Neutrophil extracellular traps(NETs)have emerged as key mediators of cardiovascular diseases(CVDs),linking innate immune activation to vascular injury,thrombosis,and maladaptive remodeling.This review synthesizes rece...Neutrophil extracellular traps(NETs)have emerged as key mediators of cardiovascular diseases(CVDs),linking innate immune activation to vascular injury,thrombosis,and maladaptive remodeling.This review synthesizes recent insights into the molecular and cellular pathways driving NET formation,including post-translational modifications,metabolic reprogramming,inflammasome signaling,and autophagy.It highlights the role of NETs in atherosclerosis,thrombosis,myocardial ischemia-reperfusion injury,and hypertension,emphasizing common control points such as peptidylarginine deiminase 4(PAD4)-dependent histone citrullination and nicotinamide adenine dinucleotide phosphate oxidases 2(NOX2)-mediated oxidative stress.Mechanistic interpretation of circulating biomarkers,includingmyeloperoxidase(MPO)-DNA complexes,citrullinated histoneH3,and cell-free DNA,provides a translational bridge between NET biology and patient stratification.Therapeutic strategies targeting NETs are examined through three main approaches:inhibition of NET initiation,enhancement of chromatin clearance,and neutralization of toxic extracellular components,with attention to both established and emerging interventions.In contrast to previous reviews,this study highlights the novelty of a mechano-therapeutic framework by providing a mechanistic roadmap linking NET formation pathways to therapeutic targeting in cardiovascular disease.Moving forward,integrating mechanistic information with biomarker discovery,precision profiling,and targeted therapies offers innovative strategies to reduce vascular inflammation and improve outcomes in cardiovascular disease.展开更多
The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2...The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2019(COVID-19).Nucleic acid-based drug gene therapies have emerged as exceptionally promising avenues for combating disease.Furthermore,lipid nanoparticles(LNPs)are ideal carriers for nucleic acid delivery owing to their ionic nature,which enables nucleic acids to electrostatically interact with intracellular membranes,thereby promoting efficient intracellular nucleic acid release.Unfortunately,the effectiveness of LNPs in targeting organs beyond the liver is relatively poor.Thus,enhanced extrahepatic targeting is another important property that would lead to improved in vivo delivery by LNPs.This review focuses on the fundamental characteristics and functions of LNPs developed to facilitate cellular uptake and ensure effective intracellular release of m RNAs.Promising applications,possible advantages and potential challenges associated with use of LNPs in organ specific delivery and release of m RNAs are summarized.Furthermore,the need for future research to address limitations of currently developed LNPs for clinical applications of the m RNA technology is emphasized.展开更多
In recent years,proteolysis-targeting chimeras(PROTACs)have gained widespread attention as an emerging therapeutic approach.PROTACs are bifunctional molecules composed of a target protein-binding ligand,an E3 ubiquiti...In recent years,proteolysis-targeting chimeras(PROTACs)have gained widespread attention as an emerging therapeutic approach.PROTACs are bifunctional molecules composed of a target protein-binding ligand,an E3 ubiquitin ligase ligand,and a linker connecting these ligands.By harnessing the cell’s intrinsic ubiquitin-proteasome system(UPS),they promote the ubiquitination of specific target proteins,leading to their degradation and therapeutic effects.PROTACs show exceptional promise in targeting conventional“undruggable”targets compared to traditional small-molecule inhibitors.This review provides an overview of PROTACs,including their molecular mechanism of action,therapeutic benefits,development history,key design aspects,current research and development challenges,and future trends in nextgeneration PROTAC technology.展开更多
Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achie...Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achieve specific targeting of activated hepatic stellate cells(a HSCs) and precise treatment of hepatic fibrosis,this study developed a dual-functional drug delivery system(SIL/c RGD-PEG-PPS PMs) with both targeting and responsive release capabilities.It aims to target the αvβ 3 receptor specifically expressed on the surface of a HSCs using the cyclic peptide c(RGDyk),and to exploit the high reactive oxygen species(ROS) level in the cellular microenvironment to achieve concentrated burst release of drugs at the pathological sites of hepatic fibrosis.Based on multiple assessments,SIL/c RGD-PEG-PPS PMs specifically enhanced the targeted delivery of silybin(SIL) to a HSCs,inhibited the proliferation and migration of a HSCs,and exhibited good biosafety.Additionally,it demonstrated excellent anti-fibrotic activity in fibrotic mice.In summary,this study shows great potential in targeted treatment of hepatic fibrosis and provides a multifunctional tool for advancing the research and therapeutic strategies of hepatic fibrosis.展开更多
Peripheral immunity forms the foundation of tumor immunity,while tumor immunity represents a more refined adaptation of peripheral immune responses.The tumor microenvironment(TME),a localized niche surrounding tumor c...Peripheral immunity forms the foundation of tumor immunity,while tumor immunity represents a more refined adaptation of peripheral immune responses.The tumor microenvironment(TME),a localized niche surrounding tumor cells,is inherently immunosuppressive(1,2).Effective tumor therapy necessitates the dismantling of this microenvironment,aiming to eradicate tumors from the host system.展开更多
Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxyge...Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.展开更多
Momordica antiviral protein 30 kD(MAP30)is a type I ribosome-inactivating protein(RIP)with antibacterial,anti-HIV and antitumor activities but lacks the ability to target tumor cells.To increase its tumor-targeting ab...Momordica antiviral protein 30 kD(MAP30)is a type I ribosome-inactivating protein(RIP)with antibacterial,anti-HIV and antitumor activities but lacks the ability to target tumor cells.To increase its tumor-targeting ability,the arginine-glycine-aspartic(RGD)peptide and the epidermal growth factor receptor interference(EGFRi)peptide were fused with MAP30,which was named ELRL-MAP30.The efficiency of targeted therapy for triple-negative breast cancer(TNBC)MDA-MB-231 cells,which lack the expression of estrogen receptor(ER),Progesterone receptor(PgR)and human epidermal growth factor receptor-2(HER2),is limited.In this study,we focus on exploring the effect and mechanism of ELRL-MAP30 on TNBC MDA-MB-231 cells.First,we discovered that ELRL-MAP30 significantly inhibited the migration and invasion of MDA-MB-231 cells and induced MDA-MB-231 cell apoptosis.Moreover,ELRL-MAP30 treatment resulted in a significant increase in Bax expression and a decrease in Bcl-2 expression.Furthermore,ELRL-MAP30 triggered apoptosis via the Fak/EGFR/Erk and Ilk/Akt signaling pathways.In addition,recombinant ELRL-MAP30 can inhibit chicken embryonic angiogenesis,and also inhibit the tube formation ability of human umbilical vein endothelial cells(HUVECs),indicating its potential therapeutic effects on tumor angiogenesis.Collectively,these results indicate that ELRL-MAP30 has significant tumor-targeting properties in MDA-MB-231 cancer cells and reveals potential therapeutic effects on angiogenesis.These findings indicate the potential role of ELRL-MAP30 in the targeted treatment of the TNBC cell line MDA-MB-231.展开更多
The published article titled“Overexpression of miR-1283 Inhibits Cell Proliferation and Invasion of Glioma Cells by Targeting ATF4”has been retracted from Oncology Research,Vol.27,No.3,2019,pp.325–334.
The published article titled“Swainsonine inhibits invasion and the EMT process in esophageal carcinoma cells by targeting twist1”has been retracted from Oncology Research,Vol.26,No.8,2018,pp.1207–1213.
The published article titled“MicroRNA-133b Inhibits Cell Proliferation and Invasion in Osteosarcoma by Targeting Sirt1”has been retracted from Oncology Research,Vol.25,No.9,2017,pp.1421–1430.
Nanobodies have been extensively demonstrated in biomedical imaging and therapy. However, nanobody probes often suffer from rapid renal clearance due to its small size. Herein, we reported a recombinant nanobody with ...Nanobodies have been extensively demonstrated in biomedical imaging and therapy. However, nanobody probes often suffer from rapid renal clearance due to its small size. Herein, we reported a recombinant nanobody with a 200 amino-acid polypeptide chain consisting of Pro, Ala, and Ser (PAS) at the C-terminal, which can be easily expressed in Escherichia coli with a high yield. The PASylated nanobody was functionalized with a fluorescent dye and the cell labeling properties were characterized by flow cytometry and confocal microscopy. In vivo fluorescence imaging indicated that the PASylated nanobody showed comparable blood circulation time, but ∼1.5 times higher tumor targeting ability as compared to the PEGylated nanobody of comparable molecular weight. Our findings demonstrate that nanobody PASylation is a promising approach to produce long-circulating nanobody probes for imaging and therapeutic applications.展开更多
Developing novel anti-infective drugs is essential to combat antimicrobial resistance,address emerging pathogens,and safeguard global health against evolving infectious threats.A recent publication in the esteemed jou...Developing novel anti-infective drugs is essential to combat antimicrobial resistance,address emerging pathogens,and safeguard global health against evolving infectious threats.A recent publication in the esteemed journal Nature by Qisen Deng et al.reported on the comprehensive evaluation of the therapeutic efficacy of mandimycin against multidrug-resistant(MDR)fungal pathogens.The polyene macrolide antifungal antibiotic,mandimycin,was discovered using a phylogeny-guided natural-product discovery platform.Authors utilized various in vivo mouse models such as systemic and soft-tissue infections to assess the antifungal activity of mandimycin.The efficacy was measured by quantifying the fungal burden in major organs and assessing survival rates.In systemic infections,mandimycin demonstrated significant dose-dependent antifungal efficacy,as compared to amphotericin B,particularly in cases where the latter was ineffective against MDR C.auris.Furthermore,mandimycin showed a favorable safety profile,with low toxicity and no observed side effects at effective doses.The study's findings contribute valuable insights into the potential of mandimycin as a novel antifungal agent,offering hope for improved treatment options against challenging fungal infections.The results pave the way for further research and clinical applications in the fight against antifungal resistance.展开更多
Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we ha...Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we have developed a novel charge-reversible nanogel to deliver paclitaxel(PTX)dimers(DPP)with enhanced stability and targeting precision.The nanogels exhibit a dynamic charge-reversal mechanism responsive to the acidic tumor microenvironment(TME),optimizing the cellular uptake of prodrugs.In the high glutathione(GSH)conditions within cancer cells,the disulfide bonds in the DPP are cleaved,resulting in the intracellular release of active PTX and reduced drug toxicity to normal cells.In vivo pharmacokinetic studies revealed an extended plasma elimination half-life for the charge-reversible nanocarriers,and antitumor efficacy studies demonstrated superior tumor suppression with minimal systemic toxicity.This research underscores the potential of integrating charge-reversal and responsive release mechanisms into one nanocarrier system,balancing the long circulation and high tumor cell internalization capacity of the nanocarrier,and providing a promising strategy for targeted delivery of nanomedicine.展开更多
The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting...The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting photodynamic oxidizer(designated as PhotoOx)is fabricated to boost the antitumor immunity by integrating photodynamic therapy(PDT)induced immunogenic cell death(ICD)with indoleamine 2,3-dioxygenase 1(IDO1)inhibition.Among which,an ER targeting photosensitizer-peptide conjugate called PhotoPe is rationally designed for optimal functionality and amphiphilicity,which could self-assemble into nano-micelles co-delivering chlorin e6 and NLG919.PhotoOx exhibits a good stability to enable ER targeting drug delivery,which could induce ER rupture to intensify PDT induced ICD and release damage associated molecular patterns(DAMPs).Furthermore,PhotoOx could effectively initiate immunological cascades,leading to the suppression of regulatory T cells(Tregs)and activation of CD8^(+)T cells when combines with IDO inhibition.Furthermore,the multi-synergistic effects of PhotoOx activate a robust systemic anti-tumor immune response,resulting in the eradication of lung and liver metastases.Such a medication strategy might inspire the rational design of biomedicine for precise drug delivery,which also provides a sophisticated mechanism for addressing the challenges of solid tumor treatment.展开更多
Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the...Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.展开更多
Antimicrobial resistance(AMR)is a growing public health crisis that requires innovative solutions.Emerging multidrug resistant(MDR)Salmonella typhimurium has raised concern for its effect on pathogenic infection and m...Antimicrobial resistance(AMR)is a growing public health crisis that requires innovative solutions.Emerging multidrug resistant(MDR)Salmonella typhimurium has raised concern for its effect on pathogenic infection and mortality in humans caused by enteric diseases.To combat these MDR Salmonella typhimurium pathogens,highly effective and broad-spectrum antibiotics such as flufenicol(FFC)need to be evaluated for their potent antibacterial activity against Salmonella typhimurium.However,the low solubility and low oral bioavailability of flufenicol need to be addressed to better combat AMR.In this work,we develop a novel nano-formulation,flufenicol nano-micelles(FTPPM),which are based on d-α-tocopherol polyethylene glycol 1,000 succinate(TPGS)/poloxamer 188(P188),for the targeted treatment of biofilms formed by drug-resistant Salmonella typhimurium in the intestine.Herein,FTPPM were prepared via a thin film hydration method.The preparation process for the mixed micelles is simple and convenient compared with other existing nanodrug delivery systems,which can further decrease production costs.The optimized FTPPM demonstrated outstanding stability and sustained release.An evaluation of the in vivo anti-drug-resistant Salmonella typhimurium efficacy demonstrated that FTPPM showed a stronger efficacy(68.17%)than did florfenicol-loaded TPGS polymer micelles(FTPM),flufenicol active pharmaceutical ingredients(FFC-API),and flufenicol commercially available medicine(FFC-CAM),and also exhibited outstanding biocompatibility.Notably,FTPPM also inhibited drug-resistant Salmonella typhimurium from forming biofilms.More importantly,FTPPM effectively restored intestinal flora disorders induced by drug-resistant Salmonella typhimurium in mice.In summary,FTPPM significantly improved the solubility and oral bioavailability of florfenicol,enhancing its efficacy against drug-resistant Salmonella typhimurium both in vitro and in vivo.FTPPM represent a promising drug-resistant Salmonella typhimurium treatment for curbing bacterial resistance via oral administration.展开更多
BACKGROUND Unraveling the pathogenesis of colorectal cancer(CRC)can aid in developing prevention and treatment strategies.Aurora kinase A(AURKA)is a key participant in mitotic control and interacts with its co-activat...BACKGROUND Unraveling the pathogenesis of colorectal cancer(CRC)can aid in developing prevention and treatment strategies.Aurora kinase A(AURKA)is a key participant in mitotic control and interacts with its co-activator,the targeting protein for Xklp2(TPX2)microtubule nucleation factor.AURKA is associated with poor clinical outcomes and high risks of CRC recurrence.AURKA/TPX2 co-overexpression in cancer may contribute to tumorigenesis.Despite its pivotal role in CRC development and progression,the action mechanism of AURKA remains unclear.Further research is needed to explore the complex interplay between AURKA and TPX2 and to develop effective targeted treatments for patients with CRC.AIM To compare effects of AURKA and TPX2 and their combined knockdown on CRC cells.METHODS We evaluated three CRC gene datasets about CRC(GSE32323,GSE25071,and GSE21510).Potential hub genes associated with CRC onset were identified using the Venn,search tool for the retrieval of interacting genes,and KOBAS platforms,with AURKA and TPX2 emerging as significant factors.Subsequently,cell models with knockdown of AURKA,TPX2,or both were constructed using SW480 and LOVO cells.Quantitative real-time polymerase chain reaction,western blotting,cell counting kit-8,cell cloning assays,flow cytometry,and Transwell assays were used.RESULTS Forty-three highly expressed genes and 39 poorly expressed genes overlapped in cancer tissues compared to controls from three datasets.In the protein-protein interaction network of highly expressed genes,AURKA was one of key genes.Its combined score with TPX2 was 0.999,and their co-expression score was 0.846.In CRC cells,knockdown of AURKA,TPX2,or both reduced cell viability and colony number,while blocking G0/G1 phase and enhancing cell apoptosis.Additionally,they were weakened cell proliferation and migration abilities.Furthermore,the expression levels of B-cell lymphoma-2-Associated X,caspase 3,and tumor protein P53,and E-cadherin increased with a decrease in B-cell lymphoma-2,N-cadherin,and vimentin proteins.These effects were amplified when both AURKA and TPX2 were concurrently downregulated.CONCLUSION Combined knockdown of AURKA and TPX2 was effective in suppressing the malignant phenotype in CRC.Coinhibition of gene expression is a potential developmental direction for CRC treatment.展开更多
The published article titled“MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1”has been retracted from Oncology Research,Vol.25,No.7,2017,pp.1117...The published article titled“MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1”has been retracted from Oncology Research,Vol.25,No.7,2017,pp.1117–1127.展开更多
Targeted cancer therapy has emerged as a promising alternative to conventional chemotherapy,which is often plagued by poor selectivity,off-target effects,and drug resistance.Among the various targeting agents in devel...Targeted cancer therapy has emerged as a promising alternative to conventional chemotherapy,which is often plagued by poor selectivity,off-target effects,and drug resistance.Among the various targeting agents in development,peptides stand out for their unique advantages,including minimal immunogenicity,high tissue penetration,and ease of modification.Their small size,specificity,and flexibility allow them to target cancer cells while minimizing damage to healthy tissue selectively.Peptide-based therapies have shown great potential in enhancing the efficacy of drug delivery,improving tumor imaging,and reducing adverse effects.With cancer responsible for millions of deaths worldwide,the development of peptide-based therapeutics offers new hope in addressing the limitations of current treatments.As detailed studies on different aspects of targeting peptides are crucial for optimizing drug development,this review provides a comprehensive overview of the literature on tumor-targeting peptides,including their structure,sources,modes of action,and their application in cancer therapy—both as standalone agents and in fusion drugs.Additionally,various computational tools for peptide-based tumor-targeting drug design and validation are explored.The promising results from these studies highlight peptides as ideal candidates for targeted cancer therapies,offering valuable insights for researchers and accelerating the discovery of novel anti-tumor peptide base drug candidates.展开更多
The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of...The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect,as the core of energy metabolism and apoptosis regulation.Mutations in mitochondrial DNA(mtDNA)and dysregulation of mitochondrial autophagy(mitophagy)further enhance the invasive and metastatic capabilities of liver cancer.Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes,regulating calcium homeostasis,repairing mtDNA,and activating mitochondrial apoptotic pathways.Although these approaches have shown therapeutic effects,challenges persist,such as tumor heterogeneity,insufficient drug specificity,and drug resistance.Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction,development of targeted delivery systems,optimization of combination therapy regimens,and screening of biomarkers to provide new pathways for individualized treatment.With advances in technology,targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.展开更多
文摘Neutrophil extracellular traps(NETs)have emerged as key mediators of cardiovascular diseases(CVDs),linking innate immune activation to vascular injury,thrombosis,and maladaptive remodeling.This review synthesizes recent insights into the molecular and cellular pathways driving NET formation,including post-translational modifications,metabolic reprogramming,inflammasome signaling,and autophagy.It highlights the role of NETs in atherosclerosis,thrombosis,myocardial ischemia-reperfusion injury,and hypertension,emphasizing common control points such as peptidylarginine deiminase 4(PAD4)-dependent histone citrullination and nicotinamide adenine dinucleotide phosphate oxidases 2(NOX2)-mediated oxidative stress.Mechanistic interpretation of circulating biomarkers,includingmyeloperoxidase(MPO)-DNA complexes,citrullinated histoneH3,and cell-free DNA,provides a translational bridge between NET biology and patient stratification.Therapeutic strategies targeting NETs are examined through three main approaches:inhibition of NET initiation,enhancement of chromatin clearance,and neutralization of toxic extracellular components,with attention to both established and emerging interventions.In contrast to previous reviews,this study highlights the novelty of a mechano-therapeutic framework by providing a mechanistic roadmap linking NET formation pathways to therapeutic targeting in cardiovascular disease.Moving forward,integrating mechanistic information with biomarker discovery,precision profiling,and targeted therapies offers innovative strategies to reduce vascular inflammation and improve outcomes in cardiovascular disease.
基金supported by Guang Dong Basic and Applied Basic Research Foundation(No.2023B1515120001)Shenzhen University 2035 Program for Excellent Research(Nos.00000208 and 00000225)。
文摘The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2019(COVID-19).Nucleic acid-based drug gene therapies have emerged as exceptionally promising avenues for combating disease.Furthermore,lipid nanoparticles(LNPs)are ideal carriers for nucleic acid delivery owing to their ionic nature,which enables nucleic acids to electrostatically interact with intracellular membranes,thereby promoting efficient intracellular nucleic acid release.Unfortunately,the effectiveness of LNPs in targeting organs beyond the liver is relatively poor.Thus,enhanced extrahepatic targeting is another important property that would lead to improved in vivo delivery by LNPs.This review focuses on the fundamental characteristics and functions of LNPs developed to facilitate cellular uptake and ensure effective intracellular release of m RNAs.Promising applications,possible advantages and potential challenges associated with use of LNPs in organ specific delivery and release of m RNAs are summarized.Furthermore,the need for future research to address limitations of currently developed LNPs for clinical applications of the m RNA technology is emphasized.
文摘In recent years,proteolysis-targeting chimeras(PROTACs)have gained widespread attention as an emerging therapeutic approach.PROTACs are bifunctional molecules composed of a target protein-binding ligand,an E3 ubiquitin ligase ligand,and a linker connecting these ligands.By harnessing the cell’s intrinsic ubiquitin-proteasome system(UPS),they promote the ubiquitination of specific target proteins,leading to their degradation and therapeutic effects.PROTACs show exceptional promise in targeting conventional“undruggable”targets compared to traditional small-molecule inhibitors.This review provides an overview of PROTACs,including their molecular mechanism of action,therapeutic benefits,development history,key design aspects,current research and development challenges,and future trends in nextgeneration PROTAC technology.
基金supported by the financial assistance from Natural Science Fund Project of Science and Technology Department of Jilin Province (Nos.YDZJ202301ZYTS141,YDZJ202501ZYTS793)。
文摘Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achieve specific targeting of activated hepatic stellate cells(a HSCs) and precise treatment of hepatic fibrosis,this study developed a dual-functional drug delivery system(SIL/c RGD-PEG-PPS PMs) with both targeting and responsive release capabilities.It aims to target the αvβ 3 receptor specifically expressed on the surface of a HSCs using the cyclic peptide c(RGDyk),and to exploit the high reactive oxygen species(ROS) level in the cellular microenvironment to achieve concentrated burst release of drugs at the pathological sites of hepatic fibrosis.Based on multiple assessments,SIL/c RGD-PEG-PPS PMs specifically enhanced the targeted delivery of silybin(SIL) to a HSCs,inhibited the proliferation and migration of a HSCs,and exhibited good biosafety.Additionally,it demonstrated excellent anti-fibrotic activity in fibrotic mice.In summary,this study shows great potential in targeted treatment of hepatic fibrosis and provides a multifunctional tool for advancing the research and therapeutic strategies of hepatic fibrosis.
文摘Peripheral immunity forms the foundation of tumor immunity,while tumor immunity represents a more refined adaptation of peripheral immune responses.The tumor microenvironment(TME),a localized niche surrounding tumor cells,is inherently immunosuppressive(1,2).Effective tumor therapy necessitates the dismantling of this microenvironment,aiming to eradicate tumors from the host system.
基金support from the National Natural Science Foundation of China(Nos.22277056,21977052)the Distinguished Young Scholars of Jiangsu Province(No.BK20230006)+2 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20230977,BK20231090)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.23KJB150020)the Jiangsu Excellent Postdoctoral Program(No.2022ZB758)。
文摘Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.
文摘Momordica antiviral protein 30 kD(MAP30)is a type I ribosome-inactivating protein(RIP)with antibacterial,anti-HIV and antitumor activities but lacks the ability to target tumor cells.To increase its tumor-targeting ability,the arginine-glycine-aspartic(RGD)peptide and the epidermal growth factor receptor interference(EGFRi)peptide were fused with MAP30,which was named ELRL-MAP30.The efficiency of targeted therapy for triple-negative breast cancer(TNBC)MDA-MB-231 cells,which lack the expression of estrogen receptor(ER),Progesterone receptor(PgR)and human epidermal growth factor receptor-2(HER2),is limited.In this study,we focus on exploring the effect and mechanism of ELRL-MAP30 on TNBC MDA-MB-231 cells.First,we discovered that ELRL-MAP30 significantly inhibited the migration and invasion of MDA-MB-231 cells and induced MDA-MB-231 cell apoptosis.Moreover,ELRL-MAP30 treatment resulted in a significant increase in Bax expression and a decrease in Bcl-2 expression.Furthermore,ELRL-MAP30 triggered apoptosis via the Fak/EGFR/Erk and Ilk/Akt signaling pathways.In addition,recombinant ELRL-MAP30 can inhibit chicken embryonic angiogenesis,and also inhibit the tube formation ability of human umbilical vein endothelial cells(HUVECs),indicating its potential therapeutic effects on tumor angiogenesis.Collectively,these results indicate that ELRL-MAP30 has significant tumor-targeting properties in MDA-MB-231 cancer cells and reveals potential therapeutic effects on angiogenesis.These findings indicate the potential role of ELRL-MAP30 in the targeted treatment of the TNBC cell line MDA-MB-231.
文摘The published article titled“Overexpression of miR-1283 Inhibits Cell Proliferation and Invasion of Glioma Cells by Targeting ATF4”has been retracted from Oncology Research,Vol.27,No.3,2019,pp.325–334.
文摘The published article titled“Swainsonine inhibits invasion and the EMT process in esophageal carcinoma cells by targeting twist1”has been retracted from Oncology Research,Vol.26,No.8,2018,pp.1207–1213.
文摘The published article titled“MicroRNA-133b Inhibits Cell Proliferation and Invasion in Osteosarcoma by Targeting Sirt1”has been retracted from Oncology Research,Vol.25,No.9,2017,pp.1421–1430.
基金support by the National Key R&D Program of China(Grant No.2020YFA0909000)National Natural Science Foundation of China(Grant Nos.62235007 and 22204070)+2 种基金Shenzhen Science and Technology Program(Grant Nos.KQTD20170810111314625,JCYJ20210324115807021,and SGDX20211123114002003)Shenzhen Bay Laboratory(SZBL 2021080601002)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022 B1212010003).
文摘Nanobodies have been extensively demonstrated in biomedical imaging and therapy. However, nanobody probes often suffer from rapid renal clearance due to its small size. Herein, we reported a recombinant nanobody with a 200 amino-acid polypeptide chain consisting of Pro, Ala, and Ser (PAS) at the C-terminal, which can be easily expressed in Escherichia coli with a high yield. The PASylated nanobody was functionalized with a fluorescent dye and the cell labeling properties were characterized by flow cytometry and confocal microscopy. In vivo fluorescence imaging indicated that the PASylated nanobody showed comparable blood circulation time, but ∼1.5 times higher tumor targeting ability as compared to the PEGylated nanobody of comparable molecular weight. Our findings demonstrate that nanobody PASylation is a promising approach to produce long-circulating nanobody probes for imaging and therapeutic applications.
基金the National Key Research and Development Program of China(2023YFD1700500)the College Student Research Training Program(202110307002T)Bayer Grants4Ag Initiative for their support.
文摘Developing novel anti-infective drugs is essential to combat antimicrobial resistance,address emerging pathogens,and safeguard global health against evolving infectious threats.A recent publication in the esteemed journal Nature by Qisen Deng et al.reported on the comprehensive evaluation of the therapeutic efficacy of mandimycin against multidrug-resistant(MDR)fungal pathogens.The polyene macrolide antifungal antibiotic,mandimycin,was discovered using a phylogeny-guided natural-product discovery platform.Authors utilized various in vivo mouse models such as systemic and soft-tissue infections to assess the antifungal activity of mandimycin.The efficacy was measured by quantifying the fungal burden in major organs and assessing survival rates.In systemic infections,mandimycin demonstrated significant dose-dependent antifungal efficacy,as compared to amphotericin B,particularly in cases where the latter was ineffective against MDR C.auris.Furthermore,mandimycin showed a favorable safety profile,with low toxicity and no observed side effects at effective doses.The study's findings contribute valuable insights into the potential of mandimycin as a novel antifungal agent,offering hope for improved treatment options against challenging fungal infections.The results pave the way for further research and clinical applications in the fight against antifungal resistance.
基金supported by the Natural Science Foundation of Jilin Province(No.20240101003JJ)the National Natural Science Foundation of China(Nos.22275065,52073116)。
文摘Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we have developed a novel charge-reversible nanogel to deliver paclitaxel(PTX)dimers(DPP)with enhanced stability and targeting precision.The nanogels exhibit a dynamic charge-reversal mechanism responsive to the acidic tumor microenvironment(TME),optimizing the cellular uptake of prodrugs.In the high glutathione(GSH)conditions within cancer cells,the disulfide bonds in the DPP are cleaved,resulting in the intracellular release of active PTX and reduced drug toxicity to normal cells.In vivo pharmacokinetic studies revealed an extended plasma elimination half-life for the charge-reversible nanocarriers,and antitumor efficacy studies demonstrated superior tumor suppression with minimal systemic toxicity.This research underscores the potential of integrating charge-reversal and responsive release mechanisms into one nanocarrier system,balancing the long circulation and high tumor cell internalization capacity of the nanocarrier,and providing a promising strategy for targeted delivery of nanomedicine.
基金supported by the National Natural Science Foundation of China(No.32371394)the National Key R&D Program of China(No.2021YFD1800600)+3 种基金the Special Projects in Key Areas of Colleges and Universities in Guangdong Province(No.2022ZDZX2046)the Open Project of State Key Laboratory of Respiratory Disease(No.SKLRD-OP-202502)the Postdoctoral Fellowship Program of CPSF(No.GZC20230619)Postdoctoral startup funding of Guangzhou Medical University(No.Q0301–130)。
文摘The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting photodynamic oxidizer(designated as PhotoOx)is fabricated to boost the antitumor immunity by integrating photodynamic therapy(PDT)induced immunogenic cell death(ICD)with indoleamine 2,3-dioxygenase 1(IDO1)inhibition.Among which,an ER targeting photosensitizer-peptide conjugate called PhotoPe is rationally designed for optimal functionality and amphiphilicity,which could self-assemble into nano-micelles co-delivering chlorin e6 and NLG919.PhotoOx exhibits a good stability to enable ER targeting drug delivery,which could induce ER rupture to intensify PDT induced ICD and release damage associated molecular patterns(DAMPs).Furthermore,PhotoOx could effectively initiate immunological cascades,leading to the suppression of regulatory T cells(Tregs)and activation of CD8^(+)T cells when combines with IDO inhibition.Furthermore,the multi-synergistic effects of PhotoOx activate a robust systemic anti-tumor immune response,resulting in the eradication of lung and liver metastases.Such a medication strategy might inspire the rational design of biomedicine for precise drug delivery,which also provides a sophisticated mechanism for addressing the challenges of solid tumor treatment.
基金supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-026,China).
文摘Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.
基金supported by the grants from the National Key Research and Development Program of China(Grant No.:2024YFE0106300)the Key Projects of Natural Science Foundation of Anhui Provincial Department of Education,China(Grant No.:2023AH051017)+2 种基金the Outstanding Youth Scientific Research Foundation of the Anhui Education Department,China(Grant No.:2024AH030019)the National Natural Science Foundation of China(Grant No.:32302923)Natural Science Foundation of Anhui Province,China(Grant No.:2208085MC79).
文摘Antimicrobial resistance(AMR)is a growing public health crisis that requires innovative solutions.Emerging multidrug resistant(MDR)Salmonella typhimurium has raised concern for its effect on pathogenic infection and mortality in humans caused by enteric diseases.To combat these MDR Salmonella typhimurium pathogens,highly effective and broad-spectrum antibiotics such as flufenicol(FFC)need to be evaluated for their potent antibacterial activity against Salmonella typhimurium.However,the low solubility and low oral bioavailability of flufenicol need to be addressed to better combat AMR.In this work,we develop a novel nano-formulation,flufenicol nano-micelles(FTPPM),which are based on d-α-tocopherol polyethylene glycol 1,000 succinate(TPGS)/poloxamer 188(P188),for the targeted treatment of biofilms formed by drug-resistant Salmonella typhimurium in the intestine.Herein,FTPPM were prepared via a thin film hydration method.The preparation process for the mixed micelles is simple and convenient compared with other existing nanodrug delivery systems,which can further decrease production costs.The optimized FTPPM demonstrated outstanding stability and sustained release.An evaluation of the in vivo anti-drug-resistant Salmonella typhimurium efficacy demonstrated that FTPPM showed a stronger efficacy(68.17%)than did florfenicol-loaded TPGS polymer micelles(FTPM),flufenicol active pharmaceutical ingredients(FFC-API),and flufenicol commercially available medicine(FFC-CAM),and also exhibited outstanding biocompatibility.Notably,FTPPM also inhibited drug-resistant Salmonella typhimurium from forming biofilms.More importantly,FTPPM effectively restored intestinal flora disorders induced by drug-resistant Salmonella typhimurium in mice.In summary,FTPPM significantly improved the solubility and oral bioavailability of florfenicol,enhancing its efficacy against drug-resistant Salmonella typhimurium both in vitro and in vivo.FTPPM represent a promising drug-resistant Salmonella typhimurium treatment for curbing bacterial resistance via oral administration.
文摘BACKGROUND Unraveling the pathogenesis of colorectal cancer(CRC)can aid in developing prevention and treatment strategies.Aurora kinase A(AURKA)is a key participant in mitotic control and interacts with its co-activator,the targeting protein for Xklp2(TPX2)microtubule nucleation factor.AURKA is associated with poor clinical outcomes and high risks of CRC recurrence.AURKA/TPX2 co-overexpression in cancer may contribute to tumorigenesis.Despite its pivotal role in CRC development and progression,the action mechanism of AURKA remains unclear.Further research is needed to explore the complex interplay between AURKA and TPX2 and to develop effective targeted treatments for patients with CRC.AIM To compare effects of AURKA and TPX2 and their combined knockdown on CRC cells.METHODS We evaluated three CRC gene datasets about CRC(GSE32323,GSE25071,and GSE21510).Potential hub genes associated with CRC onset were identified using the Venn,search tool for the retrieval of interacting genes,and KOBAS platforms,with AURKA and TPX2 emerging as significant factors.Subsequently,cell models with knockdown of AURKA,TPX2,or both were constructed using SW480 and LOVO cells.Quantitative real-time polymerase chain reaction,western blotting,cell counting kit-8,cell cloning assays,flow cytometry,and Transwell assays were used.RESULTS Forty-three highly expressed genes and 39 poorly expressed genes overlapped in cancer tissues compared to controls from three datasets.In the protein-protein interaction network of highly expressed genes,AURKA was one of key genes.Its combined score with TPX2 was 0.999,and their co-expression score was 0.846.In CRC cells,knockdown of AURKA,TPX2,or both reduced cell viability and colony number,while blocking G0/G1 phase and enhancing cell apoptosis.Additionally,they were weakened cell proliferation and migration abilities.Furthermore,the expression levels of B-cell lymphoma-2-Associated X,caspase 3,and tumor protein P53,and E-cadherin increased with a decrease in B-cell lymphoma-2,N-cadherin,and vimentin proteins.These effects were amplified when both AURKA and TPX2 were concurrently downregulated.CONCLUSION Combined knockdown of AURKA and TPX2 was effective in suppressing the malignant phenotype in CRC.Coinhibition of gene expression is a potential developmental direction for CRC treatment.
文摘The published article titled“MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1”has been retracted from Oncology Research,Vol.25,No.7,2017,pp.1117–1127.
文摘Targeted cancer therapy has emerged as a promising alternative to conventional chemotherapy,which is often plagued by poor selectivity,off-target effects,and drug resistance.Among the various targeting agents in development,peptides stand out for their unique advantages,including minimal immunogenicity,high tissue penetration,and ease of modification.Their small size,specificity,and flexibility allow them to target cancer cells while minimizing damage to healthy tissue selectively.Peptide-based therapies have shown great potential in enhancing the efficacy of drug delivery,improving tumor imaging,and reducing adverse effects.With cancer responsible for millions of deaths worldwide,the development of peptide-based therapeutics offers new hope in addressing the limitations of current treatments.As detailed studies on different aspects of targeting peptides are crucial for optimizing drug development,this review provides a comprehensive overview of the literature on tumor-targeting peptides,including their structure,sources,modes of action,and their application in cancer therapy—both as standalone agents and in fusion drugs.Additionally,various computational tools for peptide-based tumor-targeting drug design and validation are explored.The promising results from these studies highlight peptides as ideal candidates for targeted cancer therapies,offering valuable insights for researchers and accelerating the discovery of novel anti-tumor peptide base drug candidates.
基金supported by the National Natural Science Foundation of China(Grant No.81860653)Qiankehe Foundation[Grant No.QN(2025)383].
文摘The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect,as the core of energy metabolism and apoptosis regulation.Mutations in mitochondrial DNA(mtDNA)and dysregulation of mitochondrial autophagy(mitophagy)further enhance the invasive and metastatic capabilities of liver cancer.Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes,regulating calcium homeostasis,repairing mtDNA,and activating mitochondrial apoptotic pathways.Although these approaches have shown therapeutic effects,challenges persist,such as tumor heterogeneity,insufficient drug specificity,and drug resistance.Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction,development of targeted delivery systems,optimization of combination therapy regimens,and screening of biomarkers to provide new pathways for individualized treatment.With advances in technology,targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.
