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1.
Epigenetic scores for the circulating proteome as tools for disease prediction.
Gadd, DA, Hillary, RF, McCartney, DL, Zaghlool, SB, Stevenson, AJ, Cheng, Y, Fawns-Ritchie, C, Nangle, C, Campbell, A, Flaig, R, et al
eLife. 2022
Abstract
Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.
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Innate immune remodeling by short-term intensive fasting.
Qian, J, Fang, Y, Yuan, N, Gao, X, Lv, Y, Zhao, C, Zhang, S, Li, Q, Li, L, Xu, L, et al
Aging cell. 2021;(11):e13507
Abstract
Previous studies have shown that long-term light or moderate fasting such as intermittent fasting can improve health and prolong lifespan. However, in humans short-term intensive fasting, a complete water-only fasting has little been studied. Here, we used multi-omics tools to evaluate the impact of short-term intensive fasting on immune function by comparison of the CD45+ leukocytes from the fasting subjects before and after 72-h fasting. Transcriptomic and proteomic profiling of CD45+ leukocytes revealed extensive expression changes, marked by higher gene upregulation than downregulation after fasting. Functional enrichment of differentially expressed genes and proteins exposed several pathways critical to metabolic and immune cell functions. Specifically, short-term intensive fasting enhanced autophagy levels through upregulation of key members involved in the upstream signals and within the autophagy machinery, whereas apoptosis was reduced by down-turning of apoptotic gene expression, thereby increasing the leukocyte viability. When focusing on specific leukocyte populations, peripheral neutrophils are noticeably increased by short-term intensive fasting. Finally, proteomic analysis of leukocytes showed that short-term intensive fasting not only increased neutrophil degranulation, but also increased cytokine secretion. Our results suggest that short-term intensive fasting boost immune function, in particular innate immune function, at least in part by remodeling leukocytes expression profile.
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3.
Integration of molecular profiles in a longitudinal wellness profiling cohort.
Tebani, A, Gummesson, A, Zhong, W, Koistinen, IS, Lakshmikanth, T, Olsson, LM, Boulund, F, Neiman, M, Stenlund, H, Hellström, C, et al
Nature communications. 2020;(1):4487
Abstract
An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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4.
The aqueous humor proteome of primary open angle glaucoma: An extensive review.
Hubens, WHG, Mohren, RJC, Liesenborghs, I, Eijssen, LMT, Ramdas, WD, Webers, CAB, Gorgels, TGMF
Experimental eye research. 2020;:108077
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Abstract
BACKGROUND We reviewed the literature on the aqueous humor (AH) proteome of primary open angle glaucoma (POAG) patients in order to obtain deeper insight into the pathophysiology of POAG. METHODS We searched Pubmed and Embase up to May 2019 for studies that compared AH protein composition between POAG (cases) and cataract (controls). Untargeted studies (measuring the whole proteome, by LC-MS/MS) were divided into two subgroups depending on the type of surgery during which POAG AH was collected: glaucoma filtration surgery (subgroup 1) or cataract surgery (subgroup 2). We reanalyzed the raw data (subgroup 1) or combined the reported data (subgroup 2) to perform GO enrichment (GOrilla) and pathway analysis (Pathvisio). RESULTS Out of 93 eligible proteomic studies, seven were untargeted studies that identified 863 AH proteins. We observed 73 differentially expressed proteins in subgroup 1 and 87 differentially expressed proteins in subgroup 2. Both subgroups were characterized by activation of the acute immune response, dysregulation of folate metabolism and dysregulation of the selenium micronutrient network. For subgroup 1 but not for subgroup 2, proteins of the complement system were significantly enriched. CONCLUSION AH proteome of POAG patients shows strong activation of the immune system. In addition, analysis suggests dysregulation of folate metabolism and dysregulation of selenium as underlying contributors. In view of their glaucoma surgery, POAG patients of subgroup 1 most likely are progressive whereas POAG patients in subgroup 2 most likely have stable POAG. The proteome difference between these subgroups suggests that the complement system plays a role in POAG progression.
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5.
The Functional Power of the Human Milk Proteome.
Zhu, J, Dingess, KA
Nutrients. 2019;(8)
Abstract
Human milk is the most complete and ideal form of nutrition for the developing infant. The composition of human milk consistently changes throughout lactation to meet the changing functional needs of the infant. The human milk proteome is an essential milk component consisting of proteins, including enzymes/proteases, glycoproteins, and endogenous peptides. These compounds may contribute to the healthy development in a synergistic way by affecting growth, maturation of the immune system, from innate to adaptive immunity, and the gut. A comprehensive overview of the human milk proteome, covering all of its components, is lacking, even though numerous analyses of human milk proteins have been reported. Such data could substantially aid in our understanding of the functionality of each constituent of the proteome. This review will highlight each of the aforementioned components of human milk and emphasize the functionality of the proteome throughout lactation, including nutrient delivery and enhanced bioavailability of nutrients for growth, cognitive development, immune defense, and gut maturation.
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Changes in Human Tear Proteome Following Topical Treatment of Dry Eye Disease: Cyclosporine A Versus Diquafosol Tetrasodium.
Ji, YW, Kim, HM, Ryu, SY, Oh, JW, Yeo, A, Choi, CY, Kim, MJ, Song, JS, Kim, HS, Seo, KY, et al
Investigative ophthalmology & visual science. 2019;(15):5035-5044
Abstract
PURPOSE To compare the changes in human tear proteome and clinical effects following topical cyclosporine A (CsA) 0.05% or diquafosol tetrasodium (DQS) 3% treatment of dry eye disease (DED), and to identify biomarkers for determining disease severity and treatment effectiveness in DED. METHODS A total of 18 patients were diagnosed with non-Sjögren DED. Nine patients in each group were treated with topical CsA 0.05% or DQS 3% for 4 weeks. Tear samples were collected after evaluation of tear breakup time, corneal and conjunctival erosion staining, and results of Schirmer's test 1 before and after treatment. Proteomes were characterized using liquid chromatography mass spectrometry, and proteins exhibiting a fold change >1.5 or <0.67 (P < 0.05) were considered differentially expressed (DEP). RESULTS A total of 794 proteins were identified, with no significant difference observed between pretreatment and posttreatment conditions. Proteomic analysis identified 54 and 106 DEPs between treatment groups (CsA and DQS, respectively), with gene ontology analysis indicating that both treatments enhanced innate and adaptive immune responses and cellular detoxification. Protein-network analysis showed that inflammation associated with the immune response was primarily responsible for the therapeutic process in both groups. CONCLUSIONS These results provide insight into the broad scope of changes at the ocular surface in DED and indicated that although both drugs improved the clinical parameters, the activated tear-specific biomarkers differed significantly between treatments. Our findings suggest that the DEPs identified here and those correlated with the clinical parameters might represent candidate biomarkers for DED.
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7.
Novel mediators of statin effects on plaque in HIV: a proteomics approach.
deFilippi, C, Lo, J, Christenson, R, Grundberg, I, Stone, L, Zanni, MV, Lee, H, Grinspoon, SK
AIDS (London, England). 2018;(7):867-876
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Abstract
OBJECTIVE HIV patients have increased atherosclerotic coronary vascular disease (ASCVD), thought to be mediated through inflammatory mechanisms. We hypothesized that among asymptomatic HIV-infected patients with subclinical coronary plaque, statin therapy would modulate unique inflammatory and cardiovascular proteins in relation to change in subclinical coronary plaque volume. We tested this hypothesis using a novel proteomics approach. DESIGN Forty HIV-infected participants were randomized to atorvastatin (40 mg/day) versus placebo, and underwent computed tomography coronary angiography to quantify plaque volume at baseline and 1 year. METHODS We used Olink Cardiovascular III and Cardiometabolic panels based on dual antibody epitope recognition with linked DNA amplification to compare change over time in 184 proteins in treatment versus placebo and in relation to change in coronary plaque volume. RESULTS Six proteins (TFPI, CCL24, NT-Pro BNP, MBL2, LTBR, PCOLCE) changed significantly in the atorvastatin versus placebo group, many in innate immune and other novel inflammatory pathways. Twenty-six proteins changed significantly in relationship to total coronary plaque volume over 1 year. Notably, many of these proteins changed only weakly in relationship to change in low-density lipoprotein (LDL). Overlapping these two broad discovery approaches, proteins involved in myocardial fibrosis/collagen formation and monocyte chemoattraction changed with statin treatment, in relationship to plaque volume, but not LDL. CONCLUSION This proof-of-concept study employing a proteomic discovery platform offers insight into statin effects on novel immune pathways relevant to ASCVD progression in HIV. Novel biomarker discovery may enhance precision medicine strategies to estimate the efficacy of targeted therapies to reduce ASCVD progression and events in HIV.
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Proteome-wide analysis of human motif-domain interactions mapped on influenza a virus.
García-Pérez, CA, Guo, X, Navarro, JG, Aguilar, DAG, Lara-Ramírez, EE
BMC bioinformatics. 2018;(1):238
Abstract
BACKGROUND The influenza A virus (IAV) is a constant threat for humans worldwide. The understanding of motif-domain protein participation is essential to combat the pathogen. RESULTS In this study, a data mining approach was employed to extract influenza-human Protein-Protein interactions (PPI) from VirusMentha,Virus MINT, IntAct, and Pfam databases, to mine motif-domain interactions (MDIs) stored as Regular Expressions (RegExp) in 3DID database. A total of 107 RegExp related to human MDIs were searched on 51,242 protein fragments from H1N1, H1N2, H2N2, H3N2 and H5N1 strains obtained from Virus Variation database. A total 46 MDIs were frequently mapped on the IAV proteins and shared between the different strains. IAV kept host-like MDIs that were associated with the virus survival, which could be related to essential biological process such as microtubule-based processes, regulation of cell cycle check point, regulation of replication and transcription of DNA, etc. in human cells. The amino acid motifs were searched for matches in the immune epitope database and it was found that some motifs are part of experimentally determined epitopes on IAV, implying that such interactions exist. CONCLUSION The directed data-mining method employed could be used to identify functional motifs in other viruses for envisioning new therapies.
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Identification of Host-Response in Cerebral Malaria Patients Using Quantitative Proteomic Analysis.
Kumar, M, Varun, CN, Dey, G, Ravikumar, R, Mahadevan, A, Shankar, SK, Prasad, TSK
Proteomics. Clinical applications. 2018;(4):e1600187
Abstract
PURPOSE The objective of this study was to study the altered proteome in the frontal lobe of patients with CM. Unbiased analysis of differentially abundant proteins could lead to identification of host responses against Plasmodium falciparum infection, which will aid in better understanding of the molecular mechanism of pathophysiology in CM. EXPERIMENTAL DESIGN TMT-based quantitative proteomic analysis using high-resolution mass spectrometry is employed. In brief, proteins are isolated from frontal lobe samples, which are collected at autopsy from three cases of CM and three control subjects. Equal amounts of protein from each case are digested using trypsin and labeled with different TMT reagents. The pooled sample is fractionated using strong cation exchange chromatography and analyzed on Orbitrap Fusion in triplicates. For accurate quantitation of peptides, the samples are analyzed in MS3 mode. The data is searched against a combined database of human and P. falciparum proteins using Sequest and Mascot search engines. RESULTS A total of 4174 proteins are identified, of which, 107 are found to be differentially abundant in the test samples with significant p-value (<0.05). Proteins associated with biological processes such as innate immune response, complement system, coagulation, and platelet activation are found to be elevated in CM cases. In contrast, proteins associated with myelination, oxidative phosphorylation, regulation of reactive oxygen species, and sodium and calcium ions transport are found to be depleted in response to CM. In addition, three P. falciparum proteins exclusively in CM brain samples are also identified. CONCLUSIONS AND CLINICAL RELEVANCE The study signifies neuronal assault due to axonal injury, altered sodium and calcium ion channels, deregulated inflammation and demyelination as a part of host response to CM. Enhanced oxidative stress, repressed oxidative phosphorylation, and demyelination of axons may contribute to the severity of the disease. Further validation of these results on a large cohort can provide leads in the development of neuroprotective therapies for CM.
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[Advances in the knowledge about human milk proteins].
Brunser, O
Revista chilena de pediatria. 2018;(2):261-269
Abstract
The mammary gland and maternal milk are the product of millions of years of evolution that resul ted in an optimal composition that sustains the growth and development of newborns and infants. Maternal milk supports the growth, adaptation and survival of this immature organism. Recent studies have detected 1606 different proteins in human milk, most of them synthesized in the acini of the glandular tissue while others originate from distant organs such as the lymphoid tissue and the digestive tract. Maternal milk enzymes modify its proteins and liberate peptides with antimicrobial, antihypertensive or stimulatory activities. This proteolytic activity occurs at specific sites in peptide chains. To prevent the extemporaneous activation of these proteolytic enzymes, that would result in inflammatory processes, maternal milk also contains inhibitory peptides that together with the stimulatory peptides conform a complex regulatory system. Some enzymes in maternal milk main tain their activity in the gastrointestinal tract of infants and compensate for the decreased activity of digestive tract enzymes in newborns. Thus, the milk enterokynase stimulates the release of pancreatic proteases as it induces the liberation of cholecystokynin/pancreozymin. The bile salt-activated lipase of human milk is activated in the duodenum by the infants' bile salts and partially compensates for the low levels of pancreatic lipase in newborns. These milk enzymes probably contribute to the nutrition of premature infants as they increase the availability of amino acids and peptides in their upper gastrointestinal tract; furthermore, as their intestinal epithelium is more permeable to peptides and partially digested protein this may help induce immune tolerance. The most relevant issues in the physiology and composition of the maternal milk are presented in this review.