Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic...Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.展开更多
Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote i...Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.展开更多
Objective:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease of the central nervous system(CNS).Soluble interleukin-2 receptor alpha(sIL-2Rα)has been implicated inMS pathogenesis,but its mechanisms...Objective:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease of the central nervous system(CNS).Soluble interleukin-2 receptor alpha(sIL-2Rα)has been implicated inMS pathogenesis,but its mechanisms remain unclear.This study investigates how sIL-2Rαexacerbates MS by modulating microglial activation and antibody-dependent cellular cytotoxicity(ADCC)in an experimental autoimmune encephalomyelitis(EAE)mouse model.Methods:Female C57BL/6J mice were induced with EAE and treated with sIL-2Rα.Clinical symptoms,histopathology,and molecular changes were analyzed.Microglial activation was assessed via immunohistochemistry,Western blot,and RNA sequencing.In vitro,ADCC-mediated oligodendrocyte injury was evaluated using Fc receptor inhibition and PI3K-Akt pathway blockade.Results:sIL-2Rα accelerated EAE onset and severity,increasingmicroglial M1 polarization and CNS inflammation.RNA-seq revealed PI3K-Akt pathway activation,upregulating Fc receptors(FcγR)on microglia,which enhanced ADCC against oligodendrocytes(p<0.001).Inhibiting FcγR or PI3K-Akt reduced oligodendrocyte damage.Conclusion:sIL-2Rαexacerbates MS by activating microglia via the PI3K-Aktaxis,promoting ADCC and demyelination.Targeting this pathway may offer novel therapeutic strategies for MS.展开更多
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well ...Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.展开更多
Aerobic exercise facilitates synaptic plasticity,thereby improving cognitive functions such as learning and memory.The 5-hydroxytryptamine system has been indicated in these processes.5-Hydroxytryptamine type 3 recept...Aerobic exercise facilitates synaptic plasticity,thereby improving cognitive functions such as learning and memory.The 5-hydroxytryptamine system has been indicated in these processes.5-Hydroxytryptamine type 3 receptors are necessary for exercise-induced hippocampal neurogenesis.Some antipsychotic drugs with 5-hydroxytryptamine type 3 receptor antagonistic properties may impede the amelioration of cognitive impairment and hippocampal plasticity induced by exercise.However,the mechanisms underlying the facilitation of synaptic plasticity by aerobic exercise have not yet been elucidated.In this study,we found that 5-hydroxytryptamine type 3 receptors played an important role in aerobic exercise-mediated improvement of hippocampal-dependent spatial and exploratory memory in mice.While 5-hydroxytryptamine type 3 receptors did not affect baseline neurogenesis in the hippocampal dentate gyrus,5-hydroxytryptamine type 3 receptors were required for aerobic exercise-induced neurogenesis and astrocyte proliferation in this region.In addition,5-hydroxytryptamine type 3 receptors were crucial for maintaining long-term potentiation in the CA1,dentate gyrus,and CA3 regions of the hippocampus.The long-term potentiation changes induced by aerobic exercise in sub-regions of the hippocampus were heterogeneous:5-hydroxytryptamine type 3 receptors were essential for aerobic exercise to enhance long-term potentiation in the CA3,but not the CA1 or dentate gyrus,regions of the hippocampus.Furthermore,aerobic exercise up-regulated 5-hydroxytryptamine type 3 receptor expression and increased brain-derived neurotrophic factor release in the hippocampus in a 5-hydroxytryptamine type 3 receptor-dependent manner.These results suggest that aerobic exercise increases hippocampal dentate gyrus neurogenesis and astrocyte proliferation via the up-regulation of 5-hydroxytryptamine type 3 receptors,leading to more brain-derived neurotrophic factor production and release from these cells,which results in long-term potentiation facilitation in the hippocampal CA3 region and help improve memory.Our findings provide insight into the mechanisms by which physical activity enhances memory and may have implications for improving memory through modulating 5-hydroxytryptamine type 3 receptor.展开更多
BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicate...BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.展开更多
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
BACKGROUND Epidermal growth factor receptor(EGFR)is a transmembrane protein that is differentially expressed in gestational diabetes mellitus(GDM).Endothelial dy-sfunction is a hallmark of GDM and plays a key role in ...BACKGROUND Epidermal growth factor receptor(EGFR)is a transmembrane protein that is differentially expressed in gestational diabetes mellitus(GDM).Endothelial dy-sfunction is a hallmark of GDM and plays a key role in its pathogenesis.EGFR is associated with endothelial dysfunction in the context of various diseases.How-ever,the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown,particularly its regulation at the transcriptional and protein levels.METHODS Quantitative real-time polymerase chain reaction was used to detect the ex-pression of EGFR and H19.Western blotting was used to detect the expression of endothelial cell dysfunction markers.A cell counting kit 8 assay was used to assess cell viability,flow cytometry was used to assess apoptosis,scratch and Transwell assays were used to assess cell migration,and a tube formation assay was used to assess cell vascular formation.Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.RESULTS In this study,EGFR was upregulated in clinical samples,GDM animal models and GDM cell models,and the knockdown of EGFR could mitigate the effect of streptozotocin(STZ)and high glucose(HG);promoted the proliferation,migration and vascularization of human umbilical vein endothelial cells(HUVECs);inhibited cell apoptosis and the expression of endothelial cell dysfunction markers(vascular cell adhesion molecule-1,tumor necrosis factor-α,vascular endothelial growth factor-A,and intercellular cell adhesion molecule-1);and alleviated the process of GDM in vivo.Mechanistically,EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA,thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice.In addition,ERRFI1 also regulated the expression of EGFR,and ERRFI1 inhibited EGFR activity by binding to EGFR,thereby inhibiting HG-induced HUVECs dysfunction.CONCLUSION Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan(Trp)-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics and dextran so...The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan(Trp)-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics and dextran sodium sulfate.Several Lactobacillus strains isolated from the healthy human fecal sample was found to utilize Trp to produce indole derivatives.The results of Trp metabolism indicated that the ability of Lactobacillus to metabolize Trp to produce indole-3-lactic acid(ILA),indole-3-carboxaldehyde(I3C),and indole-3-acetic acid varies in vitro and in vivo.The effect of Lactobacillus with high-yielding indole derivatives on disease activity index,colon length,and intestinal permeability was significantly better than that of Lactobacillus with low-yielding indole derivatives in a high Trp diet.And Lactobacillus combined with Trp intervention also had a certain regulatory effect on the intestinal flora of male BALB/c mice.Among them,Lactiplantibacillus plantarum DPUL-S164 produced more ILA both in vivo and in vitro,and the combination of L.plantarum DPUL-S164 and Trp significantly decreased the expression level of the serum pro-inflammatory cytokine interleukin(IL)-6 and increased the expression level of the anti-inflammatory cytokine IL-10,significantly improved the number of goblet cells in the mouse mucous layer and increased mucin and tight junction protein expression.Furthermore,L.plantarum DPUL-S164 combined with Trp intervention activated the aryl hydrocarbon receptors(Ah R)signaling pathway.Furthermore,we found that the expression of colonic tight junction protein was positively correlated with the expression of colonic Ah R,and the expression of Ah R was positively correlated with the concentrations of ILA and I3C in vivo.Therefore,we conclude that the ILA as Ah R ligand produced by L.plantarum DPUL-S164 regulated the Ah R pathway,thus up-regulating the expression of the tight junction protein and protecting the integrity of the epithelial barrier.展开更多
Diabetic foot ulcer(DFU)is an increasing global burden due to the rising prevalence of diabetes,and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment.In thi...Diabetic foot ulcer(DFU)is an increasing global burden due to the rising prevalence of diabetes,and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment.In this study,naringenin(NAR)was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type(WT)mice by reducing oxidative stress,as assessed through histological assay.NAR also alleviated the inhibition of proliferation,inflammation,cell senescence,and apoptosis in HaCaT cells induced by high glucose(HG).Mechanistically,the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin(Parkin/PRKN/Prkn).NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation,thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control(MQC).Moreover,the wound healingpromoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout(Prkn^(-/-))DFU mice.Inhibition of NAR binding to estrogen receptors(ERs)using tamoxifen(TAM)abolished the protective effects of NAR in HG-induced HaCaT cells.The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element(ERE),thereby upregulating Parkin transcription.Additionally,the cellular thermal shift assay(CETSA)revealed that NAR specifically bound to ERa.In conclusion,NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERa,highlighting its potential as a promising therapeutic candidate.展开更多
Objective:To examine the effect of an neurokinin 3 receptor(NK3R)agonist,senktide,on neuronal nitric oxide synthase(nNOS)activation in the median eminence-arcuate nucleus(ME-ARC)and preoptic area(POA)regions of the hy...Objective:To examine the effect of an neurokinin 3 receptor(NK3R)agonist,senktide,on neuronal nitric oxide synthase(nNOS)activation in the median eminence-arcuate nucleus(ME-ARC)and preoptic area(POA)regions of the hypothalamus across proestrus,diestrus,and ovariectomized states in female rats and its correlation with luteinizing hormone(LH)secretion.Methods:Adult female Sprague-Dawley rats were examined for proestrus and diestrus phases of the estrous cycle.Female rats were categorized into proestrus and diestrus groups,and each was further divided into four subgroups(n=4).In both the diestrus and proestrus categories,Group 1 was the control group.Groups 2,3,and 4 received senktide(100μg/kg-1),NK3R antagonist SB222200(10 mg/kg-1),and SB222200 followed by senktide,respectively.To evaluate the effect of sex steroids on NK3R agonist-induced nNOS activation,female rats underwent bilateral ovariectomy and were divided into four groups(n=3).Group 1 served as the control.Group 2 received a subcutaneous injection of 17β-estradiol 3-benzoate(E2,3μg/rat).Group 3 received E2 and progesterone(30μg/rat).Group 4 was administered senktide(100μg/kg).Female rats from each group were sacrificed,blood was collected for LH ELISA,and hypothalamic tissues were collected for Western blotting.Results:Senktide increased nNOS phosphorylation in the ME-ARC during both the proestrus and diestrus phases.In the POA,senktide increased nNOS phosphorylation only during the diestrus phase.In ovariectomized rats,senktide activated nNOS independent of sex steroid levels.Senktide also increased serum LH concentration in diestrus and ovariectomized female rats.Conclusions:Senktide,an NK3R agonist,activates nNOS in the POA and ME-ARC regions of the hypothalamus in a phase dependent manner.The activation of nNOS by senktide suggests a potential mechanism by which neurokinin B triggers nNOS activation in the ARC and POA regions and regulates GnRH/LH secretion.展开更多
The study of ligand-receptor interactions is of great significance in food flavor perception.In this study,a computer simulation method was used to investigate the mechanism of interaction between umami peptides and T...The study of ligand-receptor interactions is of great significance in food flavor perception.In this study,a computer simulation method was used to investigate the mechanism of interaction between umami peptides and T1R1/T1R3-Venus-flytrap domain(VFT)receptor.The binding site,conformational changes,and binding free energy between umami peptides and T1R1/T1R3-VFT were analyzed through molecular modeling,molecular docking,and molecular dynamics simulations.The receptor model constructed using AlphaFold2 has the best rationality.The molecular docking results showed that umami peptides primarily bound to T1R1-VFT through hydrogen bonding,with key binding residues such as Thr149,Arg151,and Asp108.The binding of umami peptides led to a more stable complex system,and the positively charged amino acids contributed positively to the overall binding free energy.This study provides theoretical support for the development of a better understanding of the interaction between umami substances and the umami receptor.展开更多
A deficiency ofγδT cells has been described in Crohn's disease(CD).AIM To analyze the gene expression of interleukin 7(IL-7)and its receptors in the tissues of patients with CD.METHODS We studied the peripheral ...A deficiency ofγδT cells has been described in Crohn's disease(CD).AIM To analyze the gene expression of interleukin 7(IL-7)and its receptors in the tissues of patients with CD.METHODS We studied the peripheral blood of 80 patients with CD,comparing them with a group of 80 healthy subjects.The number and apoptosis ofαβandγδT cells in peripheral blood and the proportion ofαβandγδT cells in the intestinal tissues of patients with CD(n=25)were studied.The gene and protein expression of IL-7,IL-2 receptor subunitγ[cluster of differentiation 132(CD132)],receptorα(CD127),and caspase-3 in tissues was analyzed by quantitative PCR.Serum IL-7 levels were also analyzed.RESULTS In patients with CD,a decreased number ofγδT cells and an increase in the apoptosis of CD56+αβandγδT cells in peripheral blood was observed(P<0.0001 and P<0.01)respectively,and there was an inverse correlation among T subsets and their apoptosis.In addition,IL-7 gene expression and IL-7 protein in the tissues of these patients were increased.The titers of caspase-3 in tissues were low vs control group(P>0.01).The percentage of CD8+γδT cells decreased in tissues(P<0.01),and was directly related to IL-7 levels in peripheral blood.The expression of IL-2 receptor subunitγ(CD132)was greatly decreased in the tissues of patients with CD(P<0.05).CONCLUSION There may be a cause-effect relationship between the lower gene expression of the IL-2 receptor subunitγ(CD132)in tissues of patients with CD andγδT cells immunodeficiency.展开更多
This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique...This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.展开更多
Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying...Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.展开更多
Toll-like receptor 3(TLR3)is a member of the TLR family,mediating the transcriptional induction of type I interferons(IFNs),proinflammatory cytokines,and chemokines,thereby collectively establishing an antiviral host ...Toll-like receptor 3(TLR3)is a member of the TLR family,mediating the transcriptional induction of type I interferons(IFNs),proinflammatory cytokines,and chemokines,thereby collectively establishing an antiviral host response.Studies have shown that unlike other TLR family members,TLR3 is the only RNA sensor that is utterly dependent on the Tollinterleukin-1 receptor(TIR)-domain-containing adaptor-inducing IFN-β(TRIF).However,the details of how the TLR3-TRIF signaling pathway works in an antiviral response and how it is regulated are unclear.In this review,we focus on recent advances in understanding the antiviral mechanism of the TRIF pathway and describe the essential characteristics of TLR3 and its antiviral effects.Advancing our understanding of TLR3 may contribute to disease diagnosis and could foster the development of novel treatments for viral diseases.展开更多
Objective To study the effect of β3 adrenergic receptor （β3AR） Trp64Arg and peroxisome proliferator activated receptor gamma 2 （PPAR72） Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight...Objective To study the effect of β3 adrenergic receptor （β3AR） Trp64Arg and peroxisome proliferator activated receptor gamma 2 （PPAR72） Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment （HOMA）. PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state （IBS） was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%, and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio （WHR）, blood glucose （GLU）, and insulin （INS）, homeostasis model assessment insulin resistance index （HOMA-IR） of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA4R had statistic significance. For PPAR3t2 Prol2Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index （BMI）, WHR, percent of body fat （PBF） and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Condusions β3AR Trp64Arg and PPAR）,2 Pro 12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.展开更多
Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was app...Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 （P2X3） receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:82260007Jilin Province Health Commission,Grant/Award Number:2024A062+1 种基金Jilin Provincial Department of Education,Grant/Award Number:JJKH20240698KJJilin Province Science and Technology Department,Grant/Award Number:20240404025ZP and 20240602100RC。
文摘Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.
基金supported by the National Natural Science Foundation of China(Grant No.82060479)Key Research and Development Program of Ningxia Hui Autonomous Region(Grant No.2021BEG03062)Ningxia Natural Science Fund Key Project(Grant No.2024AAC02080).
文摘Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.
基金supported by the National Natural Science Foundation of China[82201489,2022].
文摘Objective:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease of the central nervous system(CNS).Soluble interleukin-2 receptor alpha(sIL-2Rα)has been implicated inMS pathogenesis,but its mechanisms remain unclear.This study investigates how sIL-2Rαexacerbates MS by modulating microglial activation and antibody-dependent cellular cytotoxicity(ADCC)in an experimental autoimmune encephalomyelitis(EAE)mouse model.Methods:Female C57BL/6J mice were induced with EAE and treated with sIL-2Rα.Clinical symptoms,histopathology,and molecular changes were analyzed.Microglial activation was assessed via immunohistochemistry,Western blot,and RNA sequencing.In vitro,ADCC-mediated oligodendrocyte injury was evaluated using Fc receptor inhibition and PI3K-Akt pathway blockade.Results:sIL-2Rα accelerated EAE onset and severity,increasingmicroglial M1 polarization and CNS inflammation.RNA-seq revealed PI3K-Akt pathway activation,upregulating Fc receptors(FcγR)on microglia,which enhanced ADCC against oligodendrocytes(p<0.001).Inhibiting FcγR or PI3K-Akt reduced oligodendrocyte damage.Conclusion:sIL-2Rαexacerbates MS by activating microglia via the PI3K-Aktaxis,promoting ADCC and demyelination.Targeting this pathway may offer novel therapeutic strategies for MS.
基金Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
基金supported by the National Natural Science Foundation of China,Nos.31972914,31771175(both to YH).
文摘Aerobic exercise facilitates synaptic plasticity,thereby improving cognitive functions such as learning and memory.The 5-hydroxytryptamine system has been indicated in these processes.5-Hydroxytryptamine type 3 receptors are necessary for exercise-induced hippocampal neurogenesis.Some antipsychotic drugs with 5-hydroxytryptamine type 3 receptor antagonistic properties may impede the amelioration of cognitive impairment and hippocampal plasticity induced by exercise.However,the mechanisms underlying the facilitation of synaptic plasticity by aerobic exercise have not yet been elucidated.In this study,we found that 5-hydroxytryptamine type 3 receptors played an important role in aerobic exercise-mediated improvement of hippocampal-dependent spatial and exploratory memory in mice.While 5-hydroxytryptamine type 3 receptors did not affect baseline neurogenesis in the hippocampal dentate gyrus,5-hydroxytryptamine type 3 receptors were required for aerobic exercise-induced neurogenesis and astrocyte proliferation in this region.In addition,5-hydroxytryptamine type 3 receptors were crucial for maintaining long-term potentiation in the CA1,dentate gyrus,and CA3 regions of the hippocampus.The long-term potentiation changes induced by aerobic exercise in sub-regions of the hippocampus were heterogeneous:5-hydroxytryptamine type 3 receptors were essential for aerobic exercise to enhance long-term potentiation in the CA3,but not the CA1 or dentate gyrus,regions of the hippocampus.Furthermore,aerobic exercise up-regulated 5-hydroxytryptamine type 3 receptor expression and increased brain-derived neurotrophic factor release in the hippocampus in a 5-hydroxytryptamine type 3 receptor-dependent manner.These results suggest that aerobic exercise increases hippocampal dentate gyrus neurogenesis and astrocyte proliferation via the up-regulation of 5-hydroxytryptamine type 3 receptors,leading to more brain-derived neurotrophic factor production and release from these cells,which results in long-term potentiation facilitation in the hippocampal CA3 region and help improve memory.Our findings provide insight into the mechanisms by which physical activity enhances memory and may have implications for improving memory through modulating 5-hydroxytryptamine type 3 receptor.
基金Supported by Hebei Province Medical Science Research Project Plan,No.20230755.
文摘BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
基金Supported by the Youth Talent Program of Yunnan“Ten-thousand Talents Program”,No.YNWR-QNBJ-2018-169the Science Project of Yunnan Science and Technology Department,No.202201AY070001-068.
文摘BACKGROUND Epidermal growth factor receptor(EGFR)is a transmembrane protein that is differentially expressed in gestational diabetes mellitus(GDM).Endothelial dy-sfunction is a hallmark of GDM and plays a key role in its pathogenesis.EGFR is associated with endothelial dysfunction in the context of various diseases.How-ever,the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown,particularly its regulation at the transcriptional and protein levels.METHODS Quantitative real-time polymerase chain reaction was used to detect the ex-pression of EGFR and H19.Western blotting was used to detect the expression of endothelial cell dysfunction markers.A cell counting kit 8 assay was used to assess cell viability,flow cytometry was used to assess apoptosis,scratch and Transwell assays were used to assess cell migration,and a tube formation assay was used to assess cell vascular formation.Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.RESULTS In this study,EGFR was upregulated in clinical samples,GDM animal models and GDM cell models,and the knockdown of EGFR could mitigate the effect of streptozotocin(STZ)and high glucose(HG);promoted the proliferation,migration and vascularization of human umbilical vein endothelial cells(HUVECs);inhibited cell apoptosis and the expression of endothelial cell dysfunction markers(vascular cell adhesion molecule-1,tumor necrosis factor-α,vascular endothelial growth factor-A,and intercellular cell adhesion molecule-1);and alleviated the process of GDM in vivo.Mechanistically,EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA,thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice.In addition,ERRFI1 also regulated the expression of EGFR,and ERRFI1 inhibited EGFR activity by binding to EGFR,thereby inhibiting HG-induced HUVECs dysfunction.CONCLUSION Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
基金project was supported by the National Key Research and Development Program(2021YFD2100700)。
文摘The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan(Trp)-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics and dextran sodium sulfate.Several Lactobacillus strains isolated from the healthy human fecal sample was found to utilize Trp to produce indole derivatives.The results of Trp metabolism indicated that the ability of Lactobacillus to metabolize Trp to produce indole-3-lactic acid(ILA),indole-3-carboxaldehyde(I3C),and indole-3-acetic acid varies in vitro and in vivo.The effect of Lactobacillus with high-yielding indole derivatives on disease activity index,colon length,and intestinal permeability was significantly better than that of Lactobacillus with low-yielding indole derivatives in a high Trp diet.And Lactobacillus combined with Trp intervention also had a certain regulatory effect on the intestinal flora of male BALB/c mice.Among them,Lactiplantibacillus plantarum DPUL-S164 produced more ILA both in vivo and in vitro,and the combination of L.plantarum DPUL-S164 and Trp significantly decreased the expression level of the serum pro-inflammatory cytokine interleukin(IL)-6 and increased the expression level of the anti-inflammatory cytokine IL-10,significantly improved the number of goblet cells in the mouse mucous layer and increased mucin and tight junction protein expression.Furthermore,L.plantarum DPUL-S164 combined with Trp intervention activated the aryl hydrocarbon receptors(Ah R)signaling pathway.Furthermore,we found that the expression of colonic tight junction protein was positively correlated with the expression of colonic Ah R,and the expression of Ah R was positively correlated with the concentrations of ILA and I3C in vivo.Therefore,we conclude that the ILA as Ah R ligand produced by L.plantarum DPUL-S164 regulated the Ah R pathway,thus up-regulating the expression of the tight junction protein and protecting the integrity of the epithelial barrier.
基金supported by the National Natural Science Foundation of China(Grant Nos.82270613 and 82170844)the open fund of Metabolic Vascular Diseases Key Laboratory of Sichuan Province,China(Grant Nos.:2022MVDKL-G3 and 2022MVDKL-G4).
文摘Diabetic foot ulcer(DFU)is an increasing global burden due to the rising prevalence of diabetes,and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment.In this study,naringenin(NAR)was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type(WT)mice by reducing oxidative stress,as assessed through histological assay.NAR also alleviated the inhibition of proliferation,inflammation,cell senescence,and apoptosis in HaCaT cells induced by high glucose(HG).Mechanistically,the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin(Parkin/PRKN/Prkn).NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation,thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control(MQC).Moreover,the wound healingpromoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout(Prkn^(-/-))DFU mice.Inhibition of NAR binding to estrogen receptors(ERs)using tamoxifen(TAM)abolished the protective effects of NAR in HG-induced HaCaT cells.The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element(ERE),thereby upregulating Parkin transcription.Additionally,the cellular thermal shift assay(CETSA)revealed that NAR specifically bound to ERa.In conclusion,NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERa,highlighting its potential as a promising therapeutic candidate.
基金supported by DST-Science and Engineering Research Board(SERB)Early carrier research grant ECR/2015/000240Core research grant CRG/2020/003257,the University Grants Commission(UGC start-up grant F.30-318/2016)the Central University of Punjab RSM grant-CUPB/CC/16/00/13.
文摘Objective:To examine the effect of an neurokinin 3 receptor(NK3R)agonist,senktide,on neuronal nitric oxide synthase(nNOS)activation in the median eminence-arcuate nucleus(ME-ARC)and preoptic area(POA)regions of the hypothalamus across proestrus,diestrus,and ovariectomized states in female rats and its correlation with luteinizing hormone(LH)secretion.Methods:Adult female Sprague-Dawley rats were examined for proestrus and diestrus phases of the estrous cycle.Female rats were categorized into proestrus and diestrus groups,and each was further divided into four subgroups(n=4).In both the diestrus and proestrus categories,Group 1 was the control group.Groups 2,3,and 4 received senktide(100μg/kg-1),NK3R antagonist SB222200(10 mg/kg-1),and SB222200 followed by senktide,respectively.To evaluate the effect of sex steroids on NK3R agonist-induced nNOS activation,female rats underwent bilateral ovariectomy and were divided into four groups(n=3).Group 1 served as the control.Group 2 received a subcutaneous injection of 17β-estradiol 3-benzoate(E2,3μg/rat).Group 3 received E2 and progesterone(30μg/rat).Group 4 was administered senktide(100μg/kg).Female rats from each group were sacrificed,blood was collected for LH ELISA,and hypothalamic tissues were collected for Western blotting.Results:Senktide increased nNOS phosphorylation in the ME-ARC during both the proestrus and diestrus phases.In the POA,senktide increased nNOS phosphorylation only during the diestrus phase.In ovariectomized rats,senktide activated nNOS independent of sex steroid levels.Senktide also increased serum LH concentration in diestrus and ovariectomized female rats.Conclusions:Senktide,an NK3R agonist,activates nNOS in the POA and ME-ARC regions of the hypothalamus in a phase dependent manner.The activation of nNOS by senktide suggests a potential mechanism by which neurokinin B triggers nNOS activation in the ARC and POA regions and regulates GnRH/LH secretion.
基金funded by the National Natural Science Foundation of China(32001824,31972198)supported by the Startup Fund for Young Faculty at SJTU(Shanghai Jiao Tong University)High Level Innovation Team and Distinguished Scholar Project of Guangxi Universities and Colleges(2020[6]).
文摘The study of ligand-receptor interactions is of great significance in food flavor perception.In this study,a computer simulation method was used to investigate the mechanism of interaction between umami peptides and T1R1/T1R3-Venus-flytrap domain(VFT)receptor.The binding site,conformational changes,and binding free energy between umami peptides and T1R1/T1R3-VFT were analyzed through molecular modeling,molecular docking,and molecular dynamics simulations.The receptor model constructed using AlphaFold2 has the best rationality.The molecular docking results showed that umami peptides primarily bound to T1R1-VFT through hydrogen bonding,with key binding residues such as Thr149,Arg151,and Asp108.The binding of umami peptides led to a more stable complex system,and the positively charged amino acids contributed positively to the overall binding free energy.This study provides theoretical support for the development of a better understanding of the interaction between umami substances and the umami receptor.
文摘A deficiency ofγδT cells has been described in Crohn's disease(CD).AIM To analyze the gene expression of interleukin 7(IL-7)and its receptors in the tissues of patients with CD.METHODS We studied the peripheral blood of 80 patients with CD,comparing them with a group of 80 healthy subjects.The number and apoptosis ofαβandγδT cells in peripheral blood and the proportion ofαβandγδT cells in the intestinal tissues of patients with CD(n=25)were studied.The gene and protein expression of IL-7,IL-2 receptor subunitγ[cluster of differentiation 132(CD132)],receptorα(CD127),and caspase-3 in tissues was analyzed by quantitative PCR.Serum IL-7 levels were also analyzed.RESULTS In patients with CD,a decreased number ofγδT cells and an increase in the apoptosis of CD56+αβandγδT cells in peripheral blood was observed(P<0.0001 and P<0.01)respectively,and there was an inverse correlation among T subsets and their apoptosis.In addition,IL-7 gene expression and IL-7 protein in the tissues of these patients were increased.The titers of caspase-3 in tissues were low vs control group(P>0.01).The percentage of CD8+γδT cells decreased in tissues(P<0.01),and was directly related to IL-7 levels in peripheral blood.The expression of IL-2 receptor subunitγ(CD132)was greatly decreased in the tissues of patients with CD(P<0.05).CONCLUSION There may be a cause-effect relationship between the lower gene expression of the IL-2 receptor subunitγ(CD132)in tissues of patients with CD andγδT cells immunodeficiency.
基金supported by National Natural Science Foundation of China(No.30271500)Science and Tech-nology Research Project Fund from the Department of Edu-cation of Hubei Province of China(No.B20115101)
文摘This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.
基金the National Natural Science Foundation of China(81871852,81200935,81671862,and 81871529)Liaoning Revitalization Talents Program(XLYC1807137)+1 种基金the Scientific Research Foundation for Overseas Scholars of the Education Ministry of China(20151098)the Natural Science Foundation of Liaoning Province,China(20170541030)。
文摘Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.
基金supported by the National Key R&D Program of China(No.2018YFD0501705)the Chongqing Basic Research Program(No.cstc2018jcyj AX0615)the Fundamental Research Funds for the Central Universities(Nos.XDJK2018C059 and XDJK2018C060),China。
文摘Toll-like receptor 3(TLR3)is a member of the TLR family,mediating the transcriptional induction of type I interferons(IFNs),proinflammatory cytokines,and chemokines,thereby collectively establishing an antiviral host response.Studies have shown that unlike other TLR family members,TLR3 is the only RNA sensor that is utterly dependent on the Tollinterleukin-1 receptor(TIR)-domain-containing adaptor-inducing IFN-β(TRIF).However,the details of how the TLR3-TRIF signaling pathway works in an antiviral response and how it is regulated are unclear.In this review,we focus on recent advances in understanding the antiviral mechanism of the TRIF pathway and describe the essential characteristics of TLR3 and its antiviral effects.Advancing our understanding of TLR3 may contribute to disease diagnosis and could foster the development of novel treatments for viral diseases.
基金This study was supported by the National Natural Science Foundation of China (30371223)the Major State Basic Research Development Program of China (2001CB510310).
文摘Objective To study the effect of β3 adrenergic receptor （β3AR） Trp64Arg and peroxisome proliferator activated receptor gamma 2 （PPAR72） Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment （HOMA）. PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state （IBS） was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%, and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio （WHR）, blood glucose （GLU）, and insulin （INS）, homeostasis model assessment insulin resistance index （HOMA-IR） of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA4R had statistic significance. For PPAR3t2 Prol2Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index （BMI）, WHR, percent of body fat （PBF） and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Condusions β3AR Trp64Arg and PPAR）,2 Pro 12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.
文摘Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 （P2X3） receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.
