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
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
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: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
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
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
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
BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progr...BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.展开更多
Protein-energy malnutrition (PEM) as a result of poor nutrition, especially for deprived resourced households, is a big health concern in the world. According to the World Health Organisation, PEM accounts for 49% of ...Protein-energy malnutrition (PEM) as a result of poor nutrition, especially for deprived resourced households, is a big health concern in the world. According to the World Health Organisation, PEM accounts for 49% of the 10.4 million deaths of children under five that take place in developing countries. The aim of this study was to evaluate the influence of gum Arabic (GA) and texturized soy protein (TSP) and their interactive effect on proximate, functional, and textural properties of the protein-rich snack stick produced from ground green maize, GA powder, and ground TSP. GA varied at 0%, 4%, 8%, and 12%, while TSP varied at 0%, 12%, 24% and 36%. The 5 cm long protein-rich snack sticks were made using a sausage stuffer and baked in an oven at 110˚C for 1 hr 30 minutes. The snack sticks were subjected to proximate, functional and textural analysis using the standard methods. Increasing GA resulted in a significant (p p < 0.05) increased the protein content (32.46%), Ash content (3.6%), fat (11.96%), and moisture content (16.25%) of protein-rich snack sticks. The interactive effect between GA and TSP led to a decrease in fibre and carbohydrates. Results from this study show GA and TSP significantly enhanced the physico-chemical properties of protein-rich snack sticks. A sample with 4% GA and 36% TSP is recommended for the best physico-chemical attributes of the protein-rich snack stick.展开更多
Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein ...Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.展开更多
BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchyma...BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchymal stem cells(MSCs)derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors.The mechanism through which MSCs from AS patients achieve this inhibition remains unclear.AIM To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis(AS-MSCs)inhibit osteoclastogenesis.METHODS We analysed fat mass and obesity-associated(FTO)protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase,nuclear factor of activated T cells 1 and cathepsin K.RESULTS We found that FTO,an enzyme responsible for removing methyl groups from RNA,was more abundantly expressed in MSCs from AS patients than in those from healthy donors.Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development.Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage(NORAD)by altering its N6-methyladenosine methylation status.Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284,which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research.CONCLUSION This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.展开更多
Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and com...BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.展开更多
The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enh...The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.展开更多
The awn can contribute to photosynthesis and carbohydrates,enhancing grain yield in wheat.We mapped QAwn.sxau-5A,a major QTL for awn development in wheat(Triticum aestivum).This QTL was delimited to a 994-kb interval ...The awn can contribute to photosynthesis and carbohydrates,enhancing grain yield in wheat.We mapped QAwn.sxau-5A,a major QTL for awn development in wheat(Triticum aestivum).This QTL was delimited to a 994-kb interval at the B1 locus on chromosome 5A,which included the candidate gene encoding a zinc finger protein(TraesCS5A01G542800)as an awn length inhibitor(ALI).The Ali-A1 allele for the awnless trait showed abundant sequence differences in the promoter regions compared to the ali-A1 allele for the long-awn trait.The results of the swap experiment on the promoters from the two ALI-A1 alleles showed that the two promoters caused a difference in the protein level,indicating the gene was regulated at the transcript level.However,the ali-A1 allele contained an SNP that caused a premature stop codon in its coding region,resulting in a truncated protein compared to the functional Ali-A1 protein.The Ali-A1 protein contained two ethylene-responsive element binding factor-associated amphiphilic repression(EAR)motifs,one at the N terminus(EAR-N)and the other at the C terminus(EAR-C),and they were involved in interactions with the wheat co-repressor protein TOPLESS(TPL1).The ali-A1 protein retained the EAR-N motif but lost the EAR-C motif,resulting in the attenuated ability to interact with TPL1.The tpl1 mutant produced a longer awn compared to the wild type.Ali-A1 repressed the transcription of two downstream genes,TaLRP-A1 and TaARF-B1,involved in endogenous auxin concentrations and auxin responses in wheat.We concluded that the awn length is regulated not only by the ALI-A1 gene at transcript levels but also by Ali-A1 and TPL1 at the protein level in wheat.展开更多
BACKGROUND Neonatal sepsis is a serious health problem,with high morbidity and mortality during the first 28 days of life.Clinical diagnosis at presentation is challenging due to the nonspecific signs and symptoms.Alt...BACKGROUND Neonatal sepsis is a serious health problem,with high morbidity and mortality during the first 28 days of life.Clinical diagnosis at presentation is challenging due to the nonspecific signs and symptoms.Although blood culture is the gold standard for diagnosis,it is not always positive.AIM To evaluate the diagnostic and prognostic utility of D-dimer and heparin-binding protein(HBP)in neonatal sepsis.METHODS This prospective case-control study included 90 neonates in two groups:A sepsis group(n=45)and a control group(n=45)without sepsis.Sepsis group was further subdivided based on blood culture results into proven sepsis(n=28 culturepositive sepsis)and suspected sepsis(n=17 culture-negative sepsis).All neonates underwent complete history taking,thorough clinical examination and investigations[complete blood count,C-reactive protein(CRP),liver and kidney function tests,plasma D-dimer and HBP].RESULTS Levels of CRP,D-dimer and HBP were significantly higher in the sepsis group compared to the controls.At a cutoff value above 517.9 ng/mL,D-dimer outperformed CRP and HBP in distinguishing sepsis group from controls with 95.6%sensitivity and 97.8%specificity.D-dimer was also a better prognostic marker than the neonatal sequential organ failure assessment(nSOFA)for predicting mortality,with 100%sensitivity and 92.5%specificity vs 80%sensitivity and 82.5%specificity.There was a significant positive correlation between CRP,D-dimer and HBP.CONCLUSION D-dimer demonstrated superior diagnostic accuracy compared to CRP and HBP in predicting sepsis,and demonstrated superior prognostic accuracy compared to nSOFA in predicting the outcome of neonatal sepsis.展开更多
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.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 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.
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 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 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.
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.
基金Supported by the Fundamental Research Program of Shanxi Province,No.202203021222418Research Program of Shanxi Provincial Health Commission,No.2023061+2 种基金Fundamental Research Cooperation Program of Beijing-Tianjin-Hebei Region of Natural Science Foundation of Tianjin,No.22JCZXJC00140Tianjin Major Science and Technology Project,No.21ZXJBSY00110Tianjin Health and Science and Technology Project,No.TJWJ2024ZK001.
文摘BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.
文摘Protein-energy malnutrition (PEM) as a result of poor nutrition, especially for deprived resourced households, is a big health concern in the world. According to the World Health Organisation, PEM accounts for 49% of the 10.4 million deaths of children under five that take place in developing countries. The aim of this study was to evaluate the influence of gum Arabic (GA) and texturized soy protein (TSP) and their interactive effect on proximate, functional, and textural properties of the protein-rich snack stick produced from ground green maize, GA powder, and ground TSP. GA varied at 0%, 4%, 8%, and 12%, while TSP varied at 0%, 12%, 24% and 36%. The 5 cm long protein-rich snack sticks were made using a sausage stuffer and baked in an oven at 110˚C for 1 hr 30 minutes. The snack sticks were subjected to proximate, functional and textural analysis using the standard methods. Increasing GA resulted in a significant (p p < 0.05) increased the protein content (32.46%), Ash content (3.6%), fat (11.96%), and moisture content (16.25%) of protein-rich snack sticks. The interactive effect between GA and TSP led to a decrease in fibre and carbohydrates. Results from this study show GA and TSP significantly enhanced the physico-chemical properties of protein-rich snack sticks. A sample with 4% GA and 36% TSP is recommended for the best physico-chemical attributes of the protein-rich snack stick.
基金supported by the National Natural Science Foundation of China,Nos.82001178(to LW),81901129(to LH),82001175(to FX)Shanghai Sailing Program,No.20YF1439200(to LW)+1 种基金the Natural Science Foundation of Shanghai,China,No.23ZR1450800(to LH)and the Fundamental Research Funds for the Central Universities,No.YG2023LC15(to ZX)。
文摘Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.
基金Supported by Guangdong Provincial Clinical Research Center for Orthopedic Diseases,No.2023B110001the Excellent Medical Innovation Talent Program of the Eighth Affiliated Hospital of Sun Yat-sen University,No.YXYXCXRC202101+3 种基金the National Natural Science Foundation of China,No.82172349,No.82372372,No.22105229,No.32170708,No.82102530,No.82102541,No.82103098,No.82103909,No.82104182,No.82104350,No.82170427,No.82171291,No.82172215,No.82172385,and No.82302661Guangdong Natural Science Foundation,No.2023A1515010568 and No.2021A1515111057Shenzhen Science and Technology Program,No.JCYJ20220530144201004 and No.RCBS20210609104445097Futian Healthcare Research Project,No.FTWS2022022,No.FTWS2021013,No.FTWS2023072,and No.FTWS2022047.
文摘BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchymal stem cells(MSCs)derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors.The mechanism through which MSCs from AS patients achieve this inhibition remains unclear.AIM To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis(AS-MSCs)inhibit osteoclastogenesis.METHODS We analysed fat mass and obesity-associated(FTO)protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase,nuclear factor of activated T cells 1 and cathepsin K.RESULTS We found that FTO,an enzyme responsible for removing methyl groups from RNA,was more abundantly expressed in MSCs from AS patients than in those from healthy donors.Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development.Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage(NORAD)by altering its N6-methyladenosine methylation status.Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284,which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research.CONCLUSION This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
基金Science and Technology Program of Guangzhou,No.202102010077International Science Foundation of Guangzhou Fuda Cancer Hospital,No.Y2020-ZD-03.
文摘BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.
基金supported by the National Natural Science Foundation of China,No.82003965the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS167(to LH)+2 种基金the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022033(to LH)the Improvement Plan for the'Xinglin Scholar'Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine,No.XKTD2023002(to LH)the 2023 National Project of the College Students'Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine,No.202310633028(to FD)。
文摘The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
基金supported by the Grand Science and Technology Special Project in Shanxi Province(202201140601025-2)the National Natural Science Foundation of China(32201749)supported by the Agriculture and Food Research Initiative Competitive Grant 2022-68013-36439(WheatCAP)from the USDA National Institute of Food and Agriculture.
文摘The awn can contribute to photosynthesis and carbohydrates,enhancing grain yield in wheat.We mapped QAwn.sxau-5A,a major QTL for awn development in wheat(Triticum aestivum).This QTL was delimited to a 994-kb interval at the B1 locus on chromosome 5A,which included the candidate gene encoding a zinc finger protein(TraesCS5A01G542800)as an awn length inhibitor(ALI).The Ali-A1 allele for the awnless trait showed abundant sequence differences in the promoter regions compared to the ali-A1 allele for the long-awn trait.The results of the swap experiment on the promoters from the two ALI-A1 alleles showed that the two promoters caused a difference in the protein level,indicating the gene was regulated at the transcript level.However,the ali-A1 allele contained an SNP that caused a premature stop codon in its coding region,resulting in a truncated protein compared to the functional Ali-A1 protein.The Ali-A1 protein contained two ethylene-responsive element binding factor-associated amphiphilic repression(EAR)motifs,one at the N terminus(EAR-N)and the other at the C terminus(EAR-C),and they were involved in interactions with the wheat co-repressor protein TOPLESS(TPL1).The ali-A1 protein retained the EAR-N motif but lost the EAR-C motif,resulting in the attenuated ability to interact with TPL1.The tpl1 mutant produced a longer awn compared to the wild type.Ali-A1 repressed the transcription of two downstream genes,TaLRP-A1 and TaARF-B1,involved in endogenous auxin concentrations and auxin responses in wheat.We concluded that the awn length is regulated not only by the ALI-A1 gene at transcript levels but also by Ali-A1 and TPL1 at the protein level in wheat.
基金Supported by National Liver Institute,Menoufia University,and Damietta General Hospital,Damietta,Egypt.
文摘BACKGROUND Neonatal sepsis is a serious health problem,with high morbidity and mortality during the first 28 days of life.Clinical diagnosis at presentation is challenging due to the nonspecific signs and symptoms.Although blood culture is the gold standard for diagnosis,it is not always positive.AIM To evaluate the diagnostic and prognostic utility of D-dimer and heparin-binding protein(HBP)in neonatal sepsis.METHODS This prospective case-control study included 90 neonates in two groups:A sepsis group(n=45)and a control group(n=45)without sepsis.Sepsis group was further subdivided based on blood culture results into proven sepsis(n=28 culturepositive sepsis)and suspected sepsis(n=17 culture-negative sepsis).All neonates underwent complete history taking,thorough clinical examination and investigations[complete blood count,C-reactive protein(CRP),liver and kidney function tests,plasma D-dimer and HBP].RESULTS Levels of CRP,D-dimer and HBP were significantly higher in the sepsis group compared to the controls.At a cutoff value above 517.9 ng/mL,D-dimer outperformed CRP and HBP in distinguishing sepsis group from controls with 95.6%sensitivity and 97.8%specificity.D-dimer was also a better prognostic marker than the neonatal sequential organ failure assessment(nSOFA)for predicting mortality,with 100%sensitivity and 92.5%specificity vs 80%sensitivity and 82.5%specificity.There was a significant positive correlation between CRP,D-dimer and HBP.CONCLUSION D-dimer demonstrated superior diagnostic accuracy compared to CRP and HBP in predicting sepsis,and demonstrated superior prognostic accuracy compared to nSOFA in predicting the outcome of neonatal sepsis.
