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1.
Artigo em Inglês | MEDLINE | ID: mdl-32077274

RESUMO

Abundant pyridinic nitrogen in the triazine units of covalent triazine frameworks (CTFs) is very useful in various heterogeneous catalysis reaction. Herein, a tunable CTF platform with the same porous structure was designed and synthesized to study the interaction between palladium / platinum (Pd / Pt) and pyridinic nitrogen of CTFs. The smaller Pd nanoparticles were formed because of the stronger interaction between Pd and pyridinic nitrogen of CTFs, which is more beneficial for the separation of photogenerated electron-hole pairs. Moreover, the stronger interaction between the Pd nanoparticles and CTFs is also beneficial for photoelectron transfer. Under the same conditions, the hydrogen evolution rate of 1wt%Pd@CTF-HC6 is up to 11 times more than that of 1wt%Pt@CTF-HC6. The hydrogen evolution rate of 1wt%Pd@CTF-N approaches 10556 µmol h-1g-1 and is about 5 times more than that of 1wt%Pt@CTF-N.

2.
J Cell Mol Med ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970902

RESUMO

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP-activated protein kinase (AMPK) produces anti-inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin-1 beta (IL-1ß), IL-6 and tumour necrosis factor alpha (TNF-α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP-activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose-dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL-1ß, IL-6 and TNF-α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS-induced macrophage activation if AMPK was in deficient through siRNA-mediated approaches. Further, the anti-inflammatory effects produced by VitB6 or AICAR in LPS-treated macrophages were abolished in DOK3 gene knockout (DOK3-/- ) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS-induced both systemic inflammation and acute pneumonia in wild-type mice, but not in DOK3-/- mice. VitB6 prevents LPS-induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.

3.
Theranostics ; 10(3): 1213-1229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31938061

RESUMO

The merits of nanomedicines are significantly impacted by the surrounding biological environment. Similar to the protein corona generated on the surface of nanoparticles in the circulation system, the intracellular protein corona (IPC) might be formed on nanoparticles when transported inside the cells. However, little is known currently about the formation of IPC and its possible biological influence. Methods: Caco-2 cells, a classical epithelial cell line, were cultured in Transwell plates to form a monolayer. Gold nanoparticles (AuNPs) were prepared as the model nanomedicine due to their excellent stability. Here we focused on identifying IPC formed on the surface of AuNPs during cell transport. The nanoparticles in the basolateral side of the Caco-2 monolayer were collected and analyzed by multiple techniques to verify IPC formation. High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was utilized to analyze the composition of IPC proteins. In particular, we established a dual-filtration strategy to exclude various interference in IPC identification. Based on the subcellular localization of specific IPC proteins, we elicited the nano-trafficking network of AuNPs. The transport pathways of AuNPs identified by proteomic analysis were also verified by various conventional technologies. Finally, we explored the influence of IPC on the uptake and stress response of endothelium. Results: The existence of IPC was demonstrated on the surface of AuNPs, in which 227 proteins were identified. Among them, 40 proteins were finally ascertained as the specific IPC proteins. The subcellular location analysis indicated that these "specific" IPC proteins could back-track the transport pathways of nanoparticles in the epithelial cell monolayer. According to the subcellular distribution of IPC proteins and co-localization, we discovered a new pathway of nanoparticles from endosomes to secretory vesicles which was dominant during the transcytosis. After employing conventional imageology and pharmacology strategies to verify the result of proteomic analysis, we mapped a comprehensive intracellular transport network. Our study also revealed the merits of IPC analysis, which could readily elucidate the molecular mechanisms of transcytosis. Besides, the IPC proteins increased the uptake and stress response of endothelium, which was likely mediated by extracellular matrix and mitochondrion-related IPC proteins. Conclusion: The comprehensive proteomic analysis of IPC enabled tracing of transport pathways in epithelial cells as well as revealing the biological impact of nanoparticles on endothelium.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31967775

RESUMO

High-performance HCHO sensors are of great importance in various application fields such as indoor air quality assessments. Herein, bimetallic Ag-Pt nanoparticles are synthesized as high-performance catalysts for ZnO-based gas sensors. Spherical aberration (Cs)-corrected transmission electron microscopy images with atomic resolution clearly indicate that the prepared nanoparticles exhibit a novel Ag@Pt core-shell nanostructure with a pentagram shape. For high-performance HCHO sensor construction, integrated micro-electrodes are first fabricated with the microelectromechanical system (MEMS) technology. Then, the hydrothermal route is used to self-assemble well-aligned ZnO nanowire arrays onto the sensing microregion. After that, the pentagram-shaped Ag@Pt nanoparticles are loaded onto the surface of ZnO nanowires with the inkjet printing technique to form MEMS sensors with Ag@Pt@ZnO as the sensing material. The thoroughly sensing experiments indicate that the Ag@Pt nanoparticles exhibit satisfied catalytic activation to HCHO molecules. The experimental observed detection limit of our sensor to HCHO reaches the parts per billion level. To elucidate the HCHO-sensing mechanism, the online mass spectrum (online MS) is utilized to analyze the components of exhaust gas stream of HCHO flowing through the Ag@Pt@ZnO material. The online MS indicates that with the Ag@Pt catalyst, HCHO molecules are partially oxidized to HCOOH molecules at low temperatures and are completely oxidized to CO2 molecules at high temperatures.

5.
Mol Pharm ; 17(1): 239-250, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31800258

RESUMO

Oral administration is an ideal alternative for drug delivery due to its convenience and safety. However, oral protein delivery is limited by biological barriers such as the mucus barrier and epithelial barrier, which hamper drugs from entering the blood successfully. Here we presented PC6/CS NPs, a thiolated-polymer-based nanodrug delivery system in the form of poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, PC6), which is a kind of preactivated thiolated polymer, coated on chitosan (CS) nanoparticles (NPs). Its ability to overcome the mucus barrier and epithelial barrier was investigated. The existence of PC6 made the NPs prone to penetrate the mucus layer as well as strengthened the transcellular transport of insulin on epithelial cells. PC6/CS NPs efficiently enhanced the oral bioavailability of insulin to 16.2%. The improvement resulted from the function of PC6: (1) "diluting" mucus to promote nanoparticle penetration, (2) opening a tight junction to help insulin transport via the paracellular pathway, (3) making the nanoparticle more electrically neutral during the penetration process, and (4) uncoating from PC6/CS NPs so that positive CS NPs were adhered and uptaken by epithelial cells. Our study proves that PC6/CS NPs, which can achieve mucus penetration and epithelial permeation efficiently, are a potential nanocarrier for oral protein delivery.

6.
J Pharmacol Exp Ther ; 372(1): 107-118, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31732698

RESUMO

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (CFTR). Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in CF, two biomolecular activities are required, namely, correctors to increase the amount of properly folded F508delCFTR levels at the cell surface and potentiators to allow the effective opening, i.e., function of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary triple combination therapy consisting of two corrector molecules, type 1 (C1) and type 2, with additive mechanisms along with a potentiator are being investigated in the clinic for maximum restoration of mutated CFTR function. We report the identification and in vitro biologic characterization of ABBV-2222/GLPG2222 (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid),-a novel, potent, and orally bioavailable C1 corrector developed by AbbVie-Galapagos and currently in clinical trials-which exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug interaction (DDI) compared with 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (VX-809, Lumacaftor) and improvements in potency and efficacy compared with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide (VX-661, Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 value <10 nM. SIGNIFICANCE STATEMENT: To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in cystic fibrosis, AbbVie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent, and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222, which is currently in clinical trials, exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and substantial improvements over the existing C1 correctors.

7.
Biochem Biophys Res Commun ; 521(2): 449-456, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31676068

RESUMO

Acute liver failure (ALF) can be the consequence of various etiologies, which immune response plays a pivotal role in the pathogenesis. For the diversity of etiologies, more animal models are still needed in this field. Here, we developed a new acute liver injury mouse model induced by a fungal lectin AAGL (Agrocybe aegerita galectin). Intravenous injection of AAGL could induce the infiltration and activation of T, NKT and NK cells in liver and T cell played an important role in the pathogenesis. However, compared with the widely used concanavalin A model, AAGL model showed different immune mechanism. Transcriptome analysis of live tissue suggested that inflammation mediated by chemokine and cytokine signaling pathway was different between AAGL and Con A model. Fluorescent quantitative PCR verification assay showed that IL-1ß was expressed much higher in AAGL-treated mice and anti-IL-1ß could ameliorate AAGL-induced liver injury by inhibiting NF-κB and p38 signaling pathway. The expression of CXCL9 which was responsible for T cell infiltration in liver was also inhibited in AAGL model. We found a critical role of IL-1ß in the pathogenesis of AAGL model through recruiting T cells to liver, which highlighted that IL-1ß antibody might be a candidate therapy for ALF.

8.
Accid Anal Prev ; 134: 105350, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715549

RESUMO

Previous studies have acknowledged the impact of risk perception on safety behavior, but were largely controversial. This study aims to clarify this conflict and the mechanism through which risk perception can have an impact on safety behavior. From the perspective of the dual attribute of the job demand concept in job demands-resources theory, we posit that risk perception can be considered as a job hindrance or a job challenge depending on the context, thereby resulting in a negative or positive impact on safety behavior, respectively. The current research context is the construction industry and the hypotheses were tested using hierarchically nested data collected from 311 workers in 35 workgroups. Risk perception was demonstrated to be a job hindrance exerting a negative impact on safety behavior and safety motivation mediated this effect. In addition, two dimensions of group-level safety climate--supervisor's and coworkers'--were expected to alleviate or even reverse the detrimental effects of hindrance risk perception on safety motivation and on safety behavior via motivation. A moderation model and a first-stage moderated mediation model were established, respectively, for testing the moderating roles of safety climate in the relationship between risk perception and safety motivation, and in the indirect relationship of risk perception with safety behavior via motivation. Surprisingly, contrary to the hypotheses, when supervisor's safety climate changed from a low level to a high level, the impact of risk perception on safety motivation changed from positive to negative, and the negative effect of risk perception on safety behavior via safety motivation was not alleviated but worsened. As expected, for workers in a positive coworkers' safety climate, the negative effect of risk perception on motivation and the indirect negative effect of risk perception on behavior were both reversed to the positive. This indicates that coworkers' safety climate helped to change perceived risk from a job hindrance to a challenge. This research contributes to workplace risk perception and safety behavior research by theoretically viewing risk perception as a dual job hindrance-challenge concept and proposing two competing hypotheses concerning the impact of risk perception on safety behavior. The empirical investigation confirmed the hindrance attribute of risk perception in the construction context. It provides a theoretical framework and empirical evidence for future research to synthesize the conflict risk perception-safety behavior relationship. We also contribute to the literature by pointing out the potential negative role of certain supervisor safety activities such as paternalistic leadership in influencing employee safety.


Assuntos
Cultura Organizacional , Gestão da Segurança/organização & administração , Prevenção de Acidentes/métodos , Adulto , Indústria da Construção/organização & administração , Feminino , Humanos , Masculino , Motivação , Saúde do Trabalhador
9.
Nat Commun ; 10(1): 5791, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857576

RESUMO

Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.

10.
ACS Med Chem Lett ; 10(11): 1543-1548, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31749908

RESUMO

Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

11.
Glycobiology ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31616917

RESUMO

Glycosylation plays important roles in many cellular processes, such as signal transduction, cell cycle progression, and transcriptional regulation. However, the identification and analysis of glycosylation are severely hampered by the low specificity or avidity of anti-glycan antibodies and lectins. We have reported that a lectin AANL, which has high specificity for terminal GlcNAc glycans and contains six CBSs (carbohydrate binding sites), was used to enrich O-GlcNAcylated peptides. To further improve AANL binding specificity, we designed a CBS-homogenization strategy and restructured six mutant lectins, known as AANL1 to AANL6. Affinity chromatography with GlcNAc and ITC (isothermal titration calorimetry) analysis indicated that the two mutants (AANL3 and AANL6) all maintained GlcNAc binding activity. AANL6 and AANL3 showed higher specificity for terminal GlcNAc glycans than AANL, as shown by the hemagglutination assay, cell binding assays and glycan microarray analysis, and AANL6 exhibited the highest specificity. The binding activity of AANL6 for O-GlcNAcylated peptides was shown by SPR (surface plasmon resonance) assays. By AANL6 affinity chromatography enrichment and mass spectrometry analysis, 79 high-confidence and 21 putative O-GlcNAcylated sites were identified on 85 peptides mapped onto 54 proteins. Most of these sites were new sites compared with reported data. These results indicate that the enrichment capacity of AANL6 is higher than that of wild-type AANL. In conclusion, the CBS-homogenization mutation strategy was successful, and AANL6 was identified as a powerful tool for O-GlcNAcylation enrichment. Our research suggests that the CBS-homogenization strategy is valuable for improving the specificity of lectins with multiple CBSs.

12.
Nat Commun ; 10(1): 4827, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645592

RESUMO

Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.

13.
AAPS PharmSciTech ; 20(8): 316, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31602546

RESUMO

Glucocorticoids have been confirmed to be effective in the treatment of a variety of inflammatory diseases. However, their application encounters limitations in terms of tissue distribution and bioavailability in vivo. To address these key issues, we designed and developed a nanopreparation by using egg yolk lecithin/sodium glycocholate (EYL/SGC) and utilize such mixed micelles (MMs) to encapsulate dexamethasone palmitate (DMP) for the treatment of rheumatoid arthritis (RA). The prepared DMP-MMs had an average particle size of 49.18 ± 0.43 nm and were compared with an emulsion-based dexamethasone palmitate. Pharmacokinetic and in vivo fluorescence imaging showed that mixed micelles had higher bioavailability and targeting efficiency in inflammatory sites. An arthritis rat model was established via induction by Complete Freund's Adjuvant (CFA), followed by the efficacy studies by the observations of paw volume, histology, spleen index, pro-inflammatory cytokines, and CT images. It was confirmed that intravenous injection of DMP-MMs exhibited advantages in alleviating joint inflammation compared with the emulsion system. Composed of pharmaceutical adjuvants only, the nanoscale mixed micelles seem a promising carrier system for the RA treatment with lipophilic drugs.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Dexametasona/administração & dosagem , Sistemas de Liberação de Medicamentos , Palmitatos/administração & dosagem , Animais , Artrite Experimental/tratamento farmacológico , Dexametasona/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Emulsões , Masculino , Micelas , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley
14.
Gigascience ; 8(9)2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518402

RESUMO

BACKGROUND: The Chinese white wax scale insect, Ericerus pela, is best known for producing wax, which has been widely used in candle production, casting, Chinese medicine, and wax printing products for thousands of years. The secretion of wax, and other unusual features of scale insects, is thought to be an adaptation to their change from an ancestral ground-dwelling lifestyle to a sedentary lifestyle on the higher parts of plants. As well as helping to improve its economic value, studies of E. pela might also help to explain the adaptation of scale insects. However, no genomic data are currently available for E. pela. FINDINGS: To assemble the E. pela genome, 303.92 Gb of data were generated using Illumina and Pacific Biosciences sequencing, producing 277.22 Gb of clean data for assembly. The assembled genome size was 0.66 Gb, with 1,979 scaffolds and a scaffold N50 of 735 kb. The guanine + cytosine content was 33.80%. A total of 12,022 protein-coding genes were predicted, with a mean coding sequence length of 1,370 bp. Twenty-six fatty acyl-CoA reductase genes and 35 acyltransferase genes were identified. Evolutionary analysis revealed that E. pela and aphids formed a sister group and split ∼241.1 million years ago. There were 214 expanded gene families and 2,219 contracted gene families in E. pela. CONCLUSION: We present the first genome sequence from the Coccidae family. These results will help to increase our understanding of the evolution of unique features in scale insects, and provide important genetic information for further research.

15.
Nanomedicine (Lond) ; 14(18): 2423-2440, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31549585

RESUMO

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

16.
OMICS ; 23(12): 631-639, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31526239

RESUMO

Type 2 diabetes mellitus (T2DM) is a common complex trait arising from interactions among multiple environmental, genomic, and postgenomic factors. We report here the first attempt to investigate the association between immunoglobulin G (IgG) N-glycan patterns, T2DM, and their clinical risk factors in an Australian population. N-glycosylation of proteins is one of the most frequently observed co- and post-translational modifications, reflecting, importantly, the real-time status of the interplay between the genomic and postgenomic factors. In a community-based case-control study, 849 participants (217 cases and 632 controls) were recruited from an urban community in Busselton, Western Australia. We applied the ultraperformance liquid chromatography method to analyze the composition of IgG N-glycans. We then conducted Spearman's correlation analyses to explore the association between glycan biomarker candidates and clinical risk factors. We performed area under the curve (AUC) analysis of the receiver operating characteristic curves by fivefold cross-validation for clinical risk factors, IgG glycans, and their combination. Two directly measured and four derived glycan peaks were significantly associated with T2DM, after correction for extensive clinical confounders and false discovery rate, thus suggesting that IgG N-glycan traits are highly correlated with T2DM clinical risk factors. Moreover, adding the IgG glycan profiles to fasting blood glucose in the logistic regression model increased the AUC from 0.799 to 0.859. The AUC for IgG glycans alone was 0.623 with a 95% confidence interval 0.580-0.666. In addition, our study provided new evidence of diversity in T2DM complex trait by IgG N-glycan stratification. Six IgG glycan traits were firmly associated with T2DM, which reflects an increased proinflammatory and biological aging status. In summary, our study reports novel associations between the IgG N-glycome and T2DM in an Australian population and the putative role of proinflammatory mechanisms. Furthermore, IgG N-glycomic alterations offer future prospects as inflammatory biomarker candidates for T2DM diagnosis, and monitoring of T2DM progression to cardiovascular disease or renal failure.

17.
FEBS J ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31482685

RESUMO

Non-small cell lung cancer (NSCLC) is the main type of lung cancer, with a low 5-year survival rate because of the absence of effective clinical biomarkers for early diagnosis. Based on the immunosurveillance theory, we proposed that changes in the immune system are more pronounced than tumour-associated antigens during the early stage of cancer. Therefore, a new strategy was designed to screen early diagnostic biomarkers from peripheral leukocytes in early-stage NSCLCs with transcriptome sequencing. A total of 358 immune-related differentially expressed genes were identified between early-NSCLC patients and healthy individuals. Orosomucoid-1 (ORM1, a acute phase protein), the total ORM and chitotriosidase-1 (involved in degradation of chitobiose) were selected for further verification in 210 serum samples by western blotting, ELISA and nephelometry immunoassay (based on immuno-scatter turbidmetry). Receiver operating characteristic curve analysis show that ORM1 and total ORM have excellent diagnostic efficacies, with area under the curve of 0.862 and 0.920, respectively, which significantly distinguished very early-NSCLC (IA) from healthy samples. Flow cytometry results showed that CD15+ neutrophils made up 73% of ORM1+ peripheral leukocytes. In mouse lung cancer model, serum ORM1, but not liver ORM1, changed significantly in the early stage of NSCLC. ORM1 expression in peripheral leukocytes was regulated by TGF-ß and mediated by the TGF-ß/Smad signalling pathway. Our results indicated that combined ORM and TGF-ß could be a promising clinical biomarker in the diagnosis of early NSCLC.

18.
OMICS ; 23(12): 649-659, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31313980

RESUMO

Cardiovascular disease is a common complex trait that calls for next-generation biomarkers for precision diagnostics and therapeutics. The most common type of post-translational protein modification involves glycosylation. Glycans participate in key intercellular and intracellular functions, such as protein quality control, cell adhesion, cell-cell recognition, signal transduction, cell proliferation, and cell differentiation. In this context, immunoglobulin G (IgG) N-glycans affect the anti-inflammatory and proinflammatory responses of IgG, and are associated with cardiometabolic risk factors such as aging, central obesity, dyslipidemia, and hyperglycemia. Yet, the role of such glycomic biomarkers requires evaluation in diverse world populations. We report here original observations on association of IgG N-glycan biosignatures with 15 cardiometabolic risk factors in a community-based cross-sectional study conducted in 701 Chinese Han participants. After controlling for age and sex, we found that the 16, 21, and 18 IgG N-glycan traits were significantly different in participants with and without metabolic syndrome, hypertriglyceridemic waist phenotype, or abdominal obesity, respectively. The canonical correlation analysis showed that IgG N-glycan profiles were significantly associated with cardiometabolic risk factors (r = 0.469, p < 0.001). Classification models based on IgG N-glycan traits were able to differentiate participants with (1) metabolic syndrome, (2) hypertriglyceridemic waist phenotype, or (3) abdominal obesity from controls, with an area under receiver operating characteristic curves (AUC) of 0.632 (95% confidence interval [CI], 0.574-0.691, p < 0.001), 0.659 (95% CI, 0.587-0.730, p < 0.001), and 0.610 (95% CI, 0.565-0.656, p < 0.001), respectively. These new data suggest that IgG N-glycans may play an important role in cardiometabolic disease pathogenesis by regulating the proinflammatory or anti-inflammatory responses of IgG. Looking into the future, IgG N-glycan biosignatures warrant further research in other world population samples with a view to applications in clinical cardiology and public health practice.

19.
Adv Drug Deliv Rev ; 143: 177-205, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201837

RESUMO

Extensive studies on nanomedicines have been conducted for drug delivery and disease diagnosis (especially for cancer therapy). However, the intracellular and in vivo biofate of nanomedicines, which is significantly associated with their clinical therapeutic effect, is poorly understood at present. This is because of the technical challenges to quantify the disassembly and behaviour of nanomedicines. As a fluorescence- and distance-based approach, the Förster Resonance Energy Transfer (FRET) technique is very successful to study the interaction of nanomedicines with biological systems. In this review, principles on how to select a FRET pair and construct FRET-based nanomedicines have been described first, followed by their application to study structural integrity, biodistribution, disassembly kinetics, and elimination of nanomedicines at intracellular and in vivo levels, especially with drug nanocarriers including polymeric micelles, polymeric nanoparticles, and lipid-based nanoparticles. FRET is a powerful tool to reveal changes and interaction of nanoparticles after delivery, which will be very useful to guide future developments of nanomedicine.

20.
J Cell Physiol ; 234(12): 21601-21612, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31115050

RESUMO

Circular RNAs (circRNAs) are stable and abundantly expressed in vivo but are abnormally expressed in several diseases. This study aimed to identify circRNAs acting as potential biomarkers for cardiovascular disease (CVD). Research were retrieved from the articles published by September 2018 in eight databases to compare circRNA expression profiles between CVD and non-CVD in human and animal models. Meta-analysis under a random effects model was conducted. Subgroup analysis of tissue, species, and disease-specific circRNAs was examined. Sensitivity analysis was performed to explain the uncertainty among all studies. Diagnostic accuracy of circRNAs in CVD was analyzed to testify the discriminative ability. Bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was conducted. Among 6,284 differentially expressed circRNAs from 32 original studies, only 322 circRNAs were reported in three or more studies. The meta-analysis identified 63 significantly dysregulated circRNAs, 44 upregulated and 19 downregulated. Among the tissue-specific or disease-specific circRNAs identified in the subgroup analysis, two circRNAs (circCDKN2BAS and circMACF1) showed the potential to be circulating biomarkers for CVD. Sensitivity analysis demonstrated 69% of circRNAs were in conformity with the overall analysis. The pooled diagnostic odds ratio was 2.94 (95% confidence interval [CI], 2.35-3.58), and the overall area under the curve value was 0.86 (95% CI, 0.83-0.89). GO and KEGG enrichment analyses indicated that the target genes of circRNAs participate in cardiogenesis-related processes and pathways. This study demonstrates circRNAs have a high diagnostic value as potential biomarkers for CVD, and two candidate circRNAs, circCDKN2BAS and circMACF1, are potential circulating biomarkers for CVD diagnosis and treatment.

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