Background:Cancer-related fatigue(CRF)is a common and debilitating symptom experienced by patients with advanced-stage cancer,especially those undergoing antitumor therapy.This study aimed to evaluate the efficacy and...Background:Cancer-related fatigue(CRF)is a common and debilitating symptom experienced by patients with advanced-stage cancer,especially those undergoing antitumor therapy.This study aimed to evaluate the efficacy and safety of Renshenguben(RSGB)oral solution,a ginseng-based traditional Chinese medicine,in alleviating CRF in patients with advanced hepatocellular carcinoma(HCC)receiving antitumor treatment.Methods:In this prospective,open-label,controlled,multicenter study,patients with advanced HCC at BCLC stage C and a brief fatigue inventory(BFI)score of≥4 were enrolled.Participants were assigned to the RSGB group(RSGB,10 mL twice daily)or the control group(with supportive care).Primary and secondary endpoints were the change in multidimensional fatigue inventory(MFI)score,and BFI and functional assessment of cancer therapy-hepatobiliary(FACT-Hep)scores at weeks 4 and 8 after enrollment.Adverse events(AEs)and toxicities were assessed.Results:A total of 409 participants were enrolled,with 206 assigned to the RSGB group.At week 4,there was a trend towards improvement,but the differences were not statistically significant.At week 8,the RSGB group exhibited a significantly lower MFI score(P<0.05)compared to the control group,indicating improved fatigue levels.Additionally,the RSGB group showed significantly greater decrease in BFI and FACT-Hep scores at week 8(P<0.05).Subgroup analyses among patients receiving various antitumor treatments showed similar results.Multivariate linear regression analyses revealed that the RSGB group experienced a significantly substantial decrease in MFI,BFI,and FACT-Hep scores at week 8.No serious drug-related AEs or toxicities were observed.Conclusions:RSGB oral solution effectively reduced CRF in patients with advanced HCC undergoing antitumor therapy over an eight-week period,with no discernible toxicities.These findings support the potential of RSGB oral solution as an adjunctive treatment for managing CRF in this patient population.展开更多
Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is...Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.展开更多
Rubble deposits with a high concentration of rock debris were created after the powerful earthquakes in Jiuzhaigou.Because of the restricted soil resources,water leaks,and nutrient deficits,these deposits pose serious...Rubble deposits with a high concentration of rock debris were created after the powerful earthquakes in Jiuzhaigou.Because of the restricted soil resources,water leaks,and nutrient deficits,these deposits pose serious obstacles for vegetation regeneration.The purpose of this study was to investigate the main mechanisms controlling soil water retention and evaluate the effects of different amendments on the hydraulic characteristics and water-holding capacity of collapsed rubble soils.Finegrained soil,forest humus,crushed straw,and organic components that retain water were added to the altered soils to study the pore structure images and soil-water characteristic curves.Comparing understory humus to other supplements,the results showed a considerable increase in the soil's saturated and wilting water content.The saturated water content and wilting water content rose by 17.9%and 4.3%,respectively,when the percentage of understory soil reached 30%.Additionally,the enhanced soil's microporosity and total pore volume increased by 45.33%and 11.27%,respectively,according to nuclear magnetic imaging.It was shown that while clay particles and organic matter improved the soil's ability to adsorb water,they also increased the soil's total capacity to store water.Fine particulate matter did this by decreasing macropores and increasing capillary pores.These results offer an essential starting point for creating strategies for soil repair that would encourage the restoration of plants on slopes that have been damaged.展开更多
The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tum...The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.展开更多
Artificial intelligence(AI)is revolutionizing traditional drug discovery and development models by seamlessly integrating data,computational power,and algorithms.This synergy enhances the efficiency,accuracy,and succe...Artificial intelligence(AI)is revolutionizing traditional drug discovery and development models by seamlessly integrating data,computational power,and algorithms.This synergy enhances the efficiency,accuracy,and success rates of drug research,shortens development timelines,and reduces costs.Coupled with machine learning(ML)and deep learning(DL),AI has demonstrated significant advancements across various domains,including drug characterization,target discovery and validation,small molecule drug design,and the acceleration of clinical trials.Through molecular generation techniques,AI facilitates the creation of novel drug molecules,predicting their properties and activities,while virtual screening(VS)optimizes drug candidates.Additionally,AI enhances clinical trial efficiency by predicting outcomes,designing trials,and enabling drug repositioning.However,AI's application in drug development faces challenges,including the need for robust data-sharing mechanisms and the establishment of more comprehensive intellectual property protections for algorithms.AI-driven pharmaceutical companies must also integrate biological sciences and algorithms effectively,ensuring the successful fusion of wet and dry laboratory experiments.Despite these challenges,the potential of AI in drug development remains undeniable.As AI technology evolves and these barriers are addressed,AI-driven therapeutics are poised for a broader and more impactful future in the pharmaceutical industry.展开更多
BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor ...BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor progression.Suppressor of cytokine signaling 2(SOCS2),a key immune regulator,may modulate Treg activity and impact LIHC growth and metastasis.AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis,Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data,and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration.Key prognostic genes were identified using Weighted Gene Coexpression Network Analysis and machine learning.In vitro,co-culture experiments,migration assays,apoptosis detection,and enzyme-linked immunosorbent assay were conducted.In vivo,tumor growth,metastasis,and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining,Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling,and immunohistochemistry analyses.RESULTS SOCS2 overexpression inhibited Treg cell activity,reducing LIHC cell migration and invasion while increasing apoptosis.In vivo,SOCS2 suppressed tumor growth and metastasis,confirming its therapeutic potential.CONCLUSION SOCS2 modulates CD4+T function in the TME,contributing to LIHC progression.Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.展开更多
Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregati...Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregation,and alleviates scopolamine-induced cognitive impairment,similar to the phase Ⅲ clinical drug resveratrol.In this study,we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology.Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment,promoted fibrillar amyloid-β clearance from the hippocampus and cortex,suppressed oxidative stress,and inhibited activation of microglia and astrocytes.D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression.Notably,we demonstrated that exogenous fibrillar amyloid-βintroduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain,and this increase was blocked by D30.Considering the role of D30 in clearing amyloid-β,inhibiting neuroinflammation,protecting synapses,and improving cognition,this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.展开更多
Background:Lung adenocarcinoma,the most prevalent lung cancer subtype,is increasingly diagnosed in non-smokers and females.The cell cycle regulator CDC20(Cell Division Cycle 20),a crucial activator of the Anaphase-Pro...Background:Lung adenocarcinoma,the most prevalent lung cancer subtype,is increasingly diagnosed in non-smokers and females.The cell cycle regulator CDC20(Cell Division Cycle 20),a crucial activator of the Anaphase-Promoting Complex/Cyclosome(APC/C),is frequently overexpressed in various cancers,including lung adenocarcinoma,and is implicated in tumorigenesis.Preclinical studies indicate that inhibiting the CDC20-APC/C signaling axis can enhance chemotherapy-induced apoptosis.Analysis of The Cancer Genome Atlas(TCGA)data confirms that elevated CDC20 expression in lung adenocarcinoma is significantly associated with poorer patient prognosis and correlates with immune cell infiltration.These collective findings highlight CDC20 as a promising prognostic biomarker and a potential novel therapeutic target for lung adenocarcinoma.Methods:We collected 539 patients with LUAD and 59 normal controls of clinical data from the Cancer Genome Atlas(TCGA)for bioinformatics analysis to investigate the role of CDC20 in LUAD and address the above questions.We evaluated the association between CDC20 expression and clinicopathological features using the Kruskal Wallis test and multivariate logistic regression.Prognostic values were assessed using Cox regression and Kaplan-Meier survival analyses.We further used single-sample gene set enrichment analysis(ssGSEA)to explore correlations between CDC20 expression and immune infiltration levels.Results:CDC20 expression in LUAD tissues was significantly higher than that in normal controls(p<0.001)and showed high diagnostic accuracy(AUC[area under the curve]=0.979).Kaplan-Meier analysis revealed that high CDC20 expression predicted poorer overall survival(OS;HR=1.47,95%CI:1.10–1.97,p=0.009),although no significant association emerged with progression-free interval(p=0.172).ssGSEA indicated a strong positive correlation between CDC20 and T helper 2 cell infiltration(R=0.764,p<0.001),but negative correlations with mast cells(R=−0.469,p<0.001)and eosinophils(R=−0.343,p<0.001).Functional enrichment analyses(Gene ontology/Kyoto Encyclopedia of Genes and Genomes[GO/KEGG])of CDC20-associated genes provided additional mechanistic insights.Conclusions:The significantly elevated expression of CDC20 in LUAD tissues,coupled with its high diagnostic accuracy(AUC=0.979),underscores its potential utility in differentiating LUAD from normal tissue.More importantly,the strong association between high CDC20 expression and poorer overall survival(OS)establishes its independent prognostic value for predicting adverse patient outcomes.Beyond its correlation with clinical parameters,our findings illuminate potential mechanisms underlying CDC20's oncogenic role.The distinct positive correlation with T helper 2(Th2)cell infiltration and negative correlations with mast cells and eosinophils suggest that CDC20 may actively shape an immunosuppressive tumor microenvironment,potentially facilitating tumor immune evasion and progression.Functional enrichment analyses of CDC20-coexpressed genes further support its involvement in key oncogenic pathways,including cell cycle regulation and mitotic processes.Collectively,this study not only validates CDC20 as a valuable prognostic factor but also provides novel mechanistic insights linking its overexpression to altered immune landscapes in LUAD.展开更多
Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and ...Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive.Here,we show that the mechanical protein Polysyctin-1(PC1,Pkd1)regulates CTSK lineage tendon-derived mesenchymal stem cell(TDMSC)fate and ECM organization,thus affecting HO progression.First,we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model.Moreover,we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation.Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis,fibrogenesis and ECM organization,and consequently attenuate HO progression.These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.展开更多
A decomposable and sono-enzyme co-triggered nanoparticle(p TCP-CR NP)with“AND gate”logic was synthesized,combining a meso–carboxyl-porphyrin-based sonosensitizer(5,10,15,20-tetrakis(carboxyl)porphyrin,TCP)and a thi...A decomposable and sono-enzyme co-triggered nanoparticle(p TCP-CR NP)with“AND gate”logic was synthesized,combining a meso–carboxyl-porphyrin-based sonosensitizer(5,10,15,20-tetrakis(carboxyl)porphyrin,TCP)and a thiophenyl-croconium(2,5-bis[(2-(2-(2-hydroxyethoxy)ethoxy)ethyl-4-carboxylate-piperidylamino)thiophenyl]-croconium,CR)via ester groups.TCP releases carbon monoxide(CO)under ultrasound(US)irradiation,offering both sonodynamic and gas therapy.CR decomposes into stronger reactive oxygen species(ROS)compared to oxygen-based radicals.The F?rster resonance energy transfer(FRET)effect between TCP and CR inhibits ROS and CO generation until triggered by tumor cell overexpressed carboxylesterase(CEs).p TCP-CR NPs“AND gate”logic ensures activation only in the presence of both CEs and US,targeting tumor cells while safety in normal tissues.The ROS and CO generation abilities,as well as the releasing of SO_(4)^(·-)have been systemically examined.p TCP-CR can be thoroughly decomposed into low-toxic molecules post the treatment,showing the safety with negligible phototoxic reactions.In vivo anti-cancer therapy has been evaluated using mice bearing hepatocellular carcinoma.展开更多
The preparation,functionalization,and investigations in host-vip properties of high-level pillararene macrocycles have long been a big challenge because of the lack of efficient synthetic methods.Herein,a novel type...The preparation,functionalization,and investigations in host-vip properties of high-level pillararene macrocycles have long been a big challenge because of the lack of efficient synthetic methods.Herein,a novel type of pillararene derivative,namely desymmetrized pillar[8]arene(DP[8]A),has been successfully synthesized via a facile two-step strategy with high yield.Compared with its pillar[8]arene counterpart,DP[8]A is composed of four alkoxy-substituted benzene units and four bare benzene rings.Single crystal analysis has been performed in order to unveil the molecular conformation and packing mode of DP[8]A,which indicated that DP[8]A possesses a unique chair-like structure and much smaller steric hindrance.Density functional theory(DFT)calculations and electrostatic potential map suggested the inhomogeneous electronic distribution in the DP[8]A cavity.Water-soluble carboxylate-modified DP[8]A,that is,CDP[8]A,was also prepared to investigate the host-vip properties in aqueous solution with methyl viologen(MV),where the binding constant and morphologies of the formed host-vip complexes have been studied.In all,this new version of eight-membered pillararene derivative might potentially serve as a powerful macrocycle candidate for further applications in supramolecular chemistry.展开更多
Unhealthy diets are associated with various diseases that can disrupt brain energy metabolism,which significantly increased the risk of cognitive impairment and chronic neurodegenerative diseases.Early intervention wi...Unhealthy diets are associated with various diseases that can disrupt brain energy metabolism,which significantly increased the risk of cognitive impairment and chronic neurodegenerative diseases.Early intervention with nutritional supplements may have long-lasting positive effects on diet-related glucose metabolism and potentially mediate the progression of neurodegeneration in middle-aged and elderly people.We previously reported that cyanidin 3-O-β-galactoside(Cy3Gal),an anthocyanin from black chokeberry(Aronia melanocarpa(Michx.)Elliott),alleviated cognitive impairment in aging mice through regulating brain energy metabolism.However,it remains unclear whether Cy3Gal can also exert beneficial effects in mice fed with a high-fat/high-sugar diet.Here we revealed that Cy3Gal treatment conserved the health of neurons and synapses,as well as cognitive function of mice.Furthermore,we observed that Cy3Gal effectively improved glucose uptake and metabolism of skeletal muscle by enhancing glycolysis both in vivo and in vitro models,which is essential for maintaining a stable glucose supply to the brain.Additionally,Cy3Gal significantly increased the levels of glucose-derived tricarboxylic acid cycle intermediates in the mice brain(P<0.05),and regulated the activities of mitochondrial respiratory chain complexes(P<0.01).The positive influence on peripheral and brain bioenergetics explained how the Cy3Gal exerted neuroprotective effect.In conclusion,our study illustrated that early dietary intervention of Cy3Gal had significant advantages in terms of neuroprotection and cognition under the challenge of HFHS diet-induced glucose metabolism disorder.展开更多
This study explores a novel educational model of generative AI-empowered interdisciplinary project-based learning(PBL).By analyzing the current applications of generative AI technology in information technology curric...This study explores a novel educational model of generative AI-empowered interdisciplinary project-based learning(PBL).By analyzing the current applications of generative AI technology in information technology curricula,it elucidates its advantages and operational mechanisms in interdisciplinary PBL.Combining case studies and empirical research,the investigation proposes implementation pathways and strategies for the generative AI-enhanced interdisciplinary PBL model,detailing specific applications across three phases:project preparation,implementation,and evaluation.The research demonstrates that generative AI-enabled interdisciplinary project-based learning can effectively enhance students’learning motivation,interdisciplinary thinking capabilities,and innovative competencies,providing new conceptual frameworks and practical approaches for educational model innovation.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a globally prevalent malignancy associated with high morbidity and mortality.Transfer RNA(tRNA)-derived small RNAs(tsRNAs),a class of small non-coding RNAs originating from t...BACKGROUND Hepatocellular carcinoma(HCC)is a globally prevalent malignancy associated with high morbidity and mortality.Transfer RNA(tRNA)-derived small RNAs(tsRNAs),a class of small non-coding RNAs originating from tRNA,have emerged as potential therapeutic targets in cancers,including HCC.However,the specific tsRNAs involved in HCC and their precise mechanisms remain largely unknown.In this study,we identify and characterize specific tsRNAs involved in the development and progression of HCC,discovering their potential as novel biomarkers for early detection and potential therapeutic targets.AIM To investigate differentially expressed tsRNAs in HCC,identify potential biomarkers,and elucidate the functions and mechanisms of tsRNAs in HCC.METHODS Differentially expressed tsRNAs in Barcelona Clinic Liver Cancer 0/A-stage HCC tissues were identified through high-throughput sequencing.Agarose gel electrophoresis,Sanger sequencing,and quantitative polymerase chain reaction were conducted to detect 5’-tRNA halve(tiRNA)-lysine(Lys)-CTT in tissues and serum samples.The diagnostic performance of 5’-tiRNA-Lys-CTT was evaluated using receiver operating characteristic analysis.HCC cell proliferation was examined using the Cell Counting Kit-8 assay,colony formation assay,and 5-ethynyl-2’-deoxyuridine staining.Additionally,the migratory capability of HCC cells was investigated using Transwell assays.RESULTS The 5’-tiRNA-Lys-CTT demonstrated excellent stability and can be easily detected.Its expression was significantly upregulated in 50 HCC tissues,110 HCC serum samples,and 5 HCC cell lines vs control groups,and the differences were all significant.This elevated expression was strongly associated with clinicopathological characteristics,particularly tumor size,Barcelona Clinic Liver Cancer stage,and cirrhosis of the liver.Receiver operating characteristic analysis revealed superior detection efficiency of 5’-tiRNA-Lys-CTT exhibits for early-stage HCC compared to established markers.Functional assays revealed that 5’-tiRNA-Lys-CTT overexpression promoted cell proliferation and migration,while its inhibition had the opposite effect.Bioinformatics predictions suggest that 5’-tiRNA-Lys-CTT may influence the development and progression of liver cancer by targeting downstream mRNA via metabolic pathways,cancer pathways,and HCC-specific pathways.CONCLUSION The 5’-tiRNA-Lys-CTT levels were higher in early HCC patients.5’-tiRNA-Lys-CTT is a promising diagnostic biomarker for early-stage HCC and may play an oncogenic role in HCC by interacting with downstream mRNA targets via specific pathways.展开更多
Background:Hypertensive disorders of pregnancy(HDP)stands as a significant contributor to adverse maternal and fetal outcomes worldwide.However,current biomarkers lack specificity in distinguishing HDP from chronic hy...Background:Hypertensive disorders of pregnancy(HDP)stands as a significant contributor to adverse maternal and fetal outcomes worldwide.However,current biomarkers lack specificity in distinguishing HDP from chronic hypertension.Hence,we employed proteome-wide Mendelian randomization(MR)and colocalization analysis to decipher sensitive and specific markers for HDP via integrating multi-omics data.Methods:Genetic associations for plasma proteins were obtained from large-scale proteomic studies(e.g.,Iceland,Fenland,and UK Biobank).The summarized GWAS data of HDP and hypertension were acquired from the FinnGen consortium.A proteome-wide Mendelian randomization(MR)study was then implemented to identify the causal role of plasma proteins in HDP and hypertension.The results were further confirmed by transcriptome-wide association studies(TWAS)and colocalization analyses.Results:Proteome-wide MR identified 13 plasma proteins with potential causal links to HDP.Among them,peroxisomal acyl-coenzyme A oxidase 1(ACOX1)and glycine N-methyltransferase(GNMT)were classified as highly sensitive and specific markers differentiating from hypertension by integrating multi-omics evidence from expression quantitative trait loci(eQTL),protein quantitative trait loci(pQTL)and colocalization analyses.ACOX1 was identified as a risk factor,whereas GNMT demonstrated a protective effect.Enrichment analysis and protein-protein interaction(PPI)network mapping offered insights into underlying biological pathways.Conclusion:This study establishes the causal associations between 13 identified proteins and HDP,nominates that ACOX1 and GNMT are highly sensitive and specific markers for HDP distinguished from hypertension.Our findings offer valuable insights into the pathogenesis of HDP,paving the path for novel strategies in diagnosis and prevention.展开更多
High-entropy alloys(HEAs)have emerged as promising catalysts for the hydrogen evolution reaction(HER)due to their compositional diversity and synergistic effects.In this study,machine learning-accelerated density func...High-entropy alloys(HEAs)have emerged as promising catalysts for the hydrogen evolution reaction(HER)due to their compositional diversity and synergistic effects.In this study,machine learning-accelerated density functional theory(DFT)calculations were employed to assess the catalytic performance of PtPd-based HEAs with the formula PtPdXYZ(X,Y,Z=Fe,Co,Ni,Cu,Ru,Rh,Ag,Au;X≠Y≠Z).Among 56 screened HEA(111)surfaces,PtPdRuCoNi(111)was identified as the most promising,with adsorption energies(E_(ads))between−0.50 and−0.60 eV and high d-band center of−1.85 eV,indicating enhanced activity.This surface showed the hydrogen adsorption free energy(ΔG_(H^(*)))of−0.03 eV for hydrogen adsorption,outperforming Pt(111)by achieving a better balance between adsorption and desorption.Machine learning models,particularly extreme gradient boosting regression(XGBR),significantly reduced computational costs while maintaining high accuracy(root-mean-square error,RMSE=0.128 eV).These results demonstrate the potential of HEAs for efficient and sustainable hydrogen production.展开更多
This review examines inflammation as a physiological defense mechanism against infectious agents,physical trauma,reactive oxygen species(ROS),and metabolic stress,which,under dysregulated conditions,may progress into ...This review examines inflammation as a physiological defense mechanism against infectious agents,physical trauma,reactive oxygen species(ROS),and metabolic stress,which,under dysregulated conditions,may progress into chronic diseases.Nanomedicine,which integrates nanotechnology with medicine,suppresses inflammatory signaling pathways and overexpressed pro-inflammatory cytokines,such as ROS,to address inflammationrelated pathologies.Current advances in nanomaterial design and synthesis strategies are systematically analyzed,with parallel discussions on toxicity mechanisms,influencing factors,and evaluation methods that are critical for clinical translation.Applications of functional nanomaterials are highlighted in the context of refractory inflammatory conditions,including wound healing,gastrointestinal disorders,and immune,neurological,or circulatory diseases,along with targeted delivery strategies.Persistent challenges in nanomedicine development,such as biocompatibility optimization,precise biodistribution control,and standardized toxicity assessment,are critically assessed.By bridging material innovation with therapeutic efficacy,this review establishes a framework for advancing nanomedicine to improve treatment outcomes while addressing translational barriers.展开更多
Background : Cancer-associated cardiac cachexia(CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed. Methods : This study established CAC...Background : Cancer-associated cardiac cachexia(CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed. Methods : This study established CACC models in C57BL/6J and BALB/c mice using orthotopic, intra-abdominal, and hematogenous metastatic tumor induction. Multimodal cardiac assessments, including echocardiography, transmission electron microscopy for myocardial ultrastructural and mitochondrial analysis, and ex vivo cardiomyocyte contractility assays, were systematically applied. Results : Metastatic burden triggered CACC characterized by cardiac mass reduction, epicardial fat depletion, interstitial fibrosis, and electrocardiographic abnormalities. Histopathological analysis revealed cardiomyocyte atrophy, myofibrillar disarray, mitochondrial dysfunction, and ubiquitin-mediated Myh6 degradation via Mu RF-1, accompanied by compensatory Myh7 upregulation. These findings mechanistically link tumor-induced cachexia to cardiac dysfunction through contractile protein remodeling. Conclusion : This work establishes a preclinical framework for targeting ubiquitin pathways to mitigate the morbidity of cancer-related cardiopathy. Our integrated approach delineates a hierarchical progression from subcellular dysfunction to macroscopic cardiac deterioration.展开更多
BACKGROUND The primary complication associated with gestational diabetes mellitus(GDM)is delivery of an infant that is large for gestational age(LGA).Epidemiological findings have demonstrated that irregular lipid met...BACKGROUND The primary complication associated with gestational diabetes mellitus(GDM)is delivery of an infant that is large for gestational age(LGA).Epidemiological findings have demonstrated that irregular lipid metabolism significantly con-tributes to insulin resistance,a key pathophysiological mechanism in GDM.However,the correlation between various lipid indices and the probability of delivering LGA infants remains inconsistent.AIM To explore the relationships between lipid indices and the possibility of having LGA infants among GDM-affected pregnant females.METHODS Binary logistic regression methods were employed to evaluate the odds ratios and corresponding 95%confidence intervals for LGA according to five lipid indices.Restricted cubic spline models were applied to investigate dose-response relationships.The association between lipid indices and the risk of delivering LGA infants was further investigated among different subgroups.Receiver operating characteristic curves were utilized to assess the diagnostic performance of lipid indices.RESULTS Across crude and adjusted models,females with lipid indices in the upper two tertiles presented a markedly elevated risk of delivering LGA infants compared with the lowest tertile category.Conversely,high-density lipoprotein cholesterol levels demonstrated the contrary trend.Restricted cubic spline analyses revealed linear associations between the five lipid indices,except triglyceride levels,and the prevalence of LGA.The subgroup analysis highlighted that the correlation between lipid indices and the probability of LGA was inconsistent.The five lipid indices presented significant diagnostic efficacy,as indicated by receiver operating characteristic curve areas.CONCLUSION Our research demonstrated that lipid indices were effective predictors of the incidence of LGA infants in GDM-affected pregnancies irrespective of potential confounding factors.展开更多
Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for ...Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients.The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy.Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC.However,inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy(PTT).This study modified gold nanodots(AuNDs)with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT.The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuN Ds.The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC.Moreover,owing to its stable long-term fluorescence and high X-ray attenuation coefficient,the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC,rendering it useful for early tumor detection and accurate delineation of surgical margins.In conclusion,Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.展开更多
基金This study was supported by grants from the National Natural Science Foundation of China(81972726,82273074 and 82372813)Dawn Project Foundation of Shanghai(21SG36)+2 种基金Shanghai Health Academic Leader Program(2022XD001)the Natural Science Foundation of Shanghai(22ZR1477900)Adjunct Talent Fund of Zhejiang Provincial People’s Hospital(2021-YT).
文摘Background:Cancer-related fatigue(CRF)is a common and debilitating symptom experienced by patients with advanced-stage cancer,especially those undergoing antitumor therapy.This study aimed to evaluate the efficacy and safety of Renshenguben(RSGB)oral solution,a ginseng-based traditional Chinese medicine,in alleviating CRF in patients with advanced hepatocellular carcinoma(HCC)receiving antitumor treatment.Methods:In this prospective,open-label,controlled,multicenter study,patients with advanced HCC at BCLC stage C and a brief fatigue inventory(BFI)score of≥4 were enrolled.Participants were assigned to the RSGB group(RSGB,10 mL twice daily)or the control group(with supportive care).Primary and secondary endpoints were the change in multidimensional fatigue inventory(MFI)score,and BFI and functional assessment of cancer therapy-hepatobiliary(FACT-Hep)scores at weeks 4 and 8 after enrollment.Adverse events(AEs)and toxicities were assessed.Results:A total of 409 participants were enrolled,with 206 assigned to the RSGB group.At week 4,there was a trend towards improvement,but the differences were not statistically significant.At week 8,the RSGB group exhibited a significantly lower MFI score(P<0.05)compared to the control group,indicating improved fatigue levels.Additionally,the RSGB group showed significantly greater decrease in BFI and FACT-Hep scores at week 8(P<0.05).Subgroup analyses among patients receiving various antitumor treatments showed similar results.Multivariate linear regression analyses revealed that the RSGB group experienced a significantly substantial decrease in MFI,BFI,and FACT-Hep scores at week 8.No serious drug-related AEs or toxicities were observed.Conclusions:RSGB oral solution effectively reduced CRF in patients with advanced HCC undergoing antitumor therapy over an eight-week period,with no discernible toxicities.These findings support the potential of RSGB oral solution as an adjunctive treatment for managing CRF in this patient population.
基金supported by the Notional Natural Science Foundation of Chino,No.82160690Colloborotive Innovation Center of Chinese Ministry of Education,No.2020-39Science and Technology Foundation of Guizhou Province,No.ZK[2021]-014(all to FZ)。
文摘Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.
基金jointly funded by the Sichuan Provincial Natural Science Foundation of China(Grant No.2023NSFSC0378)the Jiuzhaigou Lake Swamp and River Ecological Restoration Research Project(N5132112022000246)the Research base and Support provided by Jiuzhaigou Administration for this study。
文摘Rubble deposits with a high concentration of rock debris were created after the powerful earthquakes in Jiuzhaigou.Because of the restricted soil resources,water leaks,and nutrient deficits,these deposits pose serious obstacles for vegetation regeneration.The purpose of this study was to investigate the main mechanisms controlling soil water retention and evaluate the effects of different amendments on the hydraulic characteristics and water-holding capacity of collapsed rubble soils.Finegrained soil,forest humus,crushed straw,and organic components that retain water were added to the altered soils to study the pore structure images and soil-water characteristic curves.Comparing understory humus to other supplements,the results showed a considerable increase in the soil's saturated and wilting water content.The saturated water content and wilting water content rose by 17.9%and 4.3%,respectively,when the percentage of understory soil reached 30%.Additionally,the enhanced soil's microporosity and total pore volume increased by 45.33%and 11.27%,respectively,according to nuclear magnetic imaging.It was shown that while clay particles and organic matter improved the soil's ability to adsorb water,they also increased the soil's total capacity to store water.Fine particulate matter did this by decreasing macropores and increasing capillary pores.These results offer an essential starting point for creating strategies for soil repair that would encourage the restoration of plants on slopes that have been damaged.
文摘The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.
基金supported by the National Natural Science Foundation of China(Grant No.:82304564)the Liaoning Province Education Department Scientific Research Funding Project(Grant No.:LJKZ0777).
文摘Artificial intelligence(AI)is revolutionizing traditional drug discovery and development models by seamlessly integrating data,computational power,and algorithms.This synergy enhances the efficiency,accuracy,and success rates of drug research,shortens development timelines,and reduces costs.Coupled with machine learning(ML)and deep learning(DL),AI has demonstrated significant advancements across various domains,including drug characterization,target discovery and validation,small molecule drug design,and the acceleration of clinical trials.Through molecular generation techniques,AI facilitates the creation of novel drug molecules,predicting their properties and activities,while virtual screening(VS)optimizes drug candidates.Additionally,AI enhances clinical trial efficiency by predicting outcomes,designing trials,and enabling drug repositioning.However,AI's application in drug development faces challenges,including the need for robust data-sharing mechanisms and the establishment of more comprehensive intellectual property protections for algorithms.AI-driven pharmaceutical companies must also integrate biological sciences and algorithms effectively,ensuring the successful fusion of wet and dry laboratory experiments.Despite these challenges,the potential of AI in drug development remains undeniable.As AI technology evolves and these barriers are addressed,AI-driven therapeutics are poised for a broader and more impactful future in the pharmaceutical industry.
基金Supported by Wu Jieping Medical Foundation,No.320.6750.2021-06-30Guangdong Basic and Applied Basic Research Foundation,No.2019A1515110120National Natural Science Foundation of China,No.82002974。
文摘BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor progression.Suppressor of cytokine signaling 2(SOCS2),a key immune regulator,may modulate Treg activity and impact LIHC growth and metastasis.AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis,Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data,and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration.Key prognostic genes were identified using Weighted Gene Coexpression Network Analysis and machine learning.In vitro,co-culture experiments,migration assays,apoptosis detection,and enzyme-linked immunosorbent assay were conducted.In vivo,tumor growth,metastasis,and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining,Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling,and immunohistochemistry analyses.RESULTS SOCS2 overexpression inhibited Treg cell activity,reducing LIHC cell migration and invasion while increasing apoptosis.In vivo,SOCS2 suppressed tumor growth and metastasis,confirming its therapeutic potential.CONCLUSION SOCS2 modulates CD4+T function in the TME,contributing to LIHC progression.Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.
基金supported by the Research Foundation for Talented Scholars of Fujian Medical University,No.XRCZX2018014(to DZ)Startup Fund for Scientific Research,Fujian Medical University,No.2019QH1017(to CW)the Natural Science Foundation of Fujian Province,China,Nos.2021J01693(to DZ),2021J02032(to ZCY)。
文摘Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregation,and alleviates scopolamine-induced cognitive impairment,similar to the phase Ⅲ clinical drug resveratrol.In this study,we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology.Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment,promoted fibrillar amyloid-β clearance from the hippocampus and cortex,suppressed oxidative stress,and inhibited activation of microglia and astrocytes.D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression.Notably,we demonstrated that exogenous fibrillar amyloid-βintroduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain,and this increase was blocked by D30.Considering the role of D30 in clearing amyloid-β,inhibiting neuroinflammation,protecting synapses,and improving cognition,this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.
基金funded by the Liaoning Province Science and Technology Plan Joint Project (No.2023JH2/101700140)
文摘Background:Lung adenocarcinoma,the most prevalent lung cancer subtype,is increasingly diagnosed in non-smokers and females.The cell cycle regulator CDC20(Cell Division Cycle 20),a crucial activator of the Anaphase-Promoting Complex/Cyclosome(APC/C),is frequently overexpressed in various cancers,including lung adenocarcinoma,and is implicated in tumorigenesis.Preclinical studies indicate that inhibiting the CDC20-APC/C signaling axis can enhance chemotherapy-induced apoptosis.Analysis of The Cancer Genome Atlas(TCGA)data confirms that elevated CDC20 expression in lung adenocarcinoma is significantly associated with poorer patient prognosis and correlates with immune cell infiltration.These collective findings highlight CDC20 as a promising prognostic biomarker and a potential novel therapeutic target for lung adenocarcinoma.Methods:We collected 539 patients with LUAD and 59 normal controls of clinical data from the Cancer Genome Atlas(TCGA)for bioinformatics analysis to investigate the role of CDC20 in LUAD and address the above questions.We evaluated the association between CDC20 expression and clinicopathological features using the Kruskal Wallis test and multivariate logistic regression.Prognostic values were assessed using Cox regression and Kaplan-Meier survival analyses.We further used single-sample gene set enrichment analysis(ssGSEA)to explore correlations between CDC20 expression and immune infiltration levels.Results:CDC20 expression in LUAD tissues was significantly higher than that in normal controls(p<0.001)and showed high diagnostic accuracy(AUC[area under the curve]=0.979).Kaplan-Meier analysis revealed that high CDC20 expression predicted poorer overall survival(OS;HR=1.47,95%CI:1.10–1.97,p=0.009),although no significant association emerged with progression-free interval(p=0.172).ssGSEA indicated a strong positive correlation between CDC20 and T helper 2 cell infiltration(R=0.764,p<0.001),but negative correlations with mast cells(R=−0.469,p<0.001)and eosinophils(R=−0.343,p<0.001).Functional enrichment analyses(Gene ontology/Kyoto Encyclopedia of Genes and Genomes[GO/KEGG])of CDC20-associated genes provided additional mechanistic insights.Conclusions:The significantly elevated expression of CDC20 in LUAD tissues,coupled with its high diagnostic accuracy(AUC=0.979),underscores its potential utility in differentiating LUAD from normal tissue.More importantly,the strong association between high CDC20 expression and poorer overall survival(OS)establishes its independent prognostic value for predicting adverse patient outcomes.Beyond its correlation with clinical parameters,our findings illuminate potential mechanisms underlying CDC20's oncogenic role.The distinct positive correlation with T helper 2(Th2)cell infiltration and negative correlations with mast cells and eosinophils suggest that CDC20 may actively shape an immunosuppressive tumor microenvironment,potentially facilitating tumor immune evasion and progression.Functional enrichment analyses of CDC20-coexpressed genes further support its involvement in key oncogenic pathways,including cell cycle regulation and mitotic processes.Collectively,this study not only validates CDC20 as a valuable prognostic factor but also provides novel mechanistic insights linking its overexpression to altered immune landscapes in LUAD.
基金National Natural Science Foundation of China(Grant Nos.82261160397,82272560)Central South University Research Programme of Advanced Interdisciplinary Studies(2023QYJC011)+4 种基金National Natural Science Foundation of China(Grant Nos.82472521,81922017)Hunan Provincial Science and Technology Department(2023JJ30896)Key Research and Development Program of Hunan Province(2022SK2023)Science and Technology Innovation Program of Hunan Province(2023RC1027)Major Basic Research Projects in Hunan Province(No.2024JC0004)。
文摘Mechanical stress modulates bone formation and organization of the extracellular matrix(ECM),the interaction of which affects heterotopic ossification(HO).However,the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive.Here,we show that the mechanical protein Polysyctin-1(PC1,Pkd1)regulates CTSK lineage tendon-derived mesenchymal stem cell(TDMSC)fate and ECM organization,thus affecting HO progression.First,we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model.Moreover,we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation.Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis,fibrogenesis and ECM organization,and consequently attenuate HO progression.These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.
基金supported by grants from the National Natural Science Foundation of China(No.22375027)the Natural Science Foundation of Jiangsu Province(Nos.BK20221265,BK20211100)+1 种基金the Fundamental Research Funds for the Central Universities(No.DUT23YG133)the Research Funds from Liaoning Cancer Hospital(No.2024ZLKF-35)。
文摘A decomposable and sono-enzyme co-triggered nanoparticle(p TCP-CR NP)with“AND gate”logic was synthesized,combining a meso–carboxyl-porphyrin-based sonosensitizer(5,10,15,20-tetrakis(carboxyl)porphyrin,TCP)and a thiophenyl-croconium(2,5-bis[(2-(2-(2-hydroxyethoxy)ethoxy)ethyl-4-carboxylate-piperidylamino)thiophenyl]-croconium,CR)via ester groups.TCP releases carbon monoxide(CO)under ultrasound(US)irradiation,offering both sonodynamic and gas therapy.CR decomposes into stronger reactive oxygen species(ROS)compared to oxygen-based radicals.The F?rster resonance energy transfer(FRET)effect between TCP and CR inhibits ROS and CO generation until triggered by tumor cell overexpressed carboxylesterase(CEs).p TCP-CR NPs“AND gate”logic ensures activation only in the presence of both CEs and US,targeting tumor cells while safety in normal tissues.The ROS and CO generation abilities,as well as the releasing of SO_(4)^(·-)have been systemically examined.p TCP-CR can be thoroughly decomposed into low-toxic molecules post the treatment,showing the safety with negligible phototoxic reactions.In vivo anti-cancer therapy has been evaluated using mice bearing hepatocellular carcinoma.
基金the Natural Science Foundation of Jilin Province(No.20230101052JC)he National Natural Science Foundation of China(Nos.52173200 and 52203138)the Jilin Province Science and Technology Development Plan Project(No.#YDZJ202201ZYTS523)for financial support。
文摘The preparation,functionalization,and investigations in host-vip properties of high-level pillararene macrocycles have long been a big challenge because of the lack of efficient synthetic methods.Herein,a novel type of pillararene derivative,namely desymmetrized pillar[8]arene(DP[8]A),has been successfully synthesized via a facile two-step strategy with high yield.Compared with its pillar[8]arene counterpart,DP[8]A is composed of four alkoxy-substituted benzene units and four bare benzene rings.Single crystal analysis has been performed in order to unveil the molecular conformation and packing mode of DP[8]A,which indicated that DP[8]A possesses a unique chair-like structure and much smaller steric hindrance.Density functional theory(DFT)calculations and electrostatic potential map suggested the inhomogeneous electronic distribution in the DP[8]A cavity.Water-soluble carboxylate-modified DP[8]A,that is,CDP[8]A,was also prepared to investigate the host-vip properties in aqueous solution with methyl viologen(MV),where the binding constant and morphologies of the formed host-vip complexes have been studied.In all,this new version of eight-membered pillararene derivative might potentially serve as a powerful macrocycle candidate for further applications in supramolecular chemistry.
基金supported by the National Natural Science Foundation of China(32172210).
文摘Unhealthy diets are associated with various diseases that can disrupt brain energy metabolism,which significantly increased the risk of cognitive impairment and chronic neurodegenerative diseases.Early intervention with nutritional supplements may have long-lasting positive effects on diet-related glucose metabolism and potentially mediate the progression of neurodegeneration in middle-aged and elderly people.We previously reported that cyanidin 3-O-β-galactoside(Cy3Gal),an anthocyanin from black chokeberry(Aronia melanocarpa(Michx.)Elliott),alleviated cognitive impairment in aging mice through regulating brain energy metabolism.However,it remains unclear whether Cy3Gal can also exert beneficial effects in mice fed with a high-fat/high-sugar diet.Here we revealed that Cy3Gal treatment conserved the health of neurons and synapses,as well as cognitive function of mice.Furthermore,we observed that Cy3Gal effectively improved glucose uptake and metabolism of skeletal muscle by enhancing glycolysis both in vivo and in vitro models,which is essential for maintaining a stable glucose supply to the brain.Additionally,Cy3Gal significantly increased the levels of glucose-derived tricarboxylic acid cycle intermediates in the mice brain(P<0.05),and regulated the activities of mitochondrial respiratory chain complexes(P<0.01).The positive influence on peripheral and brain bioenergetics explained how the Cy3Gal exerted neuroprotective effect.In conclusion,our study illustrated that early dietary intervention of Cy3Gal had significant advantages in terms of neuroprotection and cognition under the challenge of HFHS diet-induced glucose metabolism disorder.
文摘This study explores a novel educational model of generative AI-empowered interdisciplinary project-based learning(PBL).By analyzing the current applications of generative AI technology in information technology curricula,it elucidates its advantages and operational mechanisms in interdisciplinary PBL.Combining case studies and empirical research,the investigation proposes implementation pathways and strategies for the generative AI-enhanced interdisciplinary PBL model,detailing specific applications across three phases:project preparation,implementation,and evaluation.The research demonstrates that generative AI-enabled interdisciplinary project-based learning can effectively enhance students’learning motivation,interdisciplinary thinking capabilities,and innovative competencies,providing new conceptual frameworks and practical approaches for educational model innovation.
基金Supported by the Scientific Research Project of Nantong Municipal Commission of Health and Family Planning,No.QN2023001.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a globally prevalent malignancy associated with high morbidity and mortality.Transfer RNA(tRNA)-derived small RNAs(tsRNAs),a class of small non-coding RNAs originating from tRNA,have emerged as potential therapeutic targets in cancers,including HCC.However,the specific tsRNAs involved in HCC and their precise mechanisms remain largely unknown.In this study,we identify and characterize specific tsRNAs involved in the development and progression of HCC,discovering their potential as novel biomarkers for early detection and potential therapeutic targets.AIM To investigate differentially expressed tsRNAs in HCC,identify potential biomarkers,and elucidate the functions and mechanisms of tsRNAs in HCC.METHODS Differentially expressed tsRNAs in Barcelona Clinic Liver Cancer 0/A-stage HCC tissues were identified through high-throughput sequencing.Agarose gel electrophoresis,Sanger sequencing,and quantitative polymerase chain reaction were conducted to detect 5’-tRNA halve(tiRNA)-lysine(Lys)-CTT in tissues and serum samples.The diagnostic performance of 5’-tiRNA-Lys-CTT was evaluated using receiver operating characteristic analysis.HCC cell proliferation was examined using the Cell Counting Kit-8 assay,colony formation assay,and 5-ethynyl-2’-deoxyuridine staining.Additionally,the migratory capability of HCC cells was investigated using Transwell assays.RESULTS The 5’-tiRNA-Lys-CTT demonstrated excellent stability and can be easily detected.Its expression was significantly upregulated in 50 HCC tissues,110 HCC serum samples,and 5 HCC cell lines vs control groups,and the differences were all significant.This elevated expression was strongly associated with clinicopathological characteristics,particularly tumor size,Barcelona Clinic Liver Cancer stage,and cirrhosis of the liver.Receiver operating characteristic analysis revealed superior detection efficiency of 5’-tiRNA-Lys-CTT exhibits for early-stage HCC compared to established markers.Functional assays revealed that 5’-tiRNA-Lys-CTT overexpression promoted cell proliferation and migration,while its inhibition had the opposite effect.Bioinformatics predictions suggest that 5’-tiRNA-Lys-CTT may influence the development and progression of liver cancer by targeting downstream mRNA via metabolic pathways,cancer pathways,and HCC-specific pathways.CONCLUSION The 5’-tiRNA-Lys-CTT levels were higher in early HCC patients.5’-tiRNA-Lys-CTT is a promising diagnostic biomarker for early-stage HCC and may play an oncogenic role in HCC by interacting with downstream mRNA targets via specific pathways.
基金supported by grants from the Natural Science Foundation of Gansu Province(24JRRA937 and 25JRRA1234)grants from the National Natural Science Foundation of China(82360469)+1 种基金Scientific research projects in the health industry of Gansu Province(GSWSKY2025-23)Research Project for Introduced Talents of Northwest Minzu University(xbmuyjrc2023020).
文摘Background:Hypertensive disorders of pregnancy(HDP)stands as a significant contributor to adverse maternal and fetal outcomes worldwide.However,current biomarkers lack specificity in distinguishing HDP from chronic hypertension.Hence,we employed proteome-wide Mendelian randomization(MR)and colocalization analysis to decipher sensitive and specific markers for HDP via integrating multi-omics data.Methods:Genetic associations for plasma proteins were obtained from large-scale proteomic studies(e.g.,Iceland,Fenland,and UK Biobank).The summarized GWAS data of HDP and hypertension were acquired from the FinnGen consortium.A proteome-wide Mendelian randomization(MR)study was then implemented to identify the causal role of plasma proteins in HDP and hypertension.The results were further confirmed by transcriptome-wide association studies(TWAS)and colocalization analyses.Results:Proteome-wide MR identified 13 plasma proteins with potential causal links to HDP.Among them,peroxisomal acyl-coenzyme A oxidase 1(ACOX1)and glycine N-methyltransferase(GNMT)were classified as highly sensitive and specific markers differentiating from hypertension by integrating multi-omics evidence from expression quantitative trait loci(eQTL),protein quantitative trait loci(pQTL)and colocalization analyses.ACOX1 was identified as a risk factor,whereas GNMT demonstrated a protective effect.Enrichment analysis and protein-protein interaction(PPI)network mapping offered insights into underlying biological pathways.Conclusion:This study establishes the causal associations between 13 identified proteins and HDP,nominates that ACOX1 and GNMT are highly sensitive and specific markers for HDP distinguished from hypertension.Our findings offer valuable insights into the pathogenesis of HDP,paving the path for novel strategies in diagnosis and prevention.
基金the Second Century Fund(C2F),Chulalongkorn UniversityThailand Science Research and Innovation Fund Chulalongkorn University(No.IND_FF_68_054_2100_009)National Science and Technology Development Agency,Thailand,Hub of Knowledge funding,and the Mid-Career Research Grant 2024,National Research Council of Thailand(No.N42A670295).
文摘High-entropy alloys(HEAs)have emerged as promising catalysts for the hydrogen evolution reaction(HER)due to their compositional diversity and synergistic effects.In this study,machine learning-accelerated density functional theory(DFT)calculations were employed to assess the catalytic performance of PtPd-based HEAs with the formula PtPdXYZ(X,Y,Z=Fe,Co,Ni,Cu,Ru,Rh,Ag,Au;X≠Y≠Z).Among 56 screened HEA(111)surfaces,PtPdRuCoNi(111)was identified as the most promising,with adsorption energies(E_(ads))between−0.50 and−0.60 eV and high d-band center of−1.85 eV,indicating enhanced activity.This surface showed the hydrogen adsorption free energy(ΔG_(H^(*)))of−0.03 eV for hydrogen adsorption,outperforming Pt(111)by achieving a better balance between adsorption and desorption.Machine learning models,particularly extreme gradient boosting regression(XGBR),significantly reduced computational costs while maintaining high accuracy(root-mean-square error,RMSE=0.128 eV).These results demonstrate the potential of HEAs for efficient and sustainable hydrogen production.
基金supported by the National Key Research and Development Program of China(Grants No.2023YFC2306500)Scientific Research Project Program of the Shanghai Municipal Health and Wellness Commission(Grant No.202140061)+3 种基金Key Science and Technology Research and Development Projects of Jiangxi Province(Grant No.20223BBH80014)“Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(Grant No.21SG39)Excellent Talents Program of Naval Medical Center of PLA(21TPZYL01)Military Projects(CHJ24C025,24AZL01,CB2023A03,JPY2022B06).
文摘This review examines inflammation as a physiological defense mechanism against infectious agents,physical trauma,reactive oxygen species(ROS),and metabolic stress,which,under dysregulated conditions,may progress into chronic diseases.Nanomedicine,which integrates nanotechnology with medicine,suppresses inflammatory signaling pathways and overexpressed pro-inflammatory cytokines,such as ROS,to address inflammationrelated pathologies.Current advances in nanomaterial design and synthesis strategies are systematically analyzed,with parallel discussions on toxicity mechanisms,influencing factors,and evaluation methods that are critical for clinical translation.Applications of functional nanomaterials are highlighted in the context of refractory inflammatory conditions,including wound healing,gastrointestinal disorders,and immune,neurological,or circulatory diseases,along with targeted delivery strategies.Persistent challenges in nanomedicine development,such as biocompatibility optimization,precise biodistribution control,and standardized toxicity assessment,are critically assessed.By bridging material innovation with therapeutic efficacy,this review establishes a framework for advancing nanomedicine to improve treatment outcomes while addressing translational barriers.
基金National Natural Science Foundation of China,Grant/Award Number:81970219, 82170261, 82200289 and 82370283National Key Research and Development Program of China,Grant/Award Number:2023YFF0724900。
文摘Background : Cancer-associated cardiac cachexia(CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed. Methods : This study established CACC models in C57BL/6J and BALB/c mice using orthotopic, intra-abdominal, and hematogenous metastatic tumor induction. Multimodal cardiac assessments, including echocardiography, transmission electron microscopy for myocardial ultrastructural and mitochondrial analysis, and ex vivo cardiomyocyte contractility assays, were systematically applied. Results : Metastatic burden triggered CACC characterized by cardiac mass reduction, epicardial fat depletion, interstitial fibrosis, and electrocardiographic abnormalities. Histopathological analysis revealed cardiomyocyte atrophy, myofibrillar disarray, mitochondrial dysfunction, and ubiquitin-mediated Myh6 degradation via Mu RF-1, accompanied by compensatory Myh7 upregulation. These findings mechanistically link tumor-induced cachexia to cardiac dysfunction through contractile protein remodeling. Conclusion : This work establishes a preclinical framework for targeting ubiquitin pathways to mitigate the morbidity of cancer-related cardiopathy. Our integrated approach delineates a hierarchical progression from subcellular dysfunction to macroscopic cardiac deterioration.
基金Supported by Nanjing Medical Science and Technique Development Foundation,No.YKK23151the Opening Foundation of Key Laboratory,No.JSHD202313+3 种基金Yingke Xinchuang Research Foundation of Jiangsu Blood Transfusion Association,No.JSYK2024006the Jiangsu Province Capability Improvement Project through Science,Technology and Education,No.ZDXYS202210Open Project of the State Key Laboratory of Reproductive Medicine of Nanjing Medical University,No.SKLRM-K202107the Jiangsu Provincial Maternal and Child Health Research Program,No.F202040.
文摘BACKGROUND The primary complication associated with gestational diabetes mellitus(GDM)is delivery of an infant that is large for gestational age(LGA).Epidemiological findings have demonstrated that irregular lipid metabolism significantly con-tributes to insulin resistance,a key pathophysiological mechanism in GDM.However,the correlation between various lipid indices and the probability of delivering LGA infants remains inconsistent.AIM To explore the relationships between lipid indices and the possibility of having LGA infants among GDM-affected pregnant females.METHODS Binary logistic regression methods were employed to evaluate the odds ratios and corresponding 95%confidence intervals for LGA according to five lipid indices.Restricted cubic spline models were applied to investigate dose-response relationships.The association between lipid indices and the risk of delivering LGA infants was further investigated among different subgroups.Receiver operating characteristic curves were utilized to assess the diagnostic performance of lipid indices.RESULTS Across crude and adjusted models,females with lipid indices in the upper two tertiles presented a markedly elevated risk of delivering LGA infants compared with the lowest tertile category.Conversely,high-density lipoprotein cholesterol levels demonstrated the contrary trend.Restricted cubic spline analyses revealed linear associations between the five lipid indices,except triglyceride levels,and the prevalence of LGA.The subgroup analysis highlighted that the correlation between lipid indices and the probability of LGA was inconsistent.The five lipid indices presented significant diagnostic efficacy,as indicated by receiver operating characteristic curve areas.CONCLUSION Our research demonstrated that lipid indices were effective predictors of the incidence of LGA infants in GDM-affected pregnancies irrespective of potential confounding factors.
基金supported by the Science and Technology Projects of Jilin Provincial Department of Science and Technology(Grant/Award Numbers:20240305037YY)National Key Research and Development Program of China(2021YFC2400603)+1 种基金the Joint Funds of the National Natural Science Foundation of China(Grant No.U23A20269)the Jilin University young teachers and students cross-disciplinary training project(Grant No.2023-JCXK-08,2024-JCXK-07)。
文摘Tongue squamous cell carcinoma(TSCC)is a prevalent malignancy that afflicts the head and neck area and presents a high incidence of metastasis and invasion.Accurate diagnosis and effective treatment are essential for enhancing the quality of life and the survival rates of TSCC patients.The current treatment modalities for TSCC frequently suffer from a lack of specificity and efficacy.Nanoparticles with diagnostic and photothermal therapeutic properties may offer a new approach for the targeted therapy of TSCC.However,inadequate accumulation of photosensitizers at the tumor site diminishes the efficacy of photothermal therapy(PTT).This study modified gold nanodots(AuNDs)with the TSCC-targeting peptide HN-1 to improve the selectivity and therapeutic effects of PTT.The Au-HN-1 nanosystem effectively targeted the TSCC cells and was rapidly delivered to the tumor tissues compared to the AuN Ds.The enhanced accumulation of photosensitizing agents at tumor sites achieved significant PTT effects in a mouse model of TSCC.Moreover,owing to its stable long-term fluorescence and high X-ray attenuation coefficient,the Au-HN-1 nanosystem can be used for fluorescence and computed tomography imaging of TSCC,rendering it useful for early tumor detection and accurate delineation of surgical margins.In conclusion,Au-HN-1 represents a promising nanomedicine for imaging-based diagnosis and targeted PTT of TSCC.
