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1.
A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma.
Ruffieux, H, Carayol, J, Popescu, R, Harper, ME, Dent, R, Saris, WHM, Astrup, A, Hager, J, Davison, AC, Valsesia, A
PLoS computational biology. 2020;(6):e1007882
Abstract
Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637.
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2.
Altered Mineral Metabolism and Disequilibrium Between Calcification Promoters and Inhibitors in Chronic Hemodialysis Patients.
Wang, CL, Lin, KP, Hsu, GW, Liu, KL, Guo, CH
Biological trace element research. 2020;(1):14-22
Abstract
Patients undergoing long-term hemodialysis (HD) are known to have abnormal blood concentrations of antioxidant minerals; concurrent oxidative stress can contribute to increased vascular calcification. This study aims to evaluate the associations between circulating antioxidant minerals and clinical biomarkers of vascular calcification in HD patients. Blood biochemical parameters, antioxidant minerals (selenium (Se), zinc (Zn), copper (Cu), and magnesium (Mg)), and several promoters and inhibitors of calcification (matrix Gla protein (MGP), fibroblast growth factor-23 (FGF-23), matrix metalloproteinases (MMP-2 and -9), and tissue inhibitors of metalloproteinase (TIMP-1 and -2)) were determined in HD patients (n = 62) and age- and sex-matched healthy individuals (n = 30). Compared with healthy subjects, HD patients had significantly lower plasma concentrations of Se and Zn, increased Cu and Mg, and higher levels of oxidative stress and inflammatory markers (Cu/Zn ratios, malondialdehyde (MDA), advanced glycation end products (AGEs), and C-reactive protein (CRP)). We observed that HD patients had significantly lower concentrations of MGP and higher levels of FGF-23, MMP-2 and -9, TIMP-1 and -2, and MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios. We also observed significant relationships between the concentrations of these minerals and calcification biomarkers in HD patients. These results suggest that changes in the homeostasis of antioxidant minerals (Se, Zn, Cu, and Mg) may contribute to the effects of oxidative stress and inflammatory status, thereby participating in the mechanism for accelerated vascular calcification in patients undergoing long-term HD.
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3.
The acid and neutral fractions of pectins isolated from ripe and overripe papayas differentially affect galectin-3 inhibition and colon cancer cell growth.
Pedrosa, LF, Lopes, RG, Fabi, JP
International journal of biological macromolecules. 2020;:2681-2690
Abstract
The water-soluble fractions of pectin extracted from the pulp of ripe papayas have already been found to exert positive effects on cancer cell cultures. However, the mechanisms that lead to these beneficial effects and the pectin characteristics that exert these effects are still not well understood. Characteristics such as molecular size, monosaccharide composition and structural conformation are known as polysaccharide factors that can cause alterations in cellular response. During fruit ripening, a major polysaccharide solubilization, depolymerization, and chemical modification occur. The aims of this work are to fractionate the pectin extracted from the pulp of papayas at two stages of ripening (fourth and ninth day after harvesting) into uronic and neutral fractions and to test them for the inhibition of human recombinant galectin-3 and the inhibition of colon cancer cell growth. The structures of the fractions were chemically characterized, and the uronic fraction extracted from the fourth day after harvesting presented the best biological effects across different concentrations in both galectin-3 inhibition and viability assays. The results obtained may help to establish a relationship between the chemical structures of papaya pectins and the positive in vitro biological effects, such as inhibiting cancer cell growth.
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4.
Serum proteome assessment in nonalcoholic fatty liver disease in children: a preliminary study.
Małecki, P, Tracz, J, Łuczak, M, Figlerowicz, M, Mazur-Melewska, K, Służewski, W, Mania, A
Expert review of proteomics. 2020;(7-8):623-632
Abstract
OBJECTIVES Nonalcoholic fatty disease (NAFLD) affects 3-10% of the pediatric population, making it the most common chronic liver disease among children. The aim of the study is to identify potential biomarkers enabling the diagnosis of NAFLD and monitoring the course of the disease. METHODS Proteome analysis was performed in a group of 30 patients (19 boys and 11 girls) in total, of whom 16 children had previously diagnosed NAFLD based on the abdominal ultrasound after excluding other diseases of this organ. RESULTS A total of 297 proteins have been identified. Thirty-seven proteins (responsible for inflammation, stress response, and regulation of this process) differentiating both experimental groups were identified. Up-regulated proteins included afamin, retinol-binding protein-4, complement components, and hemopexin; while serum protease inhibitors, clusterin, immunoglobulin chains, and vitamin D binding protein were found in the down-regulated group. The correlation between selected proteins and indicators of noninvasive assessment of liver fibrosis (APRI, FIB-4) as well as differences between the serum proteome of patients with normal weight, overweight, and obesity were also assessed. CONCLUSION The plasma protein profile is significantly altered in nonalcoholic liver disease in children and may prove to be a valuable source of biomarkers to evaluate the extent of liver disease.
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5.
Serum and follicular fluid levels of sirtuin 1, sirtuin 6, and resveratrol in women undergoing in vitro fertilization: an observational, clinical study.
Bódis, J, Sulyok, E, Kőszegi, T, Gödöny, K, Prémusz, V, Várnagy, Á
The Journal of international medical research. 2019;(2):772-782
Abstract
OBJECTIVE This observational, clinical study was designed to assess the role of sirtuin 1 (SIRT1), sirtuin 6 (SIRT6), and resveratrol in in vitro fertilization (IVF). METHODS Paired serum and follicular fluid (FF) samples were obtained from 30 consecutive patients (age: 36.43 ± 4.17 years, body mass index: 22.90 ± 2.05 kg/m2, duration of infertility: 5.10 ± 2.80 years) who received IVF treatment. SIRT1, SIRT6, and resveratrol levels were measured by enzyme-linked immunosorbent assay. RESULTS Ovarian hyperstimulation resulted in significantly higher serum SIRT1 levels in pregnant women (8 patients) compared with non-pregnant women (22 patients). SIRT6 levels remained unchanged after ovarian hyperstimulation, but were significantly lower in pregnant women compared with non-pregnant women before and after hyperstimulation. Both SIRTs were detected in FF, but they appeared to be independent of their serum levels. After correction for confounders, FF SIRT6 levels were positively related to mature oocytes (F = 6.609), whereas serum SIRT1 and SIRT6 levels were related to clinical pregnancy (F = 10.008, F = 5.268, respectively). CONCLUSIONS Our study shows that SIRT1 and SIRT6, but not resveratrol, are involved in human reproduction and they may have a role in oocyte maturation and clinical pregnancy in IVF.
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6.
Vegetarian-Based Dietary Patterns and their Relation with Inflammatory and Immune Biomarkers: A Systematic Review and Meta-Analysis.
Craddock, JC, Neale, EP, Peoples, GE, Probst, YC
Advances in nutrition (Bethesda, Md.). 2019;(3):433-451
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Abstract
Dietary patterns with substantial proportions of energy from plant sources have been associated with favorable biomarkers of low-grade inflammation. Less is known of the relation between vegetarian-based dietary patterns and markers of inflammation and immune status. This systematic review and meta-analysis aimed to determine the relation between vegetarian-based dietary patterns and inflammatory and immune markers (C-reactive protein, tumour necrosis factor α, fibrinogen, natural killer cells, leukocytes, lymphocytes, thrombocytes, interleukins, and immunoglobulins). PubMed, Medline, and Cochrane scientific databases were searched to identify relevant studies. Random effects meta-analyses were conducted to assess the weighted mean differences (WMDs) for each outcome variable between vegetarian and non-vegetarian groups. Thirty observational and 10 intervention studies were included in the review. Pooled effects of vegetarian-based dietary patterns were associated with significantly lower concentrations of CRP (WMD: -0.61 mg/L; 95% CI: -0.91, -0.32 mg/L; P = 0.0001), fibrinogen (WMD: -0.22 g/L; 95% CI: -0.41, -0.04 mg/L; P = 0.02), and total leukocyte (WMD: -0.62 × 10(3)/μL; 95% CI -1.13 × 10(3), -0.10 × 10(3)/μL; P = 0.02) compared with those following non-vegetarian dietary patterns in observational studies. Insufficient data were identified for a meta-analysis of intervention studies. This study provides evidence that vegetarian-based dietary patterns are associated with lowered serum C-reactive protein, fibrinogen, and total leukocyte concentrations. Future research should focus on large-scale intervention trials, contrasting differences in inflammation and immune status and function between vegetarian and non-vegetarian-based populations.
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Detrimental links between physical inactivity, metabolic risk and N-glycomic biomarkers of aging.
Nilsson, A, Santoro, A, Franceschi, C, Kadi, F
Experimental gerontology. 2019;:110626
Abstract
BACKGROUND N-linked enzymatic glycosylation modulates the function of proteins and contributes to development of age-related metabolic abnormalities. Whether physical activity (PA) is linked to a specific N-glycan profile and can offset detrimental links between N-glycans and metabolic risk profile has never been explored. The aim of the present study is to assess serum N-glycan profile in older women with different PA levels and metabolic risk status. MATERIALS AND METHODS Components of the metabolic syndrome (MetS) and serum N-glycans analyzed using DSA-FACE technology were assessed in 109 older community-dwelling women (65-70 yrs). Ten peaks, each representing a unique N-glycan structure were detected. Moderate-to-vigorous PA (MVPA) was assessed objectively using accelerometry. All analyses were adjusted by covariates. RESULTS Significantly elevated levels of NGA2FB (peak 2) and NA3F (peak 9) and lower level of the α(1,6)-arm monogalactosylated (NG1(6)A2F) (peak 3) were demonstrated in women with MetS compared to their healthier peers (p < 0.05). Importantly, women adhering to the PA guideline of time in MVPA had a 10% and a 12% lower level of NA3 (peak 8) and NA4 (peak 10), respectively, compared to those less active even after adjustment by MetS and covariates (p < 0.05). Interestingly, time spent in PA below the MVPA threshold was not linked to N-glycans. CONCLUSION Novel links between PA behaviors and N-glycan profile are demonstrated in older adults, regardless of metabolic risk status. This proposed effect on N-glycans requires engagement in MVPA. This supports public health efforts to promote adherence to PA guidelines in older adults across different stages of disease prevention.
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Small-protein Enrichment Assay Enables the Rapid, Unbiased Analysis of Over 100 Low Abundance Factors from Human Plasma.
Harney, DJ, Hutchison, AT, Su, Z, Hatchwell, L, Heilbronn, LK, Hocking, S, James, DE, Larance, M
Molecular & cellular proteomics : MCP. 2019;(9):1899-1915
Abstract
Unbiased and sensitive quantification of low abundance small proteins in human plasma (e.g. hormones, immune factors, metabolic regulators) remains an unmet need. These small protein factors are typically analyzed individually and using antibodies that can lack specificity. Mass spectrometry (MS)-based proteomics has the potential to address these problems, however the analysis of plasma by MS is plagued by the extremely large dynamic range of this body fluid, with protein abundances spanning at least 13 orders of magnitude. Here we describe an enrichment assay (SPEA), that greatly simplifies the plasma dynamic range problem by enriching small-proteins of 2-10 kDa, enabling the rapid, specific and sensitive quantification of >100 small-protein factors in a single untargeted LC-MS/MS acquisition. Applying this method to perform deep-proteome profiling of human plasma we identify C5ORF46 as a previously uncharacterized human plasma protein. We further demonstrate the reproducibility of our workflow for low abundance protein analysis using a stable-isotope labeled protein standard of insulin spiked into human plasma. SPEA provides the ability to study numerous important hormones in a single rapid assay, which we applied to study the intermittent fasting response and observed several unexpected changes including decreased plasma abundance of the iron homeostasis regulator hepcidin.
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Proteomics analysis of blood plasma in HIV-infected patients with chronic kidney disease.
Lavinya, AA, Lee, CS, Hashim, OH, Azwa, I, Rajasuriar, R, Lim, SK, Wong, YF
Clinical biochemistry. 2019;:90-97
Abstract
BACKGROUND Patients treated for human immunodeficiency virus (HIV) infection are prone to developing chronic kidney disease (CKD). Current methods used in assessing kidney function suffer inaccuracy in HIV-infected patients. This study aims to identify biomarkers that could complement existing methods of kidney assessment among HIV-infected subjects. METHODS Plasma protein profiling was performed for HIV patients with CKD presented with negative/trace proteinuria (non-proteinuric) (n = 8) and their matched non-CKD controls, using two-dimensional gel electrophoresis (2DE); selected protein candidates were identified using mass spectrometry. Subsequently, altered plasma abundance of protein candidates were verified using Western blotting in HIV-infected subjects with non-proteinuric CKD (n = 8), proteinuric CKD (n = 5), and their matched non-CKD controls, as well as in HIV-uninfected subjects with impaired kidney function (n = 3) and their matched controls. RESULTS Analysis of 2DE found significantly altered abundance of five protein candidates between HIV-infected patients with non-proteinuric CKD and without CKD: alpha-1-microglobulin (A1M), serum albumin (ALB), zinc-alpha-2-glycoprotein (AZGP1), haptoglobin (HP), and retinol binding protein (RBP4). Western blotting showed an increased abundance of A1M and HP in HIV-infected patients with non-proteinuric CKD compared to their non-CKD controls, whereas A1M, AZGP1, and RBP4 were significantly increased in HIV-infected patients with proteinuric CKD compared to their non-CKD controls. Such pattern was not found in HIV-uninfected subjects with impaired kidney function. CONCLUSION The data suggests four proteins that may be used as biomarkers of CKD in HIV-infected patients. Further validation in a larger cohort of HIV-infected patients is necessary for assessing the clinical use of these proposed biomarkers for CKD.
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Differentially expressed plasma proteins of β-thalassemia/hemoglobin E patients in response to curcuminoids/vitamin E antioxidant cocktails.
Panachan, J, Chokchaichamnankit, D, Weeraphan, C, Srisomsap, C, Masaratana, P, Hatairaktham, S, Panichkul, N, Svasti, J, Kalpravidh, RW
Hematology (Amsterdam, Netherlands). 2019;(1):300-307
Abstract
OBJECTIVE Iron overload and oxidative stress are the major causes of serious complications and mortality in thalassemic patients. Our previous work supports the synergistic effects of antioxidant cocktails (curcuminoids or vitamin E, N-acetylcysteine, and deferiprone) in treatment of β-thalassemia/Hb E patients. This further 2-DE-based proteomic study aimed to identify the plasma proteins that expressed differentially in response to antioxidant cocktails. METHODS Frozen plasma samples of ten normal subjects and ten β-thalassemia/Hb E patients at three-time points (baseline, month 6, and month 12) were reduced the dynamic range of proteome using ProteoMiner kit and separated proteins by two-dimensional gel electrophoresis. Differentially expressed proteins were identified using tandem mass spectrometry. Several plasma proteins were validated by ELISA and Western blot analysis. RESULTS Thirteen and 11 proteins were identified with altered expression levels in the curcuminoids- and vitamin E cocktail groups, respectively. The associations between vitronectin (VTN) expression and total bilirubin levels, as well as between serum paraoxonase/arylesterase 1 (PON1) expression and blood reactive oxygen species were observed. Validation results were consistent with proteomics results. DISCUSSION AND CONCLUSIONS These plasma proteins may provide better understanding of the mechanisms underlying the therapeutic effects of antioxidant cocktails in thalassemic patients.