 and HO-1 plus SOD activity,and increasing ROS concentrations.However,protein expression of GPX4,ACSL4 and S100A4 in bMECs,all factors that regulate ferroptosis,was downregulated by K.pneumoniae.Furthermore,this bacterium compromised tight junctions in murine mammary tissue,with low expression of ZO-1 and Occludin,whereas protein expression of Nrf2 and GPX4 was also decreased in mammary tissue.Adding C-EVs,M-EVs or CMEVs reduced oxidative stress and ferroptosis in K.pneumoniae-infected bMECs in vitro and murine mammary tissues in vivo.Conclusion In conclusion,all 3 sources of milk-derived EVs alleviated oxidative stress and ferroptosis in K.pneumoniae-infected bMECs and mammary tissues.
基金German research Foundation(DFG,grant numbers:CH2321/1–1 and SCHO1231/7–1)JH has received a scholarship from the Chinese Scholarship Council(CSC No.:201908350115).
文摘The oviduct epithelium is the initial maternal contact site for embryos after fertilization,offering the microenviron-ment before implantation.This early gestation period is particularly sensitive to stress,which can cause reduced fertil-ity and reproductive disorders in mammals.Nevertheless,the local impact of elevated stress hormones on the ovi-duct epithelium has received limited attention to date,except for a few reports on polyovulatory species like mice and pigs.In this study,we focused on the effects of chronic maternal stress on cattle,given its association with infertil-ity issues in this monoovulatory species.Bovine oviduct epithelial cells(BOEC)differentiated at the air–liquid interface(ALI)were stimulated with 250 nmol/L cortisol for 1 or 3 weeks.Subsequently,they were assessed for morphology,bioelectrical properties,and gene expression related to oviduct function,glucocorticoid pathway,cortisol metabo-lism,inflammation,and apoptosis.Results revealed adverse effects of cortisol on epithelium structure,featured by deciliation,vacuole formation,and multilayering.Additionally,cortisol exposure led to an increase in transepithelial potential difference,downregulated mRNA expression of the major glucocorticoid receptor(NR3C1),upregulated the expression of cortisol-responsive genes(FKBP5,TSC22D3),and significant downregulation of oviductal glycopro-tein 1(OVGP1)and steroid receptors PGR and ESR1.The systematic comparison to a similar experiment previously performed by us in porcine oviduct epithelial cells,indicated that bovine cultures were more susceptible to elevated cortisol levels than porcine.The distinct responses between both species are likely linked to their divergence in the cortisol-induced expression changes of HSD11B2,an enzyme controlling the cellular capacity to metabolise cortisol.These findings provide insights into the species-specific reactions and reproductive consequences triggered by maternal stress.
基金supported by the Department of Agriculture and Rural Affairs of Jiangxi Province,China (JXARS-09)Science and Technology Program of Guangdong Province,China (2020B1212060060)。
文摘Pigeons and certain other avian species produce a milklike secretion in their crop sacs to nourish offspring,yet the detailed processes involved are not fully elucidated.This study investigated the crop sacs of 225-day-old unpaired non-lactating male pigeons(MN)and males initiating lactation on the first day after incubation(ML).Using RNA sequencing,ribosomeprofiling,andsingle-cell transcriptome sequencing(scRNA-seq),we identified a significant up-regulation of genes associated with ribosome assembly and protein synthesis in ML compared to MN.Results from scRNA-seq analysis identified 12distinct cell types and 22 clusters,with secretory epithelial cells(SECs)exhibiting marked expression of plasma cell markers,including IGLL1 and MZB1.RNA fluorescence in situ hybridization(RNA FISH)and IgY quantification confirmed the critical role of SECs in producing endogenous IgY during lactation.We propose that fibroblast-derived BAFF signals activate SECs,mimicking B cell transformation and enhancing protein production through the unfolded protein response(UPR).These findings shed light on the cellular dynamics of pigeon milk production and contribute to a broader understanding of avian biology.
文摘Dear Editor,Historically,dipeptidyl peptidase 4(DPP4),found in alveolar regions,has been recognized as the primary receptor for several merbecoviruses like MERS-CoV(Meyerholz et al.,2016).However,angiotensin-converting enzyme 2(ACE2),highly expressed in the motile cilia of human airway epithelial cells(Sungnak et al.,2020),has been identified as the functional receptor for sarbecoviruses(e.g.,SARS-CoV-2,SARS-CoV)and setracoviruses(e.g.,HCoV-NL63).Recent studies have shown that some bat-circulating MERS-related coronaviruses(MERSr-CoVs),such as MOW15-22,PnNL2018B and HKU5,can use ACE2 to enter cells(Ma et al.,2025;Park et al.,2025).Even more worrying is that one novel bat-infecting merbecovirus HKU5-CoV lineage 2(BtHKU5-CoV-2)has been reported to use human ACE2 as a cell entry receptor(Chen et al.,2025).These ACE2-utilizing merbecoviruses expand the diversity,geographic distribution,and transmission potential of coronaviruses,posing a significant threat of spillover to humans.If an ACE2-utilizing MERSr-CoV acquire the high lethality of MERS-CoV and the high transmissibility of SARS-CoV-2 using ACE2 as a receptor,it could trigger a global pandemic with catastrophic consequences for humanity.Therefore,it is essential to evaluate serological cross-reactivity in sera from SARS-CoV-2-infected individuals against ACE2-using MERSr-CoVs,and urgent to develop preventive vaccines and pan-coronavirus antivirals confront the potential threat(Jiang and Wu,2025).
基金supported by the Fundamental Research Funds for the National Natural Science Foundation of China(Nos.22177084 and 82104373)the Fundamental Research Funds of Science&Technology Department of Sichuan Province(No.2022YFQ0054).
文摘Background:EMP2 is a tumor-associated membrane protein belonging to the GAS-3/PMP22 gene family.EMP2 expression demonstrates significant tissue specificity and heterogeneity in various human tissues and tumor tissues,where it may play a role in either promoting or inhibiting tumor growth.This study aimed to investigate the expression level,biological functions,and molecular mechanisms of EMP2 in liver cancer.Methods:we analyzed the mRNA expression levels of EMPs family genes in hepatocellular carcinoma(HCC)tissues and normal liver tissues based on the TCGA database and immunohistochemical analysis of tissue microarrays.Subsequently,we constructed HCC cell lines with either knockdown or overexpression of EMP2 to examine the biological functions and molecular mechanisms of EMP2 in tumorigenesis in vivo and in vitro.Results:Bioinformatic and immunohistochemical analysis of tissue microarrays have confirmed the significant upregulation of EMP2 in HCC tissues.In vitro and in vivo studies have shown that downregulation of EMP2 results in a moderate reduction in the proliferation and invasive capacity of HCC cells.Conversely,overexpression of EMP2 enhances the invasive capacity of HCC cells and induces autophagy.Initial investigations into the molecular mechanisms underlying EMP2-mediated enhancement of HCC cell invasion have revealed the dual regulation of EMP2-induced autophagy and the integrin pathway,which synergistically influence the invasive and metastatic potential of HCC cells.Conclusion:EMP2 holds promise as a diagnostic marker for HCC metastasis and a potential target for targeted therapy.
基金supported by grants from the Seoul National University Bundang Hospital(SNUBH)Research Fund(Grant no.02-2020-0008)the Creative-Pioneering Researchers Program of Seoul National University(Grant no.860-20240109).
文摘Background:Oral cancer remains a significant global health challenge,as it has high morbidity and mortality rates.Current treatments show limited efficacy and have severe side effects,prompting searches for new therapeutic agents.SH003,a traditional herbal formulation comprising Astragalus membranaceus,Angelica gigas,and Trichosanthes kirilowii,has demonstrated potential anticancer properties in previous studies.However,its specific efficacy against oral cancer and the role of its key components,particularly Cucurbitacin D,remain underexplored.Methods:The cytotoxic effects of SH003 and its major components—i.e.,Cucurbitacin D,Decursin,Formononetin,and Nodakenin—were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide(MTT),Trypan Blue exclusion,and Lactate Dehydrogenase(LDH)release assays.Cell migration was analyzed via wound healing assays,and apoptosis induction was assessed using cell cycle analysis and caspase activation assays.Epithelial-tomesenchymal transition(EMT)marker expression(E-cadherin and N-cadherin)was measured using Western blotting and Quantitative reverse transcription PCR(qRT-PCR).Results:SH003 significantly reduced cell viability in a dosedependent manner,with YD-8 and YD-9 cells showing greater sensitivity than YD-38 cells.Of the individual compounds,Cucurbitacin D was identified as a key active agent,as it exhibited potent inhibition of cell migration and significant modulation of EMT markers,including the upregulation of E-cadherin and downregulation of N-cadherin.These effects were most pronounced in YD-9 cells.Conclusions:Taken together,these findings suggest that Cucurbitacin D plays a crucial role mediating the anticancer activity of SH003,particularly via the reversal of EMT and the reduction of migratory and invasive potential of oral cancer cells.This study provides valuable insight into the mechanistic basis of SH003,highlighting its potential as a therapeutic agent against oral cancer.Further research,including in vivo studies and clinical trials,is needed to elucidate its precise mechanisms and potential applications against other cancer types.
基金funded by Namibe UniversityInstituto Nacional de Gestao de Bolsas de Estudo/Angola government through a PhD studentship program+1 种基金the TENOVUS Scotland(S20-02 to Xinhua Shu,the Chief Scientist Office/the RS Macdonald Charitable Trust(SNRF2021 to Xinhua Shu)the Lotus Scholarship Program of Hunan Province,China(2019-23 to Xinhua Shu)。
文摘Domoic acid(DA),a biotoxin,is produced by several species of marine dinoflagellate and diatom during harmful algal bloom events.DA is a neurotoxin,in humans and non-human primates,oral exposure to DA results in gastrointestinal effects,while DA at higher doses leads to neurological symptoms,seizures and memory deficiency.Exposure of humans to DA occurs mainly through consumption of contaminated seafoods containing an accumulation of the toxin.Previously,it was unclear if DA can have toxic effects on the retina.We assessed the toxicity of DA in human retinal cells(ARPE-19)and in zebrafish embryos.DA significantly lowered ARPE-19 cell viability dose-dependently,and decreased anti-oxidative capacity,increased inflammation,and promoted cell death,possibly through modulating the NRF2 and NF-κB signalling pathways.Zebrafish embryos exposed to DA for 4 days from 1 day post fertilization(dpf)had an increase in mortality and a decrease in both hatching and heartbeat rate and exhibited morphological abnormalities.DA treatment also significantly downregulated expression of antioxidant genes and upregulated expression of inflammation mediators,as well as causing photoreceptor death in zebrafish embryos.The results demonstrate that consuming seafood containing DA will have potential toxic effects in human retinas.
基金supported by grants from the National Natural Science Foundation of China(Grant nos.82201011,82370958 and 81870770).
文摘Smoking is a well-established risk factor for periodontitis,yet the precise mechanisms by which smoking contributes to periodontal disease remain poorly understood.Recent advances in spatial transcriptomics have enabled a deeper exploration of the periodontal tissue microenvironment at single-cell resolution,offering new opportunities to investigate these mechanisms.In this study,we utilized Visium HD single-cell spatial transcriptomics to profile gingival tissues from 12 individuals,including those with periodontitis,those with smoking-associated periodontitis,and healthy controls.Our analysis revealed that smoking disrupts the epithelial barrier integrity,induces fibroblast alterations,and dysregulates fibroblast–epithelial cell communication,thereby exacerbating periodontitis.The spatial analysis showed that endothelial cells and macrophages are in close proximity and interact,which further promotes the progression of smoking-induced periodontal disease.Importantly,we found that targeting the endothelial CXCL12 signalling pathway in smoking-associated periodontitis reduced the proinflammatory macrophage phenotype,alleviated epithelial inflammation,and reduced alveolar bone resorption.These findings provide novel insights into the pathogenesis of smoking-associated periodontitis and highlight the potential of targeting the endothelial–macrophage interaction as a therapeutic strategy.Furthermore,this study establishes an essential information resource for investigating the effects of smoking on periodontitis,providing a foundation for future research and therapeutic development for this prevalent and debilitating disease.
基金Supported by the National Natural Science Foundation of China(No.82103563)the Key Research and Development Program of Shaanxi Province(No.2020ZDLSF02-06).
文摘AIM:To investigate the effect of skullcapflavone II(SCF-II)on the epithelial-mesenchymal transition(EMT)induced by transforming growth factor beta(TGF-β)in human corneal epithelial cells(HCECs),as well as to identify the signaling pathways that may be involved.METHODS:HCECs were cultured in vitro.At a SCFII(5,10μmol/L)dose,cell viability was analysed with a cell counting kit-8(CCK-8)assay,and cell migration was monitored with wound healing and Transwell migration assays.There were 4 groups:SCF-II,TGF-β,SCF-II+TGF-βand Control.Western blotting and immunofluorescence were performed to show the expression of EMT markers and the translocation of nuclear factor kappa-B(NF-κB)into the nucleus in the 4 groups.RESULTS:Treatment with SCF-II decreased HCEC viability in a dose-dependent manner.A concentration below 10μmol/L did not present obvious cell toxicity,and survival rates were more than 70%at 48h.Treatment with SCF-II(5 and 10μmol/L)significantly impeded migration in wound healing and Transwell migration assays(P<0.05),and EMT markers and NF-κB translocation into the nucleus were inhibited.After both TGF-βand SCF-II treatment,the migration of TGF-β-treated HCECs were suppressed by SCF-II(P<0.05).The expression levels of the mesenchymal markers N-cadherin(P<0.05),α-smooth muscle actin(α-SMA;P<0.05)and NF-κB(P<0.05)in both TGF-β-and SCF-II-treated HCECs were lower than those in the HCECs treated with TGF-βalone and higher than those in HCECs treated with SCF-II alone.Immunofluorescence showed that the entry of NF-κB into the nucleus in both TGF-β-and SCF-IItreated HCECs was less than that in the TGF-β-treated HCECs.CONCLUSION:SCF-II inhibit TGF-β-induced EMT in HCECs by potentially regulating the NF-κB signalling pathway.Thus,SCF-II represents a candidate putative therapeutic agent in corneal fibrotic diseases.
文摘Dear Editor,A microsporidial infection of the cornea predominantly manifests in two forms,the more common epithelial keratoconjunctivitis(MKC),and the less common stromal keratitis(MSK)^([1]).MKC typically presents as multifocal,coarse,punctate,raised,corneal epithelial lesions,with a characteristic“stuck-on”appearance.This form is usually selfresolving,either with or without leaving any residual scar^([2-3]).In contrast,MSK is generally infective,runs a chronic indolent course,and presents as suppurative,mid-stromal,multifocal corneal infiltrates^([4]).
基金Supported by Hubei Provincial Natural Science Foundation,No.2023AFB732and Scientific Research Project of Hubei Provincial Health Commission,No.WJ2023M053.
文摘BACKGROUND Diabetic nephropathy(DN)is a leading cause of chronic kidney disease and endstage renal disease,and is a significant global healthcare burden.Although proximal tubular epithelial cells(PTECs)and podocytes are involved in DN progression,the specific molecular interactions between these cells are not well understood.AIM To elucidate the role of interleukin-6(IL-6)/Rab5 signaling in mediating crosstalk between PTECs and podocytes,and to evaluate the protective effects of nicotinamide mononucleotide(NMN)against DN progression.METHODS We utilized in vitro and in vivo models to investigate the pathogenesis of DN.In vitro,human PTECs and murine podocytes were cultured under high-glucose conditions,and IL-6 neutralizing antibodies or NMN treatments were applied.Podocyte injury was assessed by measurements of nephrin endocytosis,Rab5 activity,cytoskeletal organization,cell adhesion,and cell-spreading assays.In vivo,DN was induced in mice using streptozotocin,and mice then received NMN,insulin,or both treatments over an 8-week period.Renal tissues were analyzed histologically,ultrastructurally,and immunochemically,and urinary albumin excretion was measured to assess renal function.Statistical analyses were conducted using one-way ANOVA and Tukey's test.RESULTS High-glucose conditions induced the epithelial-mesenchymal transition(EMT)in PTECs,increased IL-6 secretion,and activated Rab5 signaling in podocytes,leading to increased nephrin endocytosis and podocyte injury.Blocking IL-6 significantly attenuated these effects.NMN treatment of diabetic mice markedly reduced podocyte injury,glomerular hypertrophy,foot-process effacement,and urinary albumin excretion.Mechanistically,NMN suppressed the EMT and IL-6 secretion by PTECs,inhibited Rab5 activation in podocytes,and prevented nephrin endocytosis,thereby preserving the cytoskeletal integrity and function of podocytes.CONCLUSION Our findings reveal a novel pathogenic mechanism of DN in which IL-6 released from glucose-stressed PTECs activates Rab5 signaling in podocytes,followed by nephrin endocytosis and structural injury of podocytes.Importantly,NMN treatment effectively disrupted this pathological pathway of intercellular communication,and provided significant protection against DN progression.These results suggest that NMN supplementation and targeting the IL-6/Rab5 signaling axis has promise as a therapeutic strategy for managing DN.
