Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular inj... more Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide,...
Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. A... more Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. As hydrogen sulfide (H 2 S) has pro-angiogenic and anti-oxidative characteristics, we hypothesized that H 2 S levels could play a role in the pathogenesis of preeclampsia and studied the placental expression of the H 2 S-producing enzymes cystathionine-g-lyase (CSE) and cystathionine-b-synthase (CBS). CBS and CSE protein are expressed in the fetal-placental endothelium and CBS only in Hofbauer cells. CBS mRNA expression is decreased (p ¼ 0.002) in early-onset preeclampsia, while CSE mRNA is unchanged. Thus, down regulation of CBS during early-onset preeclampsia may result in less H 2 S-production and may aid in the anti-angiogenic state.
Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stre... more Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population.Methods: Female participants (n = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events.Results: Postmenopausal women had significantly reduced levels of serum f...
The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tis... more The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r...
We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and ... more We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and the association between OS and cardiometabolic outcomes in women with obesity and infertility. From 2009 to 2012, infertile women with a BMI ≥ 29 kg/m2 were randomly assigned to a six-month lifestyle intervention followed by infertility treatment (N = 289) or to prompt infertility treatment (N = 285). Fasting serum free thiols (FT) concentrations were determined by colorimetry at baseline, at three and six months after randomization. Generalized estimating equations and restricted cubic spline regressions were used to estimate mean differences in serum FT levels between groups and to explore associations between serum FT levels and cardiometabolic outcomes. Baseline serum FT levels did not differ between the two groups (N = 203 in the intervention group vs. N = 226 in the control group, 222.1 ± 48.0 µM vs. 229.9 ± 47.8 µM, p = 0.09). Body weight decreased by 3.70 kg in the intervention g...
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 =...
Animal models are a valuable tool in preclinical research. However, limited predictivity of human... more Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGFβ or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation; (2) expression of markers of TGFβ and PDGF signaling; and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponde...
Islet transplantation into subcutaneous polymer scaffolds has shown to successfully induce normog... more Islet transplantation into subcutaneous polymer scaffolds has shown to successfully induce normoglycemia in type 1 diabetes models. Vascularization of these scaffolds is imperative for optimal control of glucose levels. We studied the effect of the vascular stimulator hydrogen sulfide (H2S) on the degree of vascularization of a scaffold and the role of the immune system in this process. Scaffolds were subcutaneously implanted in immunocompetent C57BL/6 and immunocompromised nude mice. Mice received twice-daily intraperitoneal injections of the fast-releasing H2S donor sodium hydrosulfide (NaHS, 25 or 50 μmol/kg) or saline for 28 days. After 63 days the vascular network was analyzed by histology and gene expression. Here we showed that the vascularization of a subcutaneous scaffold in nude mice was significantly impaired by H2S treatment. Both the CD31 gene and protein expression were reduced in these scaffolds compared to the saline-treated controls. In C57BL/6 mice, the opposite wa...
Background Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stress... 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 biochemi...
Aberrant production of hydrogen sulfide (H2S) has been linked to preeclampsia. We hypothesized th... more Aberrant production of hydrogen sulfide (H2S) has been linked to preeclampsia. We hypothesized that sodium thiosulfate (STS), a H2S donor, reduces hypertension and proteinuria, and diminishes fetal growth restriction in the Dahl salt-sensitive (S) rat, a spontaneous model of superimposed preeclampsia. In addition to a control group (n = 13), two groups received STS via drinking water at a dose of 2 g (n = 9) or 3 g per kg body weight per day (n = 8) from gestational day (GD) 10 to 20. Uterine artery resistance index was measured (GD18), urinary protein excretion rate was determined (GD19), and blood pressure and fetal outcomes were evaluated (GD20). At 2 g, STS had no effect on preeclamptic symptoms or fetal outcome. At 3 g, STS reduced maternal hypertension (121.8 ± 3.0 vs. 136.3 ± 2.9), but increased proteinuria (89 ± 15 vs. 56 ± 5 mg/24 h), and relative kidney weight (0.86 ± 0.04 vs. 0.73 ± 0.02%). Fetal/placental weight ratio was reduced (3.83 ± 0.07 vs. 4.31 ± 0.08) without aff...
Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative ... more Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but...
Taurine is a sulfur containing nutrient that has been shown to protect against oxidative stress, ... more Taurine is a sulfur containing nutrient that has been shown to protect against oxidative stress, which has been implicated in the pathophysiology leading to late graft failure after renal transplantation. We prospectively investigated whether high urinary taurine excretion, reflecting high taurine intake, is associated with low risk for development of late graft failure in renal transplant recipients (RTR). Urinary taurine excretion was measured in a longitudinal cohort of 678 stable RTR. Prospective associations were assessed using Cox regression analyses. Graft failure was defined as the start of dialysis or re-transplantation. In RTR (58% male, 53 ± 13 years old, estimated glomerular filtration rate (eGFR) 45 ± 19 mL/min/1.73 m2), urinary taurine excretion (533 (210–946) µmol/24 h) was significantly associated with serum free sulfhydryl groups (β = 0.126; P = 0.001). During median follow-up for 5.3 (4.5–6.0) years, 83 (12%) patients developed graft failure. In Cox regression anal...
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. Conclusion: 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.
Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associa... more Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (H2S), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that H2S-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia.Methods: We postulated that H2S might be a primary mediator of EPO synthesis during hypoxia, which was tested using an in vivo murine model of whole-body hypoxia and in clinical samples obtained from CKD patients.Results: Following a 72-hour period of hypoxia (11% O2), partial H2S knockout mice (lacking the H2S biosynthetic enzyme cystathionine γ-lyase [CSE]) displayed lower levels of hemoglobin, EPO and cystathionine-β-synthase (CBS) (another H2S biosynthetic enzyme) compared to wild-type ...
Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). ... more Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). The kidney recycles iron back into the circulation. However, the localization of proteins relevant for physiological tubular iron handling and their potential role in CKD remain unclear. We examined associations between iron deposition, expression of iron handling proteins and tubular injury in kidney biopsies from CKD patients and healthy controls using immunohistochemistry. Iron was deposited in proximal (PT) and distal tubules (DT) in 33% of CKD biopsies, predominantly in pathologies with glomerular dysfunction, but absent in controls. In healthy kidney, PT contained proteins required for iron recycling including putative iron importers ZIP8, ZIP14, DMT1, iron storage proteins L- and H-ferritin and iron exporter ferroportin, while DT only contained ZIP8, ZIP14, and DMT1. In CKD, iron deposition associated with increased intensity of iron importers (ZIP14, ZIP8), storage proteins (L-, ...
A correction to this article has been published and is linked from the HTML and PDF versions of t... more A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular inj... more Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide,...
Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. A... more Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. As hydrogen sulfide (H 2 S) has pro-angiogenic and anti-oxidative characteristics, we hypothesized that H 2 S levels could play a role in the pathogenesis of preeclampsia and studied the placental expression of the H 2 S-producing enzymes cystathionine-g-lyase (CSE) and cystathionine-b-synthase (CBS). CBS and CSE protein are expressed in the fetal-placental endothelium and CBS only in Hofbauer cells. CBS mRNA expression is decreased (p ¼ 0.002) in early-onset preeclampsia, while CSE mRNA is unchanged. Thus, down regulation of CBS during early-onset preeclampsia may result in less H 2 S-production and may aid in the anti-angiogenic state.
Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stre... more Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population.Methods: Female participants (n = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events.Results: Postmenopausal women had significantly reduced levels of serum f...
The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tis... more The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r...
We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and ... more We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and the association between OS and cardiometabolic outcomes in women with obesity and infertility. From 2009 to 2012, infertile women with a BMI ≥ 29 kg/m2 were randomly assigned to a six-month lifestyle intervention followed by infertility treatment (N = 289) or to prompt infertility treatment (N = 285). Fasting serum free thiols (FT) concentrations were determined by colorimetry at baseline, at three and six months after randomization. Generalized estimating equations and restricted cubic spline regressions were used to estimate mean differences in serum FT levels between groups and to explore associations between serum FT levels and cardiometabolic outcomes. Baseline serum FT levels did not differ between the two groups (N = 203 in the intervention group vs. N = 226 in the control group, 222.1 ± 48.0 µM vs. 229.9 ± 47.8 µM, p = 0.09). Body weight decreased by 3.70 kg in the intervention g...
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 =...
Animal models are a valuable tool in preclinical research. However, limited predictivity of human... more Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGFβ or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation; (2) expression of markers of TGFβ and PDGF signaling; and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponde...
Islet transplantation into subcutaneous polymer scaffolds has shown to successfully induce normog... more Islet transplantation into subcutaneous polymer scaffolds has shown to successfully induce normoglycemia in type 1 diabetes models. Vascularization of these scaffolds is imperative for optimal control of glucose levels. We studied the effect of the vascular stimulator hydrogen sulfide (H2S) on the degree of vascularization of a scaffold and the role of the immune system in this process. Scaffolds were subcutaneously implanted in immunocompetent C57BL/6 and immunocompromised nude mice. Mice received twice-daily intraperitoneal injections of the fast-releasing H2S donor sodium hydrosulfide (NaHS, 25 or 50 μmol/kg) or saline for 28 days. After 63 days the vascular network was analyzed by histology and gene expression. Here we showed that the vascularization of a subcutaneous scaffold in nude mice was significantly impaired by H2S treatment. Both the CD31 gene and protein expression were reduced in these scaffolds compared to the saline-treated controls. In C57BL/6 mice, the opposite wa...
Background Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stress... 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 biochemi...
Aberrant production of hydrogen sulfide (H2S) has been linked to preeclampsia. We hypothesized th... more Aberrant production of hydrogen sulfide (H2S) has been linked to preeclampsia. We hypothesized that sodium thiosulfate (STS), a H2S donor, reduces hypertension and proteinuria, and diminishes fetal growth restriction in the Dahl salt-sensitive (S) rat, a spontaneous model of superimposed preeclampsia. In addition to a control group (n = 13), two groups received STS via drinking water at a dose of 2 g (n = 9) or 3 g per kg body weight per day (n = 8) from gestational day (GD) 10 to 20. Uterine artery resistance index was measured (GD18), urinary protein excretion rate was determined (GD19), and blood pressure and fetal outcomes were evaluated (GD20). At 2 g, STS had no effect on preeclamptic symptoms or fetal outcome. At 3 g, STS reduced maternal hypertension (121.8 ± 3.0 vs. 136.3 ± 2.9), but increased proteinuria (89 ± 15 vs. 56 ± 5 mg/24 h), and relative kidney weight (0.86 ± 0.04 vs. 0.73 ± 0.02%). Fetal/placental weight ratio was reduced (3.83 ± 0.07 vs. 4.31 ± 0.08) without aff...
Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative ... more Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but...
Taurine is a sulfur containing nutrient that has been shown to protect against oxidative stress, ... more Taurine is a sulfur containing nutrient that has been shown to protect against oxidative stress, which has been implicated in the pathophysiology leading to late graft failure after renal transplantation. We prospectively investigated whether high urinary taurine excretion, reflecting high taurine intake, is associated with low risk for development of late graft failure in renal transplant recipients (RTR). Urinary taurine excretion was measured in a longitudinal cohort of 678 stable RTR. Prospective associations were assessed using Cox regression analyses. Graft failure was defined as the start of dialysis or re-transplantation. In RTR (58% male, 53 ± 13 years old, estimated glomerular filtration rate (eGFR) 45 ± 19 mL/min/1.73 m2), urinary taurine excretion (533 (210–946) µmol/24 h) was significantly associated with serum free sulfhydryl groups (β = 0.126; P = 0.001). During median follow-up for 5.3 (4.5–6.0) years, 83 (12%) patients developed graft failure. In Cox regression anal...
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. Conclusion: 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.
Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associa... more Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (H2S), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that H2S-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia.Methods: We postulated that H2S might be a primary mediator of EPO synthesis during hypoxia, which was tested using an in vivo murine model of whole-body hypoxia and in clinical samples obtained from CKD patients.Results: Following a 72-hour period of hypoxia (11% O2), partial H2S knockout mice (lacking the H2S biosynthetic enzyme cystathionine γ-lyase [CSE]) displayed lower levels of hemoglobin, EPO and cystathionine-β-synthase (CBS) (another H2S biosynthetic enzyme) compared to wild-type ...
Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). ... more Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). The kidney recycles iron back into the circulation. However, the localization of proteins relevant for physiological tubular iron handling and their potential role in CKD remain unclear. We examined associations between iron deposition, expression of iron handling proteins and tubular injury in kidney biopsies from CKD patients and healthy controls using immunohistochemistry. Iron was deposited in proximal (PT) and distal tubules (DT) in 33% of CKD biopsies, predominantly in pathologies with glomerular dysfunction, but absent in controls. In healthy kidney, PT contained proteins required for iron recycling including putative iron importers ZIP8, ZIP14, DMT1, iron storage proteins L- and H-ferritin and iron exporter ferroportin, while DT only contained ZIP8, ZIP14, and DMT1. In CKD, iron deposition associated with increased intensity of iron importers (ZIP14, ZIP8), storage proteins (L-, ...
A correction to this article has been published and is linked from the HTML and PDF versions of t... more A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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