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Disease-specific protein corona formed in pathological intestine enhances the oral absorption of nanoparticles

药学学报:英文版 2023年第9期13卷 3876-3891页

作者： Jiawei Wu Liyun Xing Yaxian Zheng Yinglan Yu Ruinan Wu Xi Liu Lian Li Yuan Huang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Protein corona(PC)has been identified to impede the transportation of intravenously injected nanoparticles(NPs)from blood circulation to their targeted sites.However,how intestinal PC(IPC)affects the delivery of orally administered NPs are still needed to be elucidated.Here,we found that IPC exerted“positive effect”or“negative effect”depending on different pathological conditions in the gastrointestinal tract.We prepared polystyrene nanoparticles(PS)adsorbed with different IPC derived from the intestinal tract of healthy,diabetic,and colitis rats(H-IPC@PS,D-IPC@PS,C-IPC@PS).proteomics analysis revealed that,compared with healthy IPC,the two disease-specific IPC consisted of a higher proportion of proteins that were closely correlated with transepithelial transport across the intestine.Consequently,both D-IPC@PS and C-IPC@PS mainly exploited the recycling endosome and ER-Golgi mediated secretory routes for intracellular trafficking,which increased the transcytosis from the epithelium.Together,disease-specific IPC endowed NPs with higher intestinal absorption.D-IPC@PS posed“positive effect”on intestinal absorption into blood circulation for diabetic therapy.Conversely,CIPC@PS had“negative effect”on colitis treatment because of unfavorable absorption in the intestine before arriving colon.These results imply that different or even opposite strategies to modulate the disease-specific IPC need to be adopted for oral nanomedicine in the treatment of variable diseases.

关键词： Oral nanoparticles Pathological intestine Disease-specific Intestinal protein corona proteomics analysis Intracellular trafficking Transepithelial transport Intestinal absorption

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Drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network

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Cancer Biology & Medicine 2022年第1期19卷 74-89页

作者： Xi Cheng Wensi Zhao Mengdi Zhu Bo Wang Xuege Wang Xiaoyun Yang Yuqi Huang Minjia Tan Jing Li Department of Bioinformatics and Biostatistics School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China The Chemical proteomics Center and State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of Sciences(CAS)Shanghai 200031China

Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

关键词： Database drug repurposing machine learning network random walk proteomics analysis

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Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect

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Neural Regeneration Research 2023年第9期18卷 2037-2046页

作者： Piniel Alphayo Kambey Wen-Ya Liu Jiao Wu Bakwatanisa Bosco Iqra Nadeem Kouminin Kanwore Dian-Shuai Gao Xuzhou Key Laboratory of Neurobiology Department of Neurobiology and AnatomyXuzhou Medical UniversityXuzhouJiangsu ProvinceChina Organization of African Academic Doctors NairobiKenya Department of Bioinformatics Nanjing Medical UniversityNanjingJiangsu ProvinceChina

Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.

关键词： 6-hydroxydopamine dopaminergic neurons dopamine transporter nuclear receptor-related factor 1 Parkinson’s disease proteomics analysis Seurat clustering single-nuclei RNA sequencing substantia nigra tyrosine hydroxylase

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Degradation of differently processed Mg-based implants leads to distinct foreign body reactions(FBRs)through dissimilar signaling pathways

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镁合金学报(英文) 2023年第6期11卷 2106-2124页

作者： Xiaosong Liu Guoqiang Chen Xiongxiong Zhong Tianfang Wang Xiaohong He Weipeng Yuan Pingping Zhang Ying Liu Dongming Cao Shu Chen Ken-ichi Manabe Zhengyi Jiang Tsuyoshi Furushima Damon Kent Yang Chen Guoying Ni Mingyong Gao Hejie Li Cancer Research Institute First People’s Hospital of FoshanFoshanGuangdong 528000China Department of Rheumatology First People’s Hospital of FoshanFoshanGuangdong 528000China The Second Clinical Medical College of Jinan University Shenzhen People’s HospitalShenzhenGuangdong 510632China Genecology Research Centre University of the Sunshine CoastMaroochydore BCQLD 4558Australia Department of Medical Imaging First People’s Hospital of FoshanFoshanGuangdong 528000China Department of Surgery First People’s Hospital of FoshanFoshanGuangdong 528000China Department of Mechanical Engineering Graduate School of Science and EngineeringTokyo Metropolitan University1-1 Minami-osawaHachiojiTokyo 192-0397Japan School of Mechanical MaterialsMechatronic and Biomedical EngineeringFaculty of Engineering and Information SciencesUniversity of WollongongNorthfields AveWollongong NSW 2522Australia Institute of Industrial Science Department of Mechanical and Biofunctional Systemsthe University of Tokyo4-6-1KomabaMeguroTokyo 153-8505Japan School of Science Technology and EngineeringUniversity of the Sunshine CoastMaroochydore BCQLD 4558Australia

Mg alloys have mechanical properties compatible with human bones.However,their rapid degradation and associated foreign body reactions in vivo significantly limit their application for human implants.In this study,three differently processed Mg alloys,pure Mg(PM),cold extruded Mg alloy AZ31(CE AZ31),and fully annealed AZ31 Mg alloy(FA AZ31)were comparatively investigated for their potential as implants using a rat model.All three implanted Mg alloys do not show any impact on hepato-and renal function,nor any signs of observable changes to vital organs.proteomics analysis of tissues directly contacting the implants 2.5 months post implantation revealed that FA AZ31 activates very few inflammation and immune associated signaling pathways;while the CE AZ31 and PM produce more significant inflammatory responses as confirmed by cytokine array analyses.Further,FA AZ31 activated pathways for cell organization and development that may improve the recovery of injured tissues.Structurally,EBSD analysis reveals that the FA AZ31 alloy has a higher ratio of first-order pyramidal orientated(10–11){10–1–2}grain texture with a value of 0.25,while PM and CE AZ31 alloys have lower ratios of first-order pyramidal orientated texture with the values of 0.16 and 0.17,respectively.This is associated with recovery and recrystallisation during annealing which promotes grain texture which exhibits enhanced degradation behaviours and induces a more limited immune response in vivo.In conclusion,the FA AZ31 demonstrated better biocompatibility and corrosion resistance and is a promising candidate for metal-based degradable implants which warrants further investigation.

关键词： Toxicity test proteomics analysis Signaling pathway Biocompatibility and corrosion resistance First-order pyramidal slip system Recovery and recrystallization Foreign body reactions(FBRs)

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iTRAQ proteomics reveals the regulatory response to Xanthomonas campestris pv.vesicatoria in resistant vs.susceptible pepper genotypes

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Horticultural Plant Journal 2022年第6期8卷 747-756页

作者： Fei Wang Shenghua Gao Juntawong Niran Ning Li Yanxu Yin Chuying Yu Chunhai Jiao Minghua Yao Hubei Academy of Agricultural Sciences Hubei Key Laboratory of Vegetable Germplasm Enhancement and Genetic ImprovementCash Crops Research InstituteHubei Academy of Agricultural SciencesWuhanHubei 430070China Kasetsart University Bangkok 10900Thailand

Bacterial spot(BS)is a severe bacterial disease induced by Xanthomonas campestris pv.vesicatoria(Xcv),a pathogen that causes serious damage to pepper growth and yield.It is therefore important to study the mechanisms of pepper resistance to Xcv and to breed and promote Xcvresistant pepper varieties.However,studies of the responses to Xcv infection in peppers at the protein level are limited.Here,we examined Xcv-induced proteomic changes in leaves of the BS susceptible bell pepper ECW and the resistant bell pepper VI037601 using the isobaric tags for relative and absolute quantitation(iTRAQ)-based protein labeling technology.A total of 6,120 distinct proteins were identified,and there were 1,289 significantly differentially accumulated proteins(DAPs)in ECW and VI037601 leaves after Xcv inoculation.Among these,339(250up-and 89 down-regulated)and 479(300 up-and 179 down-regulated)DAPs were specifically identified in ECW and VI037601,respectively,with 459(364 up-and 95 down-regulated)similarly expressed DAPs being shared by ECW and VI037601.Based on bioinformatics analysis,many defense-associated proteins were identified as up-regulated in ECW and VI037601,especially the proteins involved in plant-pathogen interaction,phenylpropanoid biosynthesis,protein processing in the endoplasmic reticulum,and MAPK signaling pathway-plant.Moreover,we evaluated transcript levels of six differentially expressed genes from the iTRAQ results by q RT-PCR.The analysis revealed transcriptional changes that were consistent with the changes at the protein level.This study will provide a valuable resource for understanding the molecular basis of pepper resistance to Xcv infection and for improving the disease resistance of pepper cultivars.

关键词： Pepper proteomics analysis Bacterial spot Xanthomonas campestris pv.vesicatoria

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Changes of hepatic biochemical parameters and proteomics in broilers with cold-induced ascites

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Journal of Animal Science and Biotechnology 2013年第4期4卷 278-286页

作者： Yongwei Wang Yuming Guo Dong Ning Yunzhi Peng Hong Cai Jianzhuang Tan Ying Yang Dan Liu State Key Lab of Animal Nutrition College of Animal Science and Technology China Agricultural University

Ascites syndrome is still a problem for chicken industry in various parts of the world. Despite the intensive investigations of this syndrome for many years, its pathogenesis remains unclear. The objective of this study was to analyze the difference in hepatic proteomics between ascites and healthy broilers by two-dimensional electrophoresis （2-DE） and matrix-assisted laser desorption/ionization-time of flight mass spectrometry （MALDI-TOF-MS）. Changes of biochemical parameters of liver and blood were also determined. The results indicated that red blood cell counts （RBC）, hematocrit （HCT） and haemoglobin （HGB） of ascites broilers were significantly greater than healthy broilers. Hepatic malondialdehyde （MDA） level of ascites broilers was significantly increased, and the activity of total superoxide dismutase （T-SOD） was significantly decreased. Hepatic lactic acid （LD） level of ascitic broilers were significantly lower than healthy ones, Serum glucose and cholesterol level of ascites broilers were significantly increased, and serum globulin level was significantly decreased in ascites broilers. There was no significant difference in triglyceride （TG） and blood urea nitrogen （BUN） level. The activity of liver hexokinase （HK） and succinodehydrogenase （SDH） in ascites broilers was significantly decreased, and there was no significant difference in the activity of liver pyruvate kinase （PK） and Na＋-K＋-ATPase. The hepatic proteomics analysis showed that 18 proteins expression difference were identified between ascites and healthy broilers. These proteins were mainly involved in： 1） cytoskeleton; 2） glucose, lipids and amino acid metabolism; 3） cell secretion; 4） cell apoptosis; 5） signal transduction; 6） immune and inflammatory response; and 7） cellular redox homeostasis. Mitochondrial isoform phosphoenolpyruvate carboxykinase （M-PEPCK） mainly participates in gluconeogenesis of chicken liver. In conclusion, liver oxidative damage was significantly aggravated, but antioxidant capacity was decreased in cold-induced asci

关键词： Ascites Broilers Biochemical parameters proteomics analysis

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