Peptide-and drug-protected gold nanoclusters(Au NCs)with atomic precision have attracted research attention in the last few years owing to their ultrasmall size(<2 nm),well-defined structures,tunable photoluminesce...Peptide-and drug-protected gold nanoclusters(Au NCs)with atomic precision have attracted research attention in the last few years owing to their ultrasmall size(<2 nm),well-defined structures,tunable photoluminescence from the visible to near-infrared range,water solubility,and good biocompatibility.These features,combined with low toxicity and efficient renal clearance,make such Au NCs promising candidates for biomedical use,including diagnosis,therapy,and theranostic.The incorporation of peptides or drugs into Au NCs enhances the stability,targeting specificity,cellular uptake,and prolonged circulation,enabling precise modulation of biological responses.Despite notable advances in achieving atomic precision employing complex ligands such as peptides or drugs,the synthetic methods of this new class of NCs remain a challenge.Careful control of molar ratio(Au:peptide/drug),reducing agent,temperature,and reaction time is required,because these factors directly influence the cluster size,optical properties,and in vivo performance.In this review,we highlight different synthetic approaches of atomically precise peptide-and drug-protected Au NCs,emphasizing the role of rational ligand design and reaction conditions,as well as the challenges associated with structural determination.We further discuss the optical and photoluminescence properties of peptide-protected Au NCs-the mostly explored features for biomedical applications.Finally,we conclude by outlining the current challenges,opportunities for scale-up synthesis,and future design perspectives for these emerging nanomaterials.展开更多
The blood-brain barrier(BBB)is a major challenge in drug delivery for the treatment of central nervous system diseases.Walnut derived peptide TWLPLPR(TW-7)has been proved to promote neuronal mitochondrial autophagy an...The blood-brain barrier(BBB)is a major challenge in drug delivery for the treatment of central nervous system diseases.Walnut derived peptide TWLPLPR(TW-7)has been proved to promote neuronal mitochondrial autophagy and enhance hippocampal neuronal synaptic plasticity,thereby improving learning and memory abilities in mice.We investigated the internalization mechanism and intracellular transport pathway for the walnut-derived peptide,TW-7,using b End.3 cells in an in vitro BBB model system.TW-7 was taken up by the b End.3 cells in a concentration-,temperature-,and energy-dependent manner;this involved increases in caveolin-1 and caveolin-2 protein expression and phosphorylation and inhibition of P-glycoprotein-mediated efflux.Subcellular localization of TW-7 in b End.3 cells was observed,indicating that the plasma membrane,endoplasmic reticulum,Golgi apparatus,lysosomes,and mitochondria participated in intracellular trafficking and that the peptide escaped from lysosomes over time.Caveolae may be critical for TW-7 uptake by brain microvascular endothelial cells,assisting TW-7 to cross the BBB.The results of this study provide a theoretical basis for the mechanism of active peptide penetrating the BBB,and provide a reference for developing neuroprotective active peptide products.展开更多
目的探讨血清表面活性蛋白D(surfactant protein D,SP-D)、黏蛋白1(mucin 1,MUC1)、锌指蛋白A20(zinc finger protein A20,A20)水平对输血相关性急性肺损伤(transfusion-related acute lung injury,TRALI)患者临床预后的预测价值,以期...目的探讨血清表面活性蛋白D(surfactant protein D,SP-D)、黏蛋白1(mucin 1,MUC1)、锌指蛋白A20(zinc finger protein A20,A20)水平对输血相关性急性肺损伤(transfusion-related acute lung injury,TRALI)患者临床预后的预测价值,以期临床个体化干预提供参考。方法选取2020年3月—2025年3月河北省胸科医院收治的TRALI患者249例为研究对象,根据输血后30 d内预后情况,分别纳入预后良好组(178例)、预后不良组(71例)。比较2组一般临床资料及血清SP-D、MUC1、A20水平,Logistic回归分析血清SP-D、MUC1、A20水平对TRALI患者预后不良的影响因素,受试者工作特征(receiver operating characteristic,ROC)曲线分析血清SP-D、MUC1、A20水平单独及联合检测对预后不良的预测效能,并采用一致性分析进行外部验证。结果2组输血次数、发血至输血时间、过敏史、急性生理与慢性健康评分系统Ⅱ(acute physiology and chronic health evaluationⅡ,APACHEⅡ)评分比较,差异有统计学意义(P<0.05);预后不良组血清SP-D、MUC1、A20水平分别为(89.54±21.36)g/L、(22.97±5.14)kU/L、(14.53±1.96)mg/L,明显高于预后良好组的(78.61±18.05)g/L、(16.28±4.32)kU/L、(12.67±1.84)mg/L,差异有统计学意义(P<0.05);Logistic回归分析显示,输血次数、发血至输血时间、过敏史均是TRALI患者预后不良的影响因素(P<0.05),APACHEⅡ评分及血清SP-D、MUC1、A20均与TRALI患者预后不良显著相关(P<0.05);ROC分析显示,血清SP-D、MUC1、A20联合预测预后不良的曲线下面积(area under the curve,AUC)为0.904(95%CI:0.860~0.938),优于各指标单独预测价值(Z=2.507、3.016、3.042,均P<0.05),且外部验证显示,联合预测预后不良与临床实际的符合率为95.00%,Kappa值为0.870(95%CI:0.617~0.982)差异有统计学意义(P<0.05)。结论血清SP-D、MUC1、A20均是TRALI患者预后不良的独立影响因素,联合检测对预后不良具有较高预测价值,可作为TRALI患者预后的潜在预测因子,并可指导临床工作。展开更多
Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety...Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety profiles. This review provides a comprehensive overview of the major trends in peptide drug discovery and development, emphasizing preclinical strategies aimed at improving peptide stability, specificity, and pharmacokinetic properties. It assesses the current applications and challenges of peptide-based drugs in these diseases, illustrating the pharmaceutical areas where peptide-based drugs demonstrate significant potential. Furthermore, this review analyzes the obstacles that must be overcome in the future,aiming to provide valuable insights and references for the continued advancement of peptidebased drugs.展开更多
The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-a...The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-associated infections exacerbate this problem due to their inherent antibiotic resistance and complex structure.Current antibiotic treatments struggle to penetrate biofilms and eradicate persister cells,leading to prolonged antibiotic use and increased resistance.Host defense peptides(HDPs)have shown promise,but their clinical application is limited by factors such as enzymatic degradation and difficulty in largescale preparation.Synthetic HDP mimics,such as poly(2-oxazoline),have emerged as effective alter-natives.Herein,we found that the poly(2-oxazoline),Gly-POX_(20),demonstrated rapid and potent activity against clinically isolated multidrug-resistant Gram-positive strains.Gly-POX_(20) showed greater stability under physiological conditions compared to natural peptides,including resistance to protease degradation.Importantly,Gly-POX_(20) inhibited biofilm formation and eradicated mature biofilm and demonstrated superior in vivo therapeutic efficacy to vancomycin in a MRSA biofilm-associated mouse keratitis model,suggesting its potential as a novel antimicrobial agent against drug-resistant Gram-positive bacteria,especially biofilm-associated infections.展开更多
Solid lipid nanoparticles(SLN)could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport.Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen so...Solid lipid nanoparticles(SLN)could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport.Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment.They are mainly transported by oligopeptide transporter-1(PepT-1)which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption.Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway.This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation.Herein,two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1(GLP-1)analogue exenatide as model drugs.These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6mice and type II diabetic KKAymice.Compared with un-modified SLN,dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake.Interestingly,after internalization,more SLN could access the systemic circulation via lymphatic transport pathway,highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.展开更多
In order to study the effects of Saussurea laniceps polysaccharides(SLPs)on the expression of inflammatory factors and antimicrobial peptide LL-37 in UVB-induced keratinocytes,SLPs were extracted by the ethanol therma...In order to study the effects of Saussurea laniceps polysaccharides(SLPs)on the expression of inflammatory factors and antimicrobial peptide LL-37 in UVB-induced keratinocytes,SLPs were extracted by the ethanol thermal reflux method,and SLPs at different concentrations were used to examine the inhibitory effect of COX-2(a key mediator of inflammatory pathway).A cell model of UVB irradiation-induced inflammation was established to determine the influence of SLPs on prostaglandin E2(PGE-2),TNF-αand IL-1βinflammatory factors,as well as the relationships of SLPs with LL-37 expression.An enzyme-linked immunosorbent assay(ELISA)and western blot analysis were used to detect the production of inflammatory factors and LL-37 antimicrobial peptide.The results showed that the inhibition rate of COX-2 was 82.41%at 1000μg/mL,and the expression of PGE-2,TNF-αand IL-1βinflammatory factors in HaCaT cells was significantly downregulated at 100μg/mL(P<0.01).In addition,SLPs at 50μg/mL and 100μg/mL concentrations enhanced the expression of LL-37 antimicrobial peptide(P<0.01),thereby down-regulating the expression of TNF-αand IL-1βinflammatory factors,then reducing skin inflammation.Conclusion:SLP can significantly inhibit the inflammatory response induced by UVB,and can further slow down the damage caused by inflammation to the skin by regulating LL-37 antimicrobial peptides,which has the potential to prevent skin inflammatory damage caused by UVB irradiation.展开更多
Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug deliv...Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.展开更多
基金RGM is grateful to CNPq for the PDE fellowship(200437/2025-9),MTM acknowledges CNPq research scholarship(314470/2023-9)FAPESP fundings(2022/01825-22025/063196).
文摘Peptide-and drug-protected gold nanoclusters(Au NCs)with atomic precision have attracted research attention in the last few years owing to their ultrasmall size(<2 nm),well-defined structures,tunable photoluminescence from the visible to near-infrared range,water solubility,and good biocompatibility.These features,combined with low toxicity and efficient renal clearance,make such Au NCs promising candidates for biomedical use,including diagnosis,therapy,and theranostic.The incorporation of peptides or drugs into Au NCs enhances the stability,targeting specificity,cellular uptake,and prolonged circulation,enabling precise modulation of biological responses.Despite notable advances in achieving atomic precision employing complex ligands such as peptides or drugs,the synthetic methods of this new class of NCs remain a challenge.Careful control of molar ratio(Au:peptide/drug),reducing agent,temperature,and reaction time is required,because these factors directly influence the cluster size,optical properties,and in vivo performance.In this review,we highlight different synthetic approaches of atomically precise peptide-and drug-protected Au NCs,emphasizing the role of rational ligand design and reaction conditions,as well as the challenges associated with structural determination.We further discuss the optical and photoluminescence properties of peptide-protected Au NCs-the mostly explored features for biomedical applications.Finally,we conclude by outlining the current challenges,opportunities for scale-up synthesis,and future design perspectives for these emerging nanomaterials.
基金supported by the National Natural Science Foundation of China(22378368).
文摘The blood-brain barrier(BBB)is a major challenge in drug delivery for the treatment of central nervous system diseases.Walnut derived peptide TWLPLPR(TW-7)has been proved to promote neuronal mitochondrial autophagy and enhance hippocampal neuronal synaptic plasticity,thereby improving learning and memory abilities in mice.We investigated the internalization mechanism and intracellular transport pathway for the walnut-derived peptide,TW-7,using b End.3 cells in an in vitro BBB model system.TW-7 was taken up by the b End.3 cells in a concentration-,temperature-,and energy-dependent manner;this involved increases in caveolin-1 and caveolin-2 protein expression and phosphorylation and inhibition of P-glycoprotein-mediated efflux.Subcellular localization of TW-7 in b End.3 cells was observed,indicating that the plasma membrane,endoplasmic reticulum,Golgi apparatus,lysosomes,and mitochondria participated in intracellular trafficking and that the peptide escaped from lysosomes over time.Caveolae may be critical for TW-7 uptake by brain microvascular endothelial cells,assisting TW-7 to cross the BBB.The results of this study provide a theoretical basis for the mechanism of active peptide penetrating the BBB,and provide a reference for developing neuroprotective active peptide products.
文摘目的探讨血清表面活性蛋白D(surfactant protein D,SP-D)、黏蛋白1(mucin 1,MUC1)、锌指蛋白A20(zinc finger protein A20,A20)水平对输血相关性急性肺损伤(transfusion-related acute lung injury,TRALI)患者临床预后的预测价值,以期临床个体化干预提供参考。方法选取2020年3月—2025年3月河北省胸科医院收治的TRALI患者249例为研究对象,根据输血后30 d内预后情况,分别纳入预后良好组(178例)、预后不良组(71例)。比较2组一般临床资料及血清SP-D、MUC1、A20水平,Logistic回归分析血清SP-D、MUC1、A20水平对TRALI患者预后不良的影响因素,受试者工作特征(receiver operating characteristic,ROC)曲线分析血清SP-D、MUC1、A20水平单独及联合检测对预后不良的预测效能,并采用一致性分析进行外部验证。结果2组输血次数、发血至输血时间、过敏史、急性生理与慢性健康评分系统Ⅱ(acute physiology and chronic health evaluationⅡ,APACHEⅡ)评分比较,差异有统计学意义(P<0.05);预后不良组血清SP-D、MUC1、A20水平分别为(89.54±21.36)g/L、(22.97±5.14)kU/L、(14.53±1.96)mg/L,明显高于预后良好组的(78.61±18.05)g/L、(16.28±4.32)kU/L、(12.67±1.84)mg/L,差异有统计学意义(P<0.05);Logistic回归分析显示,输血次数、发血至输血时间、过敏史均是TRALI患者预后不良的影响因素(P<0.05),APACHEⅡ评分及血清SP-D、MUC1、A20均与TRALI患者预后不良显著相关(P<0.05);ROC分析显示,血清SP-D、MUC1、A20联合预测预后不良的曲线下面积(area under the curve,AUC)为0.904(95%CI:0.860~0.938),优于各指标单独预测价值(Z=2.507、3.016、3.042,均P<0.05),且外部验证显示,联合预测预后不良与临床实际的符合率为95.00%,Kappa值为0.870(95%CI:0.617~0.982)差异有统计学意义(P<0.05)。结论血清SP-D、MUC1、A20均是TRALI患者预后不良的独立影响因素,联合检测对预后不良具有较高预测价值,可作为TRALI患者预后的潜在预测因子,并可指导临床工作。
基金supported by the National Natural Science Foundation of China (Nos. 82173674 and 82204195)。
文摘Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety profiles. This review provides a comprehensive overview of the major trends in peptide drug discovery and development, emphasizing preclinical strategies aimed at improving peptide stability, specificity, and pharmacokinetic properties. It assesses the current applications and challenges of peptide-based drugs in these diseases, illustrating the pharmaceutical areas where peptide-based drugs demonstrate significant potential. Furthermore, this review analyzes the obstacles that must be overcome in the future,aiming to provide valuable insights and references for the continued advancement of peptidebased drugs.
基金financially supported by the National Key Research and Development Program of China(no.2022YFC2303100)National Natural Science Foundation of China(nos.T2325010,22305082,52203162,and 22075078)+1 种基金Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission),the Fundamental Research Funds for the Central Universities(nos.JKVD1241029 and JKD01241701)Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry(Changchun Institute of Applied Chemistry,Chinese Academy of Sciences),the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology(Ministry of Education,no.R202201).
文摘The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-associated infections exacerbate this problem due to their inherent antibiotic resistance and complex structure.Current antibiotic treatments struggle to penetrate biofilms and eradicate persister cells,leading to prolonged antibiotic use and increased resistance.Host defense peptides(HDPs)have shown promise,but their clinical application is limited by factors such as enzymatic degradation and difficulty in largescale preparation.Synthetic HDP mimics,such as poly(2-oxazoline),have emerged as effective alter-natives.Herein,we found that the poly(2-oxazoline),Gly-POX_(20),demonstrated rapid and potent activity against clinically isolated multidrug-resistant Gram-positive strains.Gly-POX_(20) showed greater stability under physiological conditions compared to natural peptides,including resistance to protease degradation.Importantly,Gly-POX_(20) inhibited biofilm formation and eradicated mature biofilm and demonstrated superior in vivo therapeutic efficacy to vancomycin in a MRSA biofilm-associated mouse keratitis model,suggesting its potential as a novel antimicrobial agent against drug-resistant Gram-positive bacteria,especially biofilm-associated infections.
基金supported by National Key Research and Development Program of China(Grant No.2021YFE0115200)the Regional Innovation and Development Joint Fund of National Natural Science Foundation of China(Grant No.U22A20356).
文摘Solid lipid nanoparticles(SLN)could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport.Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment.They are mainly transported by oligopeptide transporter-1(PepT-1)which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption.Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway.This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation.Herein,two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1(GLP-1)analogue exenatide as model drugs.These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6mice and type II diabetic KKAymice.Compared with un-modified SLN,dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake.Interestingly,after internalization,more SLN could access the systemic circulation via lymphatic transport pathway,highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.
文摘In order to study the effects of Saussurea laniceps polysaccharides(SLPs)on the expression of inflammatory factors and antimicrobial peptide LL-37 in UVB-induced keratinocytes,SLPs were extracted by the ethanol thermal reflux method,and SLPs at different concentrations were used to examine the inhibitory effect of COX-2(a key mediator of inflammatory pathway).A cell model of UVB irradiation-induced inflammation was established to determine the influence of SLPs on prostaglandin E2(PGE-2),TNF-αand IL-1βinflammatory factors,as well as the relationships of SLPs with LL-37 expression.An enzyme-linked immunosorbent assay(ELISA)and western blot analysis were used to detect the production of inflammatory factors and LL-37 antimicrobial peptide.The results showed that the inhibition rate of COX-2 was 82.41%at 1000μg/mL,and the expression of PGE-2,TNF-αand IL-1βinflammatory factors in HaCaT cells was significantly downregulated at 100μg/mL(P<0.01).In addition,SLPs at 50μg/mL and 100μg/mL concentrations enhanced the expression of LL-37 antimicrobial peptide(P<0.01),thereby down-regulating the expression of TNF-αand IL-1βinflammatory factors,then reducing skin inflammation.Conclusion:SLP can significantly inhibit the inflammatory response induced by UVB,and can further slow down the damage caused by inflammation to the skin by regulating LL-37 antimicrobial peptides,which has the potential to prevent skin inflammatory damage caused by UVB irradiation.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2023MC168the National Natural Science Foundation of China,No.31670989the Key R&D Program of Shandong Province,No.2019GSF107037(all to CS).
文摘Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.
