微粒体环氧化物水解酶基因多态性与膀胱移行细胞癌发生的关系

目的 探讨微粒体环氧化物水解酶(mEH)基因型与膀胱移行细胞癌(BTCC)的相关性.方法 应用聚合酶链反应—限制性片段长度多态性分析方法检测BTCC患者(BTCC组,216例)和健康人群(对照组,300例)mEH基因型频率的分布.设计流行病学调查问卷进行面访调查.结果 BTCC组野生型、杂合型和变异型mEH第3外显子(mEH-exon3)分别占60.6％、27.3％和12.0％,对照组分别占46.3％、39.0％和14.7％ (P＜0.05);杂合型mEH-exon3为BTCC发生的保护性因素(OR=0.56,95％ CI=0.41-0.82).BTCC组野生型、杂合型和变异型mEH第4外显子(mEH-exon4)分别占85.6％、13.4％和0.9％,对照组分别占82.3％、15.0％和2.7％(P＞0.05).吸烟的mEH-exon3野生型人群的BTCC风险高于不吸烟者(P＜0.05).结论 mEH-exon3非野生型可能是BTCC发生、发展中的保护性因素之一;吸烟为BTCC发生的重要危险因素.而mEH-exon4基因多态性和BTCC的发生无明显相关性.     

Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren‐2 transgenic hypertensive rats with aorto‐caval fistula

The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren‐2 transgenic rats (TGR), a model of angiotensin II (ANG II)‐dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto‐caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin‐angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy]benzoic acid (c‐AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin‐converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.     

Hazard identification of cis/trans-zearalenone through the looking-glass

Among the food-related health issues, the presence of contaminants has a prominent role, due to the wide range of exogenous compounds that can occur in food commodities and to their large differences in structure and biological activity. A comprehensive assessment of the related risk is thus actually demanding in terms of time and facilities involved. In this context, the use of computational strategies can be an effective choice for supporting the hazard identification procedure at the early stage. In this work, we focused on the food contaminant zearalenone by comparing the trans and cis isomers, respectively the well-known mycoestrogen and its still largely understudied isomer. We estimated the possible effects exerted by human metabolism on the xenoestrogenicity of cis-ZEN by using a validated in silico strategy based on docking simulations and rescoring procedures. Similarly, the exploitation of the most promising enzymatic detoxifying routes designed for trans-ZEN – which relies on the enzyme lactono hydrolase from Clonostachys rosea – has been assessed for the cis-isomer as well. Our results showed that both isomers can act as functional analogues with respect to xenoestrogenic activity, and several cis-ZEN metabolites with high biological potential have been identified. On the contrary, in spite of the high degree of structural analogy, the cis isomer showed a pattern of interaction with the degrading enzyme in stark contrast with that observed for trans-ZEN. For these reasons, the outcomes presented herein strongly support the inclusion of cis-ZEN in further studies of occurrence, metabolism and bioactivity assessment, and suggest the need for a dedicated handling for the cis isomer in risk assessment studies.     

Temporal changes in N‐acylethanolamine content and metabolism throughout the peri‐adolescent period

Fatty acid amide hydrolase (FAAH) regulates tissue concentrations of N‐acylethanolamines (NAEs), including the endocannabinoid, N‐arachidonylethanolamide (anandamide, AEA). FAAH activity and NAEs are widely distributed throughout the brain and FAAH activity regulates an array of processes including emotion, cognition, inflammation, and feeding. However, there is relatively little research describing how this system develops throughout adolescence, particularly within limbic circuits regulating stress and reward processing. Thus, this study characterized temporal changes in NAE content (AEA, oleoylethanolamine [OEA], and palmitoylethanolamide [PEA]) and FAAH activity across the peri‐adolescent period, in four corticolimbic structures (amygdala, hippocampus, prefrontal cortex, and hypothalamus). Brain tissue of male Sprague–Dawley rats was collected on postnatal days (PND) 25, 35, 45, and 70, representing pre‐adolescence, early‐ to mid‐adolescence, late adolescence, and adulthood, respectively. Tissue was analyzed for AEA, OEA, and PEA content as well as FAAH activity at each time point. AEA, OEA, and PEA exhibited a similar temporal pattern in all four brain regions. NAE concentrations were lowest at PND 25 and highest at PND 35. NAE concentrations decreased between PNDs 35 and 45 and increased between PNDs 45 and 70. FAAH activity mirrored the pattern of NAE content in which it decreased between PNDs 25 and 35, increased between PNDs 35 and 45, and decreased between PNDs 45 and 70. These age‐dependent patterns of NAE content and FAAH activity demonstrate temporal specificity to the development of this system and could contribute to alterations in stress sensitivity, emotionality, and executive function which also fluctuate during this developmental period. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Role of asymmetrical dimethylarginine in the progression of renal disease

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.     

Evaluation of safety and tolerance of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation: A randomized,placebo-controlled,double-blind study

Probiotic organisms have shown promise in treating diseases. Previously, we have reported on the efficacy of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation at lowering serum cholesterol levels in otherwise healthy hypercholesterolemic adults. This study investigates the safety and toxicology of oral ingestion of microencapsulated L. reuteri NCIMB 30242 in a yogurt formulation. A randomized group of 120 subjects received a dose of 5 × 10¹⁰ CFU microencapsulated L. reuteri NCIMB 30242 in yogurt (n = 59) or placebo yogurt (n = 61) twice/day for 6 weeks. Clinical chemistry and hematological parameters of safety were analyzed. Fecal samples were collected at these time points for the analysis of deconjugated bile acids. The frequency, duration and intensity of adverse events (AEs) and clinical significance of safety parameters were recorded for both groups. No clinically significant differences between the probiotic yogurt and placebo yogurt treated groups were detected in either the blood clinical chemistry or hematology results and there was no significant increase in fecal deconjugated bile acids (P > 0.05) between treated and control groups. The frequency and intensity of AEs was similar in the two groups. These results demonstrate the safe use of this formulation in food.     

Discovery of soluble epoxide hydrolase inhibitors from natural products

With the goal of developing soluble epoxide hydrolase (sEH) inhibitors with novel chemical structures, the sEH inhibitory activities of 30 natural compounds were evaluated using both a fluorescent substrate, 3-phenyl-cyano(6-methoxy-2-naphthalenyl)methyl ester- 2-oxiraneacetic acid, and a physiological substrate, 14,15-epoxyeicosatrienoic acid. To evaluate the selectivity of sEH inhibition, the inhibition of microsomal epoxide hydrolase (mEH), which plays a critical role in detoxification of toxic epoxides, was determined using human liver microsomes. Honokiol and β-amyrin acetate, isolated from Magnolia officinalis and Acer mandshuricum, respectively, displayed strong inhibition of sEH activity, with respective IC₅₀ values of 0.57 μM and 3.4 μM determined using the fluorescent substrate, and 1.7 μM and 6.1 μM determined using 14,15-epoxyeicosatrienoic acid. mEH activity was decreased to 49% or 61% of control activity by 25 μM honokiol or β-amyrin acetate, respectively. These results suggest that β-amyrin acetate and honokiol exhibit sEH inhibitory activity, although their sEH selectivity should be improved.     

sEHi对颈动脉狭窄患者晚期内皮祖细胞功能的影响

目的研究不同浓度可溶性环氧化物水解酶抑制剂(soluble epoxide hydrolase inhibitor,s EHi)AUDA对颈动脉狭窄(carotid stenosis,CS)患者外周血来源的晚期内皮祖细胞(late endothelial progenitor cell,late EPC)的影响。方法入选研究对象60例,分成颈动脉狭窄组(n=35)和对照组(n=25)。密度梯度离心法,从外周血获取单个核细胞培养至21 d后鉴定内皮祖细胞;以不同浓度AUDA(0,0.1,1,10μmol/L)和晚期EPC共培养24 h,分别采用MTT法,黏附能力测定实验和Transwell小室来观察其增殖,黏附,迁移能力。同时采用Western blot法观察AUDA处理后其VEGF的表达。结果体外培养21 d时,细胞呈典型长梭形,21 d时,呈铺路石样,并可摄取FITCUEA-I和Dil-ac LDL。与对照组相比,CS患者late EPC的增殖,黏附和迁移能力均显著下降(P0.05);与处理前(0umol/L)相比,AUDA呈剂量依赖性地增强CS患者late EPC增殖,黏附和迁移能力并促进CS患者late EPC表达VEGF。结论 s EHi具有促进late EPC增殖,黏附和迁移等功能的作用,其有望成为一类治疗CS的新型药物。