Biomedical subjects

Jean-Paul Cristol

Publications and source records attributed to Jean-Paul Cristol.

At least 19 recordsLinked to original sources

PubMed2006

Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats.

BACKGROUND AND AIM: In type 2 diabetes, the interplay between cells and inflammatory mediators up-regulates CD36 expression in macrophages. The aim of this work was to investigate advanced glycation end products (AGE)-induced CD36 expression and its regulation by insulin in aortic vascular smooth muscle cells (VSMCs) from Goto-Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes. The context of overexpression of CD36 in aortas was also evaluated. METHODS AND RESULTS: VSMCs were isolated and cultured from the aortas of GK rats and non-diabetic rats. The expression of proteins was evaluated by Western blot. The aortic production of superoxide anion (O(2)(.-)) was measured by luminescence on isolated tissue. AGEs and advanced oxidation protein products (AOPPs) were determined in plasma by fluorescence spectroscopy and spectrophotometry, respectively. AGE receptor (RAGE), NF-kappaB, and CD36 protein expression as well as O(2)(.-) production were higher in GK aortas than in control aortas, and AGEs and AOPPs were higher in GK plasma. In VSMCs from non-diabetic rats, insulin was able to reduce (10 nM) or suppress (100 nM) the protein overexpression of CD36 induced by AGEs-BSA. In contrast, in VSMCs from GK rats, insulin was unable to reduce AGEs-BSA-induced CD36 overexpression. CONCLUSIONS: The results suggest an overexpression of CD36 in VSMCs from GK rats and impaired control by insulin. In the context of increased plasma AGEs, aortic RAGE overexpression and increased oxidative stress markers, the data are compatible with an AGEs induced CD36 overexpression in diabetes.

Animals↗

PubMed2006

Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.

CONTEXT: Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress. OBJECTIVE: To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) in Montpellier, France. MAIN OUTCOME MEASURES: Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F2alpha (8-iso PGF2alpha). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve [AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period. RESULTS: Mean (SD) urinary 8-iso PGF2alpha excretion rates were higher in the 21 patients with diabetes (482 [206] pg/mg of creatinine) compared with controls (275 [85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF2alpha excretion rates. Relationships between 8-iso PGF2alpha excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R2 = 0.72 for the model including MAGE and multiple R2 = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp. CONCLUSIONS: Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A1c and mean glucose concentrations but also acute glucose swings.

Aged↗

PubMed2006

Assay for measurement of intact B-type natriuretic peptide prohormone in blood.

BACKGROUND: B-Type natriuretic peptide (BNP1-32) as well as the N-terminal fragment of the prohormone containing residues 1-76 (NT-proBNP1-76), both cleavage products of the precursor proBNP1-108, are reported to be powerful markers for prognosis and risk stratification of heart failure. However, the intact precursor also circulates in the bloodstream. Assays for the detection of these cleavage products have been developed, but most of these assays may overestimate the concentrations of the cleavage products because they also measure the precursor form. It is therefore important to develop an immunoassay that specifically measures solely proBNP1-108 in plasma. METHODS: After carefully designing the peptide used to immunize mice, we selected a specific monoclonal antibody (mAb Hinge76) that recognizes the cleavage site of proBNP1-108, an epitope present only in the precursor form. mAb Hinge76 recognizes recombinant proBNP1-108 in a dose-dependent manner, without any significant cross-reactivity with either recombinant NT-proBNP1-76 or synthetic BNP1-32. By combining mAb Hinge76 with a polyclonal antibody directed against BNP1-32, we were able to set up a proBNP1-108-specific sandwich immunoassay able to confirm the presence of proBNP1-108 in blood samples. RESULTS: From a cohort of 50 healthy persons and 170 patients with congestive heart failure (CHF), our assay was able to differentiate healthy individuals from CHF patients (P <0.005). Interestingly, plasma proBNP1-108 concentrations were correlated with New York Heart Association classification. Moreover, a close relationship between proBNP1-108 and BNP1-32 concentrations may exist, as a good correlation (r2= 0.89) was obtained when their respective concentrations were compared. CONCLUSION: mAb Hinge76 is the first proBNP1-108-specific mAb produced that allows accurate estimation of proBNP1-108 concentrations in plasma.

Adult↗

PubMed2006

Intradialytic parenteral nutrition: comparison of olive oil versus soybean oil-based lipid emulsions.

Lipid, oxidative and inflammatory parameters are frequently altered in dialysis patients and may be worsened by intravenous lipid emulsions (ILE). We assessed the efficacy and tolerance of olive as compared with standard soybean oil-based ILE during intradialytic parenteral nutrition (IDPN). IDPN mixtures containing amino acids, glucose, and either olive oil (OO group, n 17) or soybean oil-based ILE (SO group, n 18) were administered in a 5-week randomized, double-blind study. On days 0 and 35, patients' nutritional status was assessed by BMI, normalized protein catabolic rate, predialytic creatinine, serum albumin and transthyretin; lipid metabolism by plasma LDL- and HDL-cholesterol, triacylglycerols, phospholipids, apo A-I, A-II, B, C-II, C-III, E and lipoprotein (a); oxidative status by alpha-tocopherol, retinol, selenium, glutathione peroxidase, malondialdehyde and advanced oxidized protein products; inflammatory status by serum C-reactive protein, orosomucoid, IL-2 and IL-6. No serious adverse event was observed. Significant changes were observed from day 0 to day 35 (P<0.05): nutritional criteria improved (albumin in OO; albumin, transthyretin and creatinine in SO); LDL-cholesterol, apo B, C-II, C-III and apo A-I/A-II ratio increased in both groups. HDL-cholesterol decreased in OO; apo E increased and lipoprotein (a) decreased in SO; alpha-tocopherol/cholesterol ratio increased in OO; malondialdehyde decreased in both groups; IL-2 increased in both groups. The between-group comparison only showed the following differences: alpha-tocopherol/cholesterol increased in OO; lipoprotein (a) decreased in SO. From these data, it was concluded that OO- and SO-based IDPNs similarly improved nutritional status and influenced plasma lipid, oxidative, inflammatory and immune parameters.

Aged↗

PubMed2006

Overview of clinical studies in hemodiafiltration: what do we need now ?

Despite several technical advances in dialysis treatment modalities and a better patient care management including correction of anemia, suppression of secondary hyperparathyroidism, lipid and oxidative stress profiles improvement, the morbidity and the mortality of dialysis patients still remain still elevated. Recent prospective interventional trials in hemodialysis (HEMO study and 4D study) were not very conclusive in showing any significant improvement in dialysis patient outcomes. High-efficiency convective therapies, such as online hemodiafiltration (HDF), are claimed to be superior to conventional diffusive hemodialysis (HD) in improving the dialysis efficacy and in reducing intradialytic morbidity and all-cause and cardiovascular mortality in dialysis patients. The aim of this report was, first, to review the evidence-based facts tending to prove the superiority of HDF vs. HD in terms of efficacy and tolerance, and, second, to analyze the needs to prove the clinical superiority of HDF in terms of reducing morbidity and all-cause mortality of dialysis patients. A systematic review of studies comparing HDF and HD has been performed in the microbiological safety of online production, the solute removal capacity of small and medium-size uremic toxins, and its implication in the reduction of the bioactive dialysis system vs. patient interaction. Major planned randomized international studies comparing HDF and HD in terms of morbidity and mortality have been reviewed. To conclude, it is thought that these long-term prospective randomized trials will clarify on a scientific evidence-based level the putative beneficial role of high-efficiency HDF modalities on dialysis patient outcomes.

Cardiovascular Diseases↗

PubMed2006

Association of aminothiols with the clinical outcome in hemodialysis patients: comparison of chromatography and immunoassay for homocysteine determination.

BACKGROUND: Controversial results on hyperhomocysteinemia and cardiovascular risk in hemodialysis (HD) could be due in part to the methodology used for homocysteine (Hcy) determination. OBJECTIVE: The aim of this study was to compare the influence of the method used for Hcy determination (chromatography or immunoassay) with regard to the association of Hcy with cardiovascular mortality rate in HD patients in a 3-year prospective study. METHODS: A total of 162 patients undergoing HD were included in a cohort study. Baseline Hcy levels were measured by HPLC and fluorescence polarization immunoassay (FPIA). Cysteine and cysteinylglycine were determined simultaneously with Hcy measurement by HPLC. RESULTS: Hcy levels obtained with both methods were highly correlated (r(2)=0.927, p<0.0001). An increased relative risk (RR) for cardiovascular mortality (n=31) was found between the highest against lowest tertile of Hcy for both HPLC (RR 2.74, 95% CI 1.07-7.02; p<0.05) and FPIA (RR 2.76, 95% CI 0.99-7.70; p=0.05). Interestingly, increased cysteine (> or =452 micromol/L) and cysteinylglycine (> or =36.6 micromol/L) levels were associated with a decreased RR of non-cardiovascular death (n=26) (RR 0.27, 95% CI 0.09-0.79; p=0.02) for cysteine and (RR 0.28, 95% CI 0.09-0.90; p=0.03) for cysteinylglycine when compared to the first tertile. CONCLUSIONS: This study demonstrated an increased risk of cardiovascular mortality in HD patients with Hcy values in the third tertile, independent of the method used. HPLC offers the advantage of simultaneous determination of other aminothiols that appear to be associated with non-cardiovascular mortality.

Adult↗

PubMed2005

Polyphenols-enriched Chardonnay white wine and sparkling Pinot Noir red wine identically prevent early atherosclerosis in hamsters.

The effects of a white wine enriched with polyphenols (PEWW) from Chardonnay grapes and of a sparkling red wine (SRW) from Pinot Noir and Chardonnay grapes were studied for the first time on early atherosclerosis in hamsters. Animals were fed an atherogenic diet for 12 weeks. They received by force-feeding PEWW, SRW, ethanol 12% (ETH), or water as control (mimicking a moderate consumption of approximately 2 red wine glasses per meal for a 70 kg human). Plasma cholesterol concentrations were lower in groups that consumed PEWW and SRW accompanied by an increase in the ratio apo A-1/apo B. Liver-specific activities of superoxide dismutase and catalase were significantly increased by PEWW (38 and 16%, respectively) and by SRW (48 and 15%, respectively). PEWW and ETH significantly increased plasma antioxidant capacity and vitamin A concentrations. Aortic fatty streak area (AFSA) was significantly strongly reduced in the groups receiving PEWW (85%) and SRW (89%) in comparison with the control. AFSA was reduced by ethanol to a lesser extent (58%). These data suggest that tannins from the phenolics-enriched white wine induce a protective effect against early atherosclerosis comparable to that produced by sparkling red wine containing tanins and anthocyanins and dissociated from the antioxidant action of these compounds.

Animals↗

PubMed2005

Plasma osteoprotegerin is associated with mortality in hemodialysis patients.

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone > or =300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein > or =12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

Adult↗

PubMed2005

Is tenofovir involved in hypophosphatemia and decrease of tubular phosphate reabsorption in HIV-positive adults?

OBJECTIVES: Tubulopathy with hypophosphatemia have been observed in HIV-positive patients receiving a tenofovir-containing regimen. However, the real incidence and prevalence of hypophosphatemia and their relation to tubular reabsorption disorders in tenofovir-treated patients remain uncertain. The aim of our study was to explore the effect of tenofovir on phosphatemia and on tubular phosphate reabsorption. METHODS: In a first transversal study, 145 HIV-positive adults (44+/-9 years) receiving tenofovir 300 mg daily with a mean exposure of 11+/-9 months were included. In a second prospective study, 29 HIV-positive antiretroviral experienced adults (44+/-10 years) were evaluated before introduction of tenofovir 300 mg daily (M0) and at 3 months (M3) and 6 months (M6), thereafter. Phosphate, creatinine, glucose and protein levels were determined in plasma and urine. The ratio of maximal reabsorption capacity (TmPO4)/glomerular filtration rate (GFR) was determined by using the normogramm of Walton and Bijvoet. RESULTS: In the transversal study, 26% of patients had hypophosphatemia (<0.84 mmol/l) while 47% of patients had a decreased TmPO4/GFR (<0.8 mmol/l). In the prospective study, baseline prevalence of hypophosphatemia (<0.84 mmol/l) and decreased TmPO4/GFR (<0.8mmol/l) was 31 and 41%, respectively. Three and 6 months after starting tenofovir, there is no significant change in mean phosphate levels (M0:0.91 mmol/l, M3:0.97 mmol/l, M6:0.98 mmol/l) and mean TmPO4/GFR (M0:0.80 mmol/l, M3:0.88 mmol/l, M6:0.84 mmol/l). Moreover, prevalence of hypophosphatemia (M3:28%, M6:28%) and decreased TmPO4/GFR (M3:41%, M6:45%) remained stable. CONCLUSION: Hypophosphatemia linked to a decreased proximal tubular reabsorption was frequently observed in HIV-positive adults independently of the use of tenofovir. In this preliminary study, no worsening effect on phosphatemia and tubular phosphate reabsorption was observed 6 months after introduction of tenofovir in treatment experienced patients.

Adenine↗

PubMed2005

Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation.

The effects of the phenolic compounds catechin (Cat), quercetin (Qer), and resveratrol (Res) present in red wine on early atherosclerosis were studied in hamsters. Hamsters (n = 32) were divided into 4 groups of 8 and fed an atherogenic diet for 12 weeks. They received by force-feeding 7.14 mL/(kg of body wt.day) Cat, Qer, or Res in water [2.856 mg/(kg of body wt.day) for Cat and 0.1428 mg/(kg of body wt.dday) for Qer and Res], mimicking a moderate consumption of alcohol-free red wine (equivalent to that supplied by the consumption of about two glasses of red wine per meal for a 70 kg human), or water as control. Plasma cholesterol concentration was lower in groups that consumed phenolics than in controls. The increase in plasma apolipoprotein (Apo) A1 concentration was mainly due to Cat (26%) and Qer (22%) and to a lesser extent, but nonsignificantly, Res (19%). Apo-B was not affected. Plasma antioxidant capacity was not improved, and there was no sparing effect on plasma vitamins A and E. Plasma iron and copper concentrations were not modified nor were liver super oxide dismutase and catalase activities. A sparing effect of Qer on liver glutathione peroxidase activity appeared, whereas Cat and Res exhibited a smaller effect. Aortic fatty streak area was significantly reduced in the groups receiving Cat (84%) or Qer (80%) or Res (76%) in comparison with the controls. These findings demonstrate that catechin, quercetin, and resveratrol at nutritional doses prevent the development of atherosclerosis through several indirect mechanisms.

Animals↗

PubMed2005

Extracts enriched in different polyphenolic families normalize increased cardiac NADPH oxidase expression while having differential effects on insulin resistance, hypertension, and cardiac hypertrophy in high-fructose-fed rats.

Insulin resistance and oxidative stress act synergistically in the development of cardiovascular complications. The present study compared the efficacy of three polyphenolic extracts in their capacity to prevent hypertension, cardiac hypertrophy, increased production of reactive oxygen species (ROS) by the aorta or the heart, and increased expression of cardiac NAD(P)H oxidase in a model of insulin resistance. Rats were fed a 60%-enriched fructose food and were treated once a day (gavage) for 6 weeks with 10 mL/kg of water only (F group) or the same amount of solution containing a red grape skin polyphenolic extract enriched in anthocyanins (ANT), a grape seed extract enriched in procyanidins and rich in galloylated procyanidins (PRO), or the commercial preparation Vitaflavan (VIT), rich in catechin oligomers. All treatments were administered at the same dose of 21 mg/kg of polyphenols. Our data indicate that (a) the ANT treatment prevented hypertension, cardiac hypertrophy, and production of ROS, (b) the PRO treatment prevented insulin resistance, hypertriglyceridemia, and overproduction of ROS but had only minor effects on hypertension or hypertrophy, while (c) Vitaflavan prevented hypertension, cardiac hypertrophy, and overproduction of ROS. All polyphenolic treatments prevented the increased expression of the p91phox NADPH oxidase subunit. In summary, our study suggest that (a) the pathogeny of cardiac hypertrophy in the fructose-fed rat disease involves both hypertension and hyperproduction of ROS, (b) polyphenolic extracts enriched in different types of polyphenols possess differential effects on insulin resistance, hypertension, and cardiac hypertrophy, and (c) polyphenols modulate the expression of NAD(P)H oxidase.

Animals↗

PubMed2005

Albumin and transthyretin as risk factors for cataract: the POLA study.

OBJECTIVE: To assess the associations of markers of protein nutrition (plasma albumin and transthyretin) with cataract. METHODS: The Pathologies Oculaires Liées à l'Age (POLA) Study (1995-1997) is a population-based study on age-related eye diseases, performed in 2584 residents of Sète (South of France), aged 60 to 95 years. Cataract classification was based on a standardized lens examination at slitlamp according to Lens Opacities Classification System III. RESULTS: After multivariate adjustment, the risk for cataract (any type) was increased by about 50% in the lowest quintile of plasma albumin concentration (<38.28 g/L) and transthyretin concentration (<0.21 g/L) (odds ratio [OR], 1.49 [95% confidence interval (CI), 1.04-2.14]) and OR, 1.48 [95% CI, 1.03-2.13], respectively). The associations were stronger with mixed cataract (OR, 1.87 [95% CI, 0.95-3.68] and OR, 2.37 [95% CI, 1.22-4.59] for albumin and transthyretin levels, respectively) and nuclear cataract (OR, 2.39 [95% CI, 1.20-4.76] for low transthyretin levels). There were no significant associations with the other types of cataract. There were no associations of cataracts with high-sensitivity C-reactive protein and orosomucoid levels. CONCLUSIONS: This study is suggestive of an association of protein undernutrition with increased risk of cataract. Low protein intake may induce deficiencies of specific amino acids that are needed to maintain the health of the lens, or other nutritional deficiencies, particularly niacin, thiamin, and riboflavin.

Aged↗

PubMed2005

Comparison of 3 automated assays for C-reactive protein in end-stage renal disease: clinical and epidemiological implications.

Chronic inflammation has been repeatedly reported in individuals undergoing hemodialysis. C-reactive protein (CRP) is considered a marker of chronic inflammation, as well as a mediator of the atherosclerotic process. Clinical and epidemiologic studies are based on plasma values obtained with the use of various automated methods. Our aim was to test 3 commercially available methods and compare the values obtained with the use of these tests in a population of individuals undergoing hemodialysis. We compared the following methods: immunoturbidimetry (AU2700 biochemistry analyzer; Olympus, Rungis, France) laser nephelometry (Behring Diagnostics, Marburg, Germany), and nephelometry (Beckman Instruments, Fullerton, Calif. The 3 methods were used in 3 different centers: Montpellier, France; and Pisa and Turin, Italy, respectively. We prepared samples for the estimation of imprecision values (ie, coefficient of variation [CV]) from the plasma of normal patients by adding purified C-reactive protein at concentrations ranging from 2.6 to 180 mg/L for intraassay variation and concentrations of 0, 1, 2, 3, 5, 10, 20, 50, 100, 150, and 180 mg/L for interassay variation. Intraassay imprecision was determined with the use of 10 replicate analyses on the same sample of the same day. We assessed interassay imprecision using the same sample, divided into aliquots and measured on 5 consecutive days. Agreement between methods was assessed on predialysis serum samples collected from patients with stable chronic kidney disease who were undergoing long-term hemodialysis at the 3 different centers (Montpellier,192; Pisa, 56; Turin,98). Serum was separated from the red cells and stored in 3 aliquots at -70 degrees C until it could be analyzed. Samples were thawed only once, circulated among the 3 centers, and each tested with all 3 of the methods. The Beckman method yielded the most precise results, with intraassay CVs ranging from 1 to 2 and interassay CVs ranging from 1 to 4. The Behring method was the least precise, with intraassay and interassay CVs ranging from 12 to 15 and 7 to 16, respectively. The results of the Olympus method fell between those of the other 2 methods. Agreement between the results of the Olympus and Behring methods was satisfactorily. The Beckman and Olympus methods yielded, on average, similar results over the entire range of CRP values. We detected significant disagreement between the Beckman method and the other 2 methods, obtaining results 10 to 100 times lower with the Beckman method. This became evident in terms of kappa-statistics. Our findings emphasize the need for careful assessment of the methods used to detect CRP in serum samples. Failure to do so may ultimately have a negative impact on the real relevance of CRP as a marker and on the role of chronic implication particularly in epidemiologic studies.

Biomarkers↗

PubMed2005

Inhibitors of NADPH oxidase reduce the organ injury in hemorrhagic shock.

Reactive oxygen species contribute to the multiple organ dysfunction syndrome in hemorrhagic shock. Here, we investigate the effects of two chemically distinct inhibitors of NADPH oxidase on the circulatory failure and the organ dysfunction and injury associated with hemorrhagic shock in the anesthetized rat. Hemorrhage (sufficient to lower mean arterial blood pressure of 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure and in renal dysfunction and liver injury. Treatment of rats upon resuscitation with the NADPH oxidase inhibitors diphenylene iodonium (DPI, 1 mg/kg i.v.) reduced renal dysfunction and liver injury, whereas apocynin (3 mg/kg i.p.) did reduce the liver injury, but not the renal dysfunction caused by hemorrhagic shock. DPI and apocynin also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. In the liver, DPI and apocynin abolished the increase in the formation of superoxide anions associated with hemorrhagic shock. However, neither DPI nor apocynin had a significant effect on the delayed circulatory failure caused by hemorrhage and resuscitation. In addition, DPI and apocynin did not reduce the increase in nitric oxide synthesis caused by hemorrhagic shock. Moreover, DPI reduced the activation of the transcription factor activator protein-1 caused by severe hemorrhage and resuscitation in the liver. Thus, we propose that an enhanced formation of superoxide anions by NADPH oxidase contributes to the liver injury caused by hemorrhagic shock, and that inhibitors of NADPH oxidase may represent a novel therapeutic approach for the therapy of hemorrhagic shock.

Acetophenones↗

PubMed2005

Overproduction of reactive oxygen species in end-stage renal disease patients: a potential component of hemodialysis-associated inflammation.

During the past decade, hemodialysis (HD)-induced inflammation has been linked to the development of long-term morbidity in end-stage renal disease (ESRD) patients on regular renal replacement therapy. Because interleukins and anaphylatoxins produced during HD sessions are potent activators for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an example of an enzyme that is responsible for overproduction of reactive oxygen species (ROS), this may constitute a link between leukocyte activation and cell or organ toxicity. Oxidative stress, which results from an imbalance between oxidant production and antioxidant defense mechanisms, has been documented in ESRD patients using lipid and/or protein oxidative markers. Characterization of HD-induced oxidative stress has included identification of potential activators for NADPH oxidase. Uremia per se could prime phagocyte oxidative burst. HD, far from improving the oxidative status, results in an enhancement of ROS owing to hemoincompatibility of the dialysis system, hemoreactivity of the membrane, and trace amounts of endotoxins in the dialysate. In addition, the HD process is associated with an impairment in antioxidant mechanisms. The resulting oxidative stress has been implicated in long-term complications including anemia, amyloidosis, accelerated atherosclerosis, and malnutrition. Prevention of oxidative stress in HD might focus on improving the hemocompatibility of the dialysis system, supplementation of deficient patients with antioxidants, and modulation of NADPH oxidase by pharmacologic approaches.

Anaphylatoxins↗

PubMed2005

Association between novel indices of malnutrition-inflammation complex syndrome and cardiovascular disease in hemodialysis patients.

BACKGROUND: Inflammation and malnutrition are recognized as important risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Owing to substantial short-term variability of serum C-reactive protein (CRP), more reliable markers of malnutrition-inflammation complex syndrome should be sought with stronger associations with the risk of CVD in HD patients. We therefore explored the clinical relevance of a composite inflammatory index (prognostic inflammatory and nutritional index [PINI]) and of muscle protein mass indicators, derived from creatinine kinetics. METHODS: This cross-sectional study included 177 HD patients (89 women and 88 men; median age, 67.73 years). CVD and risk factors were assessed using medical charts, clinical examination, and biochemical measurements performed at inclusion. Lean body mass (LBM) was derived from creatinine kinetic modeling, whereas PINI was calculated as the ratio (CRP xalpha1-acid-glycoprotein)/(albumin x transthyretin). Patients were divided according to the presence or absence of established CVD. RESULTS: The traditional risk factors diabetes (odds ratio [OR], 5.83; p = 0.0045) and smoking (OR, 3.50; p < 0.02) were associated with an increase in prevalent CVD. Low transthyretin (OR, 3.79; p < 0.02) and high levels of CRP (OR, 2.70; p < 0.05), PINI (OR, 3.44; p < 0.02), observed LBM (OR, 3.01; p < 0.05), and the ratio of observed/expected LBM (OR, 4.24; p < 0.01) were associated with CVD after adjustment for age, sex, dialysis center, and dialysis vintage. After additional adjustment for diabetes and smoking, only PINI (OR, 2.85; p = 0.0446) and observed/expected LBM (OR, 2.96; p = 0.0361) were still significant. CONCLUSION: PINI and LBM are associated with increased relative risk for having CVD and could be used routinely to examine the degree of severity of malnutrition inflammation complex syndrome.

Adult↗

PubMed2005

Elevated plasma cysteinylglycine levels caused by cilastatin-associated antibiotic treatment.

Imipenem (thienamycin formamidine), a broad-spectrum beta-lactam antibiotic, is always used in combination with cilastatin in order to avoid the premature breakdown of imipenem by renal tubular dipeptidase. As this dipeptidase also hydrolyzes the glutathione metabolite cysteinylglycine, the therapeutic association of imipenem and cilastatin might cause an accumulation of the aminothiol cysteinylglycine. We demonstrate here that when patients are treated with imipenem-cilastatin, their plasma levels of cysteinylglycine are significantly and specifically increased, while cysteine levels are decreased and homocysteine levels are unaffected. We conclude that antibiotic treatment using imipenem-cilastatin induces important metabolic changes that should not remain unrecognized.

Anti-Bacterial Agents↗

PubMed2004

Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat.

Growing evidences suggest a role of oxidative stress in hypertension and cardiac hypertrophy. The fructose (60%)-fed rat represents a model of metabolic syndrome, associating insulin resistance and high blood pressure. In this model, hypertension, cardiac and vessels hypertrophy and markers of oxidative stress were determined. In addition, the production of reactive oxygen species (ROS) was evaluated at different times after the initiation of fructose-enriched diet in aorta, heart and polymorphonuclear cells. High fructose feeding was associated with an early (1-week) increase in ROS production by aorta, heart and circulatory polymorphonuclear cells, in association with enhanced markers of oxidative stress. Vascular and cardiac hypertrophy was also rapidly observed, while the rise in blood pressure was significant only after 3 weeks. In summary, our study suggests that the production of reactive oxygen species can be a key-event in the initiation and development of cardiovascular complications associated with insulin resistance.

Animals↗