Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide first isolated from swine duodenum. VIP is a neurotransmitter that is extensively distributed in tissues. According to published reports, VPAC1 and VP...Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide first isolated from swine duodenum. VIP is a neurotransmitter that is extensively distributed in tissues. According to published reports, VPAC1 and VPAC2 act as VIP receptors and are widely present in the central nervous system and peripheral tissues. VIP exerts diverse actions on the cardiovascular system, pancreas, digestive tract, respiratory system, and urological system. Recent reports indicated that VIP has immunological and neuroprotective effects and also affects cell growth. While primary investigations for developing therapeutic applications for various pathological conditions and diseases are underway, the structure and function of VIP should be analyzed in more detail.展开更多
Exposure in water-damaged buildings (WDB) to airborne bioaerosols including metabolic products of toxigenic fungi, bacteria and actinomycetes;and inflammagens, can lead to a persistent innate immune inflammatory illne...Exposure in water-damaged buildings (WDB) to airborne bioaerosols including metabolic products of toxigenic fungi, bacteria and actinomycetes;and inflammagens, can lead to a persistent innate immune inflammatory illness. This illness, termed a chronic inflammatory response syndrome (CIRS-WDB), is systemic with symptoms acquired from multiple organ systems. Treatment of CIRS-WDB has progressed rapidly as a better understanding of the inflammatory pathophysiology has led to targeted, sequential therapies. The fundamental basis of uncontrolled innate immune responses, the humoral deficiency of regulatory neuropeptides melanocyte stimulating hormone (MSH) or vasoactive intestinal polypeptide (VIP), seen in over 98% of pa tients, has not consistently responded to any treatment modality. Use of replacement VIP has been attempted anecdotally;VIP replacement therapies show promise in short term studies but longer therapies have not been attempted. Here we report an open label trial of 20 patients with refractory CIRS-WDB illness who took replacement VIP in a nasal spray for at least 18 months with confirmation of durable efficacy and absence of significant side effects. These 20 patients were similar in symptoms and lab find- ings to three previously published cohorts in- volving 1829 patients and 169 controls. Dosage of VIP was titrated downwards from four to zero doses a day to determine minimum effective dose, and retitrated upwards for maximum improvement over time. The trial showed that VIP therapy safely 1) reduced refractory symptoms to equal controls;2) corrected inflammatory parameters C4a, TGF beta-1, VEGF, MMP9;3) corrected estradiol, testosterone and 25-OH Vitamin D;4) returned pulmonary artery systolic pressure (PASP) during exercise to normal;and 5) enhanced quality of life in 100% of trial patients. Subsequent identification of correction of T-regulatory cell levels supports the potential role of VIP in both innate and adaptive immune function.展开更多
Natural antimicrobial peptides(AMPs)are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens.They have found extensive applications in the fields of m...Natural antimicrobial peptides(AMPs)are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens.They have found extensive applications in the fields of medicine,food,and agriculture.However,efficiently screening AMPs from natural sources poses several challenges,including low efficiency and high antibiotic resistance.This review focuses on the action mechanisms of AMPs,both through membrane and non-membrane routes.We thoroughly examine various highly efficient AMP screening methods,including whole-bacterial adsorption binding,cell membrane chromatography(CMC),phospholipid membrane chromatography binding,membranemediated capillary electrophoresis(CE),colorimetric assays,thin layer chromatography(TLC),fluorescence-based screening,genetic sequencing-based analysis,computational mining of AMP databases,and virtual screening methods.Additionally,we discuss potential developmental applications for enhancing the efficiency of AMP discovery.This review provides a comprehensive framework for identifying AMPs within complex natural product systems.展开更多
Ganoderma lingzhi is a new species of the prize medicinal mushroom Ganoderma(Agaricomycetes).Using angiotensin I-converting enzyme(ACE)as a target,a tripeptide Ser-Tyr-Pro(SYP)was discovered with preponderant ACE inhi...Ganoderma lingzhi is a new species of the prize medicinal mushroom Ganoderma(Agaricomycetes).Using angiotensin I-converting enzyme(ACE)as a target,a tripeptide Ser-Tyr-Pro(SYP)was discovered with preponderant ACE inhibitory activity with an 50%inhibiting concentration(IC_(50))value of 62.50μg/mL attribute to the formed salt bridge and hydrogen bonds between SYP and ACE.SYP even maintained superior bioactivity after intestinal digestion,and exerted no cytotoxicity,but presented incomplete bioavailability in blood of spontaneous hypertensive rats(SHRs).Furthermore,it performed antihypertensive effect in vivo by inhibiting the influx of Ca^(2+)through activating endothelial NO synthase(e NOS)/NO/guanosine 3',5'-cyclic monophosphate(c GMP)pathway,accompanied by attenuating angiotensin II(Ang II)/NADPH oxidase(NOX)/reactive oxygen species(ROS)pathway.This work not only discoverers a novel pharmacological ingredient from medicinal mushroom G.lingzhi for hypertension therapy,but also provides an insight into molecular mechanism of the ACE inhibitory peptide(ACEIP)on lowering blood pressure.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
碳排放连续在线监测法作为一种高效、可溯源的方法,在我国碳计量领域中逐渐应用。然而,由于烟囱管道的大直径、复杂烟气流场,以及流量计检修维护、粉尘堵塞导致的监测数据中断与异常,烟气流量的准确监测成为一大挑战。为此,提出一种融...碳排放连续在线监测法作为一种高效、可溯源的方法,在我国碳计量领域中逐渐应用。然而,由于烟囱管道的大直径、复杂烟气流场,以及流量计检修维护、粉尘堵塞导致的监测数据中断与异常,烟气流量的准确监测成为一大挑战。为此,提出一种融合变量投影重要性分析(variable importance in projection,VIP)、最大信息系数(maximal information coefficient,MIC)及后向搜索(sequential backward selection,SBS)算法的联合筛选方法,结合支持向量机(support vector machine,SVM)构建烟气流量软测量模型。基于某F级燃气-蒸汽联合循环发电机组,通过VIP值评估辅助变量显著性,并结合MIC和SBS算法,进行变量冗余消除与优化选择,从而提升模型的预测精度和泛化能力。实验结果显示:SVM的表现优于长短时间记忆网络模型,与反向传播神经网络相比具有较好的泛化能力;当辅助变量数量为12时,模型性能最佳,测试集的均方根误差和平均绝对百分比误差均较低,验证了变量筛选方法的有效性;在稳态和非稳态工况下,模型预测值的平均绝对百分比误差小于0.7%,并有一定的滤波作用。展开更多
Background Broiler chickens are most vulnerable immediately after hatching due to their immature immune systems,making them susceptible to infectious diseases.The yolk plays an important role in early immune defence b...Background Broiler chickens are most vulnerable immediately after hatching due to their immature immune systems,making them susceptible to infectious diseases.The yolk plays an important role in early immune defence by showing relevant antioxidant and passive immunity capabilities during broiler embryonic development.The immunomodulatory effects of phytogenic compound carvacrol have been widely reported.After in ovo delivery in the amniotic fluid during embryonic development carvacrol is known to migrate to the yolk sac.However,it is unknown whether carvacrol in the yolk could enhance defence responsiveness in the yolk sac.Therefore,the aim of this study was to improve early immune function in chicken embryos,and it was hypothesized that in ovo delivery of carvacrol would result in immunomodulatory effects in the yolk sac,potentially improving post-hatch resilience.Methods On embryonic day(E)17.5,either a saline(control)or carvacrol solution was injected into the amniotic fluid.Yolk sac tissue samples were collected at E19.5,and transcriptomic analyses using RNA sequencing were performed,following functional enrichment analyses comparing the control(saline)and carvacrol-injected groups.Results The results showed that 268 genes were upregulated and 174 downregulated in the carvacrol group compared to the control(P<0.05;logFC<-0.5 or log FC>0.5).Functional analyses of these differentially expressed genes,using KEGG,REACTOME,and Gene Ontology databases,showed enrichment of several immune-related pathways.This included the pathways‘Antimicrobial peptides’(P=0.001)and‘Chemoattractant activity’(P=0.004),amongst others.Moreover,the‘NOD-like receptor signaling’pathway was enriched(P=0.002).Antimicrobial peptides are part of the innate immune defence and are amongst the molecules produced after the nucleotide oligomeriza-tion domain(NOD)-like receptor pathway activation.While these responses may be associated with an inflammatory reaction to an exogenous threat,they could also indicate that in ovo delivery of carvacrol could prepare the newly hatched chick against bacterial pathogens by potentially promoting antimicrobial peptide production through acti-vation of NOD-like receptor signaling in the yolk sac.Conclusion In conclusion,these findings suggest that in ovo delivery of carvacrol has the potential to enhance anti-pathogenic and pro-inflammatory responses in the yolk sac via upregulation of antimicrobial peptides,and NOD-like receptor pathways.展开更多
Despite ongoing advancements in cancer treatment,the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies.The demand for...Despite ongoing advancements in cancer treatment,the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies.The demand for targeted therapeutics for multidrug-resistant cancer is more important than ever.Peptides,as emerging alternatives to current anticancer drugs,offer exquisite versatility in facilitating the design of novel oncology drugs,with the core superiorities of good biocompatibility and a low tendency to induce drug resistance.This review comprehensively introduces the pharmacological mechanisms of peptide-based drugs and strategies for overcoming multidrug resistance(MDR)in cancers,including inducing cell membrane lysis,targeting organelles,activating anticancer immune responses,enhancing drug uptake,targeting ATP-binding cassette(ABC)transporters,and targeting B-cell lymphoma-2(BCL-2)family proteins.Additionally,the current clinical applications of representative peptides in combating MDR cancers and their potential directions for medicinal chemistry research have been thoroughly discussed.This review offers essential insights into the novel treatment approaches for MDR cancers and highlights the trends and perspectives in this field.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
Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial fo...Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial for designing safe peptide-based therapeutics.While traditional experimental approaches are time-consuming and expensive,computational methods have emerged as viable alternatives,including similarity-based and machine learning(ML)-/deep learning(DL)-based methods.However,existing methods often struggle with robustness and generalizability.To address these challenges,we propose HyPepTox-Fuse,a novel framework that fuses protein language model(PLM)-based embeddings with conventional descriptors.HyPepTox-Fuse integrates ensemble PLM-based embeddings to achieve richer peptide representations by leveraging a cross-modal multi-head attention mechanism and Transformer architecture.A robust feature ranking and selection pipeline further refines conventional descriptors,thus enhancing prediction performance.Our framework outperforms state-of-the-art methods in cross-validation and independent evaluations,offering a scalable and reliable tool for peptide toxicity prediction.Moreover,we conducted a case study to validate the robustness and generalizability of HyPepTox-Fuse,highlighting its effectiveness in enhancing model performance.Furthermore,the HyPepTox-Fuse server is freely accessible at https://balalab-skku.org/HyPepTox-Fuse/and the source code is publicly available at https://github.com/cbbl-skku-org/HyPepTox-Fuse/.The study thus presents an intuitive platform for predicting peptide toxicity and supports reproducibility through openly available datasets.展开更多
Small signaling peptides,generally comprising fewer than 100 amino acids,act as crucial signaling molecules in cell-to-cell communications.Upon perception by their membrane-localized corresponding receptors or co-rece...Small signaling peptides,generally comprising fewer than 100 amino acids,act as crucial signaling molecules in cell-to-cell communications.Upon perception by their membrane-localized corresponding receptors or co-receptors,these peptide-receptor modules then(de)activate either long-distance or local signaling pathways,thereby orchestrating developmental and adaptive responses via(post)transcriptional,(post)translational,and epigenetic regulations.The physiological functions of small signaling peptides are implicated in a multitude of developmental processes and adaptive responses,including but not limited to,shoot and root morphogenesis,organ abscission,nodulation,Casparian strip formation,pollen development,taproot growth,and various abiotic stress responses such as aluminum,cadmium,drought,cold,and salinity.Additionally,they play a critical role in response to pathogenic invasions.These small signaling peptides also modulate significant agronomic and horticultural traits,such as fruit size,maize kernel development,fiber elongation,and rice awn formation.Here,we underscore the roles of several small signaling peptide families such as CLE,RALF,EPFL,mi PEP,CEP,IDA/IDL,and PSK in regulating these biological processes.These novel insights will deepen our current understanding of small signaling peptides,and offer innovative strategies for genetic breeding stress-tolerant crops and horticultural plants,contributing to establish sustainable agricultural systems.展开更多
文摘Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide first isolated from swine duodenum. VIP is a neurotransmitter that is extensively distributed in tissues. According to published reports, VPAC1 and VPAC2 act as VIP receptors and are widely present in the central nervous system and peripheral tissues. VIP exerts diverse actions on the cardiovascular system, pancreas, digestive tract, respiratory system, and urological system. Recent reports indicated that VIP has immunological and neuroprotective effects and also affects cell growth. While primary investigations for developing therapeutic applications for various pathological conditions and diseases are underway, the structure and function of VIP should be analyzed in more detail.
文摘Exposure in water-damaged buildings (WDB) to airborne bioaerosols including metabolic products of toxigenic fungi, bacteria and actinomycetes;and inflammagens, can lead to a persistent innate immune inflammatory illness. This illness, termed a chronic inflammatory response syndrome (CIRS-WDB), is systemic with symptoms acquired from multiple organ systems. Treatment of CIRS-WDB has progressed rapidly as a better understanding of the inflammatory pathophysiology has led to targeted, sequential therapies. The fundamental basis of uncontrolled innate immune responses, the humoral deficiency of regulatory neuropeptides melanocyte stimulating hormone (MSH) or vasoactive intestinal polypeptide (VIP), seen in over 98% of pa tients, has not consistently responded to any treatment modality. Use of replacement VIP has been attempted anecdotally;VIP replacement therapies show promise in short term studies but longer therapies have not been attempted. Here we report an open label trial of 20 patients with refractory CIRS-WDB illness who took replacement VIP in a nasal spray for at least 18 months with confirmation of durable efficacy and absence of significant side effects. These 20 patients were similar in symptoms and lab find- ings to three previously published cohorts in- volving 1829 patients and 169 controls. Dosage of VIP was titrated downwards from four to zero doses a day to determine minimum effective dose, and retitrated upwards for maximum improvement over time. The trial showed that VIP therapy safely 1) reduced refractory symptoms to equal controls;2) corrected inflammatory parameters C4a, TGF beta-1, VEGF, MMP9;3) corrected estradiol, testosterone and 25-OH Vitamin D;4) returned pulmonary artery systolic pressure (PASP) during exercise to normal;and 5) enhanced quality of life in 100% of trial patients. Subsequent identification of correction of T-regulatory cell levels supports the potential role of VIP in both innate and adaptive immune function.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82373835,82304437,and 82173781)Regional Joint Fund Project of Guangdong Basic and Applied Basic Research Fund,China(Grant Nos.:2023A1515110417 and 2023A1515140131)+2 种基金Regional Joint Fund-Key Project of Guangdong Basic and Applied Basic Research Fund,China(Grant No.:2020B1515120033)the Key Field Projects of General Universities in Guangdong Province,China(Grant Nos.:2020ZDZX2057 and 2022ZDZX2056)Medical Scientific Research Foundation of Guangdong Province of China(Grant No.:A2022061).
文摘Natural antimicrobial peptides(AMPs)are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens.They have found extensive applications in the fields of medicine,food,and agriculture.However,efficiently screening AMPs from natural sources poses several challenges,including low efficiency and high antibiotic resistance.This review focuses on the action mechanisms of AMPs,both through membrane and non-membrane routes.We thoroughly examine various highly efficient AMP screening methods,including whole-bacterial adsorption binding,cell membrane chromatography(CMC),phospholipid membrane chromatography binding,membranemediated capillary electrophoresis(CE),colorimetric assays,thin layer chromatography(TLC),fluorescence-based screening,genetic sequencing-based analysis,computational mining of AMP databases,and virtual screening methods.Additionally,we discuss potential developmental applications for enhancing the efficiency of AMP discovery.This review provides a comprehensive framework for identifying AMPs within complex natural product systems.
基金supported by the National Natural Science Foundation of China(32071673 and 32202573)the Program of Hunan Science and Technology Innovation Team(2021RC4063)+1 种基金the Natural Science Foundation of Hunan Province(2021JJ31151 and 2022JJ50028)the Key Scientific Research Project of Hunan Education Department(22A0538)。
文摘Ganoderma lingzhi is a new species of the prize medicinal mushroom Ganoderma(Agaricomycetes).Using angiotensin I-converting enzyme(ACE)as a target,a tripeptide Ser-Tyr-Pro(SYP)was discovered with preponderant ACE inhibitory activity with an 50%inhibiting concentration(IC_(50))value of 62.50μg/mL attribute to the formed salt bridge and hydrogen bonds between SYP and ACE.SYP even maintained superior bioactivity after intestinal digestion,and exerted no cytotoxicity,but presented incomplete bioavailability in blood of spontaneous hypertensive rats(SHRs).Furthermore,it performed antihypertensive effect in vivo by inhibiting the influx of Ca^(2+)through activating endothelial NO synthase(e NOS)/NO/guanosine 3',5'-cyclic monophosphate(c GMP)pathway,accompanied by attenuating angiotensin II(Ang II)/NADPH oxidase(NOX)/reactive oxygen species(ROS)pathway.This work not only discoverers a novel pharmacological ingredient from medicinal mushroom G.lingzhi for hypertension therapy,but also provides an insight into molecular mechanism of the ACE inhibitory peptide(ACEIP)on lowering blood pressure.
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.
文摘碳排放连续在线监测法作为一种高效、可溯源的方法,在我国碳计量领域中逐渐应用。然而,由于烟囱管道的大直径、复杂烟气流场,以及流量计检修维护、粉尘堵塞导致的监测数据中断与异常,烟气流量的准确监测成为一大挑战。为此,提出一种融合变量投影重要性分析(variable importance in projection,VIP)、最大信息系数(maximal information coefficient,MIC)及后向搜索(sequential backward selection,SBS)算法的联合筛选方法,结合支持向量机(support vector machine,SVM)构建烟气流量软测量模型。基于某F级燃气-蒸汽联合循环发电机组,通过VIP值评估辅助变量显著性,并结合MIC和SBS算法,进行变量冗余消除与优化选择,从而提升模型的预测精度和泛化能力。实验结果显示:SVM的表现优于长短时间记忆网络模型,与反向传播神经网络相比具有较好的泛化能力;当辅助变量数量为12时,模型性能最佳,测试集的均方根误差和平均绝对百分比误差均较低,验证了变量筛选方法的有效性;在稳态和非稳态工况下,模型预测值的平均绝对百分比误差小于0.7%,并有一定的滤波作用。
基金support by AgriFutures Australia’s Chicken Meat Program[grant number PRJ-011584]is gratefully acknowledged.
文摘Background Broiler chickens are most vulnerable immediately after hatching due to their immature immune systems,making them susceptible to infectious diseases.The yolk plays an important role in early immune defence by showing relevant antioxidant and passive immunity capabilities during broiler embryonic development.The immunomodulatory effects of phytogenic compound carvacrol have been widely reported.After in ovo delivery in the amniotic fluid during embryonic development carvacrol is known to migrate to the yolk sac.However,it is unknown whether carvacrol in the yolk could enhance defence responsiveness in the yolk sac.Therefore,the aim of this study was to improve early immune function in chicken embryos,and it was hypothesized that in ovo delivery of carvacrol would result in immunomodulatory effects in the yolk sac,potentially improving post-hatch resilience.Methods On embryonic day(E)17.5,either a saline(control)or carvacrol solution was injected into the amniotic fluid.Yolk sac tissue samples were collected at E19.5,and transcriptomic analyses using RNA sequencing were performed,following functional enrichment analyses comparing the control(saline)and carvacrol-injected groups.Results The results showed that 268 genes were upregulated and 174 downregulated in the carvacrol group compared to the control(P<0.05;logFC<-0.5 or log FC>0.5).Functional analyses of these differentially expressed genes,using KEGG,REACTOME,and Gene Ontology databases,showed enrichment of several immune-related pathways.This included the pathways‘Antimicrobial peptides’(P=0.001)and‘Chemoattractant activity’(P=0.004),amongst others.Moreover,the‘NOD-like receptor signaling’pathway was enriched(P=0.002).Antimicrobial peptides are part of the innate immune defence and are amongst the molecules produced after the nucleotide oligomeriza-tion domain(NOD)-like receptor pathway activation.While these responses may be associated with an inflammatory reaction to an exogenous threat,they could also indicate that in ovo delivery of carvacrol could prepare the newly hatched chick against bacterial pathogens by potentially promoting antimicrobial peptide production through acti-vation of NOD-like receptor signaling in the yolk sac.Conclusion In conclusion,these findings suggest that in ovo delivery of carvacrol has the potential to enhance anti-pathogenic and pro-inflammatory responses in the yolk sac via upregulation of antimicrobial peptides,and NOD-like receptor pathways.
基金supported by the Science and Technology Innovation Program of Hunan Province(No.2022RC1168)National Natural Science Foundation of China(Nos.82322073,82173846,82304533)+12 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2023-I2M-3-009)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(No.2060302)China Postdoctoral Science Foundation(No.2021M702215)Oriental Scholars of Shanghai Universities(No.TP2022081)Jiangxi Province Thousand Talents Program(No.jxsq2023102168)Young Talent Lifting Project of China Association of Chinese Medicine(No.CACM-(2021-QNRC2-A08))Shanghai Rising-Star Program(No.22QA1409100)Shanghai Sailing Program(No.22YF1445000)2021 Shanghai Science and Technology Innovation Action Plan(No.21S11902800)Three-year Action Plan for Shanghai TCM Development and Inheritance Program(Nos.ZY(2021-2023)-0208,ZY(2021-2023)-0401)High level Key Discipline of National Administration of Traditional Chinese Medicine(No.71)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202004)Innovation team of high-level local universities in Shanghai:Strategic Innovation Team of TCM Chemical Biology。
文摘Despite ongoing advancements in cancer treatment,the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies.The demand for targeted therapeutics for multidrug-resistant cancer is more important than ever.Peptides,as emerging alternatives to current anticancer drugs,offer exquisite versatility in facilitating the design of novel oncology drugs,with the core superiorities of good biocompatibility and a low tendency to induce drug resistance.This review comprehensively introduces the pharmacological mechanisms of peptide-based drugs and strategies for overcoming multidrug resistance(MDR)in cancers,including inducing cell membrane lysis,targeting organelles,activating anticancer immune responses,enhancing drug uptake,targeting ATP-binding cassette(ABC)transporters,and targeting B-cell lymphoma-2(BCL-2)family proteins.Additionally,the current clinical applications of representative peptides in combating MDR cancers and their potential directions for medicinal chemistry research have been thoroughly discussed.This review offers essential insights into the novel treatment approaches for MDR cancers and highlights the trends and perspectives in this field.
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.
基金supported by the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT,Republic of Korea(Grant No.:RS-2024-00344752)supported by the Department of Integrative Biotechnology,Sungkyunkwan University(SKKU)and the BK21 FOUR Project,Republic of Korea.
文摘Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial for designing safe peptide-based therapeutics.While traditional experimental approaches are time-consuming and expensive,computational methods have emerged as viable alternatives,including similarity-based and machine learning(ML)-/deep learning(DL)-based methods.However,existing methods often struggle with robustness and generalizability.To address these challenges,we propose HyPepTox-Fuse,a novel framework that fuses protein language model(PLM)-based embeddings with conventional descriptors.HyPepTox-Fuse integrates ensemble PLM-based embeddings to achieve richer peptide representations by leveraging a cross-modal multi-head attention mechanism and Transformer architecture.A robust feature ranking and selection pipeline further refines conventional descriptors,thus enhancing prediction performance.Our framework outperforms state-of-the-art methods in cross-validation and independent evaluations,offering a scalable and reliable tool for peptide toxicity prediction.Moreover,we conducted a case study to validate the robustness and generalizability of HyPepTox-Fuse,highlighting its effectiveness in enhancing model performance.Furthermore,the HyPepTox-Fuse server is freely accessible at https://balalab-skku.org/HyPepTox-Fuse/and the source code is publicly available at https://github.com/cbbl-skku-org/HyPepTox-Fuse/.The study thus presents an intuitive platform for predicting peptide toxicity and supports reproducibility through openly available datasets.
基金supported by funding from Jiangxi Agricultural University(9232308314 to Huibin Han)Science and Technology Department of Jiangxi Province(20223BCJ25037 to Huibin Han and 20202ACB215002 to Shuaiying Peng)+1 种基金the Outstanding Youth Fund Project of the Natural Science Foundation of Jiangxi Province,China(20242BAB23066 to Yong Zhou)National Natural Science Foundation of China(32060047 to Jianping Liu,32160739 to Youxin Yang,32460797 to Yong Zhou and 32460081 to Huibin Han)。
文摘Small signaling peptides,generally comprising fewer than 100 amino acids,act as crucial signaling molecules in cell-to-cell communications.Upon perception by their membrane-localized corresponding receptors or co-receptors,these peptide-receptor modules then(de)activate either long-distance or local signaling pathways,thereby orchestrating developmental and adaptive responses via(post)transcriptional,(post)translational,and epigenetic regulations.The physiological functions of small signaling peptides are implicated in a multitude of developmental processes and adaptive responses,including but not limited to,shoot and root morphogenesis,organ abscission,nodulation,Casparian strip formation,pollen development,taproot growth,and various abiotic stress responses such as aluminum,cadmium,drought,cold,and salinity.Additionally,they play a critical role in response to pathogenic invasions.These small signaling peptides also modulate significant agronomic and horticultural traits,such as fruit size,maize kernel development,fiber elongation,and rice awn formation.Here,we underscore the roles of several small signaling peptide families such as CLE,RALF,EPFL,mi PEP,CEP,IDA/IDL,and PSK in regulating these biological processes.These novel insights will deepen our current understanding of small signaling peptides,and offer innovative strategies for genetic breeding stress-tolerant crops and horticultural plants,contributing to establish sustainable agricultural systems.
