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New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 9687

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Dr. Margery A. Connelly

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Guest Editor

Labcorp, Morrisville, NC 27560, USA
Interests: lipoprotein metabolism; HDL metabolism; pharmacology; diagnostics; cardiovascular disease; chronic inflammatory diseases; metabolic disorders; metabolic syndrome; type 2 diabetes; obesity; non-alcoholic fatty liver disease (NAFLD)

Special Issue Information

Dear Colleagues,

Dr. Fernando Rubiera González

It is with great pleasure that I serve as Guest Editor of this Special Issue of Biomolecules honoring Prof. Dr. Robin P. F. Dullaart. Dr. Dullaart has published over 485 papers during his long and distinguished career as an endocrinologist at the University of Groningen, University Medical Center Groningen, in the Netherlands. His work has been cited 11500 times, resulting in an Hindex of 54. His research interests have spanned various aspects of endocrine gland function, as well as endocrine disorders such as pheochromocytoma, paraganglioma, and thyroid diseases. However, his main research focus has encompassed (diabetic) dyslipidemia, HDL metabolism and function, and the relationships between various HDL measures and cardiovascular disease (CVD), in addition to cardiometabolic diseases such as type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). His publications include investigations of the relationships between HDL modulating proteins, such as hepatic lipase, lipoprotein lipase, cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), serum amyloid A (SAA), lipoprotein phospholipase A2 (LpPLA2), myeloperoxidase and paraoxonase-1 (PON-1), and CVD. He has also explored associations of HDL activities (cholesteryl ester (CE) transfer and anti-oxidant) with CVD, as well as the associations of endocrine regulators (leptin, adiponectin, resistin, mineralocorticoids, insulin, free thyroxine, and free triiodothyronine), markers of liver disease (γ-glutamyl transferase (GGT) and bilirubin) and inflammatory markers (C-reactive protein and GlycA) with cardiometabolic and chronic inflammatory diseases. In addition to Dr. Dullaart’s many important scientific contributions, he has mentored many clinicians and scientists as Director of the Clinical Training Program in Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen, during his 21 years in this role. He has held multiple positions in the European Society for Clinical Investigation, including Member of Council, Secretary, Treasurer, and Vice President. Until 2019, he served as the President of the European Society for Clinical Investigation Trust Foundation. He has also been a member of the Scientific Advisory Board of the Dutch Diabetes Research Foundation, as well as a member of the Scientific Board of SAEM (Stichting Aandachtsgebied Endocrinologie & Metabolisme). He has played important roles in multiple consortia, including the Thyroid Studies Consortium, CORtisolNETwork (CORNET) Consortium, and the Emerging Risk Factors Collaboration, and has been an active member of the scientific advisory board of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study in Groningen, the Netherlands. Moreover, he has successfully supervised, both directly and indirectly, over 20 PhD students and research fellows.

Over the last decade, technologies such as genomics, proteomics, metabolomics, and transcriptomics have been used extensively in clinical research to identify novel circulating biomarkers of cardiometabolic and inflammatory disorders. In this special edition of Biomolecules, which is dedicated to Dr. Dullaart’s outstanding achievements in clinical research in this area, several circulating proteins and metabolites will be explored for their potential clinical use as biomarkers or in clinical tests for monitoring or diagnosing various aspects of cardiometabolic and inflammatory disorders.

Dr. Margery A. Connelly
Guest Editor

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Keywords

biomarkers
metabolites
lipoprotein metabolism
cardiovascular disease
chronic inflammatory diseases
endocrine disorders
metabolic syndrome
type 2 diabetes
obesity
non-alcoholic fatty liver disease (NAFLD)

Published Papers (6 papers)

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Research

15 pages, 2516 KiB

Open AccessArticle

Albumin Thiolation and Oxidative Stress Status in Patients with Aortic Valve Stenosis

by Carlo Savini, Elena Tenti, Elisa Mikus, Sonia Eligini, Marco Munno, Anna Gaspardo, Erica Gianazza, Arianna Greco, Stefania Ghilardi, Giancarlo Aldini, Elena Tremoli and Cristina Banfi

Biomolecules 2023, 13(12), 1713; https://doi.org/10.3390/biom13121713 - 28 Nov 2023

Cited by 1 | Viewed by 957

Abstract

Recent evidence indicates that reactive oxygen species play an important causative role in the onset and progression of valvular diseases. Here, we analyzed the oxidative modifications of albumin (HSA) occurring on Cysteine 34 and the antioxidant capacity of the serum in 44 patients with severe aortic stenosis (36 patients underwent aortic valve replacement and 8 underwent a second aortic valve substitution due to a degenerated bioprosthetic valve), and in 10 healthy donors (controls). Before surgical intervention, patients showed an increase in the oxidized form of albumin (HSA-Cys), a decrease in the native reduced form (HSA-SH), and a significant reduction in serum free sulfhydryl groups and in the total serum antioxidant activity. Patients undergoing a second valve replacement showed levels of HSA-Cys, free sulfhydryl groups, and total antioxidant activity similar to those of controls. In vitro incubation of whole blood with aspirin (ASA) significantly increased the free sulfhydryl groups, suggesting that the in vivo treatment with ASA may contribute to reducing oxidative stress. We also found that N-acetylcysteine and its amide derivative were able to regenerate HSA-SH. In conclusion, the systemic oxidative stress reflected by high levels of HSA-Cys is increased in patients with aortic valve stenosis. Thiol–disulfide breaking agents regenerate HSA-SH, thus paving the way to the use these compounds to mitigate the oxidative stress occurring in the disease. Full article

(This article belongs to the Special Issue New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart)

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11 pages, 819 KiB

Open AccessArticle

GlycA: Evaluation of a New Biomarker of Acute Pancreatitis

by Ishani Shah, William Yakah, Awais Ahmed, Steven D. Freedman, Zhenghui G. Jiang and Sunil G. Sheth

Biomolecules 2023, 13(10), 1530; https://doi.org/10.3390/biom13101530 - 16 Oct 2023

Viewed by 946

Abstract

Background: Acute pancreatitis (AP) is a leading cause of gastrointestinal hospital admissions, with up to 40% mortality in patients with moderate–severe AP. Glycoprotein acetylation (GlycA) is measured as a nuclear magnetic resonance signal (NMR) of the post-translational modification of glycosylated acute-phase proteins released during inflammation. We aimed to investigate the role of GlycA as an inflammatory biomarker of AP. Methods: We prospectively enrolled 20 AP patients and 22 healthy controls and collected EDTA plasma samples at admission and discharge. NMR spectra were acquired from these samples using a 400 MHz Vantera^® Clinical Analyzer, and GlycA concentrations were calculated (normal = 400 μmol/L). The GlycA NMR signal, at 2.00 ± 0.01 ppm in the NMR spectrum, is derived from the N-acetyl methyl group protons within the carbohydrate side chains of circulating glycoproteins such as α1-acid glycoprotein, haptoglobin, α1-antitrypsin, α1-antichymotrypsin, and transferrin. GlycA levels were then compared between AP patients and controls, as well as within the AP group, based on etiology and severity. Results: Demographic comparisons were similar, except for a higher BMI in AP patients compared to healthy controls (29.9 vs. 24.8 kg/m²; p < 0.001). AP was mild in 10 patients, moderate in 7, and severe in 3. GlycA levels were higher in AP patients than healthy controls on admission (578 vs. 376 μmol/L, p < 0.001) and at discharge (655 vs. 376 μmol/L, p < 0.001). GlycA levels were significantly higher in patients with moderate–severe AP than in those with mild AP at discharge (533 vs. 757 μmol/L, p = 0.023) but not at admission. After adjusting for BMI, multivariable regression indicated that patients with GlycA levels > 400 μmol/L had significantly higher odds of having AP of any severity (OR = 6.88; 95% CI, 2.07–32.2; p = 0.004) and mild AP (OR = 6.12; 95% CI, 1.48–42.0; p = 0.025) than controls. Conclusion: Our pilot study highlights the use of GlycA as a novel diagnostic biomarker of inflammation in patients with AP. Our study shows that GlycA levels were significantly higher in hospitalized AP patients compared to healthy controls. Patients with moderate-to-severe AP had higher GlycA levels compared to patients with mild AP at the time of their hospital discharge, suggesting persistent inflammation in patients with severe disease. Full article

(This article belongs to the Special Issue New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart)

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15 pages, 1097 KiB

Open AccessArticle

Serum Level of Cytokeratin 18 (M65) as a Prognostic Marker of High Cardiovascular Disease Risk in Individuals with Non-Alcoholic Fatty Liver Disease

by Sabrina Pagano, Stephan J. L. Bakker, Catherine Juillard, Robin P. F. Dullaart and Nicolas Vuilleumier

Biomolecules 2023, 13(7), 1128; https://doi.org/10.3390/biom13071128 - 14 Jul 2023

Cited by 2 | Viewed by 1471

Abstract

Alterations in apoptosis, as reflected by circulating Cytokeratin 18 (CK18), are involved in the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis and atherogenesis. We aimed to explore the discriminant accuracy of Cytokeratin 18 (CK18, including M65 and M30 forms) for an elevated fatty liver index (FLI) as a validated proxy of NAFLD, and cardiovascular disease (CVD) risk in the general population. Both serum CK18 forms were measured using a commercial immunoassay in randomly selected samples from 312 participants of the PREVEND general population cohort. FLI ≥ 60 was used to indicate NAFLD. Framingham Risk Score (FRS) and the SCORE2 were used to estimate the 10-year risk of CVD. The Receiver Operating Characteristic (ROC) curve, linear/logistic regression models, and Spearman’s correlations were used. Intricate associations were found between CK18, FLI, and CVD risk scores. While M30 was the only independent predictor of FLI ≥ 60, M65 best discriminated NAFLD individuals at very-high 10-year CVD risk according to SCORE2 (AUC: 0.71; p = 0.001). Values above the predefined manufacturer cutoff (400 U/L) were associated with an independent 5-fold increased risk (adjusted odds ratio: 5.44, p = 0.01), with a negative predictive value of 93%. Confirming that NAFLD is associated with an increased CVD risk, our results in a European general population-based cohort suggest that CK18 M65 may represent a candidate biomarker to identify NAFLD individuals at low CVD risk. Full article

(This article belongs to the Special Issue New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart)

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13 pages, 302 KiB

Open AccessArticle

Branched Chain Amino Acids Are Associated with Physical Performance in Patients with End-Stage Liver Disease

by Maria Camila Trillos-Almanza, Hanna Wessel, Magnolia Martínez-Aguilar, Eline H. van den Berg, Rianne M. Douwes, Han Moshage, Margery A. Connelly, Stephan J. L. Bakker, Vincent E. de Meijer, Robin P. F. Dullaart and Hans Blokzijl

Biomolecules 2023, 13(5), 824; https://doi.org/10.3390/biom13050824 - 12 May 2023

Cited by 3 | Viewed by 1838

Abstract

Decreased circulating branched chain amino acids (BCAA) represent a prominent change in amino acid profiles in patients with end-stage liver disease (ESLD). These alterations are considered to contribute to sarcopenia and hepatic encephalopathy and may relate to poor prognosis. Here, we cross-sectionally analyzed the association between plasma BCAA levels and the severity of ESLD and muscle function in participants of the liver transplant subgroup of TransplantLines, enrolled between January 2017 and January 2020. Plasma BCAA levels were measured by nuclear magnetic resonance spectroscopy. Physical performance was analyzed with a hand grip strength test, 4 m walking test, sit-to-stand test, timed up and go test, standing balance test and clinical frailty scale. We included 92 patients (65% men). The Child Pugh Turcotte classification was significantly higher in the lowest sex-stratified BCAA tertile compared to the highest tertile (p = 0.015). The times for the sit-to-stand (r = −0.352, p < 0.05) and timed up and go tests (r = −0.472, p < 0.01) were inversely correlated with total BCAA levels. In conclusion, lower circulating BCAA are associated with the severity of liver disease and impaired muscle function. This suggests that BCAA may represent a useful prognostic marker in the staging of liver disease severity. Full article

(This article belongs to the Special Issue New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart)

19 pages, 1309 KiB

Open AccessArticle

Plasma Cytokeratin-18 Fragment Level Reflects the Metabolic Phenotype in Obesity

by Joanna Goralska, Urszula Razny, Anna Gruca, Anna Zdzienicka, Agnieszka Micek, Aldona Dembinska-Kiec, Bogdan Solnica and Malgorzata Malczewska-Malec

Biomolecules 2023, 13(4), 675; https://doi.org/10.3390/biom13040675 - 14 Apr 2023

Cited by 1 | Viewed by 1598

Abstract

There is growing interest in the non-invasive identification and monitoring of the outcome of liver damage in obese patients. Plasma cytokeratin-18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis and have recently been proposed to independently predict the presence of non-alcoholic steatohepatitis (NASH). The aim of the study was to analyze the associations of CK-18 with obesity and related complications: insulin resistance, impaired lipid metabolism and the secretion of hepatokines, adipokines and pro-inflammatory cytokines. The study involved 151 overweight and obese patients (BMI 25–40), without diabetes, dyslipidemia or apparent liver disease. Liver function was assessed based on alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and the fatty liver index (FLI). CK-18 M30 plasma levels, FGF-21, FGF-19 and cytokines were determined by ELISA. CK-18 values >150 U/l were accompanied by high ALT, GGT and FLI, insulin resistance, postprandial hypertriglyceridemia, elevated FGF-21 and MCP-1 and decreased adiponectin. ALT activity was the strongest independent factor influencing high CK-18 plasma levels, even after an adjustment for age, sex and BMI [β coefficient (95%CI): 0.40 (0.19–0.61)]. In conclusion, the applied CK-18 cut-off point at 150 U/l allows to distinguish between two metabolic phenotypes in obesity. Full article

(This article belongs to the Special Issue New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart)

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15 pages, 1397 KiB

Open AccessArticle

Plasma Neutrophil Gelatinase-Associated Lipocalin Associates with New-Onset Chronic Kidney Disease in the General Population

by Arno R. Bourgonje, Amaal E. Abdulle, Martin F. Bourgonje, Lyanne M. Kieneker, Sacha la Bastide-van Gemert, Sanne J. Gordijn, Clara Hidden, Tom Nilsen, Ron T. Gansevoort, Douwe J. Mulder, Robin P. F. Dullaart, Martin H. de Borst, Stephan J. L. Bakker and Harry van Goor

Biomolecules 2023, 13(2), 338; https://doi.org/10.3390/biom13020338 - 09 Feb 2023

Cited by 2 | Viewed by 2179

Abstract

Circulating levels of neutrophil gelatinase-associated lipocalin (NGAL) have been associated with acute kidney injury and the severity and progression of chronic kidney disease (CKD). This study investigated its potential utility as a biomarker for the risk of new-onset CKD in a population-based cohort study. Individuals without CKD at baseline (n = 4660) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma NGAL concentrations were investigated for their associations with new-onset CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², urinary albumin excretion (UAE) > 30 mg/24-h, or both. Mean (±SD) plasma NGAL concentrations were 104.0 (±34.7) μg/L and median eGFR was 96 [IQR: 85.3–105.8] mL/min/1.73 m². After median follow-up of 8.3 [IQR: 7.8–8.9] years, 467 participants developed new-onset CKD. Plasma NGAL concentrations were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.35 [95% CI: 1.11–1.63], p = 0.002), even after adjustment for potentially confounding factors (1.37 [1.09–1.73], p = 0.007) except baseline eGFR (1.09 [0.86–1.37], p = 0.490). In secondary analyses, plasma NGAL concentrations were significantly associated with new-onset CKD as defined by eGFR < 60 mL/min/1.73 m² alone (adjusted HR per doubling 2.54 [1.69–3.80], p < 0.001), which was abrogated after adjustment for eGFR (1.05 [0.69–1.59], p = 0.828), also when UAE > 30 mg/24-h was set as individual outcome (1.05 [0.82–1.35], p = 0.705). Higher plasma NGAL concentrations are associated with an increased risk of developing CKD in the general population. This association is dependent on renal function, and mainly driven by new-onset CKD as defined by renal function decline. Full article

(This article belongs to the Special Issue New Biomarkers of Cardiometabolic and Inflammatory Disorders: A Themed Issue in Honor of Professor Robin Pieter Frank Dullaart)

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