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
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
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
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
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: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
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
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
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
Background: Aging-induced cardiac hypertrophy and reduced skeletal muscle strength contribute to increased disease risk and life burden in the elderly. FNDC5 acts as a protective muscle factor in both cardiac and skel...Background: Aging-induced cardiac hypertrophy and reduced skeletal muscle strength contribute to increased disease risk and life burden in the elderly. FNDC5 acts as a protective muscle factor in both cardiac and skeletal muscle. This study aims to examine the relationship between cardiac FNDC5 and aging-related cardiac hypertrophy and decreased skeletal muscle strength. Methods: Male young C57BL/6 mice (5 months old, n = 6) and aged mice (21 months old, n = 6) were utilized in the study and housed in a specific pathogen-free (SPF) environment. Prior to the experiment, grip strength tests were performed on the mice, and heart tissues were collected for morphological analysis, including the assessment of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and fibronectin type III-containing structural domain 5 (FNDC5) protein levels. Furthermore, myosin heavy chain II (MyHC II), skeletal muscle-specific transcription factor (MyoD), muscle RING-finger protein-1 (MuRF1), and FNDC5 levels were evaluated in the quadriceps muscle. The correlations between heart weight and FNDC5 expression levels, as well as skeletal muscle indices in the mice, were subsequently analyzed. Result: Aging leads to cardiac hypertrophy and reduced expression of PGC-1α and FNDC5 proteins. Concurrently, there is a decline in the strength of skeletal muscle, along with decreased expression of MyHC II and increased expression of MURF1 and MyoD. Correlation analysis demonstrated strong positive associations between myocardial FNDC5 protein levels and limb grip strength, as well as MyHC II, and strong negative associations with MyoD and MuRF1. Conclusion: There may be a significant association between aging-induced cardiac hypertrophy and decreased skeletal muscle strength, with FNDC5 potentially playing a crucial role as a regulatory molecule facilitating communication between the heart and skeletal muscle.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
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
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
This study explores how the performance of triboelectric nanogenerators can be enhanced by incorporating Fe_(3)O_(4) nanoparticles into nylon films using a spray coating technique.Five triboelectric nanogenerator prot...This study explores how the performance of triboelectric nanogenerators can be enhanced by incorporating Fe_(3)O_(4) nanoparticles into nylon films using a spray coating technique.Five triboelectric nanogenerator prototypes were created:one with regular nylon and four with nylon/Fe_(3)O_(4) nanocomposites featuring varying nanoparticle densities.The electrical output,measured by open-circuit voltage and short-circuit current,showed significant improvements in the nanocomposite-based triboelectric nanogenerators compared to the nylon-only triboelectric nanogenerator.When a weak magnetic field was applied during nanocomposite preparation,the maximum voltage and current reached 56.3 V and 4.62μA,respectively.Further analysis revealed that the magnetic field during the drying process aligned the magnetic domains,boosting output efficiency.These findings demonstrate the potential of Fe_(3)O_(4) nanoparticles to enhance electrostatic and magnetic interactions in triboelectric nanogenerators,leading to improved energy-harvesting performance.This approach presents a promising strategy for developing high-performance triboelectric nanogenerators for sustainable energy and sensor applications.展开更多
To investigate the impact of preoperative serum follicle-stimulating hormone(FSH)levels on the probability of testicular sperm retrieval,we conducted a study of nonobstructive azoospermic(NOA)men with different testic...To investigate the impact of preoperative serum follicle-stimulating hormone(FSH)levels on the probability of testicular sperm retrieval,we conducted a study of nonobstructive azoospermic(NOA)men with different testicular volumes(TVs)who underwent microdissection testicular sperm extraction(micro-TESE).A total of 177 NOA patients undergoing micro-TESE for the first time from April 2019 to November 2022 in Shenzhen Zhongshan Obstetrics and Gynecology Hospital(formerly Shenzhen Zhongshan Urology Hospital,Shenzhen,China)were retrospectively reviewed.The subjects were divided into four groups based on average TV quartiles.Serum hormone levels in each TV group were compared between positive and negative sperm retrieval subgroups.Overall sperm retrieval rate was 57.6%.FSH levels(median[interquartile range])were higher in the positive sperm retrieval subgroup compared with the negative outcome subgroup when average TV was<5 ml(first quartile[Q1:TV<3 ml]:43.32[17.92]IU l^(−1) vs 32.95[18.56]IU l−1,P=0.048;second quartile[Q2:3 ml≤TV<5 ml]:31.31[15.37]IU l^(−1) vs 25.59[18.40]IU l^(−1),P=0.042).Elevated serum FSH levels were associated with successful micro-TESE sperm retrieval in NOA men whose average TVs were<5 ml(adjusted odds ratio[OR]:1.06 per unit increase;95%confidence interval[CI]:1.01–1.11;P=0.011).In men with TVs≥5 ml,larger TVs were associated with lower odds of sperm retrieval(adjusted OR:0.84 per 1 ml increase;95%CI:0.71–0.98;P=0.029).In conclusion,elevated serum FSH levels were associated with positive sperm retrieval in micro-TESE in NOA men with TVs<5 ml.In men with TV≥5 ml,increases in average TVs were associated with lower odds of sperm retrieval.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
Background:Triple-negative(TN)breast cancer,the most aggressive subtype of breast cancer,is usually treated with high doses of paclitaxel(PX),which induces resistance.To prevent this adverse effect,metronomic chemothe...Background:Triple-negative(TN)breast cancer,the most aggressive subtype of breast cancer,is usually treated with high doses of paclitaxel(PX),which induces resistance.To prevent this adverse effect,metronomic chemotherapy based on administering low doses of PX plus carbachol(Carb),a muscarinic acetylcholine receptor(mAChR)agonist,has emerged as an alternative.Other acetylcholine receptors also present in breast tissue are nicotinic ones.When activated by nicotine(Nic),these receptors can decrease the effectiveness of conventional chemotherapy.However,whether metronomic chemotherapy with PX and Carb is affected by Nic has not yet been described.This study aimed to determine the efficacy of metronomic chemotherapy with PX and Carb in human breast tumor MDA-MB-231 cells in the presence or absence of Nic and assess the intermediaries involved.Methods:Cell viability and proliferation were determined using colorimetric assays with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and trypan blue.Nitrite levels in cell supernatant were determined using Griess reagent.The expression of proteins was determined by western blot assays.Apoptosis/necrosis and the proportion of cancer stem cells(CSC)were determined by flow cytometry.Mammosphere-forming units were determined with anchorage-free growth assays.Results:The metronomic chemotherapy combining PX and Carb effectively inhibited the viability of TN MDA-MB-231 cells in the presence and absence of Nic.These effects were mediated by the activation of mAChRs,triggering signaling pathways dependent on several kinases.These mediators induce increased expression of the inducible isoform of nitric oxide synthase(NOS).Only the inducible and endothelial isoforms were expressed in these cells,and their activity was increased by the metronomic chemotherapy with PX and Carb.Nitric oxide(NO),a product of NOS activity,may contribute to the observed increase in apoptosis.We also observed an increased sensitivity to PX in the residual cells after the metronomic chemotherapy,as well as a decrease in mammosphere-forming units and CSC proportion.We also determined a decrease in the expression of stemness proteins such as ATP-binding cassette super-family G member 2(ABCG2),sex-determining region Y-box 2(SOX2),octamer-binding transcription factor 4(OCT-4),and Nanog.Conclusions:Metronomic chemotherapy combining PX with Carb was selective for MDA-MB-231 cells and increased their sensitivity to conventional chemotherapy in the presence and absence of Nic,indicating that it could be a useful neoadjuvant strategy for the treatment of TN breast tumors.展开更多
Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice...Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice enter puberty only 4–5 days earlier than normal mice),the related research is limited.Methods:Therefore,the MKRN3-modified rabbit was developed using CRISPR(clus-tered regularly interspaced short palindromic repeats)gene editing technology.The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.Results:The first estrus of MKRN3-modified female rabbits was observed~27 days earlier than that of wild-type female rabbits,with a typical CPP phenotype.This study found increased gonadotropin releasing hormone(GnRH)and decreased gonadotropin inhibiting hormone(GnIH)in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation.Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation,it found some differentially expressed genes and potential pathways through transcriptome sequencing.Conclusions:This study established a novel CPP model:paternal MKRN3 gene-modified rabbit.It is hoped that the establishment of this model will help researchers better understand,treat,and prevent CPP in the future.展开更多
Autophagy plays a pivotal role in the development and resolution of sepsis-induced acute respiratory distress syndrome(S-ARDS),a critical condition characterized by severe inflammation,oxidative stress,apoptosis,and i...Autophagy plays a pivotal role in the development and resolution of sepsis-induced acute respiratory distress syndrome(S-ARDS),a critical condition characterized by severe inflammation,oxidative stress,apoptosis,and immune dysfunction.Traditional Chinese medicine(TCM)has emerged as a promising complementary therapy that modulates autophagy-related pathways.This review summarizes recent advances in understanding how TCM regulates autophagy to alleviate S-ARDS pathology.We highlight the mechanisms by which TCM influences autophagy to modulate inflammation,redox balance,programmed cell death,and immune responses.The integration of historical wisdom and modern molecular insights offers new therapeutic directions for S-ARDS treatment.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.
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 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 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.
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 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 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.
文摘Background: Aging-induced cardiac hypertrophy and reduced skeletal muscle strength contribute to increased disease risk and life burden in the elderly. FNDC5 acts as a protective muscle factor in both cardiac and skeletal muscle. This study aims to examine the relationship between cardiac FNDC5 and aging-related cardiac hypertrophy and decreased skeletal muscle strength. Methods: Male young C57BL/6 mice (5 months old, n = 6) and aged mice (21 months old, n = 6) were utilized in the study and housed in a specific pathogen-free (SPF) environment. Prior to the experiment, grip strength tests were performed on the mice, and heart tissues were collected for morphological analysis, including the assessment of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and fibronectin type III-containing structural domain 5 (FNDC5) protein levels. Furthermore, myosin heavy chain II (MyHC II), skeletal muscle-specific transcription factor (MyoD), muscle RING-finger protein-1 (MuRF1), and FNDC5 levels were evaluated in the quadriceps muscle. The correlations between heart weight and FNDC5 expression levels, as well as skeletal muscle indices in the mice, were subsequently analyzed. Result: Aging leads to cardiac hypertrophy and reduced expression of PGC-1α and FNDC5 proteins. Concurrently, there is a decline in the strength of skeletal muscle, along with decreased expression of MyHC II and increased expression of MURF1 and MyoD. Correlation analysis demonstrated strong positive associations between myocardial FNDC5 protein levels and limb grip strength, as well as MyHC II, and strong negative associations with MyoD and MuRF1. Conclusion: There may be a significant association between aging-induced cardiac hypertrophy and decreased skeletal muscle strength, with FNDC5 potentially playing a crucial role as a regulatory molecule facilitating communication between the heart and skeletal muscle.
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 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This study explores how the performance of triboelectric nanogenerators can be enhanced by incorporating Fe_(3)O_(4) nanoparticles into nylon films using a spray coating technique.Five triboelectric nanogenerator prototypes were created:one with regular nylon and four with nylon/Fe_(3)O_(4) nanocomposites featuring varying nanoparticle densities.The electrical output,measured by open-circuit voltage and short-circuit current,showed significant improvements in the nanocomposite-based triboelectric nanogenerators compared to the nylon-only triboelectric nanogenerator.When a weak magnetic field was applied during nanocomposite preparation,the maximum voltage and current reached 56.3 V and 4.62μA,respectively.Further analysis revealed that the magnetic field during the drying process aligned the magnetic domains,boosting output efficiency.These findings demonstrate the potential of Fe_(3)O_(4) nanoparticles to enhance electrostatic and magnetic interactions in triboelectric nanogenerators,leading to improved energy-harvesting performance.This approach presents a promising strategy for developing high-performance triboelectric nanogenerators for sustainable energy and sensor applications.
基金supported by the Shenzhen Fundamental Research Program(No.JCYJ20210324121807021).
文摘To investigate the impact of preoperative serum follicle-stimulating hormone(FSH)levels on the probability of testicular sperm retrieval,we conducted a study of nonobstructive azoospermic(NOA)men with different testicular volumes(TVs)who underwent microdissection testicular sperm extraction(micro-TESE).A total of 177 NOA patients undergoing micro-TESE for the first time from April 2019 to November 2022 in Shenzhen Zhongshan Obstetrics and Gynecology Hospital(formerly Shenzhen Zhongshan Urology Hospital,Shenzhen,China)were retrospectively reviewed.The subjects were divided into four groups based on average TV quartiles.Serum hormone levels in each TV group were compared between positive and negative sperm retrieval subgroups.Overall sperm retrieval rate was 57.6%.FSH levels(median[interquartile range])were higher in the positive sperm retrieval subgroup compared with the negative outcome subgroup when average TV was<5 ml(first quartile[Q1:TV<3 ml]:43.32[17.92]IU l^(−1) vs 32.95[18.56]IU l−1,P=0.048;second quartile[Q2:3 ml≤TV<5 ml]:31.31[15.37]IU l^(−1) vs 25.59[18.40]IU l^(−1),P=0.042).Elevated serum FSH levels were associated with successful micro-TESE sperm retrieval in NOA men whose average TVs were<5 ml(adjusted odds ratio[OR]:1.06 per unit increase;95%confidence interval[CI]:1.01–1.11;P=0.011).In men with TVs≥5 ml,larger TVs were associated with lower odds of sperm retrieval(adjusted OR:0.84 per 1 ml increase;95%CI:0.71–0.98;P=0.029).In conclusion,elevated serum FSH levels were associated with positive sperm retrieval in micro-TESE in NOA men with TVs<5 ml.In men with TV≥5 ml,increases in average TVs were associated with lower odds of sperm retrieval.
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the National Agency for Scientific and Technological Promotion(ANPCyT)[2015-2396]ORT Argentina’s 2021-2025 Scientific Research Internship Program.
文摘Background:Triple-negative(TN)breast cancer,the most aggressive subtype of breast cancer,is usually treated with high doses of paclitaxel(PX),which induces resistance.To prevent this adverse effect,metronomic chemotherapy based on administering low doses of PX plus carbachol(Carb),a muscarinic acetylcholine receptor(mAChR)agonist,has emerged as an alternative.Other acetylcholine receptors also present in breast tissue are nicotinic ones.When activated by nicotine(Nic),these receptors can decrease the effectiveness of conventional chemotherapy.However,whether metronomic chemotherapy with PX and Carb is affected by Nic has not yet been described.This study aimed to determine the efficacy of metronomic chemotherapy with PX and Carb in human breast tumor MDA-MB-231 cells in the presence or absence of Nic and assess the intermediaries involved.Methods:Cell viability and proliferation were determined using colorimetric assays with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and trypan blue.Nitrite levels in cell supernatant were determined using Griess reagent.The expression of proteins was determined by western blot assays.Apoptosis/necrosis and the proportion of cancer stem cells(CSC)were determined by flow cytometry.Mammosphere-forming units were determined with anchorage-free growth assays.Results:The metronomic chemotherapy combining PX and Carb effectively inhibited the viability of TN MDA-MB-231 cells in the presence and absence of Nic.These effects were mediated by the activation of mAChRs,triggering signaling pathways dependent on several kinases.These mediators induce increased expression of the inducible isoform of nitric oxide synthase(NOS).Only the inducible and endothelial isoforms were expressed in these cells,and their activity was increased by the metronomic chemotherapy with PX and Carb.Nitric oxide(NO),a product of NOS activity,may contribute to the observed increase in apoptosis.We also observed an increased sensitivity to PX in the residual cells after the metronomic chemotherapy,as well as a decrease in mammosphere-forming units and CSC proportion.We also determined a decrease in the expression of stemness proteins such as ATP-binding cassette super-family G member 2(ABCG2),sex-determining region Y-box 2(SOX2),octamer-binding transcription factor 4(OCT-4),and Nanog.Conclusions:Metronomic chemotherapy combining PX with Carb was selective for MDA-MB-231 cells and increased their sensitivity to conventional chemotherapy in the presence and absence of Nic,indicating that it could be a useful neoadjuvant strategy for the treatment of TN breast tumors.
基金National Natural Science Foundation of China,Grant/Award Number:82101937Guangdong Medical Science and Technology Research Fund Project,China,Grant/Award Number:B2024069Guangzhou Science and Technology Plan Project,China,Grant/Award Number:2024A04J4923 and SL2023A04J02229。
文摘Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice enter puberty only 4–5 days earlier than normal mice),the related research is limited.Methods:Therefore,the MKRN3-modified rabbit was developed using CRISPR(clus-tered regularly interspaced short palindromic repeats)gene editing technology.The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.Results:The first estrus of MKRN3-modified female rabbits was observed~27 days earlier than that of wild-type female rabbits,with a typical CPP phenotype.This study found increased gonadotropin releasing hormone(GnRH)and decreased gonadotropin inhibiting hormone(GnIH)in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation.Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation,it found some differentially expressed genes and potential pathways through transcriptome sequencing.Conclusions:This study established a novel CPP model:paternal MKRN3 gene-modified rabbit.It is hoped that the establishment of this model will help researchers better understand,treat,and prevent CPP in the future.
基金supported by the National Natural Science Foundation of China(82102311)Peking Union Medical Foundation-Rui E(Rui Yi)Emergency Medicine Research Special Fund(22222012001)+2 种基金Xuzhou Municipal Health Commission Medical Science and Technology Innovation Project(XWKYHT20240080)Xuzhou Medical University Affiliated Hospital Science and Technology Development Fund(XYFY202402)Translational Medicine Foundation from Jiangsu Society of Research Hospital(SYHKJ-XF-2025-22).
文摘Autophagy plays a pivotal role in the development and resolution of sepsis-induced acute respiratory distress syndrome(S-ARDS),a critical condition characterized by severe inflammation,oxidative stress,apoptosis,and immune dysfunction.Traditional Chinese medicine(TCM)has emerged as a promising complementary therapy that modulates autophagy-related pathways.This review summarizes recent advances in understanding how TCM regulates autophagy to alleviate S-ARDS pathology.We highlight the mechanisms by which TCM influences autophagy to modulate inflammation,redox balance,programmed cell death,and immune responses.The integration of historical wisdom and modern molecular insights offers new therapeutic directions for S-ARDS treatment.
