Project description:Background: Diclofenac is a non-steroidal anti-inflammatory drug frequently found in the aquatic environment. Previous studies have reported histological changes in the liver, kidney and gills of fish at concentrations similar to those measured in treated sewage effluents (~1 µg/L). Analyses or predictions of blood plasma levels in fish allow a direct comparison with human therapeutic plasma levels, and may therefore be used to indicate a risk for pharmacological effects in fish. To relate internal exposure to a pharmacological interaction we therefore investigated global hepatic gene expression together with bioconcentration to blood plasma and liver of rainbow trout (Oncorhynchus mykiss) exposed to waterborne diclofenac. Results: At the highest exposure (81.5µg/L) the fish plasma concentration reached ~88% of the human therapeutic levels (Cmax) after two weeks. Using an oligonucleotide microarray followed by quantitative PCR we found extensive effects on hepatic gene expression at this concentration, and some genes were regulated down to the lowest concentration tested (1.6 µg/L) corresponding to ~1.5% of the human Cmax. Functional analysis of differentially expressed genes revealed effects on biological processes such as inflammation and immune response, in agreement with the expected mode of action of diclofenac. In contrast to some previously reported results, the bioconcentration factor was found to be stable (4.02±0.75 for blood plasma and 2.54±0.36 for liver) regardless of the water concentration. Conclusions: Hepatic gene expression is affected in fish at blood levels similar to and below the human Cmax. This adds confidence to the use of fish blood plasma levels to predict risks for pharmacological responses in fish. The microarray results indicate similarities in the mode of action of diclofenac between humans and fish. The identified set of regulated genes may contain useful exposure biomarkers to be used in complex exposure scenarios.

Project description:PurposeThis study aimed to identify and quantify the association and investigate whether serum vitamin B12 alone or vitamin B12 combined with folate and plasma total homocysteine (tHcy) levels could be used to predict the risk of acute ischemic stroke.Materials and methodsThis retrospective case-control study was conducted in the Department of Neurology, First Affiliated Hospital of Chongqing Medical University. It included 259 inpatients experiencing their first-ever acute ischemic stroke and 259 age-matched, sex-matched healthy controls. Patients were categorized into groups based on the etiology of their stroke: large-artery atherosclerosis (LAAS, n = 126), cardio embolism (CEI, n = 35), small vessel disease (SVD, n = 89), stroke of other determined etiology (ODE, n = 5), and stroke of undetermined etiology (UDE, n = 4). The associations of serum vitamin B12, folate, and plasma tHcy levels with the risk of ischemic stroke were evaluated using multivariable logistic regression analysis. Receiver operator characteristic (ROC) curves were used to assess the diagnostic power of vitamin B12, folate, and tHcy levels for ischemic stroke.ResultsSerum vitamin B12 and folate levels were significantly lower in ischemic stroke patients compared to controls, while plasma tHcy levels were significantly higher. The first quartile of serum vitamin B12 levels was significantly associated with an increased risk of LAAS (aOR = 2.289, 95% CI = 1.098-4.770), SVD (aOR = 4.471, 95% CI = 1.110-4.945) and overall ischemic stroke (aOR = 3.216, 95% CI = 1.733-5.966). Similarly, the first quartile of serum folate levels was associated with an increased risk of LAAS (aOR = 3.480, 95% CI = 1.954-6.449), CEI (aOR = 2.809, 95% CI = 1.073-4.991), SVD (aOR = 5.376, 95% CI = 1.708-6.924), and overall ischemic stroke (aOR = 3.381, 95% CI = 1.535-7.449). The fourth quartile of tHcy levels was also significantly associated with an increased risk of LAAS (aOR = 2.946, 95% CI = 1.008-5.148), CEI (aOR = 2.212, 95% CI = 1.247-5.946), SVD (aOR = 2.957, 95% CI = 1.324-6.054), and overall ischemic stroke (aOR = 2.233, 95% CI = 1.586-4.592). For predicting different types of ischemic stroke, vitamin B12 alone demonstrated the best diagnostic value for SVD, evidenced by a sensitivity of 71.0% and negative predictive value of 90.3%, along with the highest positive likelihood ratio (+ LR) for SVD. Vitamin B12 + tHcy + folate are valuable in predicting different types of ischemic stroke, with the most significant effect observed in SVD, followed by LAAS, and the weakest predictive effect in CEI. Additionally, vitamin B12 alone in combination with other indicators, such as folate alone, tHcy alone, and folate + tHcy could reduce negative likelihood ratio (-LR) and improve + LR.ConclusionsVitamin B12 was an independent risk factor for acute ischemic stroke. The risk calculation model constructed with vitamin B12 + tHcy + folate had the greatest diagnostic value for SVD.

Project description:Background: Diclofenac is a non-steroidal anti-inflammatory drug frequently found in the aquatic environment. Previous studies have reported histological changes in the liver, kidney and gills of fish at concentrations similar to those measured in treated sewage effluents (~1 µg/L). Analyses or predictions of blood plasma levels in fish allow a direct comparison with human therapeutic plasma levels, and may therefore be used to indicate a risk for pharmacological effects in fish. To relate internal exposure to a pharmacological interaction we therefore investigated global hepatic gene expression together with bioconcentration to blood plasma and liver of rainbow trout (Oncorhynchus mykiss) exposed to waterborne diclofenac. Results: At the highest exposure (81.5µg/L) the fish plasma concentration reached ~88% of the human therapeutic levels (Cmax) after two weeks. Using an oligonucleotide microarray followed by quantitative PCR we found extensive effects on hepatic gene expression at this concentration, and some genes were regulated down to the lowest concentration tested (1.6 µg/L) corresponding to ~1.5% of the human Cmax. Functional analysis of differentially expressed genes revealed effects on biological processes such as inflammation and immune response, in agreement with the expected mode of action of diclofenac. In contrast to some previously reported results, the bioconcentration factor was found to be stable (4.02±0.75 for blood plasma and 2.54±0.36 for liver) regardless of the water concentration. Conclusions: Hepatic gene expression is affected in fish at blood levels similar to and below the human Cmax. This adds confidence to the use of fish blood plasma levels to predict risks for pharmacological responses in fish. The microarray results indicate similarities in the mode of action of diclofenac between humans and fish. The identified set of regulated genes may contain useful exposure biomarkers to be used in complex exposure scenarios. Juvenile rainbow trout was exposed to waterborne diclofenac at a series of different concentrations for 14 days. A flow-through system was used for eight aquaria (two per concentration), each containing 12 trouts. Nominal exposure concentrations: 1µg/L, 10 µg/L, 100 µg/L and control. Total RNA for biotinylated aRNA synthesis was extracted from the liver. Samples of aRNA from two fish from the same aquarium were pooled before the assay. In total, four biochips were analyzed corresponding to 32 microarrays. As we used two aquaria per concentration, these 32 microarrays allowed the analyses of four aRNA pools (eight fish) per aquarium, which is equal to eight pools per concentration of diclofenac.

Dataset Information

Possible Combined Effects of Plasma Folate Levels, Global DNA Methylation, and Blood Cadmium Concentrations on Renal Cell Carcinoma.

Publications

Possible Combined Effects of Plasma Folate Levels, Global DNA Methylation, and Blood Cadmium Concentrations on Renal Cell Carcinoma.

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