Influence of specific endothelin-1 receptor blockers on hemodynamic parameters and antioxidant status of plasma in LPS-induced endotoxemia

BackgroundThe potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of plasma oxidative stress seen in sepsis. The selective endothelin receptor blockers BQ123 andBQ788 were used to investigate the importance of selective endothelin receptor blockage in modulating oxidative stress during endotoxemia.MethodsThe study was performed on male Wistar rats (n = 6 per group) divided into groups: (1) saline, (2) lipopolysaccharide (LPS) (15 mg\kg)-saline, (3) BQ123 (0.5 mg\kg)-LPS, (4) BQ123 (1 mg\kg)-LPS, (5) BQ788 (3 mg\kg)-LPS. The endothelin receptor type A (ETA-R) or type B (ETB-R) antagonist was injected intravenously 30 min before LPS administration. Blood pressure was monitored and blood was taken before, 90 min and 300 min after saline or LPS administration.ResultsInjection of LPS alone resulted in a decrease in mean arterial pressure (MAP) (p < 0.05), a decrease in ferric reducing ability of plasma (FRAP) value (p < 0.01) and a marked increase in plasma tumor necrosis factor α (TNF-α) and thiobarbituric acid reactive substances (TBARS) (p < 0.001, p < 0.001, respectively). Administration of BQ123 before LPS administration deteriorated MAP in a dose dependent way. Moreover, BQ123 (1 mg\kg) decreased plasma level of TBARS and TNF-α (p < 0.01 and p < 0.05, respectively) and increased FRAP value (p < 0.001). On the contrary, BQ788 prevented LPS-induced decrease in MAP (p < 0.001) and led to a significant reduction in plasma TBARS concentration (p < 0.01).ConclusionOur study showed that blockage of ETB-R during endotoxemia improved blood hemodynamics and decreased plasma lipid peroxidation. Blockage of ETA-R improved plasma antioxidant status and decreased lipid peroxidation and TNF-a production, but it deteriorated hemodynamic conditions.     

Effects of lipoic acid on spleen oxidative stress after LPS administration

BackgroundBacterial endotoxin (lipopolysaccharide – LPS) is a strong modulator of the immune system that plays a crucial role in the pathogenesis of endotoxic shock. The aim of the study was to investigate the effects of lipoic acid (LA) on oxidative stress markers in spleen homogenates obtained from LPS-induced endotoxic shock rats.MethodsThe animals were treated with saline or lipoic acid (LA) (60 or 100 mg/kg b.w. iv) 30 min before or 30 min after LPS administration (30 mg/kg b.w. iv). Five hours after LPS, LA or saline administration, the animals were euthanized and their spleens were isolated for measurements.ResultsThe LPS-treated animals developed oxidative stress, indicated by a significant increase in thiobarbituric acid-reactive substances (TBARS) and hydrogen peroxide (H₂O₂) concentrations (p < 0.001) as well as an insignificant decrease in the level of sulfhydryl groups (-SH groups) and the glutathione redox ratio [reduced glutathione (GSH) to oxidized glutathione (GSSG) ratio] (p < 0.02) as compared with control group. Treatment with LA (60 or 100 mg/kg) before or after LPS administration resulted in an increase in -SH group content (p < 0.01) and a decrease in TBARS and H₂O₂ concentration in the spleen as compared with LPS group (p < 0.001). LA (60 or 100 mg/kg) before LPS administration decreased the level of GSSG (p < 0.05) and increased the level of GSH in spleen homogenates (p < 0.05), resulting in an increase in the GSH/GSSG ratio compared with the LPS group (p < 0.01). It also improved the LPS-induced increase in the spleen weight (SW) to body weight (BW) ratio (p < 0.001 vs. control).ConclusionThe present results have shown that LAis endowed with antioxidant properties that are protective in the spleen against the deleterious actions of Gram-negative bacterial endotoxin.     

Influence of NADPH oxidase inhibition on oxidative stress parameters in rat hearts

BackgroundThe aim of this study was to assess whether apocynin, an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase blocker, influences lipid peroxidation TBARS, hydrogen peroxide (H₂O₂) content, protein level, heart edema, tumor necrosis factor a (TNF-α) concentration or the glutathione redox system in heart homogenates obtained from endothelin 1 (ET-1)-induced oxidative stress rats.MethodsExperiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (3 μg/kg b.w., iv); Group III: apocynin (5 mg/kg b.w., iv) administered half an hour before saline; Group IV: apocynin (5 mg/kg b.w., iv) administered half an hour before ET-1 (3 μg/kg b.w., iv).ResultsInjection of ET-1 alone showed a significant (p < 0.001) increase in thiobarbituric acid reactive substances (TBARS) and the hydrogen peroxide level (p < 0.01) vs. control, as well as a decrease (p < 0.001) in the GSH level. Apocynin significantly decreased TBARS (p < 0.001) and H₂O₂ (p < 0.05) level (vs. control) as well as improved protein level (p < 0.001) in the heart. Apocynin also prevented ET-1-induced heart edema (p < 0.05). The presence of ET-1 increased the concentration of TNF-α (p < 0.05) while apocynin decreased it (p < 0.05). Our results indicate that ET-1 may induce oxidative stress in heart tissue by reducing the GSH/GSSG ratio, stimulating lipid peroxidation and increasing TNF-α concentration. Apocynin diminished these measures of oxidative stress and TNF-α.ConclusionET-1-induced formation of ROS in the heart is at least partially regulated via NADPH oxidase.     

Oxidative status in ICU patients with septic shock

The aim of this pilot study was to investigate variability of oxidative stress during sepsis evolution. ICU patients with the diagnosis of septic shock were included. Thiobarbituric-acid reactive substances, total antioxidant capacity, protein carbonyls in plasma, reduced, oxidized glutathione and catalase activity in erythrocyte lysate were assessed in the 1st, 3rd, 5th and 8th day after sepsis appearance. A total of 17 patients were divided in two groups: survivors (n = 7) and non-survivors (n = 10). APACHE II was 11.5 ± 5.4 and 19.9 ± 4.97 in survivors and non-survivors respectively (p = 0.005), while mean age and SOFA score at sepsis diagnosis, were similar between the two groups. GSH levels, catalase activity and protein carbonyls presented significant different course in time between survivors and non-survivors (p < 0.05). Catalase activity was significantly higher in survivors (238.8 ± 51.5) than non-survivors (166.4 ± 40.2; p = 0.005), while protein carbonyls levels were significantly lower in survivors (0.32 ± 0.09) than non-survivors (0.48 ± 0.16; p = 0.036) on the 1st day. Yet, non-survivors exhibited a declining course in GSH levels during time, while GSH levels were maintained in survivors. Conclusively, a longstanding antioxidant deficiency in non-surviving patients was noted. This phenomenon was clearly prominent in patients’ erythrocytes.     

Pre-treatment with melatonin decreases abamectin induced toxicity in a nocturnal insect Spodoptera litura (Lepidoptera: Noctuidae)

AimOxidative stress is an important component of the mechanism of pesticide toxicity. The aim of the present study was to investigate the time-dependent melatonin effects against abamectin-induced oxidative stress in a S.litura model. Larvae were divided into 5 different groups; (1) control group,(2) Melatonin group (4.3 × 10⁻⁵ M/100 ml diet), (3) Abamectin group 1.5 ml/L, (4) Pre-melatonin treated group (PM) (4.3 × 10⁻⁵ M/100 ml diet) before abamectin exposure 1.5 ml/L, (5) Post-melatonin treated group (TM) after abamectin exposure. Melatonin was supplemented via artificial diet in PM and TM animals during 24 h.Main methodsMidgut, fatbody, and hemolymph, were collected for the analysis of oxidative stress markers (Total ROS, GSH, nitrite, TBARS, LPO), antioxidant enzyme levels (SOD, GST, CAT, POX, APOX) in fifth instar larvae. Midgut damage was examined by using morphological analysis.Key findingsOur results observed that ABA group showed significant changes (p < 0.001) in the ROS and carbonyl content in midgut. The increase of antioxidant enzyme levels (SOD, CAT, POX, and APOX) in midgut was led by the continuous free radical scavenger cascade of melatonin. Significant (p < 0.01) increases in CAT and APOX levels were seen in the fatbody of PM and TM treated insects.SignificanceIn conclusion, the results of the study revealed that abamectin toxicity generates oxidative stress in the insect, while pre-melatonin treatment reduces this damage due to its antioxidant properties, especially POX levels in midgut, fatbody, and hemolymph. Therefore, indoleamine can play a vital role curtailing the abamectin toxicity in time dependent manner in S.litura.     

Arterial stiffness and sedentary lifestyle: Role of oxidative stress

Sedentary lifestyle is a risk factor for the development of cardiovascular disease, and leads to a quantifiable impairment in vascular function and arterial wall stiffening. We tested the hypothesis of oxidative stress as a determinant of arterial stiffness (AS) in physically inactive subjects, and challenged the reversibility of these processes after the completion of an eight-week, high-intensity exercise training (ET).AS was assessed before and after ET, measuring carotid to femoral pulse wave velocity (PWV) with a Vicorder device. At baseline and after ET, participants performed urine collection and underwent fasting blood sampling. Urinary 8-iso-PGF_2α, an in vivo marker of lipid peroxidation, total, HDL and LDL cholesterol, and triglyceride concentrations were measured.ET was associated with significantly reduced urinary 8-iso-PGF_2α(p < 0.0001) levels. PWV was significantly reduced after ET completion (p < 0.0001), and was directly related to urinary 8-iso-PGF_2α(Rho = 0.383, p = 0.021). After ET, cardiovascular fitness improved [peak oxygen consumption (p < 0.0001), peak heart rate (p < 0.0001)]. However, no improvement in lipid profile was observed, apart from a significant reduction of triglycerides (p = 0.022). PWV and triglycerides were significantly related (Rho = 0.466, p = 0.005) throughout the study period. PWV levels were also related to urinary 8-iso-PGF_2α in our previously sedentary subjects.We conclude that regular physical exercise may be a natural antioxidant strategy, lowering oxidant stress and thereby the AS degree.     

Anti-inflammatory effects of a special carbohydrate–whey protein cake after exhaustive cycling in humans

Intense exercise induces increased levels of pro-inflammatory and anti-inflammatory cytokines. Thus, the purpose of this study was to examine the effects of a special cake (consisting of carbohydrate to whey protein 3.5:1) vs. an isocaloric carbohydrate cake on inflammatory markers after exhaustive cycling in humans. Nine subjects received either the experimental or placebo cake in a counterbalanced fashion using a crossover, double-blind, repeated-measures design. They performed one trial involving a 2 h exercise on a cycle ergometer at 60–65% VO₂max followed by a 4 h recovery and then a second trial involving an 1 h exercise at 60–65% VO₂max which was increased at 95% VO₂max. Blood samples were collected pre-exercise, 30 min and 4 h post-exercise, post-time Trial and 48 h post-time Trial. Cakes were consumed immediately post-exercise and every 1 h for the next 3 h. The results showed that consumption of the experimental cake reduced significantly (p < 0.05), 4 h post-exercise, the pro-inflammatory protein levels IL-6 and CRP compared to the control group by 50% and 46% respectively. Moreover, in the experimental cake group, the level of the anti-inflammatory cytokine IL-10 was higher by 118%, 4 h post-exercise, compared to the control group but not statistically significant.     

Inhibition of sphingosine kinase-2 ablates androgen resistant prostate cancer proliferation and survival

BackgroundEndogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance.MethodsThe novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling.ResultsIt dose-dependently decreased PC-3 and LNCaP cell viability, IC₅₀ of 28 ± 6.1 μM (p < 0.05) and 25 ± 4.0 μM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC₅₀ of 14 ± 0.4 μM (p < 0.05) in PC-3 cells and 12 ± 0.9 μM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells.ConclusionsSphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.     

Chemical composition,antiproliferative and antioxidant properties of lipid classes in ordinary and dark muscles from chub mackerel (Scomber japonicus)

This study investigated to compare lipid profiles in ordinary and dark muscles from chub mackerel and to examine antiproliferative and antioxidative properties of lipid classes. The average levels of neutral lipids (NL), glycolipids (GL), and phospholipids (PL) in ordinary muscle were 92.32 ± 0.19%, 5.10 ± 0.48%, and 2.58 ± 0.46%; in dark muscle were 96.88 ± 0.15%, 2.59 ± 0.36%, and 0.54 ± 0.29%, respectively. The fatty acid composition indicated that PL had a higher percentage of PUFA (especially 22:6n?3) with lower percentages of SFA and MUFA compared to NL and GL (p < 0.05). The main ion peaks of GL in ordinary and dark muscles showed that monocharged and bischarged molecular ion were presented at m/z 876.9 and 438.8, respectively. In MTT assay, inhibition of AGS and HT-29 cell proliferation was greatest with the 0.5 and 1.0 mg mL^?1 GL treatments. The GL of ordinary muscle with 0.05 mg mL^?1 concentrations markedly decreased the levels of reactive oxygen species (ROS) induced by H₂O₂ compared to the control (p < 0.05). From our results, GL might have antiproliferative and antioxidant properties based on protective effect against the production of intracellular ROS.     

Enhanced oxidative stress in hypertrophic cardiomyopathy

Elevated plasma levels of inflammation and endothelial dysfunction markers have been reported in patients with hypertrophic cardiomyopathy (HCM). The aim of the current study was to determine whether HCM is associated with enhanced oxidative stress. We enrolled 54HCMpatients with sinus rhythm, including 21 subjects with a left ventricular outflow tract (LVOT) obstruction (gradient ≥ 30 mmHg), and 54 age- and sex-matched controls without cardiovascular diseases. Serum levels of 8-isoprostaglandin F_2α (8-iso-PGF_2α), a stable marker of oxidative stress, were determined.Serum 8-iso-PGF_2α levels were elevated in HCM patients compared with controls (35.4 ± 10.2 vs. 29.9 ± 9.9 pg/ml, p < 0.001). Patients with obstructiveHCMdisplayed higher 8-iso-PGF_2α levels compared with the non-obstructiveHCMsubgroup (41.6 ± 12.7 vs. 31.4 ± 5.4 pg/ml, p < 0.0001). Both anatomic (mitral-septal distance) and hemodynamic (subaortic gradient) indexes of LVOT obstruction, but not other echocardiographic variables, correlated with 8-iso-PGF_2α levels (r = –0.43; p < 0.05 and r = 0.39; p < 0.05, respectively).This study is the first to show that HCM is characterized by enhanced oxidative stress as evidenced by higher 8-iso-PGF_2α, which achieves its highest values in the presence of LVOT obstruction in HCM patients.     

Sulfur mustard causes oxidants/antioxidants imbalance through the overexpression of free radical producing-related genes in human mustard lungs

The aim of this study is to analyze oxidative stress (OS) and changes in expression of reactive oxygen species (ROS) producing-related genes in mustard lungs. Human lung biopsies provided from controls (n = 5) and sulfur mustard (SM)-exposed patients (n = 6). Changes in expression of dual oxidases (DUOXs), aldehyde oxidase 1 (AOX1), thyroid peroxidase (TPO), myeloperoxidase (MPO) and eosinophil Peroxidase (EPO) were measured using RT² Profiler™ PCR Array. OS was evaluated by determining bronchoalveolar lavage fluids (BALF) levels of total antioxidant capacity (TAC) and malondialdehyde (MDA). Higher TAC value was observed in BALF of controls compared with patients (0.138 ± 0.02683 μmol/l vs 0.0942 ± 0.01793 μmol/l), whereas a significant increase in MDA concentration was found in patients (0.486 ± 0.04615 nmol/l vs 0.6467 ± 0.05922 nmol/l). All ROS producing-related genes were overexpressed in the order AOX1> MPO> DUOX2> DUOX1> TPO> EPO. Upregulation of these genes may be a reason for overproduction of ROS, oxidants/antioxidants imbalance, OS and respiratory failures in mustard lungs.     

Acute effects of cigarette smoking on pulmonary function

IntroductionChronic smoking related changes in pulmonary function are reflected as accelerated decrease in FEV1 although histologic changes occur in the peripheral bronchi earlier. More sensitive pulmonary function parameters might mirror those early changes and might show a dose response.MethodsIn a randomized three-period cross-over design 57 male adult conventional cigarette (CC)-smokers (age: 45.1 ± 7.1 years) smoked either CC (tar:11 mg, nicotine:0.8 mg, carbon monoxide:11 mg [Federal Trade Commission (FTC)]), or used as a potential reduced-exposure product the electrically heated smoking system (EHCSS) (tar:5 mg, nicotine:0.3 mg, carbon monoxide:0.45 mg (FTC)) or did not smoke (NS). After each 3-day exposure period, hematology and exposure parameters were determined preceding body plethysmography.ResultsCigarette smoke exposure was significantly (p < 0.0001) higher in CC than in EHCSS and in NS: (carboxyhemoglobin: CC: 6.4 ± 1.9%; EHCSS: 1.3 ± 0.6%; NS: 0.5 ± 0.3%; serum nicotine: CC: 18.9 ± 7.4 ng/ml; EHCSS: 8.4 ± 4.3 ng/ml; NS: 1.2 ± 1.6 ng/ml). Significantly lower in CC than in EHCSS and NS were specific airway conductance (0.22 ± 0.09; 0.25 ± 0.12; 0.25 ± 0.1 1/cmH₂O × s; CC vs EHCSS: p < 0.05; CC vs NS: p < 0.01), forced expiratory flow 25% (7.6 ± 1.7; 7.8 ± 1.7; 7.9 ± 1.7 L/s; CC vs EHCSS or NS: p < 0.01). Thoracic gas volume (5.1 ± 1; 5 ± 1.1; 5 ± 1.1 L/min) changed insignificantly.ConclusionThe data indicate acute and reversible effects of cigarette smoke exposures and no-smoking on mid to small size pulmonary airways in a dose dependent manner.     

Maternal exposure to environmental tobacco smoke,GSTM1/T1 polymorphisms and oxidative stress

Environmental tobacco smoking (ETS) is known to be associated with adverse pregnancy outcomes. The purpose of this study was to investigate the relationship between maternal exposure to ETS and oxidative stress for neonates, as well as the effect of maternal genetic polymorphisms, glutathione-S-transferase M1 (GSTM1) and GSTT1, on this relationship.We used the radioimmunoassay to measure the urinary concentration of cotinine in 266 pregnant women who denied smoking cigarettes during pregnancy and in their singleton babies. In addition, the urinary concentration of malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OH-dG) were assessed using high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. We also extracted DNA from whole blood obtained from the mothers and then conducted polymerase chain reaction on the samples to determine the GSTM1 and GSTT1 genotypes.The maternal cotinine concentration was found to be significantly associated with the fetal cotinine concentration, particularly for mothers whose urine cotinine concentrations were above 120 μg/g cr (p < 0.01). The fetal urine cotinine concentration was also found to be significantly associated with the fetal urine MDA concentration (p < 0.01). When the null type maternal GSTM1 or the wild type GSTT1 was present, the maternal oxidative stress level increased significantly as the maternal continine concentration increased (MDA: p < 0.01; 8-OH-dG: p < 0.01). No significant relationships were found between maternal cotinine and fetal oxidative stress markers, however, the fetal MDA levels increased significantly as fetal cotinine levels increased.These results suggest that the maternal exposure to ETS affects the fetal urine cotinine concentration and induces production of maternal oxidative stress. In addition, maternal genetic polymorphisms of GSTM1 and GSTT1 may modify the oxidative stress by maternal exposure to ETS.     

Differential coronary resistance microvessel remodeling between type 1 and type 2 diabetic mice: Impact of exercise training

The goals of the present study were to compare coronary resistance microvessel (CRM) remodeling between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mice, and to determine the impact of aerobic exercise training on CRM remodeling in diabetes. Eight week old male mice were divided into T1DM: control sedentary (Control-SD), T1DM sedentary (T1DM-SD) induced by streptozotocin, and T1DM exercise trained (T1DM-TR); T2DM: control sedentary (Db/db-SD), T2DM sedentary (db/db-SD), and T2DM trained (db/db-TR). Aerobic exercise training (TR) was performed on a mouse treadmill for 8 weeks. CRMs were isolated and mounted on a pressure myograph to measure and record vascular remodeling and mechanics. CRM diameters, wall thickness, stress–strain, incremental modulus remained unchanged in T1DM-SD mice compared to control, and exercise training showed no effect. In contrast, CRMs isolated from db/db-SD mice exhibited decreased luminal diameter with thicker microvascular walls, which significantly increased the wall:lumen ratio (Db/db-SD: 5.8 ± 0.3 vs. db/db-SD: 8.9 ± 0.7, p < 0.001). Compared to db/db-SD mice, coronary arterioles isolated from db/db-TR mice had similar internal diameter and wall thickness, while wall:lumen ratio (6.8 ± 0.2, p < 0.05) and growth index (db/db-SD: 16.2 vs. db/db-TR: 4.3, % over Db/db) were reduced. These data show that CRMs undergo adverse inward hypertrophic remodeling only in T2DM, but not T1DM, and that aerobic exercise training can partially mitigate this process.     

Resveratrol self-emulsifying system increases the uptake by endothelial cells and improves protection against oxidative stress-mediated death

The aim of the present study was to develop and characterize a resveratrol self-emulsifying drug delivery system (Res-SEDDS), and to compare the uptake of resveratrol by bovine aortic endothelial cells (BAECs), and the protection of these cells against hydrogen peroxide-mediated cell death, versus a control resveratrol ethanolic solution.Three Res-SEDDSs were prepared and evaluated. The in vitro self-emulsification properties of these formulations, the droplet size and the zeta potential of the nanoemulsions formed on adding them to water under mild agitation conditions were studied, together with their toxicity on BAECs. An optimal atoxic formulation (20% Miglyol® 812, 70% Montanox® 80, 10% ethanol 96% v/v) was selected and further studied.Pre-incubation of BAECs for 180 min with 25 μM resveratrol in the nanoemulsion obtained from the selected SEDDS significantly increased the membrane and intracellular concentrations of resveratrol (for example, 0.076 ± 0.015 vs. ethanolic solution 0.041 ± 0.016 nmol/mg of protein after 60 min incubation, p < 0.05). Resveratrol intracellular localization was confirmed by fluorescence confocal microscopy. Resveratrol nanoemulsion significantly improved the endothelial cell protection from H₂O₂-induced injury (750, 1000 and 1500 μM H₂O₂) in comparison with incubation with the control resveratrol ethanolic solution (for example, 55 ± 6% vs. 38 ± 5% viability after 1500 μM H₂O₂ challenge, p < 0.05).In conclusion, formulation of resveratrol as a SEDDS significantly improved its cellular uptake and potentiated its antioxidant properties on BAECs.     

Dietary predictors of young children’s exposure to current-use pesticides using urinary biomonitoring

Few data exist on the association between dietary habits and urinary biomarker concentrations of pesticides in children. The objective was to examined the association between the weekly intake frequency of 65 food items and urinary biomarkers of exposure to chlorpyrifos (3,5,6-trichloro-2-pyridinol [TCP]), permethrin (3-phenoxybenzoic acid [3-PBA]), and 2,4-dichlorophenoxyacetic acid [2,4-D] in 135 preschool-aged children. TCP and 3-PBA are nonspecific biomarkers as they are also urinary metabolites of other pesticides. TCP, 3-PBA, and 2,4-D were detected in 99%, 64%, and 92% of the urine samples, respectively. Mean urinary TCP concentrations were statistically significantly higher in children consuming fresh apples (9.40 ± 15.5 ng/mL versus 5.76 ± 3.57 ng/mL, p = 0.040) and fruit juices (8.41 ± 11.5 ng/mL versus 4.11 ± 2.77 ng/mL, p = 0.020) ⩾3 times a week compared to <3 times a week. For 3-PBA, mean urinary metabolite concentrations were statistically significantly greater in children consuming chicken/turkey meats (0.79 ± 0.81 versus 0.41 ± 0.39, p = 0.013) ⩾3 times a week compared to <3 times a week. No association occurred between the consumption of any food item and children’s mean urinary 2,4-D concentrations by intake group. In conclusion, frequent consumption of fresh apples and fruit juices or chicken/turkey meats were significant dietary predictors of urinary levels of TCP or 3-PBA, respectively.     

Effects of rifampin on CYP2E1-dependent hepatotoxicity of isoniazid in rats

Isoniazid and rifampin are first line drugs used to prevent and treat tuberculosis. The effects of rifampin co-administration on isoniazid-induced oxidative stress were investigated by the determination of the changes in hepatic metabolizing enzymes and DNA damage. Rats were treated with isoniazid alone (100 mg/kg, i.p.) or co-treated with rifampin (100 mg/kg, i.g.) for 10 or 21 days. Activities of CYP2E1, CYP1A1, CYP3A and glutathione S-transferases (GSTs) were analyzed by specific substrates. DNA oxidative damage by drug treatments was analyzed in precision-cut liver slices by HPLC–MS/MS. Isoniazid significantly increased CYP2E1 activities above control levels after 10 or 21 days treatment (2.25–4.59-fold), indicated by both chlorzoxazone hydroxylase and aniline hydroxylase (p < 0.01). Isoniazid treatment decreased activities of cytosolic total GST, alpha GST and mu GST after 21 days (p < 0.01). No change in activities of CYP1A1, CYP3A, and CYP3A1 mRNA expression was observed after isoniazid treatment. Rifampin co-administration significantly attenuated isoniazid-induced CYP2E1 levels (p < 0.01) and inhibition of mu GST (p < 0.01). Rifampin did not increase the formation of DNA adducts induced by isoniazid. These results suggest that rifampin co-administration does not increase isoniazid-induced oxidative stress through hepatic CYP2E1 during short-term treatment in experimental rats.     

Citrus peel polymethoxylated flavones extract modulates liver and heart function parameters in diet induced hypercholesterolemic rats

The primary aim of this study was to investigate the effects of Ortanique peel polymethoxylated flavones extract (PMF^ort) on organ function parameters in the serum of hypercholesterolemic and normal rats. Thirty Sprague–Dawley rats were fed high cholesterol diets supplemented with 1.5% PMF^ort and niacin respectively for 49 days. Hypercholesterolemic rats fed PMF^ort had significant reductions in the activities of aspartate aminotransferase and alkaline phosphatase (69.12 ± 3.34 and 87.22 ± 8.42 U/L respectively) compared to the untreated hypercholesterolemic group (118.61 ± 4.85 and 132.62 ± 10.62 U/L respectively, p < 0.05). Supplementation of the diet with niacin or PMF^ort resulted in no significant differences in the serum levels of creatinine or urea in any of the groups. Total bilirubin was highest in the untreated hypercholesterolemic group. Supplementation of the diets of hypercholesterolemic rats with PMF^ort resulted in significant reductions in the activities of serum creatine kinase and lactate dehydrogenase (119.3 ± 25.3; 222.5 ± 50.3 U/L, p < 0.05) respectively relative to the untreated hypercholesterolemic group (257.2 ± 48.3; 648.8 ± 103 U/L, p < 0.05). The results would suggest that PMF^ort modulates hypercholesterolemia-associated organ injury in rats. PMF^ort could therefore be a suitable candidate for prophylactic and therapeutic treatment of hypercholesterolemia-associated organ injury.     

Association between chemotherapy and plasma adipokines in patients with colorectal cancer

BackgroundA link between chemotherapy, the serum level of selected adipokines and clinical outcome in colorectal patients was investigated.MethodsLeptin, adiponectin, resistin, visfatin and insulin were measured by ELISA in colorectal cancer patients before and 3 months after the administration of cancer therapy. From August 2012 to August 2013, 34 patients with pathologically documented advanced colorectal cancer (T3/T4 with metastases or nodal status up to N3) and measurable metastatic disease, who required palliative chemotherapy based on the combination of 5-fluorouracil, oxaliplatin and irinotecan, were prospectively recruited in this study. Patients previously underwent curative surgical tumour resection, but the disease was disseminated (metastases in the liver and/or lungs) at the time of admission to the hospital.ResultsOf the 34 patients in this study, 5 accomplished a chemotherapy course with partial response (PR), 23 with SD (stabilisation) and 6 with progression (PD). For further study, only patients with good prognostic outcomes (i.e., PR and SD patients) were included. The mean level of leptin before chemotherapy was 26.39 ± 19.53 ng/ml. After six courses of cancer treatment, the leptin level increased by 118–57.44 ± 27.72 ng/ml (p < 0.001). Additionally, the adiponectin level increased considerably (47%) from 9.89 ± 3.96 ng/ml to 14.51 ± 7.79 ng/ml (p < 0.001). In contrast to leptin and adiponectin, the resistin and visfatin levels decreased significantly from 7.24 ± 1.17 and 1.98 ± 0.44 to 6.36 ± 1.36 and 1.48 ± 0.34 ng/ml (p < 0.001), respectively. Insulin also declined remarkably from 16.20 ± 1.96 to 12.87 ± 1.80 (p < 0.001). There were no significant differences the between male and female patients regarding age, BMI, and leptin, adiponectin, resistin, visfatin and insulin serum levels.ConclusionsThe results of the present study are relevant because we found that chemotherapy in colorectal cancer patients, in addition to its beneficial clinical impact on the course of disease, positively affects cytokine production and release (increases the anti-inflammatory adiponectin and decreases visfatin and resistin, which are proangiogenic and promote cancer cell proliferation). The restoration of adequate adipose tissue function is essential for patients to achieve a good survival prognosis.     

Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)

Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293- Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, V_max, [159 ± 3 nmol*(mg protein)^- 1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)^? 1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values (K_m) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CL_R; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CL_sec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CL_R and CL_sec .©2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3451–3457, 2013