Background:Excessive use of inorganic trace minerals(ITMs)in swine production leads to high fecal mineral excretion and environmental risks,while most studies on organic trace minerals(OTMs)focus on single elements,wi...Background:Excessive use of inorganic trace minerals(ITMs)in swine production leads to high fecal mineral excretion and environmental risks,while most studies on organic trace minerals(OTMs)focus on single elements,with limited data on the synergistic effects and molecular mechanisms of combined OTMs(Fe,Cu,Mn,Zn)in growing-finishing pigs.Methods:This study aimed to investigate the effects of graded levels of micromineral proteinates(combined OTMs)on growth performance,mineral metabolism,and mRNA expression of mineral regulatory proteins.A total of 360 crossbred Duroc×Landrace×Large White pigs(initial body weight 47.1±4.8 kg)were randomly assigned to 6 dietary treatments:basal diet without microminerals(CON),basal diet with ITMs at commercially recommended levels(IT),and basal diets with 15%(OT 15%),25%(OT 25%),35%(OT 35%)commercially recommended levels(CRL)of combined micromineral proteinates.After a 70-day feeding trial,samples were analyzed using ICP-OES,ELISA,and RT-qPCR.Results:Results showed that reduced levels(15-35%CRL)of micromineral proteinates did not significantly affect average daily gain,average daily feed intake,or feed conversion ratio(gain-to-feed ratio)compared to IT(P>0.05),but significantly increased plasma Cu(1.73-1.83μg/mL)and Zn(1.72-1.97μg/mL)concentrations(P<0.05)and elevated activities of Cu/Zn-superoxide dismutase(32.9-35.9 U/L)and manganese superoxide dismutase(20.5-24.1 U/L)compared to CON(P<0.05),with no significant differences from IT(P>0.05).Fecal excretion of Fe,Cu,Mn,and Zn was significantly reduced by 35-50%in OT 15%-OT 35%groups compared to IT(P<0.05).OT 25%group exhibited the highest apparent absorptivity of Fe(38.5%),Cu(27.8%),and Zn(42.4%)(P<0.05),which was associated with significantly regulated mRNA expression of mineral regulatory proteins:upregulated DMT1,FPN1,ZIP4,and MT1A in the duodenum,and modulated HAMP,ATP7B,ZIP14,and ZnT1 in the liver(P<0.05).Conclusion:In conclusion,dietary supplementation with 25%CRL or less of combined micromineral proteinates can fully meet the nutritional needs of growing-finishing pigs,improve mineral absorptivity,and reduce fecal mineral excretion by regulating intestinal and hepatic mineral transport and homeostatic proteins,providing a sustainable alternative to high-dose ITMs.展开更多
With the growth of global protein demand and the development of plant-based foods,pea protein,as a low-allergenic,nutritionally balanced and environmentally friendly plant protein,has shown great potential in replacin...With the growth of global protein demand and the development of plant-based foods,pea protein,as a low-allergenic,nutritionally balanced and environmentally friendly plant protein,has shown great potential in replacing animal protein.Pea protein is mainly composed of globulin and albumin,with a protein content of 20%to 30%,and has a balanced amino acid composition,as well as being rich in minerals and dietary fiber.It also possesses good foaming,gelling,emulsifying and antioxidant functional properties.However,pea protein also has inherent defects that limit its application in the food industry.This article systematically reviews the extraction techniques,functional properties,modification methods and application fields of pea protein,and focuses on evaluating the effects of different extraction and modification strategies on protein yield and functional properties.Research shows that ultrasonic-assisted alkaline extraction can reduce solvent usage by 55%,shorten extraction time by 50%,and increase extraction rate by 12.51%;under optimized conditions,ultrafiltration membrane technology can achieve a protein purity of 91%.In terms of modification,ultrasonic treatment increases foaming capacity by 37.4%,and phenolic cross-linking increases gel strength from 3.0 kPa to 48 kPa.This article provides data support and theoretical reference for the efficient extraction and functional optimization of pea protein,and has promoting significance for its wide application in plant-based foods.展开更多
The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR...The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR.However,their clinical translation is hindered by their inherently low immunogenicity,often requiring potent adjuvants and advanced delivery systems.Biomembrane nanostructures(e.g.,liposomes,exosomes,and cell membrane-derived nanostructures),characterized by superior biocompatibility,intrinsic targeting ability,and immune-modulating properties,could serve as versatile platforms that potentiate vaccine efficacy by increasing antigen stability,enabling codelivery of immunostimulants,and facilitating targeted delivery to lymphoid tissues/antigen-presenting cells.This intrinsic immunomodulation promotes robust humoral and cellular immune responses to combat bacteria.This review critically reviews(1)key biomembrane nanostructure classes for bacterial protein antigens,(2)design strategies leveraging biomembrane nanostructures to enhance humoral and cellular immune responses,(3)preclinical efficacy against diverse pathogens,and(4)translational challenges and prospects.Biomembrane nanostructure-driven approaches represent a paradigm shift in the development of next-generation bacterial protein vaccines against resistant infections.展开更多
Directional three-dimensional carbon-based foams are emerging as highly attractive candidates for promising electromagnetic wave absorbing materials(EWAMs)thanks to their unique architecture,but their construction usu...Directional three-dimensional carbon-based foams are emerging as highly attractive candidates for promising electromagnetic wave absorbing materials(EWAMs)thanks to their unique architecture,but their construction usually involves complex procedures and extremely depends on unidirectional freezing technique.Herein,we propose a groundbreaking approach that leverages the assemblies of salting-out protein induced by ammonium metatungstate(AM)as the precursor,and then acquire directional three-dimensional carbon-based foams through simple pyrolysis.The electrostatic interaction between AM and protein ensures well dispersion of WC_(1−x)nanoparticles on carbon frameworks.The content of WC_(1−x)nanoparticles can be rationally regulated by AM dosage,and it also affects the electromagnetic(EM)properties of final carbon-based foams.The optimized foam exhibits exceptional EM absorption performance,achieving a remarkable minimum reflection loss of−72.0 dB and an effective absorption bandwidth of 6.3 GHz when EM wave propagates parallel to the directional pores.Such performance benefits from the synergistic effects of macroporous architecture and compositional design.Although there is a directional dependence of EM absorption,radar stealth simulation demonstrates that these foams can still promise considerable reduction in radar cross section with the change of incident angle.Moreover,COMSOL simulation further identifies their good performance in preventing EM interference among different electronic components.展开更多
α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immun...Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.展开更多
Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of t...Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.展开更多
The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
Maize(Zea mays),which is a vital source of food,feed,and energy feedstock globally,has significant potential for higher yields.However,environmental stress conditions,including drought and salt stress,severely restric...Maize(Zea mays),which is a vital source of food,feed,and energy feedstock globally,has significant potential for higher yields.However,environmental stress conditions,including drought and salt stress,severely restrict maize plant growth and development,leading to great yield losses.Leucine-rich repeat receptor-like kinases(LRR-RLKs)function in biotic and abiotic stress responses in the model plant Arabidopsis(Arabidopsis thaliana),but their roles in abiotic stress responses in maize are not entirely understood.In this study,we determine that the LRR-RLK ZmMIK2,a homolog of the Arabidopsis LRR-RK MALE DISCOVERER 1(MDIS1)-INTERACTING RECEPTOR LIKE KINASE 2(MIK2),functions in resistance to both drought and salt stress in maize.Zmmik2 plants exhibit enhanced resistance to both stresses,whereas overexpressing ZmMIK2 confers the opposite phenotypes.Furthermore,we identify C2-DOMAIN-CONTAINING PROTEIN 1(ZmC2DP1),which interacts with the intracellular region of ZmMIK2.Notably,that region of ZmMIK2 mediates the phosphorylation of ZmC2DP1,likely by increasing its stability.Both ZmMIK2 and ZmC2DP1 are mainly expressed in roots.As with ZmMIK2,knockout of ZmC2DP1 enhances resistance to both drought and salt stress.We conclude that ZmMIK2-ZmC2DP1 acts as a negative regulatory module in maize drought-and salt-stress responses.展开更多
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is one of the most prevalent and aggressive forms of liver cancer,with high morbidity and poor prognosis due to late diagnosis and limited treatment options.Despite advances in ...BACKGROUND Hepatocellular carcinoma(HCC)is one of the most prevalent and aggressive forms of liver cancer,with high morbidity and poor prognosis due to late diagnosis and limited treatment options.Despite advances in understanding its molecular mechanisms,effective biomarkers for early detection and targeted therapy remain scarce.Zinc finger protein 71(ZNF71),a zinc-finger protein,has been implicated in various cancers,yet its role in HCC remains largely unexplored.This gap in knowledge underscores the need for further investigation into the ZNF71 of potential as a diagnostic or therapeutic target in HCC.AIM To explore the expression levels,clinical relevance,and molecular mechanisms of ZNF71 in the progression of HCC.METHODS The study evaluated ZNF71 expression in 235 HCC specimens and 13 noncancerous liver tissue samples using immunohistochemistry.High-throughput datasets were employed to assess the differential expression of ZNF71 in HCC and its association with clinical and pathological features.The impact of ZNF71 on HCC cell line growth was examined through clustered regularly interspaced short palindromic repeat knockout screens.Co-expressed genes were identified and analyzed for enrichment using LinkedOmics and Sangerbox 3.0,focusing on significant correlations(P<0.01,correlation coefficient≥0.3).Furthermore,the relationship between ZNF71 expression and immune cell infiltration was quantified using TIMER2.0.RESULTS ZNF71 showed higher expression in HCC tissues vs non-tumorous tissues,with a significant statistical difference(P<0.05).Data from the UALCAN platform indicated increased ZNF71 levels across early to mid-stage HCC,correlating with disease severity(P<0.05).High-throughput analysis presented a standardized mean difference in ZNF71 expression of 0.55(95%confidence interval[CI]:0.34-0.75).The efficiency of ZNF71 mRNA was evaluated,yielding an area under the curve of 0.78(95%CI:0.75-0.82),a sensitivity of 0.63(95%CI:0.53-0.72),and a specificity of 0.82(95%CI:0.73-0.89).Diagnostic likelihood ratios were positive at 3.61(95%CI:2.41-5.41)and negative at 0.45(95%CI:0.36-0.56).LinkedOmics analysis identified strong positive correlations of ZNF71 with genes such as ZNF470,ZNF256,and ZNF285.Pathway enrichment analyses highlighted associations with herpes simplex virus type 1 infection,the cell cycle,and DNA replication.Negative correlations involved metabolic pathways,peroxisomes,and fatty acid degradation.TIMER2.0 analysis demonstrated positive correlations of high ZNF71 expression with various immune cell types,including CD4^(+)T cells,B cells,regulatory T cells,monocytes,macrophages,and myeloid dendritic cells.CONCLUSION ZNF71 is significantly upregulated in HCC,correlating with the disease’s clinical and pathological stages.It appears to promote HCC progression through mechanisms involving the cell cycle and metabolism and is associated with immune cell infiltration.These findings suggest that ZNF71 could be a novel target for diagnosing and treating HCC.展开更多
Objectives:Cold-acclimated organisms accumulate low molecular weight organic solutes such as sugar alcohols and soluble sugars.This study aimed to compare the efficacy of five sugar alcohols and 14 soluble sugars in s...Objectives:Cold-acclimated organisms accumulate low molecular weight organic solutes such as sugar alcohols and soluble sugars.This study aimed to compare the efficacy of five sugar alcohols and 14 soluble sugars in stabilizing proteins under freezing,freeze-drying,and air-drying stresses.Materials and methods:Glucose-6-Phosphate Dehydrogenase(G6PD)was used as the model protein.G6PD solutions with or without sugar alcohols and or sugars were subjected to freezing,freeze-drying,and air-drying stresses.The recovery of G6PD activity was measured to evaluate the protective efficacy of these compounds.Results:Without stabilizers,freezing G6PD at-20℃ or-80℃ reduced enzyme activity by around 24%,while freeze-drying or air-drying reduced activity by 90%-95%.Among the five sugar alcohols tested,pinitol,quebrachitol and sorbitol stabilized G6PD,whereas mannitol and myo-inositol destabilized it.Among 14 soluble sugars,trehalose and raffinose showed slightly lower enzyme recovery after repeated freeze-thaw cycles at-20℃.Most soluble sugars(except arabinose and xylose)protected G6PD during freeze-drying,with di-,tri-,and oligosaccharides generally outperforming monosaccharides.During air-drying,lactose was ineffective,while arabinose,galactose,and xylose were detrimental.Conclusion:The study highlights the diverse mechanisms of sugar alcohols and sugars in protein stabilization under stress,offering insights for formulating stable protein-and cell-based drugs.展开更多
BACKGROUND Gastric cancer is the most common malignancy of the digestive system and surgical resection is the primary treatment.Advances in surgical technology have reduced the risk of complications after radical gast...BACKGROUND Gastric cancer is the most common malignancy of the digestive system and surgical resection is the primary treatment.Advances in surgical technology have reduced the risk of complications after radical gastrectomy;however,post-surgical pancreatic fistula remain a serious issue.These fistulas can lead to abdominal infections,anastomotic leakage,increased costs,and pain;thus,early diagnosis and prevention are crucial for a better prognosis.Currently,C-reactive protein(CRP),procalcitonin(PCT),and total bilirubin(TBil)levels are used to predict post-operative infections and anastomotic leakage.However,their predictive value for pancreatic fistula after radical gastrectomy for gastric cancer remains unclear.The present study was conducted to determine their predictive value.AIM To determine the predictive value of CRP,PCT,and TBil levels for pancreatic fistula after gastric cancer surgery.METHODS In total,158 patients who underwent radical gastrectomy for gastric cancer at our hospital between January 2019 and January 2023 were included.The patients were assigned to a pancreatic fistula group or a non-pancreatic fistula group.Multivariate logistic analysis was conducted to assess the factors influencing development of a fistula.Receiver operating characteristic(ROC)curves were used to determine the predictive value of serum CRP,PCT,and TBil levels on day 1 postsurgery.RESULTS On day 1 post-surgery,the CRP,PCT,and TBil levels were significantly higher in the pancreatic fistula group than in the non-pancreatic fistula group(P<0.05).A higher fistula grade was associated with higher levels of the indices.Univariate analysis revealed significant differences in the presence of diabetes,hyperlipidemia,pancreatic injury,splenectomy,and the biomarker levels(P<0.05).Logistic multivariate analysis identified diabetes,hyperlipidemia,pancreatic injury,CRP level,and PCT level as independent risk factors.ROC curves yielded predictive values for CRP,PCT,and TBil levels,with the PCT level having the highest area under the curve(AUC)of 0.80[95%confidence interval(CI):0.72-0.90].Combined indicators improved the predictive value,with an AUC of 0.86(95%CI:0.78-0.93).CONCLUSION Elevated CRP,PCT,and TBil levels predict risk of pancreatic fistula post-gastrectomy for gastric cancer.展开更多
Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle p...Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.展开更多
Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial fo...Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial for designing safe peptide-based therapeutics.While traditional experimental approaches are time-consuming and expensive,computational methods have emerged as viable alternatives,including similarity-based and machine learning(ML)-/deep learning(DL)-based methods.However,existing methods often struggle with robustness and generalizability.To address these challenges,we propose HyPepTox-Fuse,a novel framework that fuses protein language model(PLM)-based embeddings with conventional descriptors.HyPepTox-Fuse integrates ensemble PLM-based embeddings to achieve richer peptide representations by leveraging a cross-modal multi-head attention mechanism and Transformer architecture.A robust feature ranking and selection pipeline further refines conventional descriptors,thus enhancing prediction performance.Our framework outperforms state-of-the-art methods in cross-validation and independent evaluations,offering a scalable and reliable tool for peptide toxicity prediction.Moreover,we conducted a case study to validate the robustness and generalizability of HyPepTox-Fuse,highlighting its effectiveness in enhancing model performance.Furthermore,the HyPepTox-Fuse server is freely accessible at https://balalab-skku.org/HyPepTox-Fuse/and the source code is publicly available at https://github.com/cbbl-skku-org/HyPepTox-Fuse/.The study thus presents an intuitive platform for predicting peptide toxicity and supports reproducibility through openly available datasets.展开更多
Arsenic-related oxidative stress and resultant diseases have attracted global concern,while longitudinal studies are scarce.To assess the relationship between arsenic exposure and systemic oxidative damage,we performe...Arsenic-related oxidative stress and resultant diseases have attracted global concern,while longitudinal studies are scarce.To assess the relationship between arsenic exposure and systemic oxidative damage,we performed two repeatedmeasures among 5236 observations(4067 participants)in theWuhan-Zhuhai cohort at the baseline and follow-up after 3 years.Urinary total arsenic,biomarkers of DNA oxidative damage(8-hydroxy-2-deoxyguanosine(8-OHdG)),lipid peroxidation(8-isoprostaglandin F2alpha(8-isoPGF2α)),and protein oxidative damage(protein carbonyls(PCO))were detected for all observations.Here we used linearmixed models to estimate the cross-sectional and longitudinal associations between arsenic exposure and oxidative damage.Exposure-response curves were constructed by utilizing the generalized additive mixed models with thin plate regressions.After adjusting for potential confounders,arsenic level was significantly and positively related to the levels of global oxidative damage and their annual increased rates in dose-response manners.In cross-sectional analyses,each 1%increase in arsenic levelwas associated with a 0.406%(95%confidence interval(CI):0.379%to 0.433%),0.360%(0.301%to 0.420%),and 0.079%(0.055%to 0.103%)increase in 8-isoPGF2α,8-OHdG,and PCO,respectively.More importantly,arsenic was further found to be associated with increased annual change rates of 8-isoPGF2α(β:0.147;95%CI:0.130 to 0.164),8-OHdG(0.155;0.118 to 0.192),and PCO(0.050;0.035 to 0.064)in the longitudinal analyses.Our study suggested that arsenic exposurewas not only positively related with global oxidative damage to lipid,DNA,and protein in cross-sectional analyses,but also associated with annual increased rates of these biomarkers in dose-dependent manners.展开更多
Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the an...Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.展开更多
Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of pro...Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.展开更多
This study aimed to investigate the effect of ultrasound-assisted alkaline extraction(UAE)(at 20 kHz and different powers of 0,200,300,400,500 and 600 W for 10 min)on the yield,structure and emulsifying properties of ...This study aimed to investigate the effect of ultrasound-assisted alkaline extraction(UAE)(at 20 kHz and different powers of 0,200,300,400,500 and 600 W for 10 min)on the yield,structure and emulsifying properties of chickpea protein isolate(CPI).Compared with the non-ultrasound group,ultrasound treatment at 400 W resulted in the largest increase in CPI yield,and both the particle size and turbidity decreased with increasing ultrasound power from 0 to 400 W.The scanning electron microscope results showed a uniform structural distribution of CPI.Moreover,itsα-helix content increased,β-sheet content decreased,and total sulfhydryl group content and endogenous fluorescence intensity rose,illustrating that UAE changed the secondary and tertiary structure of CPI.At 400 W,the solubility of the emulsion increased to 63.18%,and the best emulsifying properties were obtained;the emulsifying activity index(EAI)and emulsifying stability index(ESI)increased by 85.42%and 46.78%,respectively.Furthermore,the emulsion droplets formed were smaller and more uniform.In conclusion,proper UAE power conditions increased the extraction yield and protein content of CPI,and effectively improved its structure and emulsifying characteristics.展开更多
基金financially supported by the Hainan Province Science and Technology Special Fund(Grant no:ZDYF2024XDNY187).
文摘Background:Excessive use of inorganic trace minerals(ITMs)in swine production leads to high fecal mineral excretion and environmental risks,while most studies on organic trace minerals(OTMs)focus on single elements,with limited data on the synergistic effects and molecular mechanisms of combined OTMs(Fe,Cu,Mn,Zn)in growing-finishing pigs.Methods:This study aimed to investigate the effects of graded levels of micromineral proteinates(combined OTMs)on growth performance,mineral metabolism,and mRNA expression of mineral regulatory proteins.A total of 360 crossbred Duroc×Landrace×Large White pigs(initial body weight 47.1±4.8 kg)were randomly assigned to 6 dietary treatments:basal diet without microminerals(CON),basal diet with ITMs at commercially recommended levels(IT),and basal diets with 15%(OT 15%),25%(OT 25%),35%(OT 35%)commercially recommended levels(CRL)of combined micromineral proteinates.After a 70-day feeding trial,samples were analyzed using ICP-OES,ELISA,and RT-qPCR.Results:Results showed that reduced levels(15-35%CRL)of micromineral proteinates did not significantly affect average daily gain,average daily feed intake,or feed conversion ratio(gain-to-feed ratio)compared to IT(P>0.05),but significantly increased plasma Cu(1.73-1.83μg/mL)and Zn(1.72-1.97μg/mL)concentrations(P<0.05)and elevated activities of Cu/Zn-superoxide dismutase(32.9-35.9 U/L)and manganese superoxide dismutase(20.5-24.1 U/L)compared to CON(P<0.05),with no significant differences from IT(P>0.05).Fecal excretion of Fe,Cu,Mn,and Zn was significantly reduced by 35-50%in OT 15%-OT 35%groups compared to IT(P<0.05).OT 25%group exhibited the highest apparent absorptivity of Fe(38.5%),Cu(27.8%),and Zn(42.4%)(P<0.05),which was associated with significantly regulated mRNA expression of mineral regulatory proteins:upregulated DMT1,FPN1,ZIP4,and MT1A in the duodenum,and modulated HAMP,ATP7B,ZIP14,and ZnT1 in the liver(P<0.05).Conclusion:In conclusion,dietary supplementation with 25%CRL or less of combined micromineral proteinates can fully meet the nutritional needs of growing-finishing pigs,improve mineral absorptivity,and reduce fecal mineral excretion by regulating intestinal and hepatic mineral transport and homeostatic proteins,providing a sustainable alternative to high-dose ITMs.
文摘With the growth of global protein demand and the development of plant-based foods,pea protein,as a low-allergenic,nutritionally balanced and environmentally friendly plant protein,has shown great potential in replacing animal protein.Pea protein is mainly composed of globulin and albumin,with a protein content of 20%to 30%,and has a balanced amino acid composition,as well as being rich in minerals and dietary fiber.It also possesses good foaming,gelling,emulsifying and antioxidant functional properties.However,pea protein also has inherent defects that limit its application in the food industry.This article systematically reviews the extraction techniques,functional properties,modification methods and application fields of pea protein,and focuses on evaluating the effects of different extraction and modification strategies on protein yield and functional properties.Research shows that ultrasonic-assisted alkaline extraction can reduce solvent usage by 55%,shorten extraction time by 50%,and increase extraction rate by 12.51%;under optimized conditions,ultrafiltration membrane technology can achieve a protein purity of 91%.In terms of modification,ultrasonic treatment increases foaming capacity by 37.4%,and phenolic cross-linking increases gel strength from 3.0 kPa to 48 kPa.This article provides data support and theoretical reference for the efficient extraction and functional optimization of pea protein,and has promoting significance for its wide application in plant-based foods.
基金the National Natural Science Foundation of China(82573571)the Shanghai 2025 Basic Research Plan Natural Science Foundation(25ZR1401393)the First Batch of Open Topics of the Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices(2025QN13)。
文摘The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR.However,their clinical translation is hindered by their inherently low immunogenicity,often requiring potent adjuvants and advanced delivery systems.Biomembrane nanostructures(e.g.,liposomes,exosomes,and cell membrane-derived nanostructures),characterized by superior biocompatibility,intrinsic targeting ability,and immune-modulating properties,could serve as versatile platforms that potentiate vaccine efficacy by increasing antigen stability,enabling codelivery of immunostimulants,and facilitating targeted delivery to lymphoid tissues/antigen-presenting cells.This intrinsic immunomodulation promotes robust humoral and cellular immune responses to combat bacteria.This review critically reviews(1)key biomembrane nanostructure classes for bacterial protein antigens,(2)design strategies leveraging biomembrane nanostructures to enhance humoral and cellular immune responses,(3)preclinical efficacy against diverse pathogens,and(4)translational challenges and prospects.Biomembrane nanostructure-driven approaches represent a paradigm shift in the development of next-generation bacterial protein vaccines against resistant infections.
基金financially supported by the National Natural Science Foundation of China(Nos.22475057 and No.52373262).
文摘Directional three-dimensional carbon-based foams are emerging as highly attractive candidates for promising electromagnetic wave absorbing materials(EWAMs)thanks to their unique architecture,but their construction usually involves complex procedures and extremely depends on unidirectional freezing technique.Herein,we propose a groundbreaking approach that leverages the assemblies of salting-out protein induced by ammonium metatungstate(AM)as the precursor,and then acquire directional three-dimensional carbon-based foams through simple pyrolysis.The electrostatic interaction between AM and protein ensures well dispersion of WC_(1−x)nanoparticles on carbon frameworks.The content of WC_(1−x)nanoparticles can be rationally regulated by AM dosage,and it also affects the electromagnetic(EM)properties of final carbon-based foams.The optimized foam exhibits exceptional EM absorption performance,achieving a remarkable minimum reflection loss of−72.0 dB and an effective absorption bandwidth of 6.3 GHz when EM wave propagates parallel to the directional pores.Such performance benefits from the synergistic effects of macroporous architecture and compositional design.Although there is a directional dependence of EM absorption,radar stealth simulation demonstrates that these foams can still promise considerable reduction in radar cross section with the change of incident angle.Moreover,COMSOL simulation further identifies their good performance in preventing EM interference among different electronic components.
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
基金supported by the National Natural Science Foundation of China(Nos.82573045,82460602,82560459)the Hainan Provincial Graduate Student Innovative Research Project(No.Qhys2024-440).
文摘Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
文摘Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
基金supported by the National Key Research and Development Program of China(2021YFD1200703 and 2022YFF1001602)the National Science Foundation of China(32272024 and 32171940)+2 种基金the Pinduoduo-China Agricultural University Research Fund(PC2023B01001)the Chinese Universities Scientific Fund(2022TC142)the 2115 Talent Development Program of China Agricultural University。
文摘Maize(Zea mays),which is a vital source of food,feed,and energy feedstock globally,has significant potential for higher yields.However,environmental stress conditions,including drought and salt stress,severely restrict maize plant growth and development,leading to great yield losses.Leucine-rich repeat receptor-like kinases(LRR-RLKs)function in biotic and abiotic stress responses in the model plant Arabidopsis(Arabidopsis thaliana),but their roles in abiotic stress responses in maize are not entirely understood.In this study,we determine that the LRR-RLK ZmMIK2,a homolog of the Arabidopsis LRR-RK MALE DISCOVERER 1(MDIS1)-INTERACTING RECEPTOR LIKE KINASE 2(MIK2),functions in resistance to both drought and salt stress in maize.Zmmik2 plants exhibit enhanced resistance to both stresses,whereas overexpressing ZmMIK2 confers the opposite phenotypes.Furthermore,we identify C2-DOMAIN-CONTAINING PROTEIN 1(ZmC2DP1),which interacts with the intracellular region of ZmMIK2.Notably,that region of ZmMIK2 mediates the phosphorylation of ZmC2DP1,likely by increasing its stability.Both ZmMIK2 and ZmC2DP1 are mainly expressed in roots.As with ZmMIK2,knockout of ZmC2DP1 enhances resistance to both drought and salt stress.We conclude that ZmMIK2-ZmC2DP1 acts as a negative regulatory module in maize drought-and salt-stress responses.
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金Supported by Joint Project on Regional High Incidence Diseases Research of Guangxi Natural Science Foundation,No.2024GXNSFAA010057 and No.2024GXNSFAA010085Natural Science Foundation of Guangxi,China,No.2022GXNSFBA035657+2 种基金Guangxi Zhuang Autonomous Region Health Commission Self-Financed Scientific Research Project,No.Z20210764Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine Scientific Research Project,No.GXZYA20230270 and No.GXZYA20240305Advanced Innovation Teams and Xinghu Scholars Program of Guangxi Medical University(2022).
文摘BACKGROUND Hepatocellular carcinoma(HCC)is one of the most prevalent and aggressive forms of liver cancer,with high morbidity and poor prognosis due to late diagnosis and limited treatment options.Despite advances in understanding its molecular mechanisms,effective biomarkers for early detection and targeted therapy remain scarce.Zinc finger protein 71(ZNF71),a zinc-finger protein,has been implicated in various cancers,yet its role in HCC remains largely unexplored.This gap in knowledge underscores the need for further investigation into the ZNF71 of potential as a diagnostic or therapeutic target in HCC.AIM To explore the expression levels,clinical relevance,and molecular mechanisms of ZNF71 in the progression of HCC.METHODS The study evaluated ZNF71 expression in 235 HCC specimens and 13 noncancerous liver tissue samples using immunohistochemistry.High-throughput datasets were employed to assess the differential expression of ZNF71 in HCC and its association with clinical and pathological features.The impact of ZNF71 on HCC cell line growth was examined through clustered regularly interspaced short palindromic repeat knockout screens.Co-expressed genes were identified and analyzed for enrichment using LinkedOmics and Sangerbox 3.0,focusing on significant correlations(P<0.01,correlation coefficient≥0.3).Furthermore,the relationship between ZNF71 expression and immune cell infiltration was quantified using TIMER2.0.RESULTS ZNF71 showed higher expression in HCC tissues vs non-tumorous tissues,with a significant statistical difference(P<0.05).Data from the UALCAN platform indicated increased ZNF71 levels across early to mid-stage HCC,correlating with disease severity(P<0.05).High-throughput analysis presented a standardized mean difference in ZNF71 expression of 0.55(95%confidence interval[CI]:0.34-0.75).The efficiency of ZNF71 mRNA was evaluated,yielding an area under the curve of 0.78(95%CI:0.75-0.82),a sensitivity of 0.63(95%CI:0.53-0.72),and a specificity of 0.82(95%CI:0.73-0.89).Diagnostic likelihood ratios were positive at 3.61(95%CI:2.41-5.41)and negative at 0.45(95%CI:0.36-0.56).LinkedOmics analysis identified strong positive correlations of ZNF71 with genes such as ZNF470,ZNF256,and ZNF285.Pathway enrichment analyses highlighted associations with herpes simplex virus type 1 infection,the cell cycle,and DNA replication.Negative correlations involved metabolic pathways,peroxisomes,and fatty acid degradation.TIMER2.0 analysis demonstrated positive correlations of high ZNF71 expression with various immune cell types,including CD4^(+)T cells,B cells,regulatory T cells,monocytes,macrophages,and myeloid dendritic cells.CONCLUSION ZNF71 is significantly upregulated in HCC,correlating with the disease’s clinical and pathological stages.It appears to promote HCC progression through mechanisms involving the cell cycle and metabolism and is associated with immune cell infiltration.These findings suggest that ZNF71 could be a novel target for diagnosing and treating HCC.
基金supported by a research grant from the National University of Singapore to WQS(RP-3960366)a collaborative research grant from Sichuan Zhongke Organ Co.Ltd(Chengdu,China).
文摘Objectives:Cold-acclimated organisms accumulate low molecular weight organic solutes such as sugar alcohols and soluble sugars.This study aimed to compare the efficacy of five sugar alcohols and 14 soluble sugars in stabilizing proteins under freezing,freeze-drying,and air-drying stresses.Materials and methods:Glucose-6-Phosphate Dehydrogenase(G6PD)was used as the model protein.G6PD solutions with or without sugar alcohols and or sugars were subjected to freezing,freeze-drying,and air-drying stresses.The recovery of G6PD activity was measured to evaluate the protective efficacy of these compounds.Results:Without stabilizers,freezing G6PD at-20℃ or-80℃ reduced enzyme activity by around 24%,while freeze-drying or air-drying reduced activity by 90%-95%.Among the five sugar alcohols tested,pinitol,quebrachitol and sorbitol stabilized G6PD,whereas mannitol and myo-inositol destabilized it.Among 14 soluble sugars,trehalose and raffinose showed slightly lower enzyme recovery after repeated freeze-thaw cycles at-20℃.Most soluble sugars(except arabinose and xylose)protected G6PD during freeze-drying,with di-,tri-,and oligosaccharides generally outperforming monosaccharides.During air-drying,lactose was ineffective,while arabinose,galactose,and xylose were detrimental.Conclusion:The study highlights the diverse mechanisms of sugar alcohols and sugars in protein stabilization under stress,offering insights for formulating stable protein-and cell-based drugs.
文摘BACKGROUND Gastric cancer is the most common malignancy of the digestive system and surgical resection is the primary treatment.Advances in surgical technology have reduced the risk of complications after radical gastrectomy;however,post-surgical pancreatic fistula remain a serious issue.These fistulas can lead to abdominal infections,anastomotic leakage,increased costs,and pain;thus,early diagnosis and prevention are crucial for a better prognosis.Currently,C-reactive protein(CRP),procalcitonin(PCT),and total bilirubin(TBil)levels are used to predict post-operative infections and anastomotic leakage.However,their predictive value for pancreatic fistula after radical gastrectomy for gastric cancer remains unclear.The present study was conducted to determine their predictive value.AIM To determine the predictive value of CRP,PCT,and TBil levels for pancreatic fistula after gastric cancer surgery.METHODS In total,158 patients who underwent radical gastrectomy for gastric cancer at our hospital between January 2019 and January 2023 were included.The patients were assigned to a pancreatic fistula group or a non-pancreatic fistula group.Multivariate logistic analysis was conducted to assess the factors influencing development of a fistula.Receiver operating characteristic(ROC)curves were used to determine the predictive value of serum CRP,PCT,and TBil levels on day 1 postsurgery.RESULTS On day 1 post-surgery,the CRP,PCT,and TBil levels were significantly higher in the pancreatic fistula group than in the non-pancreatic fistula group(P<0.05).A higher fistula grade was associated with higher levels of the indices.Univariate analysis revealed significant differences in the presence of diabetes,hyperlipidemia,pancreatic injury,splenectomy,and the biomarker levels(P<0.05).Logistic multivariate analysis identified diabetes,hyperlipidemia,pancreatic injury,CRP level,and PCT level as independent risk factors.ROC curves yielded predictive values for CRP,PCT,and TBil levels,with the PCT level having the highest area under the curve(AUC)of 0.80[95%confidence interval(CI):0.72-0.90].Combined indicators improved the predictive value,with an AUC of 0.86(95%CI:0.78-0.93).CONCLUSION Elevated CRP,PCT,and TBil levels predict risk of pancreatic fistula post-gastrectomy for gastric cancer.
基金supported by The National Natural Science Foundation of China(No.31902283)Research Foundation for Master students at the Affiliated Hospital of Zunyi Medical College(No.22-2018).
文摘Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.
基金supported by the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT,Republic of Korea(Grant No.:RS-2024-00344752)supported by the Department of Integrative Biotechnology,Sungkyunkwan University(SKKU)and the BK21 FOUR Project,Republic of Korea.
文摘Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial for designing safe peptide-based therapeutics.While traditional experimental approaches are time-consuming and expensive,computational methods have emerged as viable alternatives,including similarity-based and machine learning(ML)-/deep learning(DL)-based methods.However,existing methods often struggle with robustness and generalizability.To address these challenges,we propose HyPepTox-Fuse,a novel framework that fuses protein language model(PLM)-based embeddings with conventional descriptors.HyPepTox-Fuse integrates ensemble PLM-based embeddings to achieve richer peptide representations by leveraging a cross-modal multi-head attention mechanism and Transformer architecture.A robust feature ranking and selection pipeline further refines conventional descriptors,thus enhancing prediction performance.Our framework outperforms state-of-the-art methods in cross-validation and independent evaluations,offering a scalable and reliable tool for peptide toxicity prediction.Moreover,we conducted a case study to validate the robustness and generalizability of HyPepTox-Fuse,highlighting its effectiveness in enhancing model performance.Furthermore,the HyPepTox-Fuse server is freely accessible at https://balalab-skku.org/HyPepTox-Fuse/and the source code is publicly available at https://github.com/cbbl-skku-org/HyPepTox-Fuse/.The study thus presents an intuitive platform for predicting peptide toxicity and supports reproducibility through openly available datasets.
基金supported by the National Natural Science Foundation of China(Nos.82241088 and 82203996)the China Postdoctoral Science Foundation(Nos.2022T150230 and 2021M691131).
文摘Arsenic-related oxidative stress and resultant diseases have attracted global concern,while longitudinal studies are scarce.To assess the relationship between arsenic exposure and systemic oxidative damage,we performed two repeatedmeasures among 5236 observations(4067 participants)in theWuhan-Zhuhai cohort at the baseline and follow-up after 3 years.Urinary total arsenic,biomarkers of DNA oxidative damage(8-hydroxy-2-deoxyguanosine(8-OHdG)),lipid peroxidation(8-isoprostaglandin F2alpha(8-isoPGF2α)),and protein oxidative damage(protein carbonyls(PCO))were detected for all observations.Here we used linearmixed models to estimate the cross-sectional and longitudinal associations between arsenic exposure and oxidative damage.Exposure-response curves were constructed by utilizing the generalized additive mixed models with thin plate regressions.After adjusting for potential confounders,arsenic level was significantly and positively related to the levels of global oxidative damage and their annual increased rates in dose-response manners.In cross-sectional analyses,each 1%increase in arsenic levelwas associated with a 0.406%(95%confidence interval(CI):0.379%to 0.433%),0.360%(0.301%to 0.420%),and 0.079%(0.055%to 0.103%)increase in 8-isoPGF2α,8-OHdG,and PCO,respectively.More importantly,arsenic was further found to be associated with increased annual change rates of 8-isoPGF2α(β:0.147;95%CI:0.130 to 0.164),8-OHdG(0.155;0.118 to 0.192),and PCO(0.050;0.035 to 0.064)in the longitudinal analyses.Our study suggested that arsenic exposurewas not only positively related with global oxidative damage to lipid,DNA,and protein in cross-sectional analyses,but also associated with annual increased rates of these biomarkers in dose-dependent manners.
基金funded by the Major Research Plan of the National Natural Science Foundation of China(No.92159202)the National Key Research and Development Program of China(No.2021YFA1100500)+1 种基金the Leading Innovation Team Project of Hangzhou Medical College(No.CXLJ202401)the Key Research and Development Plan of Zhejiang Provincial Department of Science and Technology(No.2024C03051)。
文摘Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.
基金supported by the Natural Science Foundation of Guangdong Province(No.2024A1515010605,2022A1515140034)Discipline Construction Project of Guangdong Medical University(No.4SG24007G,4SG22302P)+1 种基金Medical Scientific Research Fund of Guangdong Province(No.B2024193)Dongguan Social Development and Scientific Technology Project,China(No.20231800936562).
文摘Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.
文摘This study aimed to investigate the effect of ultrasound-assisted alkaline extraction(UAE)(at 20 kHz and different powers of 0,200,300,400,500 and 600 W for 10 min)on the yield,structure and emulsifying properties of chickpea protein isolate(CPI).Compared with the non-ultrasound group,ultrasound treatment at 400 W resulted in the largest increase in CPI yield,and both the particle size and turbidity decreased with increasing ultrasound power from 0 to 400 W.The scanning electron microscope results showed a uniform structural distribution of CPI.Moreover,itsα-helix content increased,β-sheet content decreased,and total sulfhydryl group content and endogenous fluorescence intensity rose,illustrating that UAE changed the secondary and tertiary structure of CPI.At 400 W,the solubility of the emulsion increased to 63.18%,and the best emulsifying properties were obtained;the emulsifying activity index(EAI)and emulsifying stability index(ESI)increased by 85.42%and 46.78%,respectively.Furthermore,the emulsion droplets formed were smaller and more uniform.In conclusion,proper UAE power conditions increased the extraction yield and protein content of CPI,and effectively improved its structure and emulsifying characteristics.
