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Molecular Systems Biology Sep 2017Clinical analysis of blood is the most widespread diagnostic procedure in medicine, and blood biomarkers are used to categorize patients and to support treatment... (Review)
Review
Clinical analysis of blood is the most widespread diagnostic procedure in medicine, and blood biomarkers are used to categorize patients and to support treatment decisions. However, existing biomarkers are far from comprehensive and often lack specificity and new ones are being developed at a very slow rate. As described in this review, mass spectrometry (MS)-based proteomics has become a powerful technology in biological research and it is now poised to allow the characterization of the plasma proteome in great depth. Previous "triangular strategies" aimed at discovering single biomarker candidates in small cohorts, followed by classical immunoassays in much larger validation cohorts. We propose a "rectangular" plasma proteome profiling strategy, in which the proteome patterns of large cohorts are correlated with their phenotypes in health and disease. Translating such concepts into clinical practice will require restructuring several aspects of diagnostic decision-making, and we discuss some first steps in this direction.
Topics: Biomarkers; Blood Proteins; Humans; Mass Spectrometry; Phenotype; Proteome; Proteomics
PubMed: 28951502
DOI: 10.15252/msb.20156297 -
International Journal of Molecular... Dec 2020Galectin-3 (Gal-3) is a β-galactoside-binding protein belonging to the lectin family with pleiotropic regulatory activities and several physiological cellular... (Review)
Review
Galectin-3 (Gal-3) is a β-galactoside-binding protein belonging to the lectin family with pleiotropic regulatory activities and several physiological cellular functions, such as cellular growth, proliferation, apoptosis, differentiation, cellular adhesion, and tissue repair. Inflammation, tissue fibrosis and angiogenesis are the main processes in which Gal-3 is involved. It is implicated in the pathogenesis of several diseases, including organ fibrosis, chronic inflammation, cancer, atherosclerosis and other cardiovascular diseases (CVDs). This review aims to explore the connections of Gal-3 with cardiovascular diseases since they represent a major cause of morbidity and mortality. We herein discuss the evidence on the pro-inflammatory role of Gal-3 in the atherogenic process as well as the association with plaque features linked to lesion stability. We report the biological role and molecular mechanisms of Gal-3 in other CVDs, highlighting its involvement in the development of cardiac fibrosis and impaired myocardium remodelling, resulting in heart failure and atrial fibrillation. The role of Gal-3 as a prognostic marker of heart failure is described together with possible diagnostic applications to other CVDs. Finally, we report the tentative use of Gal-3 inhibition as a therapeutic approach to prevent cardiac inflammation and fibrosis.
Topics: Animals; Biomarkers; Blood Proteins; Cardiovascular Diseases; Disease Models, Animal; Disease Susceptibility; Fibrosis; Galectins; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Molecular Targeted Therapy
PubMed: 33287402
DOI: 10.3390/ijms21239232 -
BMC Genomics Aug 2022Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown.
BACKGROUND
Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown.
RESULTS
We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls. We performed two-sample Mendelian randomization (MR) with multiple cis instruments as well as network and enrichment analysis using data from blood protein quantitative trait loci (pQTL) (2,965 blood proteins) measured in 3,301 individuals. Nineteen blood proteins were causally associated with HF, were not subject to reverse causality and were enriched in ligand-receptor and glycosylation molecules. Network pathway analysis of the blood proteins showed enrichment in NF-kappa B, TGF beta, lipid in atherosclerosis and fluid shear stress. Cross-phenotype analysis of HF identified genetic overlap with cardiovascular drugs, myocardial infarction, parental longevity and low-density cholesterol. Multi-trait MR identified causal associations between HF-associated blood proteins and cardiovascular outcomes. Multivariable MR showed that association of BAG3, MIF and APOA5 with HF were mediated by the blood pressure and coronary artery disease. According to the directional effect and biological action, 7 blood proteins are targets of existing drugs or are tractable for the development of novel therapeutics. Among the pathways, sialyl Lewis x and the activin type II receptor are potential druggable candidates.
CONCLUSIONS
Integrative MR analyses of the blood proteins identified causally-associated proteins with HF and revealed pleiotropy of the blood proteome with cardiovascular risk factors. Some of the proteins or pathway related mechanisms could be targeted as novel treatment approach in HF.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Blood Proteins; Heart Failure; Humans; Mendelian Randomization Analysis; Proteome; Risk Factors
PubMed: 35964012
DOI: 10.1186/s12864-022-08811-2 -
Science (New York, N.Y.) Aug 2018Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins...
Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.
Topics: Aptamers, Nucleotide; Blood Proteins; Cardiovascular Diseases; Genetic Predisposition to Disease; Genetic Variation; Humans; Iceland; Metabolic Diseases; Metabolic Networks and Pathways; Proteome; Proteomics
PubMed: 30072576
DOI: 10.1126/science.aaq1327 -
Nature Oct 2023Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets. Because previous proteogenomic...
Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.
Topics: Humans; Alleles; Biological Specimen Banks; Biomarkers; Blood Proteins; Databases, Factual; Exome; Genetic Association Studies; Genomics; Hematopoiesis; Mutation; Plasma; Proteomics; United Kingdom
PubMed: 37794183
DOI: 10.1038/s41586-023-06547-x -
Nature Jul 2020The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability....
The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.
Topics: Aging; Alkaline Phosphatase; Animals; Antibodies; Biological Transport; Blood Proteins; Blood-Brain Barrier; Brain; Drug Delivery Systems; Health; Humans; Male; Mice; Mice, Inbred C57BL; Plasma; Proteome; Receptors, Transferrin; Transcription, Genetic; Transcytosis; Transferrin
PubMed: 32612231
DOI: 10.1038/s41586-020-2453-z -
Blood Sep 2019There is increasing recognition that platelets have a functional role in the pathophysiology of sepsis, though this role has not been precisely defined. Whether sepsis...
There is increasing recognition that platelets have a functional role in the pathophysiology of sepsis, though this role has not been precisely defined. Whether sepsis alters the human platelet transcriptome and translational landscape has never been established. We used parallel techniques of RNA sequencing and ribosome footprint profiling to interrogate the platelet transcriptome and translatome in septic patients and healthy donors. We identified 1806 significantly differentially expressed (false discovery rate <0.05) transcripts in platelets from septic patients. Platelet translational events during sepsis were also upregulated. To explore the relevance of a murine model of sepsis, cecal ligation and puncture (CLP), we compared sepsis-induced changes in platelet gene expression between septic patients and mice subjected to CLP. Platelet transcriptional (ρ = 0.42, = 3.2 × 10) and translational (ρ = 0.65, = 1.09 × 10) changes were significantly correlated between septic patients and mice. We focused on , tracking and validating the expression, regulation, and functional impact of changes in during sepsis. Increased was identified in bone marrow megakaryocytes within 24 hours of sepsis onset. Subsequent increases in were seen in circulating platelets, suggesting dynamic trafficking of the messenger RNA. Transcriptional changes in were accompanied by de novo protein synthesis of αIIb and integrin αIIbβ3 activation. Increased αIIb was associated with mortality in humans and mice. These findings provide previously unrecognized evidence that human and murine sepsis similarly alters the platelet transcriptional and translational landscape. Moreover, is upregulated and functional in sepsis due to trafficking from megakaryocytes and de novo synthesis in platelets and is associated with increased mortality.
Topics: Animals; Blood Platelets; Blood Proteins; Case-Control Studies; Female; Gene Expression Profiling; Humans; Male; Mice; Protein Biosynthesis; Proteome; Proteomics; Sepsis; Severity of Illness Index; Transcription, Genetic; Transcriptome
PubMed: 31366617
DOI: 10.1182/blood.2019000067 -
Bioscience Reports Feb 2022Multimerin-1 (MMRN1) is a platelet protein with a role in haemostasis and coagulation. It is also present in endothelial cells (ECs) and the extracellular matrix (ECM),... (Review)
Review
Multimerin-1 (MMRN1) is a platelet protein with a role in haemostasis and coagulation. It is also present in endothelial cells (ECs) and the extracellular matrix (ECM), where it may be involved in cell adhesion, but its molecular functions and protein-protein interactions in these cellular locations have not been studied in detail yet. In recent years, MMRN1 has been identified as a differentially expressed gene (DEG) in various cancers and it has been proposed as a possible cancer biomarker. Some evidence suggest that MMRN1 expression is regulated by methylation, protein interactions, and non-coding RNAs (ncRNAs) in different cancers. This raises the questions if a functional role of MMRN1 is being targeted during cancer development, and if MMRN1's differential expression pattern correlates with cancer progression. As a result, it is timely to review the current state of what is known about MMRN1 to help inform future research into MMRN1's molecular mechanisms in cancer.
Topics: Blood Platelets; Blood Proteins; Endothelial Cells; Humans; Neoplasms
PubMed: 35132992
DOI: 10.1042/BSR20211248 -
Archives of Toxicology Jan 2022Chemicals are measured regularly in air, food, the environment, and the workplace. Biomonitoring of chemicals in biological fluids is a tool to determine the individual... (Review)
Review
Chemicals are measured regularly in air, food, the environment, and the workplace. Biomonitoring of chemicals in biological fluids is a tool to determine the individual exposure. Blood protein adducts of xenobiotics are a marker of both exposure and the biologically effective dose. Urinary metabolites and blood metabolites are short term exposure markers. Stable hemoglobin adducts are exposure markers of up to 120 days. Blood protein adducts are formed with many xenobiotics at different sites of the blood proteins. Newer methods apply the techniques developed in the field of proteomics. Larger adducted peptides with 20 amino acids are used for quantitation. Unfortunately, at present the methods do not reach the limits of detection obtained with the methods looking at single amino acid adducts or at chemically cleaved adducts. Therefore, to progress in the field new approaches are needed.
Topics: Biological Monitoring; Biomarkers; Blood Proteins; Hemoglobins; Proteomics; Xenobiotics
PubMed: 34773488
DOI: 10.1007/s00204-021-03165-2 -
Frontiers in Immunology 2023Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading...
BACKGROUND AND AIMS
Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR).
METHODS
A total of 21,593 protein quantitative trait loci (pQTLs) for 2297 circulating proteins were used and classified into four different groups. MR analyses were conducted in the four groups separately. Furthermore, the results were discovered and replicated in two different cohorts of PBC. Colocalization analysis and enrichment analysis were also conducted.
RESULTS
Three plasma proteins (ficolin-1, CD40 and protein FAM177A1) were identified and replicated as being associated with PBC. All of them showed significant protective effects against PBC. An increase in ficolin-1 (OR=0.890 [0.843-0.941], p=3.50×10), CD40 (OR=0.814 [0.741-0.895], p=1.96×10) and protein FAM177A1 (OR=0.822 [0.754-0.897], p=9.75×10) reduced the incidence of PBC. Ficolin-1 (PP4 = 0.994) and protein FAM177A1 (PP4 = 0.995) colocalized with the expression of the genes FCN1 and FAM177A1 in whole blood, respectively. Furthermore, CD40 (PP4 = 0.977) and protein FAM177A1 (PP4 = 0.897) strongly colocalized with PBC.
CONCLUSIONS
We expand the current biomarkers for PBC. In total, three (ficolin-1, CD40, and protein FAM177A1) plasma proteins were identified and replicated as being associated with PBC in MR analysis. All of them showed significant protective effects against PBC. These proteins can be potential biomarkers or drug targets for PBC.
Topics: Humans; Liver Cirrhosis, Biliary; Proteome; Mendelian Randomization Analysis; Biomarkers; Blood Proteins
PubMed: 36825008
DOI: 10.3389/fimmu.2023.1052616