Liposomal drugs have significantly improved cancer treatment in recent years.However,the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the m...Liposomal drugs have significantly improved cancer treatment in recent years.However,the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the multitude of auxiliary components.By replacing phospholipids and cholesterol with vitamin E succinate(VES),this study addresses these shortcomings by developing a novel modified nanoprodrug,and the new formulation is used to deliver cisplatin.Concurrently,liposomes encapsulating cisplatin were prepared by conventional formulations for comparative experiments.Moreover,VES can inhibit the expression of mitochondrial uncoupling protein 2(UCP2),further enhancing mitochondrial damage in tumor cells within the tumor microenvironment(TME)and suppressing the tricarboxylic acid cycle,thereby reducing ATP production.Additionally,cisplatin damages DNA structure,affecting the binding of Nrf2 to the antioxidant response element(ARE),thereby inhibiting the signaling expression of heme oxygenase1(HO-1).The combined action of cisplatin and VES disrupts the redox balanceleading to a significant accumulation of reactive oxygen species(ROS).The nanoprodrug effectively alters the redox state of the TME and inhibits antioxidant defenses,thereby amplifying oxidative stress damage and enhancing the efficacy of cisplatin.Notably,compared to free cisplatin,the nanoprodrug demonstrates greater efficacy in both cell line-derived xenograft(CDX)and patient-derived tumor xenograft(PDX)liver cancer models.Overall,this study successfully develops a novel mitochondrial-targeted nanoprodrug by modifying the conventional liposome formulation.This provides a new strategy for amplifying oxidative stress in order to disrupt redox balance,and enhance cisplatin efficacy.展开更多
Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In ou...Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In our design,Mn^(2+)functionalized COF was employed as a bioactive CpG carrier,which could simultaneously engineer and polarize macrophages to the antitumor phenotype,via the synergistic interaction of CpG and Mn^(2+).In the in vitro experiments,the engineered macrophages were found to secret high levels of antitumor cytokines for efficient TNBC cell inhibition.In the in vivo antitumor model,bioactive COF-engineered macrophages were found to relieve the hypoxia tumor microenvironment,enabling prevention of immune cell depletion during ACT.Thus,we realized efficient TNBC therapy and metastasis inhibition with the engineered macrophages in a long-term therapy model.This work provides a promising strategy for metastatic TNBC treatment and highlights the importance of bioactive COF in biomedicine.展开更多
Boron neutron capture therapy(BNCT)has emerged as a promising treatment for cancers,offering a unique approach to selectively target tumor cells while sparing healthy tissues.Despite its clinical utility,the widesprea...Boron neutron capture therapy(BNCT)has emerged as a promising treatment for cancers,offering a unique approach to selectively target tumor cells while sparing healthy tissues.Despite its clinical utility,the widespread use of fructose-BPA(F-BPA)has been hampered by its limited ability to penetrate the blood-brain barrier(BBB)and potential risks for patients with certain complications such as diabetes,hyperuricemia,and gout,particularly with substantial dosages.Herein,a series of novel BPA derivatives were synthesized.After the primary screening,geniposide-BPA(G-BPA)and salidroside-BPA(S-BPA)exhibited high water solubility,low cytotoxicity and safe profiles for intravenous injection.Furthermore,both G-BPA and S-BPA had demonstrated superior efficacy in vitro against the 4T1 cell line compared with F-BPA.Notably,S-BPA displayed optimal BBB penetration capability,as evidenced by in vitro BBB models and glioblastoma models in vivo,surpassing all other BPA derivative candidates.Meanwhile,GBPA also exhibited enhanced performance relative to the clinical drug F-BPA.In brief,G-BPA and S-BPA,as novel BPA derivatives,demonstrated notable safety profiles and remarkable boron delivery capabilities,thereby offering promising therapeutic options for BNCT in the clinic.展开更多
This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of tr...This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of traditional immunotherapy due to patient variability and the complexity of the tumor microenvironment,our research establishes KMnO_(4)as a potent immunomodulator that enhances the efficacy of anti-programmed death-ligand 1(αPD-L1)antibodies.The in situ synthesized MnO_(2)adjuvants in the tumor exhibit direct interactions with biological systems,leading to the reduction of MnO_(2)to Mn^(2+)within the tumor,and thereby improving the microenvironment for immune cell activity.Our in vitro and in vivo models demonstrate KMnO_(4)’s capability to induce concentration-dependent cytotoxicity in tumor cells,triggering DNA damage and apoptosis.It also potentiates immunogenic cell death by upregulating calreticulin and high mobility group box 1(HMGB1)on the cell surface.The combination of KMnO_(4)withαPD-L1 antibodies substantially inhibits tumor growth,promotes dendritic cell maturation,and enhances CD8^(+)T cell infiltration,resulting in a significant phenotypic shift in tumor-associated macrophages towards a pro-inflammatory M1 profile.Our findings advocate for further research into the long-term efficacy of KMnO_(4)and its application in diverse tumor models,emphasizing its potential to redefine immune checkpoint blockade therapy and offering a new vista in the fight against cancer.展开更多
Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent fa...Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent failure of chemotherapy.To overcome this challenge,amphiphiles(P1)carrying a nitric oxide(NO)donor(Isosorbide 5-mononitrate,ISMN)and high-density disulfide are synthesized for encapsulatingmitochondria-targeted tetravalent platinum prodrug(TPt)to construct a nanocomposite(INP@TPt).Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum,depleting glutathione,and preventing apoptosis escape through generating highly toxic peroxynitrite anion(ONOO−).To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor,an OC patient-derived tumor xenograft(PDXOC)model in BALB/c nude mice was established.INP@TPt showed the best therapeutic effects in the PDXOC model.The corresponding tumor tissues contained high ONOO−levels,which were attributed to the simultaneous release of O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.展开更多
Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(...Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(Pt(Ⅳ))is restricted by tissue penetration of external irradiation.Here,we report a novel Pt(Ⅳ)activation strategy based on endogenous luminescence of tumor microenvironment responsiveness,which completely circumvents the limitation of external irradiation.The designed Pt(Ⅳ)–Lu,a mixture of trans,trans,trans-[Pt(N_(3))_(2)(OH)_(2)(py)_(2)]and luminol(Lu),has controllable activation property:it remains inert in reductant environment and normal tissues,but under tumor microenvironment,Lu will be oxidized to produce blue luminescence,which rapidly reduce Pt(Ⅳ)to Pt(Ⅱ)without the need of any external activator.Pt(Ⅳ)–Lu shows excellent responsive antitumor ability both in vitro and in vivo.Compared to cisplatin,the median lethal dose in BALB/c mice increased by an order of magnitude.Our results suggest that Pt(Ⅳ)–Lu exhibits highly controllable activation property,superior antitumor activity,and good biosafety,which may provide a novel strategy for the design of platinum prodrugs.展开更多
Recently,the utilization of nonsteroidal anti-inflammatory drugs(NSAIDs)to sensitize cisplatin(CDDP)has gained substantial traction in the treatment of ovarian cancer(OC).However,even widely employed NSAIDs such as ce...Recently,the utilization of nonsteroidal anti-inflammatory drugs(NSAIDs)to sensitize cisplatin(CDDP)has gained substantial traction in the treatment of ovarian cancer(OC).However,even widely employed NSAIDs such as celecoxib and naproxen carry an elevated risk of cardiovascular events,notably throm-bosis.Furthermore,the diminished sensitivity to CDDP therapy in OC is multifactorial,rendering the ap-plication of NSAIDs only partially effective due to their cyclooxygenase-2(COX-2)inhibiting mechanism.Hence,in this study,reactive oxygen species(ROS)-responsive composite nano-hydrangeas loaded with the Chinese medicine small molecule allicin and platinum(IV)prodrug(DTP@AP NPs)were prepared to achieve comprehensive chemosensitization.On one front,allicin achieved COX-2 blocking therapy,en-compassing the inhibition of proliferation,angiogenesis and endothelial mesenchymal transition(EMT),thereby mitigating the adverse impacts of CDDP chemotherapy.Simultaneously,synergistic chemosensi-tization was achieved from multifaceted mechanisms by decreasing CDDP inactivation,damaging mito-chondria and inhibiting DNA repair.In essence,these findings provided an optimized approach for syner-gizing CDDP with COX-2 inhibitors,offering a promising avenue for enhancing OC treatment outcomes.展开更多
Objective:The goal of this study was to examine the prognostic performance of optical flow ratio(OFR)among patients with coronary artery disease(CAD)after percutaneous coronary intervention(PCI).Methods:We recruited p...Objective:The goal of this study was to examine the prognostic performance of optical flow ratio(OFR)among patients with coronary artery disease(CAD)after percutaneous coronary intervention(PCI).Methods:We recruited patients with CAD undergoing optical coherence tomography(OCT)-directed PCI between January 2019 and June 2021 for our single-center,hospital-based,retrospective cohort investigation.We assessed the link between post-PCI OFR and major adverse cardiovascular events(MACE)via multivariate Cox regression analy-sis.Results:Receiver operating characteristic analysis revealed that the best post-PCI OFR threshold for MACE was 0.91,and introduction of OFR into the baseline profile and OCT results markedly enhanced MACE identification after PCI.On the basis of survival curves,patients with OFR≤0.91(P<0.001)and thin-cap fibroatheroma(TCFA)(P=0.007)exhibited higher MACE incidence,and myocardial infarction(MI)incidence was considerably greater among patients with OFR≤0.91(P<0.001),compared with OFR>0.91.Multivariate Cox regression analysis suggested that OFR≤0.91(hazard ratio[HR]:3.60;95%confidence interval[CI]:1.24–10.44;P=0.019),and TCFA(HR:3.63;95%CI:1.42–9.20;P=0.007)were independent risk factors for MACE,and OFR≤0.91 was independently associated with MI(HR:14.64;95%CI:3.27–65.54;P<0.001).Conclusion:OFR after PCI is an independent MACE bio-indicator among patients with CAD.Adding OFR to post-PCI OCT results may potentially enhance MACE prediction.展开更多
BACKGROUND Dual-phenotype hepatocellular carcinoma(HCC)is a relatively new subtype of HCC.Studies have shown that in the context of chronic hepatitis,liver cirrhosis,and other liver conditions,some intrahepatic cholan...BACKGROUND Dual-phenotype hepatocellular carcinoma(HCC)is a relatively new subtype of HCC.Studies have shown that in the context of chronic hepatitis,liver cirrhosis,and other liver conditions,some intrahepatic cholangiocarcinomas(ICCs)exhibit an enhancement pattern similar to that of HCC.Both dual-phenotype HCC(DPHCC)and ICC can express biliary markers,making imaging and pathology differentiation difficult.Currently,radiomics is widely used in the differentiation,clinical staging,and prognosis assessment of various diseases.Radiomics can effectively differentiate DPHCC and ICC preoperatively.AIM To evaluate the value of radiomics in the differential diagnosis of DPHCC and ICC and to validate its clinical applicability METHODS In this retrospective study,the data of 53 DPHCC patients and 124 ICC patients were collected retrospectively and randomly divided into training and testing sets at a ratio of 7:3.After delineation of regions of interest and feature extraction and selection,radiomics models were constructed.Receiver operating characteristic curve analysis was conducted to calculate the area under the curve(AUC)for each model.The AUC values of radiologists with and without assistance from the model were also assessed.RESULTS In the training set,the AUC value of the radiomic model was the highest,and the combined model and the radiomic model had similar AUC(P>0.05);the differences in the AUC values between the combined model and the clinical-sign model was statistically significant(P<0.05).In the testing set,the AUC value of the combined model was the highest,and the differences in the AUC values between the combined model and the clinical-sign model was statistically significant(P<0.05).With model assistance,the AUC values of Doctor D(10 years of experience in abdominal imaging diagnosis)and Doctor E(5 years of experience in abdominal imaging diagnosis)both increased.CONCLUSION Radiomics can differentiate DPHCC and ICC,and with assistance from the developed model,the accuracy of less experienced doctors in the differential diagnosis of these two diseases can be improved.展开更多
BACKGROUND Endoscopic submucosal dissection(ESD)is widely utilized for the treatment of large adenomas,submucosal lesions,and early gastric cancer.A significant arti-ficial ulcer typically forms after ESD.Delayed or i...BACKGROUND Endoscopic submucosal dissection(ESD)is widely utilized for the treatment of large adenomas,submucosal lesions,and early gastric cancer.A significant arti-ficial ulcer typically forms after ESD.Delayed or incomplete healing of these ulcers can result in complications such as delayed bleeding and perforation.However,a comprehensive review of the outcomes and risk factors related to ulcer healing following ESD is currently lacking.AIM To assess ulcer healing outcomes and identify risk factors associated with delayed ulcer healing.RESULTS Our analysis included 12 studies,involving a total of 3430 patients.The meta-analysis revealed an overall healing rate of 65.55%for ulcers following ESD[odds ratio(OR)=2.71;95%confidence interval(CI):2.45-3.00].The healing rate within eight weeks was 48.32%(OR=0.76;95%CI:0.35-1.66),while the rate beyond eight weeks was 88.32%(OR=6.73;95%CI:3.82-11.87).Risk factors included Helicobacter pylori(H.pylori)infection(OR:=5.32;95%CI:1.90-14.87;P=0.001),ulcer size(OR=2.08;95%CI:1.19-3.61;P=0.01),lesion site(OR=2.08;95%CI:1.19-3.11),and pathological type(OR=1.64;95%CI:1.06-2.52).Diabetes(OR=0.56;95%CI:0.05-5.80;P=0.63)and duration of operation(OR=1.00;95%CI:0.99-1.01;P=0.96)were not significant factors.CONCLUSION The healing rate of ulcers following ESD is high after eight weeks.Risk factors affecting the healing process include H.pylori infection,ulcer size,lesion site,and pathological type.展开更多
The influenza A virus(IAV)damages intestinal mucosal tissues beyond the respiratory tract.Probiotics play a crucial role in maintaining the balance and stability of the intestinal microecosystem.Extracellular vesicles...The influenza A virus(IAV)damages intestinal mucosal tissues beyond the respiratory tract.Probiotics play a crucial role in maintaining the balance and stability of the intestinal microecosystem.Extracellular vesicles(EVs)derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect.However,the specific anti-inflammatory effects and underlying mechanisms of probiotics-derived EVs on IAV remain unclear.In the present study,we investigated the therapeutic efficacy of Lactobacillus reuteri EHA2-derived EVs(LrEVs)in a mouse model of IAV infection.Oral LrEVs were distributed in the liver,lungs,and gastrointestinal tract.In mice infected with IAV,oral LrEVs administration alleviated IAV-induced damages in the lungs and intestines,modified the microbiota compositions,and increased the levels of short-chain fatty acids in those organs.Mechanistically,LrEVs exerted their protective effects against IAV infection by blunting the pro-inflammatory IL-17 signaling.Furthermore,FISH analysis detected miR-4239,one of the most abundant miRNAs in LrEVs,in both lung and intestinal tissues.We confirmed that miR-4239 directly targets IL-17a.Our findings paved the ground for future application of LrEVs in influenza treatment and offered new mechanistic insights regarding the anti-inflammatory role of miR-4239.展开更多
Thrombosis associated with implants can severely impact therapeutic outcomes and lead to increased morbidity and mortality.Thus,developing blood-contacting materials with superior anticoagulant properties is essential...Thrombosis associated with implants can severely impact therapeutic outcomes and lead to increased morbidity and mortality.Thus,developing blood-contacting materials with superior anticoagulant properties is essential to prevent and mitigate device-related thrombosis.Herein,we propose a novel single-molecule multi-functional strategy for creating blood-compatible surfaces.The synthesized azide-modified Cu-DOTA-(Lys)3 molecule,which possesses both NO release and fibrinolysis functions,was immobilized on material surfaces via click chemistry.Due to the specificity,rapidity,and completeness of click chemistry,the firmly grafted Cu-DOTA-(Lys)3 endows the modified material with excellent antithrombotic properties of vascular endothelium and thrombolytic properties of fibrinolytic system.This surface effectively prevented thrombus formation in both in vitro and in vivo experiments,owing to the synergistic effect of anticoagulation and thrombolysis.Moreover,the modified material maintained its functional efficacy after one month of PBS immersion,demonstrating excellent stability.Overall,this single-molecule multifunctional strategy may become a promising surface engineering technique for blood-contacting materials.展开更多
Plant-derived extracellular vesicles(PEVs)have been regarded as a superior source for nanomedicine and drug delivery systems.Nevertheless,their clinical translation is hindered by the lack of clarity and even contradi...Plant-derived extracellular vesicles(PEVs)have been regarded as a superior source for nanomedicine and drug delivery systems.Nevertheless,their clinical translation is hindered by the lack of clarity and even contradiction in their biomedical applications.Herein,we conducted a comprehensive compositional analysis of four commonly used PEVs to fully understand their functional lipid contents and assess their potential therapeutic applications.The lipidomic analysis revealed the presence of cytotoxic gingerols and shogaols in ginger-derived EVs(GEVs).Subsequent in vitro and in vivo investigations substantiated the remarkable tumor cell inhibitory and tumor growth suppression efficacy of GEVs.The transcriptomic analysis indicated that GEVs regulate the cell cycle and p53 signaling pathways,thereby inducing cancer cell apoptosis.The supplementary proteomic analysis suggested the potential protein markers in PEV research.These findings highlight the value of multi-omics analyses in elucidating the potential therapeutic effects of PEVs and in advancing the development of PEV-based therapies.展开更多
Background:Chronic kidney disease(CKD)-associated anemia(CKD-anemia)is associated with poor survival,and hemoglobin targets are often not achieved with current therapies.Phase 3 trials have demonstrated the treatment ...Background:Chronic kidney disease(CKD)-associated anemia(CKD-anemia)is associated with poor survival,and hemoglobin targets are often not achieved with current therapies.Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia.This phase 4 study aims to evaluate the long-term(52-week)safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China.Methods:This Phase 4 multicenter,open-label,prospective study,conducted from 24 November 2020 to 11 November 2022,evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China.Patients aged≥18 years with CKD-anemia with or without dialysis were included.The initial oral dose was 70-120 mg(weight-based followed by dose adjustment)over 52 weeks.The primary endpoint was safety based on adverse events(AEs).The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin≥100 g/L.Effectiveness evaluable populations 1(EE1)and EE2 included roxadustat-naïve and previously roxadustat-treated patients,respectively.The safety analysis set(SAF)included all patients who received≥1 occasion.Results:The EE1,EE2,and SAF populations included 1804,193,and 2021 patients,respectively.In the SAF,the mean age was 50±14 years,and 1087 patients(53.8%)were male.Mean baseline hemoglobin was 96.9±14.0 g/L in EE1 and 100.3±12.9 g/L in EE2.In EE1,the mean(95%confidence interval)hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2(13.5-14.9)g/L and 14.3(13.5-15.0)g/L,respectively.Over weeks 24-36 and 36-52,83.3%and 86.1%of patients in EE1 and 82.7%and 84.7%in EE2 achieved mean hemoglobin≥100 g/L,respectively.In the SAF,1643(81.3%)patients experienced treatment-emergent AEs(TEAEs).Overall,219(10.8%)patients experienced drug-related TEAEs.Thirty-eight(1.9%)patients died of TEAEs(unrelated to the study drug).Vascular access thrombosis was uncommon.Conclusions:Roxadustat(52 weeks)increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety,supporting its use in real-world settings.展开更多
To the Editor:Boron neutron capture therapy(BNCT)comprises a type of radiotherapy that fuses heavy-ion cancer therapy with the delivery of boron-containing drugs,based on the principle that compounds with the boron-10...To the Editor:Boron neutron capture therapy(BNCT)comprises a type of radiotherapy that fuses heavy-ion cancer therapy with the delivery of boron-containing drugs,based on the principle that compounds with the boron-10 isotope(10B)are absorbed into the body,rapidly gather in tumor cells,and then neutron beams generated from a reactor or an accelerator can be used to irradiate the tumor.Compared with conventional radiotherapy,BNCT can more effectively kill tumor cells and cause less damage to normal cells,making it one of the most advanced cancer treatments currently available.展开更多
Hyperproliferative keratinocytes and subcutaneous inflammation contribute to the characteristic symptoms of psoriasis,including erythema,scales,or scaly plaques on the skin.These symptoms significantly affect patients...Hyperproliferative keratinocytes and subcutaneous inflammation contribute to the characteristic symptoms of psoriasis,including erythema,scales,or scaly plaques on the skin.These symptoms significantly affect patients'quality of life and cause severe physical and psychological distress.However,current treatment strategies have limited therapeutic effect and may lead to adverse side effects.In this study,we present the novel organic photosensitizer TBTDC[5-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-3-methylthiophene-2,4-dicarbonitrile]nanoparticles(NPs)with aggregation-induced emission(AIE)characteristics to mediate photodynamic therapy(TBTDC NP-PDT)for psoriasis treatment.We demonstrate that TBTDC NPs effectively generate reactive oxygen species upon light irradiation and lead to significant apoptosis of psoriatic keratinocytes.Furthermore,TBTDC NPs exhibit high cellular uptake in diseased keratinocytes and induce endoplasmic reticulum stress(ERS)-mediated autophagy,which can also enhance apoptosis.Importantly,TBTDC NPs show no cytotoxicity toward keratinocytes.These unique properties of TBTDC NPs enable remarkable therapeutic effects against psoriasis-like skin lesions and related inflammation in vivo.Overall,our AIE-active TBTDC NP-PDT represents a promising strategy for treating psoriasis in clinical settings.展开更多
Cardiovascular diseases(CVDs)are the first cause of death globally,posing a significant threat to human health.Cardiac electrophysiology is pivotal for the understanding and management of CVDs,particularly for address...Cardiovascular diseases(CVDs)are the first cause of death globally,posing a significant threat to human health.Cardiac electrophysiology is pivotal for the understanding and management of CVDs,particularly for addressing arrhythmias.A significant proliferation of micro-nano bioelectric devices and systems has occurred in the field of cardiomyocyte electrophysiology.These bioelectronic platforms feature distinctive electrode geometries that improve the fidelity of native electrophysiological signals.Despite the prevalence of planar microelectrode arrays(MEAs)for simultaneous multichannel recording of cellular electrophysiological signals,extracellular recordings often yield suboptimal signal quality.In contrast,three-dimensional(3D)MEAs and advanced penetration strategies allow highfidelity intracellular signal detection.3D nanodevices are categorized into the active and the passive.Active devices rely on external power sources to work,while passive devices operate without external power.Passive devices possess simplicity,biocompatibility,stability,and lower power consumption compared to active ones,making them ideal for sensors and implantable applications.This review comprehensively discusses the fabrication,geometric configuration,and penetration strategies of passive 3D micro/nanodevices,emphasizing their application in drug screening and disease modeling.Moreover,we summarize existing challenges and future opportunities to develop passive micro/nanobioelectronic devices from cardiac electrophysiological research to cardiovascular clinical practice.展开更多
Osteoporosis(OP)is a multifactorial metabolic bone disorder commonly observed in the elderly,particularly prevalent in postmenopausal women.However,many conventional anti-osteoporosis drugs have undesirable side effec...Osteoporosis(OP)is a multifactorial metabolic bone disorder commonly observed in the elderly,particularly prevalent in postmenopausal women.However,many conventional anti-osteoporosis drugs have undesirable side effects,limiting their long-term use.Here,we demonstrated that exosomes derived from both young and old healthy human plasma,which exhibited similar morphology,could significantly enhance the proliferation and migration of mesenchymal stem cells(MSCs).Furthermore,treatment with these exosomes increased alkaline phosphatase(ALP)activity,enhanced the mineralization of MSCs,and decreased the number of osteoclasts in vitro.When intravenously injected into rats,these exosomes accumulated in bone tissue.In vivo experiments demonstrated that both types of exosomes had a beneficial effect on osteoporosis by facilitating bone formation and suppressing osteoclast differentiation in an ovariectomized(OVX)-induced osteoporotic rat model.Strik-ingly,exosomes derived from young healthy human plasma exhibited stronger anti-osteoporosis effect.The miRNA sequencing analysis showed that miR-142-5p expression was significantly higher in the exosomes from young healthy adult plasma compared to in exosomes from older controls.Importantly,miR-142-5p over-expression exerted similar pro-osteogenic effects to those of exosomes from young healthy human plasma,while miR-142-5p downregulation had the opposite effect on osteogenic differentiation of MSCs.The anti-osteoporosis effect of exosomes from young healthy adult plasma were reversed upon miR-142-5p inhibition.In addition,ZFPM2 was a potential target of miR-142-5p involved in osteoporosis.Therefore,our study reveals the potential anti-osteoporosis effects of plasma exosomes and their underlying mechanisms,thereby providing an effective therapeutic strategy for clinical treatment of osteoporosis.展开更多
The influenza A virus(IAV),renowned for its high contagiousness and potential to catalyze global pandemics,poses significant challenges due to the emergence of drug-resistant strains.Given the critical role of RNA pol...The influenza A virus(IAV),renowned for its high contagiousness and potential to catalyze global pandemics,poses significant challenges due to the emergence of drug-resistant strains.Given the critical role of RNA polymerase in IAV replication,it stands out as a promising target for anti-IAV therapies.In this study,we identified a novel C-3-substituted oleanolic acid benzyl amide derivative,A5,as a potent inhibitor of the PA_(C)-PB1_(N) polymerase subunit interaction,with an IC_(50) value of 0.96±0.21μmol/L.A5 specifically targets the highly conserved PA_(C) domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains,including multidrug-resistant strains,with EC_(50) values ranging from 0.60 to 1.83μmol/L.Notably,when combined with oseltamivir,A5 exhibits synergistic effects both in vitro and in vivo.In a murine model,dosedependent administration of A5 leads to a significant reduction in IAV titers,resulting in a high survival rate among treated mice.Additionally,A5 treatment inhibits virus-induced Toll-like receptor 4 activation,attenuates cytokine responses,and protects against IAV-induced inflammatory responses in macrophages.In summary,A5 emerges as a novel inhibitor with high efficiency and broad-spectrum anti-influenza activity.展开更多
Surfaces with enduring and superior antithrombotic properties are essential for long-term blood-contacting devices.While current surface engineering strategies integrating anticoagulants and antiplatelet agents show p...Surfaces with enduring and superior antithrombotic properties are essential for long-term blood-contacting devices.While current surface engineering strategies integrating anticoagulants and antiplatelet agents show promise in mimicking the non-thrombogenic properties of the endothelium,their long-term effectiveness re-mains limited.Here,we report an easy-to-perform,dual-biomimetic surface engineering strategy for tailoring long-acting endothelium-mimicking anti-thrombotic surfaces.We first designed a Mytilus edulis foot protein-5(Mefp-5)mimic rich in amine and clickable alkynyl groups to polymerize-deposit a chemical robust coating onto the surface through a mussel-inspired adhesion mechanism.Then,a clickable nitric oxide(NO,an anti-platelet agent)-generating enzyme and the anticoagulant heparin were sequentially co-grafted onto the chemical robust coatings via click chemistry and carbodiimide chemistry.Our results demonstrate that this engineered surface achieved an impressive NO catalytic release efficiency of up to 88%,while heparin retained 86%of its bioactivity even after one month of exposure to PBS containing NO donor.Both in vitro and in vivo experiments confirmed that this robust endothelium-mimicking coating substantially reduces thrombosis formation.Overall,our long-acting endothelium-mimicking anti-thrombotic coatings present a promising and feasible strategy to address thrombosis-related challenges associated with blood-contacting devices.展开更多
基金financed by National Natural Science Foundation of China(Nos.81773642,52073139)Guangdong Provincial Clinical Research Center for Laboratory Medicine(No.2023B110008)the Provincial subsidies for the construction of high-level hospitals(No.K202201)。
文摘Liposomal drugs have significantly improved cancer treatment in recent years.However,the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the multitude of auxiliary components.By replacing phospholipids and cholesterol with vitamin E succinate(VES),this study addresses these shortcomings by developing a novel modified nanoprodrug,and the new formulation is used to deliver cisplatin.Concurrently,liposomes encapsulating cisplatin were prepared by conventional formulations for comparative experiments.Moreover,VES can inhibit the expression of mitochondrial uncoupling protein 2(UCP2),further enhancing mitochondrial damage in tumor cells within the tumor microenvironment(TME)and suppressing the tricarboxylic acid cycle,thereby reducing ATP production.Additionally,cisplatin damages DNA structure,affecting the binding of Nrf2 to the antioxidant response element(ARE),thereby inhibiting the signaling expression of heme oxygenase1(HO-1).The combined action of cisplatin and VES disrupts the redox balanceleading to a significant accumulation of reactive oxygen species(ROS).The nanoprodrug effectively alters the redox state of the TME and inhibits antioxidant defenses,thereby amplifying oxidative stress damage and enhancing the efficacy of cisplatin.Notably,compared to free cisplatin,the nanoprodrug demonstrates greater efficacy in both cell line-derived xenograft(CDX)and patient-derived tumor xenograft(PDX)liver cancer models.Overall,this study successfully develops a novel mitochondrial-targeted nanoprodrug by modifying the conventional liposome formulation.This provides a new strategy for amplifying oxidative stress in order to disrupt redox balance,and enhance cisplatin efficacy.
基金supported by the National Natural Science Foundation of China(No.22304073)the Dongguan Science and Technology of Social Development Program(No.20231800935782)。
文摘Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In our design,Mn^(2+)functionalized COF was employed as a bioactive CpG carrier,which could simultaneously engineer and polarize macrophages to the antitumor phenotype,via the synergistic interaction of CpG and Mn^(2+).In the in vitro experiments,the engineered macrophages were found to secret high levels of antitumor cytokines for efficient TNBC cell inhibition.In the in vivo antitumor model,bioactive COF-engineered macrophages were found to relieve the hypoxia tumor microenvironment,enabling prevention of immune cell depletion during ACT.Thus,we realized efficient TNBC therapy and metastasis inhibition with the engineered macrophages in a long-term therapy model.This work provides a promising strategy for metastatic TNBC treatment and highlights the importance of bioactive COF in biomedicine.
基金supported by Guangdong Basic and Applied Basic Research Foundation(No.2021B1515120065)National Natural Science Foundation of China(Nos.82202339,32271420,82202307)+3 种基金China Postdoctoral Science Foundation(Nos.2022M711527,2021M701640)Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province(No.B2021201038)National High-End Foreign Expert Recruitment Plan(No.G2022003007L)Natural Science Foundation of Hebei Province(No.B2023201108).
文摘Boron neutron capture therapy(BNCT)has emerged as a promising treatment for cancers,offering a unique approach to selectively target tumor cells while sparing healthy tissues.Despite its clinical utility,the widespread use of fructose-BPA(F-BPA)has been hampered by its limited ability to penetrate the blood-brain barrier(BBB)and potential risks for patients with certain complications such as diabetes,hyperuricemia,and gout,particularly with substantial dosages.Herein,a series of novel BPA derivatives were synthesized.After the primary screening,geniposide-BPA(G-BPA)and salidroside-BPA(S-BPA)exhibited high water solubility,low cytotoxicity and safe profiles for intravenous injection.Furthermore,both G-BPA and S-BPA had demonstrated superior efficacy in vitro against the 4T1 cell line compared with F-BPA.Notably,S-BPA displayed optimal BBB penetration capability,as evidenced by in vitro BBB models and glioblastoma models in vivo,surpassing all other BPA derivative candidates.Meanwhile,GBPA also exhibited enhanced performance relative to the clinical drug F-BPA.In brief,G-BPA and S-BPA,as novel BPA derivatives,demonstrated notable safety profiles and remarkable boron delivery capabilities,thereby offering promising therapeutic options for BNCT in the clinic.
基金supported by the Natural Science Foundation of Guangdong Province(No.2023A1515030291)the Dongguan Science and Technology of Social Development Program(No.20211800905282)+8 种基金the National Key Research and Development Program of China(Nos.2022YFC2303600,2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDC-202002)the CACMS Innovation Fund(Nos.CI2023E002,CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Nos.CI2023D003,CI2021B014)the Science and Technology Foundation of Shenzhen(No.JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the Shenzhen Medical Research Fund(No.B2302051)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(No.CW202002)Shenzhen Science and Technology Program(No.RCBS20210609104424065).
文摘This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of traditional immunotherapy due to patient variability and the complexity of the tumor microenvironment,our research establishes KMnO_(4)as a potent immunomodulator that enhances the efficacy of anti-programmed death-ligand 1(αPD-L1)antibodies.The in situ synthesized MnO_(2)adjuvants in the tumor exhibit direct interactions with biological systems,leading to the reduction of MnO_(2)to Mn^(2+)within the tumor,and thereby improving the microenvironment for immune cell activity.Our in vitro and in vivo models demonstrate KMnO_(4)’s capability to induce concentration-dependent cytotoxicity in tumor cells,triggering DNA damage and apoptosis.It also potentiates immunogenic cell death by upregulating calreticulin and high mobility group box 1(HMGB1)on the cell surface.The combination of KMnO_(4)withαPD-L1 antibodies substantially inhibits tumor growth,promotes dendritic cell maturation,and enhances CD8^(+)T cell infiltration,resulting in a significant phenotypic shift in tumor-associated macrophages towards a pro-inflammatory M1 profile.Our findings advocate for further research into the long-term efficacy of KMnO_(4)and its application in diverse tumor models,emphasizing its potential to redefine immune checkpoint blockade therapy and offering a new vista in the fight against cancer.
基金supported by the Guangdong Basic and Applied Basic Research Foundation of China(No.2021A1515011050)President Foundation of The Third Affiliated Hospital of SouthernMedical University[grant number YM202202].
文摘Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent failure of chemotherapy.To overcome this challenge,amphiphiles(P1)carrying a nitric oxide(NO)donor(Isosorbide 5-mononitrate,ISMN)and high-density disulfide are synthesized for encapsulatingmitochondria-targeted tetravalent platinum prodrug(TPt)to construct a nanocomposite(INP@TPt).Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum,depleting glutathione,and preventing apoptosis escape through generating highly toxic peroxynitrite anion(ONOO−).To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor,an OC patient-derived tumor xenograft(PDXOC)model in BALB/c nude mice was established.INP@TPt showed the best therapeutic effects in the PDXOC model.The corresponding tumor tissues contained high ONOO−levels,which were attributed to the simultaneous release of O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.
基金supported by the National Natural Science Foundation of China(Nos.32201171 and 82372115)the Science and Technology Program of Guangzhou(No.202102021266)。
文摘Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(Pt(Ⅳ))is restricted by tissue penetration of external irradiation.Here,we report a novel Pt(Ⅳ)activation strategy based on endogenous luminescence of tumor microenvironment responsiveness,which completely circumvents the limitation of external irradiation.The designed Pt(Ⅳ)–Lu,a mixture of trans,trans,trans-[Pt(N_(3))_(2)(OH)_(2)(py)_(2)]and luminol(Lu),has controllable activation property:it remains inert in reductant environment and normal tissues,but under tumor microenvironment,Lu will be oxidized to produce blue luminescence,which rapidly reduce Pt(Ⅳ)to Pt(Ⅱ)without the need of any external activator.Pt(Ⅳ)–Lu shows excellent responsive antitumor ability both in vitro and in vivo.Compared to cisplatin,the median lethal dose in BALB/c mice increased by an order of magnitude.Our results suggest that Pt(Ⅳ)–Lu exhibits highly controllable activation property,superior antitumor activity,and good biosafety,which may provide a novel strategy for the design of platinum prodrugs.
基金supported by the Guangdong Basic and Applied Basic Research Foundation of China(No.2021A1515011050)President Foundation of the Third Affiliated Hospital of Southern Medical University(No.YM202202)+1 种基金the Health Economics Association Research Program of Guangdong Province(No.2022-WJZD-20)the Higher Education Teaching Management Association Curriculum Thinking and Administration Program of Guangdong Province(No.X-KCSZ2021082).
文摘Recently,the utilization of nonsteroidal anti-inflammatory drugs(NSAIDs)to sensitize cisplatin(CDDP)has gained substantial traction in the treatment of ovarian cancer(OC).However,even widely employed NSAIDs such as celecoxib and naproxen carry an elevated risk of cardiovascular events,notably throm-bosis.Furthermore,the diminished sensitivity to CDDP therapy in OC is multifactorial,rendering the ap-plication of NSAIDs only partially effective due to their cyclooxygenase-2(COX-2)inhibiting mechanism.Hence,in this study,reactive oxygen species(ROS)-responsive composite nano-hydrangeas loaded with the Chinese medicine small molecule allicin and platinum(IV)prodrug(DTP@AP NPs)were prepared to achieve comprehensive chemosensitization.On one front,allicin achieved COX-2 blocking therapy,en-compassing the inhibition of proliferation,angiogenesis and endothelial mesenchymal transition(EMT),thereby mitigating the adverse impacts of CDDP chemotherapy.Simultaneously,synergistic chemosensi-tization was achieved from multifaceted mechanisms by decreasing CDDP inactivation,damaging mito-chondria and inhibiting DNA repair.In essence,these findings provided an optimized approach for syner-gizing CDDP with COX-2 inhibitors,offering a promising avenue for enhancing OC treatment outcomes.
基金supported by the Outstanding Young Talent Program of Guangdong Provincial People’s Hospital(grant number KJ012019084)the High-level Hospital Construction Project(grant number DFJH2020021).
文摘Objective:The goal of this study was to examine the prognostic performance of optical flow ratio(OFR)among patients with coronary artery disease(CAD)after percutaneous coronary intervention(PCI).Methods:We recruited patients with CAD undergoing optical coherence tomography(OCT)-directed PCI between January 2019 and June 2021 for our single-center,hospital-based,retrospective cohort investigation.We assessed the link between post-PCI OFR and major adverse cardiovascular events(MACE)via multivariate Cox regression analy-sis.Results:Receiver operating characteristic analysis revealed that the best post-PCI OFR threshold for MACE was 0.91,and introduction of OFR into the baseline profile and OCT results markedly enhanced MACE identification after PCI.On the basis of survival curves,patients with OFR≤0.91(P<0.001)and thin-cap fibroatheroma(TCFA)(P=0.007)exhibited higher MACE incidence,and myocardial infarction(MI)incidence was considerably greater among patients with OFR≤0.91(P<0.001),compared with OFR>0.91.Multivariate Cox regression analysis suggested that OFR≤0.91(hazard ratio[HR]:3.60;95%confidence interval[CI]:1.24–10.44;P=0.019),and TCFA(HR:3.63;95%CI:1.42–9.20;P=0.007)were independent risk factors for MACE,and OFR≤0.91 was independently associated with MI(HR:14.64;95%CI:3.27–65.54;P<0.001).Conclusion:OFR after PCI is an independent MACE bio-indicator among patients with CAD.Adding OFR to post-PCI OCT results may potentially enhance MACE prediction.
文摘BACKGROUND Dual-phenotype hepatocellular carcinoma(HCC)is a relatively new subtype of HCC.Studies have shown that in the context of chronic hepatitis,liver cirrhosis,and other liver conditions,some intrahepatic cholangiocarcinomas(ICCs)exhibit an enhancement pattern similar to that of HCC.Both dual-phenotype HCC(DPHCC)and ICC can express biliary markers,making imaging and pathology differentiation difficult.Currently,radiomics is widely used in the differentiation,clinical staging,and prognosis assessment of various diseases.Radiomics can effectively differentiate DPHCC and ICC preoperatively.AIM To evaluate the value of radiomics in the differential diagnosis of DPHCC and ICC and to validate its clinical applicability METHODS In this retrospective study,the data of 53 DPHCC patients and 124 ICC patients were collected retrospectively and randomly divided into training and testing sets at a ratio of 7:3.After delineation of regions of interest and feature extraction and selection,radiomics models were constructed.Receiver operating characteristic curve analysis was conducted to calculate the area under the curve(AUC)for each model.The AUC values of radiologists with and without assistance from the model were also assessed.RESULTS In the training set,the AUC value of the radiomic model was the highest,and the combined model and the radiomic model had similar AUC(P>0.05);the differences in the AUC values between the combined model and the clinical-sign model was statistically significant(P<0.05).In the testing set,the AUC value of the combined model was the highest,and the differences in the AUC values between the combined model and the clinical-sign model was statistically significant(P<0.05).With model assistance,the AUC values of Doctor D(10 years of experience in abdominal imaging diagnosis)and Doctor E(5 years of experience in abdominal imaging diagnosis)both increased.CONCLUSION Radiomics can differentiate DPHCC and ICC,and with assistance from the developed model,the accuracy of less experienced doctors in the differential diagnosis of these two diseases can be improved.
基金Supported by the National Natural Science Foundation of China,No.81860104the Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation,No.2023GXNSFDA026024+2 种基金the Development and Application of Medical and Health Appropriate Technology Project in Guangxi Zhuang Autonomous Region,No.S2018049the Self-financing Project of Health Commission of Guangxi Zhuang Autonomous Region,No.Z20200398the Innovation Project of Guangxi Graduate Education,No.YCBZ2022079.
文摘BACKGROUND Endoscopic submucosal dissection(ESD)is widely utilized for the treatment of large adenomas,submucosal lesions,and early gastric cancer.A significant arti-ficial ulcer typically forms after ESD.Delayed or incomplete healing of these ulcers can result in complications such as delayed bleeding and perforation.However,a comprehensive review of the outcomes and risk factors related to ulcer healing following ESD is currently lacking.AIM To assess ulcer healing outcomes and identify risk factors associated with delayed ulcer healing.RESULTS Our analysis included 12 studies,involving a total of 3430 patients.The meta-analysis revealed an overall healing rate of 65.55%for ulcers following ESD[odds ratio(OR)=2.71;95%confidence interval(CI):2.45-3.00].The healing rate within eight weeks was 48.32%(OR=0.76;95%CI:0.35-1.66),while the rate beyond eight weeks was 88.32%(OR=6.73;95%CI:3.82-11.87).Risk factors included Helicobacter pylori(H.pylori)infection(OR:=5.32;95%CI:1.90-14.87;P=0.001),ulcer size(OR=2.08;95%CI:1.19-3.61;P=0.01),lesion site(OR=2.08;95%CI:1.19-3.11),and pathological type(OR=1.64;95%CI:1.06-2.52).Diabetes(OR=0.56;95%CI:0.05-5.80;P=0.63)and duration of operation(OR=1.00;95%CI:0.99-1.01;P=0.96)were not significant factors.CONCLUSION The healing rate of ulcers following ESD is high after eight weeks.Risk factors affecting the healing process include H.pylori infection,ulcer size,lesion site,and pathological type.
基金supported by the National Natural Science Foundation of China(No.82172103 and No.32371428)GuangDong Basic and Applied Basic Research Foundation(No.2023B1515130005,No.2022B1515120065 and No.2020A1515110151)Dongguan Science and Technology of Social Development Program(No.G202306).
文摘The influenza A virus(IAV)damages intestinal mucosal tissues beyond the respiratory tract.Probiotics play a crucial role in maintaining the balance and stability of the intestinal microecosystem.Extracellular vesicles(EVs)derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect.However,the specific anti-inflammatory effects and underlying mechanisms of probiotics-derived EVs on IAV remain unclear.In the present study,we investigated the therapeutic efficacy of Lactobacillus reuteri EHA2-derived EVs(LrEVs)in a mouse model of IAV infection.Oral LrEVs were distributed in the liver,lungs,and gastrointestinal tract.In mice infected with IAV,oral LrEVs administration alleviated IAV-induced damages in the lungs and intestines,modified the microbiota compositions,and increased the levels of short-chain fatty acids in those organs.Mechanistically,LrEVs exerted their protective effects against IAV infection by blunting the pro-inflammatory IL-17 signaling.Furthermore,FISH analysis detected miR-4239,one of the most abundant miRNAs in LrEVs,in both lung and intestinal tissues.We confirmed that miR-4239 directly targets IL-17a.Our findings paved the ground for future application of LrEVs in influenza treatment and offered new mechanistic insights regarding the anti-inflammatory role of miR-4239.
基金supported by the National Natural Science Foundation of China(Project 32171326,82072072,32261160372,32371377,82470532)the Leading Talent Project of Guangzhou Development District(2020-L013)+2 种基金the Guang Dong Basic and Applied Basic Research Foundation(2022B1515130010,2021A1515111035)Natural Science Foundation of Guangdong Province(2022A1515011442)Dongguan Science and Technology of Social Development Program(20231800906311,20221800906322).
文摘Thrombosis associated with implants can severely impact therapeutic outcomes and lead to increased morbidity and mortality.Thus,developing blood-contacting materials with superior anticoagulant properties is essential to prevent and mitigate device-related thrombosis.Herein,we propose a novel single-molecule multi-functional strategy for creating blood-compatible surfaces.The synthesized azide-modified Cu-DOTA-(Lys)3 molecule,which possesses both NO release and fibrinolysis functions,was immobilized on material surfaces via click chemistry.Due to the specificity,rapidity,and completeness of click chemistry,the firmly grafted Cu-DOTA-(Lys)3 endows the modified material with excellent antithrombotic properties of vascular endothelium and thrombolytic properties of fibrinolytic system.This surface effectively prevented thrombus formation in both in vitro and in vivo experiments,owing to the synergistic effect of anticoagulation and thrombolysis.Moreover,the modified material maintained its functional efficacy after one month of PBS immersion,demonstrating excellent stability.Overall,this single-molecule multifunctional strategy may become a promising surface engineering technique for blood-contacting materials.
基金supported by grants from the National Natural Science Foundation of China(32322045 to Z.Li,32301162 to F.Wang,22207050 to L.Li)Guangdong Basic and Applied Basic Research Foundation,China(2021B1515120065 to Z.Li)Dongguan Science and Technology of Social Development Program(20231800925372 to Z.Li,20231800912372 to F.Wang).
文摘Plant-derived extracellular vesicles(PEVs)have been regarded as a superior source for nanomedicine and drug delivery systems.Nevertheless,their clinical translation is hindered by the lack of clarity and even contradiction in their biomedical applications.Herein,we conducted a comprehensive compositional analysis of four commonly used PEVs to fully understand their functional lipid contents and assess their potential therapeutic applications.The lipidomic analysis revealed the presence of cytotoxic gingerols and shogaols in ginger-derived EVs(GEVs).Subsequent in vitro and in vivo investigations substantiated the remarkable tumor cell inhibitory and tumor growth suppression efficacy of GEVs.The transcriptomic analysis indicated that GEVs regulate the cell cycle and p53 signaling pathways,thereby inducing cancer cell apoptosis.The supplementary proteomic analysis suggested the potential protein markers in PEV research.These findings highlight the value of multi-omics analyses in elucidating the potential therapeutic effects of PEVs and in advancing the development of PEV-based therapies.
文摘Background:Chronic kidney disease(CKD)-associated anemia(CKD-anemia)is associated with poor survival,and hemoglobin targets are often not achieved with current therapies.Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia.This phase 4 study aims to evaluate the long-term(52-week)safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China.Methods:This Phase 4 multicenter,open-label,prospective study,conducted from 24 November 2020 to 11 November 2022,evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China.Patients aged≥18 years with CKD-anemia with or without dialysis were included.The initial oral dose was 70-120 mg(weight-based followed by dose adjustment)over 52 weeks.The primary endpoint was safety based on adverse events(AEs).The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin≥100 g/L.Effectiveness evaluable populations 1(EE1)and EE2 included roxadustat-naïve and previously roxadustat-treated patients,respectively.The safety analysis set(SAF)included all patients who received≥1 occasion.Results:The EE1,EE2,and SAF populations included 1804,193,and 2021 patients,respectively.In the SAF,the mean age was 50±14 years,and 1087 patients(53.8%)were male.Mean baseline hemoglobin was 96.9±14.0 g/L in EE1 and 100.3±12.9 g/L in EE2.In EE1,the mean(95%confidence interval)hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2(13.5-14.9)g/L and 14.3(13.5-15.0)g/L,respectively.Over weeks 24-36 and 36-52,83.3%and 86.1%of patients in EE1 and 82.7%and 84.7%in EE2 achieved mean hemoglobin≥100 g/L,respectively.In the SAF,1643(81.3%)patients experienced treatment-emergent AEs(TEAEs).Overall,219(10.8%)patients experienced drug-related TEAEs.Thirty-eight(1.9%)patients died of TEAEs(unrelated to the study drug).Vascular access thrombosis was uncommon.Conclusions:Roxadustat(52 weeks)increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety,supporting its use in real-world settings.
基金This study was supported by grants from the Guangdong Basic and Applied Basic Research Fund(Guangdong-Dongguan Joint FundNo.2023B1515120072)+2 种基金the Dongguan Social Science and Technology Development Project(No.20231800900382)the National Clinical Key Specialty Cultivation Project(No.Z202303)the Open Fund of the China Spallation Neutron Source Songshan Lake Science City(No.KFKT2023A02)
文摘To the Editor:Boron neutron capture therapy(BNCT)comprises a type of radiotherapy that fuses heavy-ion cancer therapy with the delivery of boron-containing drugs,based on the principle that compounds with the boron-10 isotope(10B)are absorbed into the body,rapidly gather in tumor cells,and then neutron beams generated from a reactor or an accelerator can be used to irradiate the tumor.Compared with conventional radiotherapy,BNCT can more effectively kill tumor cells and cause less damage to normal cells,making it one of the most advanced cancer treatments currently available.
基金supported by the Natural Science Funding of Guangdong Province(2022A1515012312 and 2021A1515010023)the National Natural Science Funding of China(82070083)Dongguan Social development technology projects Science and Technology Planning Project(20231800940792).
文摘Hyperproliferative keratinocytes and subcutaneous inflammation contribute to the characteristic symptoms of psoriasis,including erythema,scales,or scaly plaques on the skin.These symptoms significantly affect patients'quality of life and cause severe physical and psychological distress.However,current treatment strategies have limited therapeutic effect and may lead to adverse side effects.In this study,we present the novel organic photosensitizer TBTDC[5-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-3-methylthiophene-2,4-dicarbonitrile]nanoparticles(NPs)with aggregation-induced emission(AIE)characteristics to mediate photodynamic therapy(TBTDC NP-PDT)for psoriasis treatment.We demonstrate that TBTDC NPs effectively generate reactive oxygen species upon light irradiation and lead to significant apoptosis of psoriatic keratinocytes.Furthermore,TBTDC NPs exhibit high cellular uptake in diseased keratinocytes and induce endoplasmic reticulum stress(ERS)-mediated autophagy,which can also enhance apoptosis.Importantly,TBTDC NPs show no cytotoxicity toward keratinocytes.These unique properties of TBTDC NPs enable remarkable therapeutic effects against psoriasis-like skin lesions and related inflammation in vivo.Overall,our AIE-active TBTDC NP-PDT represents a promising strategy for treating psoriasis in clinical settings.
文摘Cardiovascular diseases(CVDs)are the first cause of death globally,posing a significant threat to human health.Cardiac electrophysiology is pivotal for the understanding and management of CVDs,particularly for addressing arrhythmias.A significant proliferation of micro-nano bioelectric devices and systems has occurred in the field of cardiomyocyte electrophysiology.These bioelectronic platforms feature distinctive electrode geometries that improve the fidelity of native electrophysiological signals.Despite the prevalence of planar microelectrode arrays(MEAs)for simultaneous multichannel recording of cellular electrophysiological signals,extracellular recordings often yield suboptimal signal quality.In contrast,three-dimensional(3D)MEAs and advanced penetration strategies allow highfidelity intracellular signal detection.3D nanodevices are categorized into the active and the passive.Active devices rely on external power sources to work,while passive devices operate without external power.Passive devices possess simplicity,biocompatibility,stability,and lower power consumption compared to active ones,making them ideal for sensors and implantable applications.This review comprehensively discusses the fabrication,geometric configuration,and penetration strategies of passive 3D micro/nanodevices,emphasizing their application in drug screening and disease modeling.Moreover,we summarize existing challenges and future opportunities to develop passive micro/nanobioelectronic devices from cardiac electrophysiological research to cardiovascular clinical practice.
基金supported by the National Natural Science Foundation of China[grant number,82272165 to W.Xu,22207050 to L.Li]the Fundamental Research Funds for the Central Universities[grant number,YG2023ZD28 to W.Xu]+2 种基金Shanghai Jiao Tong University School of Medicine Research-Oriented Physician Program in Clinical Medicine[JYYJXYS20240822 to W.Xu]Changning District Health Committee Excellent Innovation Talent Training Project[grant number,RCJD2022S01 to W.Xu]Shanghai Jiao Tong University K.C.Wong Medical Fellowship Fund[to W.Xu].
文摘Osteoporosis(OP)is a multifactorial metabolic bone disorder commonly observed in the elderly,particularly prevalent in postmenopausal women.However,many conventional anti-osteoporosis drugs have undesirable side effects,limiting their long-term use.Here,we demonstrated that exosomes derived from both young and old healthy human plasma,which exhibited similar morphology,could significantly enhance the proliferation and migration of mesenchymal stem cells(MSCs).Furthermore,treatment with these exosomes increased alkaline phosphatase(ALP)activity,enhanced the mineralization of MSCs,and decreased the number of osteoclasts in vitro.When intravenously injected into rats,these exosomes accumulated in bone tissue.In vivo experiments demonstrated that both types of exosomes had a beneficial effect on osteoporosis by facilitating bone formation and suppressing osteoclast differentiation in an ovariectomized(OVX)-induced osteoporotic rat model.Strik-ingly,exosomes derived from young healthy human plasma exhibited stronger anti-osteoporosis effect.The miRNA sequencing analysis showed that miR-142-5p expression was significantly higher in the exosomes from young healthy adult plasma compared to in exosomes from older controls.Importantly,miR-142-5p over-expression exerted similar pro-osteogenic effects to those of exosomes from young healthy human plasma,while miR-142-5p downregulation had the opposite effect on osteogenic differentiation of MSCs.The anti-osteoporosis effect of exosomes from young healthy adult plasma were reversed upon miR-142-5p inhibition.In addition,ZFPM2 was a potential target of miR-142-5p involved in osteoporosis.Therefore,our study reveals the potential anti-osteoporosis effects of plasma exosomes and their underlying mechanisms,thereby providing an effective therapeutic strategy for clinical treatment of osteoporosis.
基金supported by the Major Scientific and Technological Projects of Guangdong Province(No.2023B1111050008,China)Science and Technology Innovation Project of Guangdong Provincial Drug Administration(No.2022ZDZ08,China)+3 种基金Post Scientist Fund awarded by Chinese Academy of Traditional Chinese Medicine(No.ZZ13-035-02,China)to Shuwen LiuThe-National Natural Science Foundation of China(No.82073722)the Guangdong Basic and Applied Basic Research Foundation(No.2025A1515010495,China)to Gaopeng SongRegional joint foundation of basic and applied basic research in guangdong province(No.2023A1515111165,China)to Chan Yang.
文摘The influenza A virus(IAV),renowned for its high contagiousness and potential to catalyze global pandemics,poses significant challenges due to the emergence of drug-resistant strains.Given the critical role of RNA polymerase in IAV replication,it stands out as a promising target for anti-IAV therapies.In this study,we identified a novel C-3-substituted oleanolic acid benzyl amide derivative,A5,as a potent inhibitor of the PA_(C)-PB1_(N) polymerase subunit interaction,with an IC_(50) value of 0.96±0.21μmol/L.A5 specifically targets the highly conserved PA_(C) domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains,including multidrug-resistant strains,with EC_(50) values ranging from 0.60 to 1.83μmol/L.Notably,when combined with oseltamivir,A5 exhibits synergistic effects both in vitro and in vivo.In a murine model,dosedependent administration of A5 leads to a significant reduction in IAV titers,resulting in a high survival rate among treated mice.Additionally,A5 treatment inhibits virus-induced Toll-like receptor 4 activation,attenuates cytokine responses,and protects against IAV-induced inflammatory responses in macrophages.In summary,A5 emerges as a novel inhibitor with high efficiency and broad-spectrum anti-influenza activity.
基金Natural Science Foundation of China (Project 32371377, 32171326, 82470532, 32471376, 32371378, 32261160372)The Third People’s Hospital of Chengdu Scientific Research Project (2023PI11)+3 种基金the Guang Dong Basic and Applied Basic Research Foundation (2022B1515130010)Dongguan Science and Technology of Social Development Program (20231800906311)the Leading Talent Project of Guangzhou Development District (2020-L013).the Analytical and Testing Centerfor their support.
文摘Surfaces with enduring and superior antithrombotic properties are essential for long-term blood-contacting devices.While current surface engineering strategies integrating anticoagulants and antiplatelet agents show promise in mimicking the non-thrombogenic properties of the endothelium,their long-term effectiveness re-mains limited.Here,we report an easy-to-perform,dual-biomimetic surface engineering strategy for tailoring long-acting endothelium-mimicking anti-thrombotic surfaces.We first designed a Mytilus edulis foot protein-5(Mefp-5)mimic rich in amine and clickable alkynyl groups to polymerize-deposit a chemical robust coating onto the surface through a mussel-inspired adhesion mechanism.Then,a clickable nitric oxide(NO,an anti-platelet agent)-generating enzyme and the anticoagulant heparin were sequentially co-grafted onto the chemical robust coatings via click chemistry and carbodiimide chemistry.Our results demonstrate that this engineered surface achieved an impressive NO catalytic release efficiency of up to 88%,while heparin retained 86%of its bioactivity even after one month of exposure to PBS containing NO donor.Both in vitro and in vivo experiments confirmed that this robust endothelium-mimicking coating substantially reduces thrombosis formation.Overall,our long-acting endothelium-mimicking anti-thrombotic coatings present a promising and feasible strategy to address thrombosis-related challenges associated with blood-contacting devices.
