Papers by Marian Bulthuis
Journal of Crohn's and colitis, 2024
Journal of Crohn's and colitis, 2024
EJNMMI Research, Dec 10, 2023
The apolipoprotein E-deficient (apoE -/-) mouse is a well-established model for studying atherosc... more The apolipoprotein E-deficient (apoE -/-) mouse is a well-established model for studying atherosclerosis. However, its small size limits its use in longitudinal positron emission tomography (PET) imaging studies. Recently, the apoE -/-rat has emerged as an alternative. With this study, we investigate the feasibility of using apoE -/-rats as an in vivo model for longitudinal atherosclerotic PET/CT imaging. Results ApoE -/-rats showed significantly higher [ 18 F]FDG uptake than controls in the aortic arch (+ 18.5%, p < 0.001) and abdominal aorta (+ 31.0%, p < 0.001) at weeks 12, 26, and 51. ApoE -/-rats exhibited hypercholesterolemia, as evidenced by plasma cholesterol levels that were up to tenfold higher, and total hepatic cholesterol levels that were up to threefold higher than the control rats at the end of the study. Fast protein liquid chromatography cholesterol profiling indicated very high levels of pro-atherogenic apoB-containing very low-density lipoprotein and lowdensity lipoprotein fractions in the apoE -/-rats. Atherosclerotic lesions cover 19.9% of the surface of the aortic arch (p = 0.0013), and there was a significantly higher subendothelial accumulation of ED1-positive macrophages in the abdominal aorta of the apoE -/-rats compared to control rats (Ctrl) (p = 0.01). No differences in neutral sterols were observed but higher levels of bile acids were found in the apoE -/-rats. These data demonstrate early signs of hypercholesterolemia, high levels of bile acids, the development of atherosclerotic lesions, and macrophage accumulation in apoE -/-rats. Therefore, this model shows promise for atherosclerosis imaging studies.
conclusion: IFN-g and TGF-b1 may be useful to identify AZA responders and IL8 and IL6 levels coul... more conclusion: IFN-g and TGF-b1 may be useful to identify AZA responders and IL8 and IL6 levels could be good predictors of response to both biological and immunosuppressive drugs. Our study is a first step for tailored therapy in IBD patients.
Free Radical Biology and Medicine, Jul 1, 2022
Background: Oxidative stress is known to be involved in the development of hypertension, but accu... more Background: Oxidative stress is known to be involved in the development of hypertension, but accurate redox biomarkers predicting the risk of developing hypertension are scarce. Serum free sulfhydryl groups (R-SH, free thiols) have been shown to accurately reflect systemic oxidative stress in various conditions. In this study, we aimed to investigate associations between serum free thiols and the risk of developing new-onset hypertension in a population-based cohort study. Methods: Subjects (n = 3,575) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of hypertension, defined as a systolic blood pressure (SBP) of at least 140 mmHg, a diastolic blood pressure (DBP) of at least 90 mmHg, or the first usage of antihypertensive medication. Subjects with hypertension at baseline were excluded from the study. Results: Mean protein-adjusted serum free thiols at baseline was 5.16 μmol/g of protein (range: 1.62-8.41 μmol/ g). Protein-adjusted serum free thiols were significantly associated with the risk of incident hypertension (hazard ratio [HR] per doubling 0.60 [95% confidence interval [CI]: 0.49-0.72, P < 0.001), also after adjustment for age and sex (HR 0.81 [95% CI: 0.66-0.91], P < 0.05), but not after additional adjustment for relevant confounding factors (HR 0.90 [95% CI: 0.70-1.15], P = 0.382). Conclusion: Higher levels of serum free thiols, i.e. less oxidative stress, are associated with a decreased risk of developing incident hypertension in subjects from the general population.
Antioxidants, May 25, 2022
Infertility problems occur in around 10% of all couples worldwide, with male-factor infertility a... more Infertility problems occur in around 10% of all couples worldwide, with male-factor infertility as the sole contributor in 20-30% of these cases. Oxidative stress (OS) is suggested to be associated with the pathophysiology of male infertility. In spermatozoa, OS can lead to damage to the cell membrane, resulting in disruption of DNA integrity and a decrease in motility. Established biomarkers for OS include free thiols and malondialdehyde (MDA), both representing different components of the reactive species interactome (RSI). This exploratory study aimed to investigate seminal plasma-free thiol and MDA levels in relation to semen parameters as defined by the World Health Organization (WHO) to determine if these markers are adequate to define local OS status. Furthermore, this study investigated if there is a relation between systemic and local OS status by comparing seminal concentrations of free thiol (R-SH, sulfhydryl groups, representing the extracellular redox status) and MDA (lipid peroxidation product) levels to those measured in serum. Free thiol and MDA measurements in both serum and semen plasma were performed in 50 males (18-55 y) of couples seeking fertility treatment. A significant positive correlation was found between seminal plasma-free thiol levels and sperm concentration and progressive motility (r = 0.383, p = 0.008 and r = 0.333, p = 0.022, respectively). In addition, a significant positive correlation was found between MDA levels in seminal plasma and sperm concentration (r = 0.314, p = 0.031). This study supports that seminal plasma-free thiols may be promising as local OS biomarkers. No associations were observed between local and systemic OS biomarker concentrations.
Antioxidants, Nov 16, 2020
Acute kidney injury (AKI) is associated with the abrupt loss of kidney function. Oxidative stress... more Acute kidney injury (AKI) is associated with the abrupt loss of kidney function. Oxidative stress plays an important role in the pathophysiology of AKI. Free thiols (R-SH) are crucial components of the extracellular antioxidant machinery and reliably reflect systemic oxidative stress. Lower levels of thiols represent higher levels of oxidative stress. In this preliminary study, we hypothesized that plasma-free thiols are associated with AKI upon admission to the intensive care unit (ICU). In this study, 301 critically ill patients were included. Plasma samples were taken upon admission, and albumin-adjusted plasma-free thiols were determined. Albumin-adjusted plasma-free thiols were lower in patients with AKI (n = 43, median (interquartile range) 7.28 µmol/g (3.52, 8.95)) compared to patients without AKI (8.50 µmol/g (5.82, 11.28); p < 0.05) upon admission to the ICU. Higher age (B = -0.72), higher levels of neutrophil gelatinase-associated lipocalin (B = -0.002), creatinine (B = -0.01) and lower serum albumin (B = 0.47) were associated with lower free thiol levels. Further, albumin-adjusted free thiol levels were significantly reduced in patients with sepsis (8.30 (5.52-10.64) µmol/g) compared to patients without sepsis (6.95 (3.72-8.92) µmol/g; p < 0.05). Together, albumin-adjusted plasma-free thiols were significantly reduced in patients with AKI and patients with sepsis compared with patients without AKI and sepsis.
Antioxidants, Dec 20, 2021
Oxidative stress has been implicated to play a critical role in the pathophysiology of coronaviru... more Oxidative stress has been implicated to play a critical role in the pathophysiology of coronavirus disease 2019 (COVID-19) and may therefore be considered as a relevant therapeutic target. Serum free thiols (R-SH, sulfhydryl groups) comprise a robust marker of systemic oxidative stress, since they are readily oxidized by reactive oxygen species (ROS). In this study, serum free thiol concentrations were measured in hospitalized and non-hospitalized patients with COVID-19 and healthy controls and their associations with relevant clinical parameters were examined. Serum free thiol concentrations were measured colorimetrically (Ellman's method) in 29 non-hospitalized COVID-19 subjects and 30 age-, sex-, and body-mass index (BMI)-matched healthy controls and analyzed for associations with clinical and biochemical disease parameters. Additional free thiol measurements were performed on seven serum samples from COVID-19 subjects who required hospitalization to examine their correlation with disease severity. Non-hospitalized subjects with COVID-19 had significantly lower concentrations of serum free thiols compared to healthy controls (p = 0.014), indicating oxidative stress. Serum free thiols were positively associated with albumin (St. β = 0.710, p < 0.001) and inversely associated with CRP (St. β = -0.434, p = 0.027), and showed significant discriminative ability to differentiate subjects with COVID-19 from healthy controls (AUC = 0.69, p = 0.011), which was slightly higher than the discriminative performance of CRP concentrations regarding COVID-19 diagnosis (AUC = 0.66, p = 0.042). This study concludes that systemic oxidative stress is increased in patients with COVID-19 compared with healthy controls. This opens an avenue of treatment options since free thiols are amenable to therapeutic modulation.
BMC Medicine, May 27, 2020
Background: Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stres... more Background: Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stress. Since serum free thiols are rapidly oxidized by reactive species, systemic oxidative stress is generally associated with reduced serum free thiol levels. Free thiols associate with favorable disease outcomes in many patient cohorts, and the current hypothesis is that oxidative stress might also play an important role in cardiovascular disease. In this study, we aimed to establish the role of serum free thiols in the general population by investigating their relationship with the risk of cardiovascular (CV) events and all-cause mortality. Methods: Participants (n = 5955) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study from the general population were included. At baseline, serum levels of free thiols were quantified and adjusted to total protein levels. Protein-adjusted serum free thiol levels were studied for their associations with clinical and biochemical parameters, as well as with the risk of CV events and all-cause mortality. Results: The mean protein-adjusted serum free thiol level was 5.05 ± 1.02 μmol/g of protein. Protein-adjusted serum free thiols significantly predicted the risk of CV events, even after adjustment for potential confounding factors (hazard ratio [HR] per doubling 0.68 [95% confidence interval [CI] 0.47-1.00], P = 0.048). Similarly, proteinadjusted serum free thiols were significantly predictive of the risk of all-cause mortality (HR per doubling 0.66 [95% CI 0.44-1.00], P = 0.050). Stratified analyses revealed lower HRs for subjects with a lower body mass index (BMI), without hypertension, and without diabetes. Conversely, HRs were lower in subjects with albuminuria.
Redox biology, Dec 1, 2021
Background Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status... more Background Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD. Therefore, we aimed to investigate associations between serum free thiols and the risk of incident CKD as defined by renal function decline and albuminuria in a population-based cohort study. Methods Subjects without CKD (n = 4,745) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, urinary 24-h albumin excretion (UAE) > 30 mg/24-h, or both. Results Median level of protein-adjusted serum free thiols at baseline was 5.14 μmol/g of protein (interquartile range [IQR]: 4.50–5.75 μmol/g) and median eGFR was 96 mL/min/1.73 m2 [IQR: 85–106]. Protein-adjusted serum free thiols were significantly associated with incident CKD (hazard ratio [HR] per doubling 0.42 [95% confidence interval [CI]: 0.36–0.52, P < 0.001), even after adjustment for traditional risk factors (HR 0.67 [95% CI: 0.47–0.94], P=0.022). In secondary analyses, the highest tertile of protein-adjusted serum free thiols was inversely associated with incident UAE >30 mg/24-h after full adjustment for confounding factors (HR per doubling 0.70 [95% CI: 0.51–0.96], P=0.028). Conclusion Higher levels of serum R-SH, reflecting less oxidative stress, are associated with a decreased risk of developing CKD in subjects from the general population. This association is primarily driven by incident CKD as defined by UAE.
Free Radical Biology and Medicine, Sep 1, 2022
Frontiers in Physiology, Apr 26, 2019
Introduction: Crohn's disease (CD) is characterized by chronic and relapsing inflammation of the ... more Introduction: Crohn's disease (CD) is characterized by chronic and relapsing inflammation of the gastro-intestinal tract. It is assumed that oxidative stress contributes to CD pathogenesis, but systemic biomarkers for oxidative stress in CD are not yet identified. A reduction in free thiol groups in plasma proteins ("plasma free thiols") reflects systemic oxidative stress since they are prime substrates for reactive oxygen species. Here, we determined the concentrations of plasma free thiols in CD patients and healthy controls and studied the putative correlation with disease parameters. Methods: Free thiols were quantified in plasma of patients with CD in clinical remission [according to the Harvey Bradshaw Index (HBI)] and healthy controls and adjusted for plasma albumin. Albumin-adjusted free thiol concentrations were analyzed for associations with clinical and biochemical disease markers. Results: Mean plasma free thiol concentrations were significantly lower in patients with CD (n = 51) compared to healthy controls (n = 27) (14.7 ± 2.4 vs. 17.9 ± 1.8 µmol/g albumin; P < 0.001). Patients with CD with above-average free thiols had significantly lower CRP levels (median 1.4 [interquartile range] [0.4; 2.6] vs. 3.6 [0.6; 7.0] mg/L; P < 0.05) and BMI (23.6 ± 4.8 vs. 27.1 ± 5.2 kg/m 2 ; P < 0.05). Patients with CD having solely colonic disease demonstrated markedly reduced plasma free thiol concentrations compared to patients with ileocolonic involvement (13.2 ± 1.8 vs. 15.2 ± 2.2 µmol/g; P < 0.05). Finally, plasma free thiol concentrations negatively correlated with biomarkers of inflammation, including hsCRP, SAA, IL-17A (all P < 0.05), and VEGF. Plasma free thiols are reduced in patients with CD in clinical remission compared to healthy controls. Thus, subclinical CD disease activity is reflected by systemic oxidative stress and plasma free thiols may be a relevant therapeutic target and biomarker to monitor disease activity in CD.
Antioxidants, Sep 1, 2019
Oxidative stress plays a pivotal role in the pathogenesis of inflammatory bowel diseases (IBD). S... more Oxidative stress plays a pivotal role in the pathogenesis of inflammatory bowel diseases (IBD). Serum free thiols (R-SH) reliably reflect systemic oxidative stress, since they are readily oxidized by reactive species. Here, we aimed to establish concentrations of serum free thiols in IBD and assessed their discriminating capacity regarding endoscopic disease activity. Albumin-adjusted serum free thiol concentrations were measured in 78 IBD patients (31 Crohn's disease (CD) and 47 ulcerative colitis (UC) patients) and 50 healthy controls and analyzed for associations with disease parameters and their discriminative value regarding endoscopic disease activity (n = 54) or fecal calprotectin (n = 36) in patients for which those data were available. Mean serum free thiol concentrations were significantly lower in both CD and UC as compared to healthy controls (19.4 ± 3.1 and 17.8 ± 3.4 vs. 21.1 ± 1.9 µmol/g albumin, P < 0.001). Free thiols highly accurately discriminated between mild and moderate-to-severe disease activity, better than fecal calprotectin (FC) levels (AUC = 0.87, P < 0.001 vs. AUC = 0.76, P < 0.05, respectively) and this was maintained after cross-validation (AUC = 0.89, P < 0.001). Serum free thiols are reduced in IBD as compared to healthy controls and strongly correlate with the degree of endoscopic disease activity. Quantifying systemic redox status in IBD may be a promising, minimally invasive strategy to monitor IBD disease activity.
Introduction: Acute kidney injury (AKI) is associated with the abrupt loss of kidney function res... more Introduction: Acute kidney injury (AKI) is associated with the abrupt loss of kidney function resulting in increased morbidity and mortality. Oxidative stress plays an important role in the pathophysiology of AKI. Free thiols (R-SH, sulfhydryl groups) are crucial components of the extracellular antioxidant machinery and reliably re ect systemic oxidative stress. Lower levels of thiols represent higher levels of oxidative stress. In this study, we hypothesized that plasma free thiols are associated with AKI upon admission to the intensive care unit (ICU). Methods: In this study, 301 critically ill patients were included for analysis. Plasma samples were taken upon admission. Plasma levels of albumin-adjusted plasma free thiols were determined and correlated with AKI stage upon ICU admission. Results: Albumin-adjusted plasma free thiols were signi cantly lower in patients with AKI (n=43, median [interquartile range] 7.28 µmol/g [3.52,8.95]) compared to patients without AKI (8.50 µmol/g [5.82, 11.28]; p < 0.05) upon admission to the ICU. Higher age (B = -0.72, p < 0.001), higher levels of neutrophil gelatinase-associated lipocalin (B = -0.002, p < 0.05), creatinine (B = -0.01, p < 0.05) and lower serum albumin (B = 0.47, p < 0.001) were associated with lower free thiol levels. Further, albumin-adjusted free thiol levels were signi cantly reduced in patients with sepsis (8.30 [5.52-10.64] µmol/g) compared to patients without sepsis (6. 95 [3.72-8.92] µmol/g; p < 0.05). Conclusion: Albumin-adjusted plasma free thiols were signi cantly reduced in patients with AKI and patients with sepsis compared with patients without AKI and sepsis. Together, these data suggest that free thiol levels are mainly reduced in sepsis-associated AKI. 'Medische Ethische Toetsingscommissie', (METc)) of the UMCG reviewed and waived this study (METC 2013/174). Initially, 361 patients were included in the database. Patients of whom plasma samples were
Antioxidants
Infertility problems occur in around 10% of all couples worldwide, with male-factor infertility a... more Infertility problems occur in around 10% of all couples worldwide, with male-factor infertility as the sole contributor in 20–30% of these cases. Oxidative stress (OS) is suggested to be associated with the pathophysiology of male infertility. In spermatozoa, OS can lead to damage to the cell membrane, resulting in disruption of DNA integrity and a decrease in motility. Established biomarkers for OS include free thiols and malondialdehyde (MDA), both representing different components of the reactive species interactome (RSI). This exploratory study aimed to investigate seminal plasma-free thiol and MDA levels in relation to semen parameters as defined by the World Health Organization (WHO) to determine if these markers are adequate to define local OS status. Furthermore, this study investigated if there is a relation between systemic and local OS status by comparing seminal concentrations of free thiol (R-SH, sulfhydryl groups, representing the extracellular redox status) and MDA (l...
Free Radical Biology and Medicine
Journal of Neurology
Serum concentrations of free thiols (key components of the extracellular antioxidant machinery) r... more Serum concentrations of free thiols (key components of the extracellular antioxidant machinery) reflect the overall redox status of the human body. The objective of this exploratory study was to determine the concentrations of serum free thiols in the acute phase after traumatic brain injury (TBI) and their association with long-term outcome. In this observational cohort study, patients with TBI of various severity were included from a biobank of prospectively enrolled TBI patients. Further eligibility criteria included an available blood sample and head computed tomography data, obtained within 24 h of injury, as well as a functional outcome assessment (Glasgow Outcome Scale Extended (GOSE)) at 6 months post-injury. Serum free thiol concentrations were markedly lower in patients with TBI (n = 77) compared to healthy controls (n = 55) (mean ± standard deviation; 210.3 ± 63.3 vs. 301.8 ± 23.9 μM, P < 0.001) indicating increased oxidative stress. Concentrations of serum free thiols...
Antioxidants, 2021
Oxidative stress has been implicated to play a critical role in the pathophysiology of coronaviru... more Oxidative stress has been implicated to play a critical role in the pathophysiology of coronavirus disease 2019 (COVID-19) and may therefore be considered as a relevant therapeutic target. Serum free thiols (R-SH, sulfhydryl groups) comprise a robust marker of systemic oxidative stress, since they are readily oxidized by reactive oxygen species (ROS). In this study, serum free thiol concentrations were measured in hospitalized and non-hospitalized patients with COVID-19 and healthy controls and their associations with relevant clinical parameters were examined. Serum free thiol concentrations were measured colorimetrically (Ellman’s method) in 29 non-hospitalized COVID-19 subjects and 30 age-, sex-, and body-mass index (BMI)-matched healthy controls and analyzed for associations with clinical and biochemical disease parameters. Additional free thiol measurements were performed on seven serum samples from COVID-19 subjects who required hospitalization to examine their correlation wit...
Redox Biology, 2021
Background Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status... more Background Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD. Therefore, we aimed to investigate associations between serum free thiols and the risk of incident CKD as defined by renal function decline and albuminuria in a population-based cohort study. Methods Subjects without CKD (n = 4,745) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, urinary 24-h albumin excretion (UAE) > 30 mg/24-h, or both. Results Median level of protein-adjusted serum free thiols at baseline was 5.14 μmol/g of protein (interquartile range [IQR]: 4.50–5.75 μmol/g) and median eGFR was 96 mL/min/1.73 m2 [IQR: 85–106]. Protein-adjusted serum free thiols were significantly associated with incident CKD (hazard ratio [HR] per doubling 0.42 [95% confidence interval [CI]: 0.36–0.52, P < 0.001), even after adjustment for traditional risk factors (HR 0.67 [95% CI: 0.47–0.94], P=0.022). In secondary analyses, the highest tertile of protein-adjusted serum free thiols was inversely associated with incident UAE >30 mg/24-h after full adjustment for confounding factors (HR per doubling 0.70 [95% CI: 0.51–0.96], P=0.028). Conclusion Higher levels of serum R-SH, reflecting less oxidative stress, are associated with a decreased risk of developing CKD in subjects from the general population. This association is primarily driven by incident CKD as defined by UAE.
United European gastroenterology journal, 2019
conclusion: IFN-g and TGF-b1 may be useful to identify AZA responders and IL8 and IL6 levels coul... more conclusion: IFN-g and TGF-b1 may be useful to identify AZA responders and IL8 and IL6 levels could be good predictors of response to both biological and immunosuppressive drugs. Our study is a first step for tailored therapy in IBD patients.
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Papers by Marian Bulthuis