Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-l...Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.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
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
Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.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
Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly atte...Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.展开更多
Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photo...Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photosensitizer dyes(sulphonated aluminum phthalocyanine,λmax 675 nm)or genetically encoded protein photosensitizers(KillerRedλmax 585 nm;mini singlet oxygen generatorλmax 450 nm),together with a pulse of light(37 mW/cm2,1-2 minutes).Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen(GPCR-ABSO):(1)CCK1R is quantitatively converted from dimer to monomer;(2)Transmembrane domain 3,a pharmacophore for permanent photodynamic CCK1R activation,can be transplanted to non-susceptible M3 acetylcholine receptor;and(3)Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation.GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs,but show some clear advantages:Enhanced selectivity(double selectivity of localized photosensitizer and light illumination),long-lasting activation with no need for repeated drug administration,antagonist-binding site remains intact when needed,ease to apply to multiple GPCR.This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.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
BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis th...BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially...Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.展开更多
OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pat...OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.展开更多
BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despi...BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.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
Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascu...Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascular disease,and other diseases,including some malignancies.Currently,the first line of management includes lifestyle modifications.However,recently,bariatric surgeries were introduced to combat obesity.The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve,and surgeries are invasive and also require a lifestyle modification and commitment.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)were initially introduced as a rising star for managing T2DM,with patients benefiting from the control of blood sugar and weight loss.These medications work by enhancing feelings of fullness,slowing down digestion,and ultimately reducing calorie intake.However,GLP-1RAs are not without side effects and have some costs.Common side effects include gastrointestinal(GI)adverse events such as nausea,vomiting,diarrhea,and a lack of GI motility,which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss,potentially resulting in treatment discontinuation.More serious,though less frequent,risks include pancreatitis,gallbladder diseases,and,rarely,thyroid Ccell cancers.This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.展开更多
The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current st...The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.展开更多
BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,...BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are arising as potential therapeutic alternatives.AIM To evaluate the impact of GLP-1 RAs on the incidence of AF.METHODS Inclusion criteria included systematic reviews(SRs)that based their analyses on clinical trials,observational studies,controlled trials and network meta-analyses.A total of 8 SRs were selected for data extraction,focusing on semaglutide,liraglutide and dulaglutide.Additionally,the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2(SGLT2)inhibitors.RESULTS Findings indicate that semaglutide,evaluated in the largest patient cohort across the 8 SRs,consistently reduced AF incidence.However,dulaglutide and liraglutide exhibited inconsistent effects.Notably,as opposed to variable outcomes associated with GLP-1 RAs,SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits,including reductions in both AF and atrial flutter.CONCLUSION GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF.However,further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.展开更多
BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein couple...BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.展开更多
BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are increasingly being used to treat type 2 diabetes mellitus(T2DM)and obesity.Although GLP-1RAs delay gastric emptying,their impact on gastric mucosal vis...BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are increasingly being used to treat type 2 diabetes mellitus(T2DM)and obesity.Although GLP-1RAs delay gastric emptying,their impact on gastric mucosal visibility during upper endoscopy remains uncertain,especially in Asian patients.AIM To investigate the association between GLP-1RA treatment and gastric mucosal visibility during upper endoscopy in Asian patients with T2DM.METHODS The study population included Korean patients who underwent esophagogastroduodenoscopy(EGD)with concomitant GLP-1RA or dipeptidyl peptidase 4 inhibitor(DPP4i)for the treatment of T2DM.A 1:2 propensity score matching between GLP-1RA and DPP4i users resulted in 198 matched patients and 295 matched patients in each group,respectively.Gastric mucosal visibility was assessed by reviewing endoscopy images with a validated scale(POLPREP).In addition,the rates of aborted and repeat EGD and pulmonary aspiration were also assessed.RESULTS Of the 493 matched patients,mean body mass index was 26.0 kg/m^(2).The rate of inadequate gastric mucosal visibility(gastric POLPREP score 0 or 1)was significantly higher in GLP-1RA group than matched DPP4i group(8.6%vs 1.4%,P=0.0007).The rates of aborted EGD and repeat EGD were also significantly higher in GLP-1RA than DPP4i group(7.6%vs 0.7%in both aborted and repeat EGD,P=0.0011).Multivariable logistic regression revealed GLP-1RA use as an independent risk factor for both inadequate gastric mucosal visibility(odds ratio=6.143,95%confidence interval:2.289,20.318,P=0.0008)and aborted EGD(odds ratio=11.099,95%confidence interval:3.172,63.760,P=0.0010).Despite gastric residue,no pulmonary aspiration was reported in either group.CONCLUSION GLP-1RA use was associated with a higher risk of inadequate gastric mucosal visibility and aborted and repeat procedures during upper gastrointestinal endoscopy in Korean patients with T2DM while pulmonary aspiration was not observed.展开更多
基金supported by the National Natural Science Foundation of China(32370295 and 32170280 to K.H.)Foundation of Science and Technology of Gansu Province(22ZD6NA049)+3 种基金the Fundamental Research Funds for the Central Universities(lzujbky-2021-kb05 to Y.F.and lzujbky-2023-kb05 to P.L.)the Science and Technology Department of Gansu Province(24JRRA392 to K.H.and 23JRRA1132 to C.X.)China Postdoctoral Science Foundation(2024M751259 and GZB20240285 to B.L.)Science and Technology Program of Gansu Province(25JRRA718 to B.L.).
文摘Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.
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 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.
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
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 Open Project Fund of Henan Provincial Research Center for Precision Diagnosis and Treatment of Pulmonary Diseases Based on Multi-omics,No.DZXGCZXKF04.
文摘Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.
基金Supported by the National Natural Science Foundation of China,No.32271278 and No.31971170.
文摘Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photosensitizer dyes(sulphonated aluminum phthalocyanine,λmax 675 nm)or genetically encoded protein photosensitizers(KillerRedλmax 585 nm;mini singlet oxygen generatorλmax 450 nm),together with a pulse of light(37 mW/cm2,1-2 minutes).Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen(GPCR-ABSO):(1)CCK1R is quantitatively converted from dimer to monomer;(2)Transmembrane domain 3,a pharmacophore for permanent photodynamic CCK1R activation,can be transplanted to non-susceptible M3 acetylcholine receptor;and(3)Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation.GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs,but show some clear advantages:Enhanced selectivity(double selectivity of localized photosensitizer and light illumination),long-lasting activation with no need for repeated drug administration,antagonist-binding site remains intact when needed,ease to apply to multiple GPCR.This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.
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.82350127 and No.82241013the Shanghai Natural Science Foundation,No.20ZR1411600+2 种基金the Shanghai Shenkang Hospital Development Center,No.SHDC2020CR4039the Bethune Ethicon Excellent Surgery Foundation,No.CESS2021TC04Xuhui District Medical Research Project of Shanghai,No.SHXH201805.
文摘BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
基金Supported by Shanxi Provincial Key Research and Development Plan Project,No.2020ZDLSF01-02Doctor Foundation of the Second Affiliated Hospital of Xi’an Medical University,No.X2Y-R11.
文摘Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.
基金National Natural Science Foundation of China:Study on the Molecular Mechanism of the Regulation of Crypt Goblet Cell Pyroptosis and Exocytosis to Repair Ulcerative Colitis Mucus Barrier by the Method of Clearing and Opening the Xuanfu from the Perspective of"Xuanfu-Crypt"(No.82305143),and National Natural Science Foundation of China:Exploring the Molecular Mechanism of"Hewei Jiangni Fang"Intervention in Non-erosive Reflux Disease Esophageal Hypersensitivity from the Perspective of Mas-related Gene X2/Stromal Interaction Molecule 1/Cell Adhesion Molecule 1 Pathway Regulation of Mast Cell/Dorsal Root Ganglion Communication based on the"Xinkai-Kujiang"Method(No.82374401)。
文摘OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.
基金Supported by Changsha Science and Technology Program,No.kq2022397Natural Science Foundation of Hunan Province(Departmental Joint Fund),No.2023JJ60440+2 种基金Research Program of Health Commission of Hunan Province,No.202303088786Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009the Scientific Research Program of FuRong Laboratory,No.2023SK2108.
文摘BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
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Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascular disease,and other diseases,including some malignancies.Currently,the first line of management includes lifestyle modifications.However,recently,bariatric surgeries were introduced to combat obesity.The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve,and surgeries are invasive and also require a lifestyle modification and commitment.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)were initially introduced as a rising star for managing T2DM,with patients benefiting from the control of blood sugar and weight loss.These medications work by enhancing feelings of fullness,slowing down digestion,and ultimately reducing calorie intake.However,GLP-1RAs are not without side effects and have some costs.Common side effects include gastrointestinal(GI)adverse events such as nausea,vomiting,diarrhea,and a lack of GI motility,which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss,potentially resulting in treatment discontinuation.More serious,though less frequent,risks include pancreatitis,gallbladder diseases,and,rarely,thyroid Ccell cancers.This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.
基金supported by the National Natural Science Foundation of China(Grant Nos.82030012,81670263,82170444,82270476,82270361,and 82100433)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.24KJA310003)。
文摘The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.
文摘BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are arising as potential therapeutic alternatives.AIM To evaluate the impact of GLP-1 RAs on the incidence of AF.METHODS Inclusion criteria included systematic reviews(SRs)that based their analyses on clinical trials,observational studies,controlled trials and network meta-analyses.A total of 8 SRs were selected for data extraction,focusing on semaglutide,liraglutide and dulaglutide.Additionally,the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2(SGLT2)inhibitors.RESULTS Findings indicate that semaglutide,evaluated in the largest patient cohort across the 8 SRs,consistently reduced AF incidence.However,dulaglutide and liraglutide exhibited inconsistent effects.Notably,as opposed to variable outcomes associated with GLP-1 RAs,SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits,including reductions in both AF and atrial flutter.CONCLUSION GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF.However,further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.
文摘BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.
文摘BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are increasingly being used to treat type 2 diabetes mellitus(T2DM)and obesity.Although GLP-1RAs delay gastric emptying,their impact on gastric mucosal visibility during upper endoscopy remains uncertain,especially in Asian patients.AIM To investigate the association between GLP-1RA treatment and gastric mucosal visibility during upper endoscopy in Asian patients with T2DM.METHODS The study population included Korean patients who underwent esophagogastroduodenoscopy(EGD)with concomitant GLP-1RA or dipeptidyl peptidase 4 inhibitor(DPP4i)for the treatment of T2DM.A 1:2 propensity score matching between GLP-1RA and DPP4i users resulted in 198 matched patients and 295 matched patients in each group,respectively.Gastric mucosal visibility was assessed by reviewing endoscopy images with a validated scale(POLPREP).In addition,the rates of aborted and repeat EGD and pulmonary aspiration were also assessed.RESULTS Of the 493 matched patients,mean body mass index was 26.0 kg/m^(2).The rate of inadequate gastric mucosal visibility(gastric POLPREP score 0 or 1)was significantly higher in GLP-1RA group than matched DPP4i group(8.6%vs 1.4%,P=0.0007).The rates of aborted EGD and repeat EGD were also significantly higher in GLP-1RA than DPP4i group(7.6%vs 0.7%in both aborted and repeat EGD,P=0.0011).Multivariable logistic regression revealed GLP-1RA use as an independent risk factor for both inadequate gastric mucosal visibility(odds ratio=6.143,95%confidence interval:2.289,20.318,P=0.0008)and aborted EGD(odds ratio=11.099,95%confidence interval:3.172,63.760,P=0.0010).Despite gastric residue,no pulmonary aspiration was reported in either group.CONCLUSION GLP-1RA use was associated with a higher risk of inadequate gastric mucosal visibility and aborted and repeat procedures during upper gastrointestinal endoscopy in Korean patients with T2DM while pulmonary aspiration was not observed.
