Neurodegenerative diseases,such as Alzheimer’s disease and Parkinson’s disease,are associated with cognitive impairment and impaired brain glucose metabolism,posing significant challenges for the public health.We pr...Neurodegenerative diseases,such as Alzheimer’s disease and Parkinson’s disease,are associated with cognitive impairment and impaired brain glucose metabolism,posing significant challenges for the public health.We previously demonstrated that cyanidin 3-O-β-galactoside(Cy3Gal)from black chokeberry alleviated cognitive impairment in aging mice through regulating brain energy metabolism in a direct way.However,the indirect mechanisms in mitigating brain glucose hypometabolism remain underexplored.Here,we utilized a bilaterally intracerebroventricular injection of streptozotocin(ICV/STZ,3 mg/kg bw)-induced brain glucose hypometabolism model to investigate the effects of Cy3Gal on cognitive impairment alleviation.Our findings revealed that Cy3Gal administration significantly improved memory deficit and cognitive impairment in ICV/STZ-administrated mice.Subsequently,Cy3Gal showed excellent abilities in inhibiting astrocyte overactivation,regulating neurotransmitters metabolism,and promoting synaptic plasticity.Furthermore,Cy3Gal enhanced brain glucose metabolism by improving glycolysis and the TCA cycle.Additionally,Cy3Gal modulated levels of gut microbiota-derived metabolites,including acetate,butyrate,histidine,glutamine,serine,valine and isoleucine,which were closely linked to brain glucose metabolism.The in vitro results further demonstrated that these metabolites played an important role in the neuron-astrocyte energy metabolism,which accounted for the alleviation of glucose hypometabolism.Overall,our findings suggest that Cy3Gal mitigates ICV/STZ-induced cognitive impairment by modulating gut microbiota-derived short-chain fatty acids and amino acids,which in turn improves brain glucose metabolism.展开更多
The fluorination strategy has been proven effective in significantly enhancing the photovoltaic performance of organic solar cells(OSCs) based on non-fused ring electron acceptors(NFREAs).However,research on the impac...The fluorination strategy has been proven effective in significantly enhancing the photovoltaic performance of organic solar cells(OSCs) based on non-fused ring electron acceptors(NFREAs).However,research on the impact of fluorination positions at side chains on NFREAs device performance remains scant.In this study,we introduce two isomeric NFREAs,designated as GA-2F-E and GA-2F,distinguished by their fluorination positions at the side chains.Both NFREAs share a thiophene[3,2-b]thiophene core,but their side chains differ:GA-2F-E features two(4-butylphenyl)-N-(4-fluorophenyl) amino groups,whereas GA-2F's side chains consist of bis(4-fluorophenyl)amino and bis(4-butylphenyl)amino groups attached to opposite sides of the core.To delve into the influence of fluorination positions on the optoelectronic properties,aggregation behavior,and overall efficiency of the acceptor molecules,a comprehensive investigation was conducted.The findings reveal that,despite similar photophysical properties and comparable absorption bandwidths,GA-2F-E,with fluorine atoms positioned on both sides of the molecular framework,demonstrates more compact π-π stacking,reduced bimolecular recombination,superior exciton transport,and a more balanced,higher mobility.As a result of these advantages,OSCs optimized with D18:GA-2F-E achieve a remarkable power conversion efficiency(PCE) of 16.45 %,surpassing the 15.83 %PCE of devices utilizing D18:GA-2F.This research underscores the potential of NFREAs in future applications and highlights the significance of fluorination positions in enhancing OSC performance,paving the way for the development of more efficient NFREAs.展开更多
Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord inj...Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.展开更多
AIM： To explore the expression of p53, bcl-2, bax, survivin and the cell apoptosis during the development of tree shrew hepatocellular carcinoma （HCC）, the relationship between expression of these genes, its impact...AIM： To explore the expression of p53, bcl-2, bax, survivin and the cell apoptosis during the development of tree shrew hepatocellular carcinoma （HCC）, the relationship between expression of these genes, its impact on HCC development, and its relation to cell apoptosis. METHODS： Tree shrew HCC was induced with aflatoxin B1 （AFB1）, and regular biopsy of liver tissues was carried out and the biopsy tissues were collected during cancer inducement. Liver biopsy tissue and HCC tissue were collected from 35 pre-cancerous experimental animals at wk 30 and 60 and at the 30^th, 60^th, and 90^th -wk. Liver biopsy tissues were collected from 13 blank control animals at wk 30, 60, and 90. Expression of p53, bcl-2, bax, and survivin at each stage was examined by immunohistochemistry method. Apoptotic cells were detected in situ by the terminal deoxynucleotidyl transferase-mediated nick end labeling （TUNEL） technique. RESULTS： The apoptosis rate of normal hepatic cells was extremely low, whereas it increased during the formation of HCC. Expression of the apoptosis-related genes p53, bcl-2, bax, and survivin during the formation of HCC presented an increasing tendency. Expression of p53 did not noticeably relate to that of bcl-2, bax, and survivin, whereas expression of bcl-2 and bax was closely related. In HCC, p53 did not present a distinct relation to cell apoptosis, whereas its high level expression was probably related to liver cell proliferation. Survivin negatively correlated apoptosis index, and its overexpression could inhibit cell apoptosis. CONCLUSION： Apoptosis-related genes p53, bcl-2, bax, and survivin are all related to the occurrence of HCC. The anti-apoptosis effect of bcl-2 is influenced by bax, and ratio bcl/bax reflects more correctly the extent of cell apoptosis.展开更多
Backgroud Efficient communication between the embryo and the endometrium is essential for the successful establishment and maintenance of pregnancy.Uterine-derived extracellular vesicles(EVs)contribute to embryomatern...Backgroud Efficient communication between the embryo and the endometrium is essential for the successful establishment and maintenance of pregnancy.Uterine-derived extracellular vesicles(EVs)contribute to embryomaternal communication,supporting early embryonic development.This study aimed to:(i)compare the protein cargo of uterine fluid EVs(UF-EVs)from CYCLIC and PREGNANT heifers;(ii)characterize the protein profile of conditioned medium(CM)-EVs from endometrial explants cultured alone(EXPL)or co-cultured with five d 7 blastocysts(EXPL+EMB)in vitro;and(iii)compare the EV protein cargo between the in vivo and in vitro models(i.e.,EXPL vs.CYCLIC and EXPL+EMB vs.PREGNANT).Results We identified 1,459 and 1,752 proteins in the UF-EVs of CYCLIC and PREGNANT heifers,respectively.Among these,12 were exclusive to CYCLIC,and 18 were exclusive to PREGNANT.Among the 1,329 proteins identified in both groups,16 were differently abundant;ten were more abundant,and six were less abundant in UF-EVs from PREGNANT heifers.In vivo,the changes in UF-EV protein cargo induced by the presence of a blastocyst were related to inflammatory and immune responses,endometrial receptivity,and support of early embryonic development by promoting cell polarity,cell–cell adhesion,and stem cell differentiation.In vitro,we identified 1,501 proteins in the CM-EVs from EXPL,1,975 in the CM-EVs from EXPL+EMB,and 82 in the CM-EVs from EMB.Additionally,50 proteins were unique to EXPL+EMB,and another 33 were differentially abundant due to the synergistic interaction between the embryo and the endometrium.These proteins are involved in embryonic development,regulation of stem cell differentiation,establishment and maintenance of cell polarity,interferon tau(IFNT)-mediated cell signaling,endometrial receptivity,and immune modulation.Although there are qualitative and quantitative differences between in vivo and in vitro-derived EVs,UF-EVs from CYCLIC heifers compared to CM-EVs from EXPL,as well as UFEVs from PREGNANT heifers compared to CM-EVs from EXPL+EMB shared common proteins.Conclusions These findings highlight the pivotal role of EVs in embryo-maternal communication,suggesting that their protein cargo may actively contribute to the modulation of the uterine environment to support early embryonic development.Understanding these molecular interactions could provide valuable insights into the mechanisms of implantation and pregnancy establishment.展开更多
Radiotherapy(RT)is considered a standard cancer treatment that directly kills tumor cells and promotes a systemic immune response.However,RT may also lead to tumor hypoxia,which further inhibits the antigen-presenting...Radiotherapy(RT)is considered a standard cancer treatment that directly kills tumor cells and promotes a systemic immune response.However,RT may also lead to tumor hypoxia,which further inhibits the antigen-presenting function of dendritic cells(DCs)and thereby weakens the systemic anti-tumor immune response induced by radiotherapy.In this study,the oxygen-loaded in situ gels carrying bacterial outer membrane(MOGel)were synthesized.As the gels slowly degraded,oxygen was gradually released to alleviate tumor hypoxia.The released bacterial outer membrane(OM)continuously activated DCs,enhancing their antigenpresenting capability.The results demonstrated that MOGel combined with RT induced the strongest tumor cell apoptosis in vitro and achieved a 80%tumor suppression rate in a colon cancer orthotopic model.Importantly,MOGel+RT induced an enhanced abscopal effect,and hypoxia and enhanced DCs activation contributed to the systemic immune response.Thus,OM-based oxygen gels may offer a novel strategy for enhancing the systemic immune response to RT.展开更多
Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control(MQC)on the aged brain.Adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)signaling responsiven...Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control(MQC)on the aged brain.Adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)signaling responsiveness declines with aging.However,whether AMPK plays a role in the exercise-mediated improvement of memory and MQC in the aged hippocampus remains to be established.5-Aminoimidazole 4-carboxamide ribonucleoside(AICAR),a pharmacological agonist of AMPK,has been proposed to be an exercise mimetic recently.However,it has not been clarified whether AICAR could mimic the effects of exercise on the aged hippocampus through improvement of MQC.In this study,AICAR(AMPK agonist)and Compound C(AMPK inhibitor)were used to investigate if AMPK plays a key role in exercise-induced improvement of MQC and if AICAR could act as an exercise mimetic through improvement of MQC in aged hippocampus.Both exercise and AICAR improved the memory of aged mice and increased AMPK phosphorylation in the aged hippocampus.Exercise,but not AICAR,improved mitochondrial respiratory function in the aged hippocampus and increased the microtubule associated protein 1 light chain 3(LC3)-II/LC3-I ratio and the protein expression of LC3-II and autophagy related protein 7(ATG7)in the lysate of whole hippocampal tissue.Both exercise and AICAR increased the ratio of LC3-II/LC3-I and the protein expression of LC3-II in the mitochondrial fractions of the hippocampus.Regarding mitochondrial dynamics,neither exercise training nor AICAR changed the protein level of mitofusin 2(Mfn2).Exercise,but not AICAR,increased the protein level of dynamin-related protein 1(Drp1).Furthermore,both exercise training and AICAR increased the protein level of peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),a modulator of mitochondrial biogenesis.Compound C abolished the exercise-induced effects on memory in aged mice,AMPK phosphorylation,autophagy,mitophagy,and mitochondrial fission in the aged hippocampus.However,Compound C did not reverse the exercise-induced increase in PGC-1αprotein levels in the aged hippocampus.Our data provide evidence that AMPK plays an important role in the exercise-induced improvement of memory and MQC in the hippocampus of aged mice.Importantly,we demonstrated for the first time that AICAR could partially mimetic the beneficial effects of endurance exercise on memory and MQC in the hippocampus of aged mice,and thus may be a promising exercise mimetic for counteracting brain aging.展开更多
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
Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society bec...Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society because of the ethical issue. This paper takes Wenzhou Medical University as an example to give a brief introduction to the ethical review about laboratory animals in the university so as to further draw attention and concerns from the public about the ethical issue of laboratory animals. We successively introduce its scientific projects, nurturing environment and ethical review of laboratory animals.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
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: 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
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
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
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
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
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
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supported by the National Natural Science Foundation of China(32172210)the Shandong Provincial Natural Science Foundation(ZR2025QC295).
文摘Neurodegenerative diseases,such as Alzheimer’s disease and Parkinson’s disease,are associated with cognitive impairment and impaired brain glucose metabolism,posing significant challenges for the public health.We previously demonstrated that cyanidin 3-O-β-galactoside(Cy3Gal)from black chokeberry alleviated cognitive impairment in aging mice through regulating brain energy metabolism in a direct way.However,the indirect mechanisms in mitigating brain glucose hypometabolism remain underexplored.Here,we utilized a bilaterally intracerebroventricular injection of streptozotocin(ICV/STZ,3 mg/kg bw)-induced brain glucose hypometabolism model to investigate the effects of Cy3Gal on cognitive impairment alleviation.Our findings revealed that Cy3Gal administration significantly improved memory deficit and cognitive impairment in ICV/STZ-administrated mice.Subsequently,Cy3Gal showed excellent abilities in inhibiting astrocyte overactivation,regulating neurotransmitters metabolism,and promoting synaptic plasticity.Furthermore,Cy3Gal enhanced brain glucose metabolism by improving glycolysis and the TCA cycle.Additionally,Cy3Gal modulated levels of gut microbiota-derived metabolites,including acetate,butyrate,histidine,glutamine,serine,valine and isoleucine,which were closely linked to brain glucose metabolism.The in vitro results further demonstrated that these metabolites played an important role in the neuron-astrocyte energy metabolism,which accounted for the alleviation of glucose hypometabolism.Overall,our findings suggest that Cy3Gal mitigates ICV/STZ-induced cognitive impairment by modulating gut microbiota-derived short-chain fatty acids and amino acids,which in turn improves brain glucose metabolism.
基金financially supported by the National Natural Science Foundation of China (Nos.22375024,21975031,51933001,and 21734009)。
文摘The fluorination strategy has been proven effective in significantly enhancing the photovoltaic performance of organic solar cells(OSCs) based on non-fused ring electron acceptors(NFREAs).However,research on the impact of fluorination positions at side chains on NFREAs device performance remains scant.In this study,we introduce two isomeric NFREAs,designated as GA-2F-E and GA-2F,distinguished by their fluorination positions at the side chains.Both NFREAs share a thiophene[3,2-b]thiophene core,but their side chains differ:GA-2F-E features two(4-butylphenyl)-N-(4-fluorophenyl) amino groups,whereas GA-2F's side chains consist of bis(4-fluorophenyl)amino and bis(4-butylphenyl)amino groups attached to opposite sides of the core.To delve into the influence of fluorination positions on the optoelectronic properties,aggregation behavior,and overall efficiency of the acceptor molecules,a comprehensive investigation was conducted.The findings reveal that,despite similar photophysical properties and comparable absorption bandwidths,GA-2F-E,with fluorine atoms positioned on both sides of the molecular framework,demonstrates more compact π-π stacking,reduced bimolecular recombination,superior exciton transport,and a more balanced,higher mobility.As a result of these advantages,OSCs optimized with D18:GA-2F-E achieve a remarkable power conversion efficiency(PCE) of 16.45 %,surpassing the 15.83 %PCE of devices utilizing D18:GA-2F.This research underscores the potential of NFREAs in future applications and highlights the significance of fluorination positions in enhancing OSC performance,paving the way for the development of more efficient NFREAs.
基金funded by the National Natural Science Foundation of China,No.82271395(to GL),the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030073(to GL)the grants from University of Macao Research Committee,China,No.MYRG2022-00074-ICMS(to CTV)Guangzhou Science and Technology Program Project,No.2025A04J4740(to GL).
文摘Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.
基金Supported by the Science and Technology Department of Guangxi,No. 0143058,No. 0144002The National Natural Science Foundation of China, No. 39860072
文摘AIM： To explore the expression of p53, bcl-2, bax, survivin and the cell apoptosis during the development of tree shrew hepatocellular carcinoma （HCC）, the relationship between expression of these genes, its impact on HCC development, and its relation to cell apoptosis. METHODS： Tree shrew HCC was induced with aflatoxin B1 （AFB1）, and regular biopsy of liver tissues was carried out and the biopsy tissues were collected during cancer inducement. Liver biopsy tissue and HCC tissue were collected from 35 pre-cancerous experimental animals at wk 30 and 60 and at the 30^th, 60^th, and 90^th -wk. Liver biopsy tissues were collected from 13 blank control animals at wk 30, 60, and 90. Expression of p53, bcl-2, bax, and survivin at each stage was examined by immunohistochemistry method. Apoptotic cells were detected in situ by the terminal deoxynucleotidyl transferase-mediated nick end labeling （TUNEL） technique. RESULTS： The apoptosis rate of normal hepatic cells was extremely low, whereas it increased during the formation of HCC. Expression of the apoptosis-related genes p53, bcl-2, bax, and survivin during the formation of HCC presented an increasing tendency. Expression of p53 did not noticeably relate to that of bcl-2, bax, and survivin, whereas expression of bcl-2 and bax was closely related. In HCC, p53 did not present a distinct relation to cell apoptosis, whereas its high level expression was probably related to liver cell proliferation. Survivin negatively correlated apoptosis index, and its overexpression could inhibit cell apoptosis. CONCLUSION： Apoptosis-related genes p53, bcl-2, bax, and survivin are all related to the occurrence of HCC. The anti-apoptosis effect of bcl-2 is influenced by bax, and ratio bcl/bax reflects more correctly the extent of cell apoptosis.
基金supported by research projects:PID2019-111641RB-I00 and PID2023-149027OB-I00 funded by MCIN/AEI/10.13039/501100011033/to DR and PRE2020-094452 to RM。
文摘Backgroud Efficient communication between the embryo and the endometrium is essential for the successful establishment and maintenance of pregnancy.Uterine-derived extracellular vesicles(EVs)contribute to embryomaternal communication,supporting early embryonic development.This study aimed to:(i)compare the protein cargo of uterine fluid EVs(UF-EVs)from CYCLIC and PREGNANT heifers;(ii)characterize the protein profile of conditioned medium(CM)-EVs from endometrial explants cultured alone(EXPL)or co-cultured with five d 7 blastocysts(EXPL+EMB)in vitro;and(iii)compare the EV protein cargo between the in vivo and in vitro models(i.e.,EXPL vs.CYCLIC and EXPL+EMB vs.PREGNANT).Results We identified 1,459 and 1,752 proteins in the UF-EVs of CYCLIC and PREGNANT heifers,respectively.Among these,12 were exclusive to CYCLIC,and 18 were exclusive to PREGNANT.Among the 1,329 proteins identified in both groups,16 were differently abundant;ten were more abundant,and six were less abundant in UF-EVs from PREGNANT heifers.In vivo,the changes in UF-EV protein cargo induced by the presence of a blastocyst were related to inflammatory and immune responses,endometrial receptivity,and support of early embryonic development by promoting cell polarity,cell–cell adhesion,and stem cell differentiation.In vitro,we identified 1,501 proteins in the CM-EVs from EXPL,1,975 in the CM-EVs from EXPL+EMB,and 82 in the CM-EVs from EMB.Additionally,50 proteins were unique to EXPL+EMB,and another 33 were differentially abundant due to the synergistic interaction between the embryo and the endometrium.These proteins are involved in embryonic development,regulation of stem cell differentiation,establishment and maintenance of cell polarity,interferon tau(IFNT)-mediated cell signaling,endometrial receptivity,and immune modulation.Although there are qualitative and quantitative differences between in vivo and in vitro-derived EVs,UF-EVs from CYCLIC heifers compared to CM-EVs from EXPL,as well as UFEVs from PREGNANT heifers compared to CM-EVs from EXPL+EMB shared common proteins.Conclusions These findings highlight the pivotal role of EVs in embryo-maternal communication,suggesting that their protein cargo may actively contribute to the modulation of the uterine environment to support early embryonic development.Understanding these molecular interactions could provide valuable insights into the mechanisms of implantation and pregnancy establishment.
基金supported by the National Key R&D Program of China(2022YFC3401600)the National Natural Science Foun-dation of China(32530061 and 32171372)+1 种基金the Science and Technology Projects of Xizang Autonomous Region,China(XZ202202YD0029C)the Fundamental Research Funds for the Central Universities(KG202511)。
文摘Radiotherapy(RT)is considered a standard cancer treatment that directly kills tumor cells and promotes a systemic immune response.However,RT may also lead to tumor hypoxia,which further inhibits the antigen-presenting function of dendritic cells(DCs)and thereby weakens the systemic anti-tumor immune response induced by radiotherapy.In this study,the oxygen-loaded in situ gels carrying bacterial outer membrane(MOGel)were synthesized.As the gels slowly degraded,oxygen was gradually released to alleviate tumor hypoxia.The released bacterial outer membrane(OM)continuously activated DCs,enhancing their antigenpresenting capability.The results demonstrated that MOGel combined with RT induced the strongest tumor cell apoptosis in vitro and achieved a 80%tumor suppression rate in a colon cancer orthotopic model.Importantly,MOGel+RT induced an enhanced abscopal effect,and hypoxia and enhanced DCs activation contributed to the systemic immune response.Thus,OM-based oxygen gels may offer a novel strategy for enhancing the systemic immune response to RT.
基金supported by grants from the National Natural Science Foundation of China(81301128,81771500,82202789,82205065)the 2022 Suzhou Health Youth Backbone Talent“National Tutorial System”Training Project(Qngg2022024)+2 种基金the Science and Technology Project of Suzhou City of China(SKJYD2021195)the Science,Technology and Innovation Commission of Shenzhen(JCYJ20220530165211026)the Postgraduate Research and Practice Innovation Program in Jiangsu Province(KYCX22_3157,KYCX24_3371,YCX25_3517).
文摘Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control(MQC)on the aged brain.Adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)signaling responsiveness declines with aging.However,whether AMPK plays a role in the exercise-mediated improvement of memory and MQC in the aged hippocampus remains to be established.5-Aminoimidazole 4-carboxamide ribonucleoside(AICAR),a pharmacological agonist of AMPK,has been proposed to be an exercise mimetic recently.However,it has not been clarified whether AICAR could mimic the effects of exercise on the aged hippocampus through improvement of MQC.In this study,AICAR(AMPK agonist)and Compound C(AMPK inhibitor)were used to investigate if AMPK plays a key role in exercise-induced improvement of MQC and if AICAR could act as an exercise mimetic through improvement of MQC in aged hippocampus.Both exercise and AICAR improved the memory of aged mice and increased AMPK phosphorylation in the aged hippocampus.Exercise,but not AICAR,improved mitochondrial respiratory function in the aged hippocampus and increased the microtubule associated protein 1 light chain 3(LC3)-II/LC3-I ratio and the protein expression of LC3-II and autophagy related protein 7(ATG7)in the lysate of whole hippocampal tissue.Both exercise and AICAR increased the ratio of LC3-II/LC3-I and the protein expression of LC3-II in the mitochondrial fractions of the hippocampus.Regarding mitochondrial dynamics,neither exercise training nor AICAR changed the protein level of mitofusin 2(Mfn2).Exercise,but not AICAR,increased the protein level of dynamin-related protein 1(Drp1).Furthermore,both exercise training and AICAR increased the protein level of peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),a modulator of mitochondrial biogenesis.Compound C abolished the exercise-induced effects on memory in aged mice,AMPK phosphorylation,autophagy,mitophagy,and mitochondrial fission in the aged hippocampus.However,Compound C did not reverse the exercise-induced increase in PGC-1αprotein levels in the aged hippocampus.Our data provide evidence that AMPK plays an important role in the exercise-induced improvement of memory and MQC in the hippocampus of aged mice.Importantly,we demonstrated for the first time that AICAR could partially mimetic the beneficial effects of endurance exercise on memory and MQC in the hippocampus of aged mice,and thus may be a promising exercise mimetic for counteracting brain aging.
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 fund of science and technology project of Wenzhou(Y20140601)
文摘Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society because of the ethical issue. This paper takes Wenzhou Medical University as an example to give a brief introduction to the ethical review about laboratory animals in the university so as to further draw attention and concerns from the public about the ethical issue of laboratory animals. We successively introduce its scientific projects, nurturing environment and ethical review of laboratory animals.
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.
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.
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 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 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.
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.
