可溶性环氧化物水解酶抑制剂对内皮祖细胞迁移功能的影响

目的 研究不同浓度可溶性环氧化物水解酶抑制剂t-AUCB对内皮祖细胞（EPCs）迁移功能的影响。方法 密度梯度离心法分离培养小鼠骨髓来源EPCs,不同浓度t-AUCB预干预EPCs,检测干预后EPCs体外迁移情况。结果 从0~100μmol/L,随着浓度增加,t-AUCB可呈浓度依赖性增强EPCs体外迁移能力。结论 可溶性环氧化物水解酶抑制剂t-AUCB参与正向调控EPCs迁移功能。     

Different mechanisms of acute versus long‐term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1‐Ren‐2 transgenic rats

Recent studies have shown that the long‐term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin‐II (AngII)‐dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII‐dependent hypertension. AngII‐dependent malignant hypertension was induced by 10 days’ dietary administration of indole‐3‐carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1‐Ren‐2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP‐lowering effects of sEH inhibition in I3C‐induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid in I3C‐induced rats elicited dose‐dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP‐lowering effect of sEH inhibition in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin–angiotensin system activity. Long‐term antihypertensive action of cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.     

Computational insights into the known inhibitors of human soluble epoxide hydrolase

Human soluble epoxide hydrolase (hsEH) is involved in the hydrolysis of epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory properties. Given that EET conversion generates nonbioactive molecules, inhibition of this enzyme would be beneficial. Past decades of work on hsEH inhibitors resulted in numerous potential compounds, of which a hundred hsEH–ligand complexes were crystallized and deposited in the Protein Data Bank (PDB). We analyzed all deposited hsEH–ligand complexes to gain insight into the binding of inhibitors and to provide feedback on the future drug design processes. We also reviewed computationally driven strategies that were used to propose novel hsEH inhibitors.     

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.     

Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats

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Antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system

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sEH抑制剂对大鼠肝缺血/再灌注损伤的影响及其机制

<正>肝脏缺血/再灌注(ischemia reperfusion,I/R)损伤是缺血/再灌注后肝脏功能障碍和结构损伤加重的现象,炎症反应是I/R损伤发生发展的重要机制之一[1-2]。可溶性表氧化物水解酶(soluble epoxide hydrolase,sEH)在肝脏等多种组织中大量表达,水解灭活抗炎物质,促进炎症的发生发展[3]。目前sEH抑制剂已被证明具有明显的抗炎作用,但其对肝脏I/R损伤的保护作用尚未见报道。本研究则观察了肝脏     

洛泰对异丙肾上腺素诱导大鼠急性心肌缺血的保护作用

目的观察三七总皂甙的新剂型———洛泰 (血塞通粉针剂 ,主要成分为三七总皂甙 )对大鼠急性心肌缺血的保护作用。方法采用微量异丙肾上腺素 (ISO)恒速静注造成大鼠急性心肌缺血的模型 ,动态观测Ⅱ导联心电图S_T段的变化 ,以ST段降低及∑ST为指标反映缺血程度。结果静脉注射洛泰50,100mg·kg-1,对ISO诱导大鼠急性心肌缺血有一定程度的保护作用,呈剂量依赖性 ,其中以100mg·kg-1组对心电图的改善作用较明显。灌胃给予洛泰对ISO诱导大鼠实验性急性心肌缺血也有一定程度的减轻作用 ,但没有统计学差异。结论采用改进的大鼠急性心肌缺血模型具有稳定性和重复性好、快捷有效、易掌握、耗费药品少等优点 ,适宜于初筛药物。同时实验结果提示静脉和灌胃两种途径给予洛泰对大鼠急性心肌缺血均具有一定程度的保护作用。     

无创性肢体缺血预适应对大鼠心脏的保护作用

目的研究无创性肢体缺血预适应(RIP)对大鼠缺血/再灌后心脏损伤的影响。方法采用无创性后肢缺血预适应的方法,观察其对心肌缺血/再灌后心脏生理学(HR、MAP、ST段)、室性心律失常的出现时间和持续时间的影响以及其对心肌缺血/再灌后梗死面积和形态学改变的影响。结果与对照组比较,处理组对心肌缺血/再灌后HR和MAP的影响差异无显著性,但是RIP能明显降低ST段的抬高幅度,推迟室性心律失常出现的时间,缩短持续时间,并且能减少心肌梗死面积,降低心肌细胞的肿胀、减少间质出血和炎性细胞的浸润。结论RIP对心肌损伤具有保护作用。     

Sevoflurane postconditioning affects post‐ischaemic myocardial mitochondrial ATP‐sensitive potassium channel function and apoptosis in ageing rats

This study investigated the effect of sevoflurane postconditioning on post‐ischaemic cardiac function, infarct size, myocardial mitochondrial ATP‐sensitive potassium channel (mitoKATP) function and apoptosis in ageing rats to determine the possible mechanism underlying the cardioprotective property of sevoflurane. Ageing rat hearts were isolated and attached to a Langendorff apparatus. The hearts were then exposed or not to sevoflurane postconditioning in the presence or absence of 100 μmol/L 5‐hydroxydecanoate (5‐HD), a selective mitoKATP inhibitor. The infarct size was measured by triphenyltetrazolium chloride (TTC) staining. Mitochondrial morphology was observed by electron microscopy and scored using FlaMeng semiquantitative analysis. In addition, the expression levels of Bax, Bcl‐2, and cytochrome‐C (Cyt‐C) were determined by Western blot analysis at the end of reperfusion. Sevoflurane postconditioning increased coronary flow, improved functional recovery, reduced Bax/Bcl‐2 and Cyt‐C phosphorylation levels, and decreased mitochondrial lesion severity and the extent of apoptosis. The protective effects of sevoflurane postconditioning were prevented by the mitoKATP inhibitor 5‐HD. Sevoflurane postconditioning significantly protected the function of ageing hearts that were subjected to ischaemia and reperfusion, and these protective effects were mediated by mitoKATP opening.     

Comparison of cardioprotective efficacy resulting from a combination of atorvastatin and ischaemic post‐conditioning in diabetic and non‐diabetic rats

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Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride‐induced acute injury in mice

Objectives Toxicity caused by pharmacological and chemical substances, including carbon tetrachloride (CCl₄), is a major pathological factor for liver injury. Therefore, strategies to prevent toxicity are needed for maintaining a healthy liver. This study was designed to determine whether recombinant bovine pancreatic trypsin inhibitor (rBPTI), a non‐specific serine protease inhibitor, prevents CCl₄‐induced liver injury in mice. Methods Mice were treated with CCl₄ in the presence or absence of co‐treatment with rBPTI. Liver sections were prepared for histopathological assessment. Liver function was evaluated by detecting serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and liver index. Liver oxidative stress and inflammation were examined by detecting the liver malondialdehyde level and glutathione and superoxide dismutase activity, and serum tumour necrosis factor‐α level, respectively. Key findings CCl₄ induced hepatocyte necrosis, inflammatory cell infiltration and fatty degeneration, which were ameliorated by co‐treatment with rBPTI in a concentration‐dependent manner. Furthermore, rBPTI prevented CCl₄‐induced disruption of liver function. Importantly, rBPTI reduced CCl₄‐induced liver oxidative stress response and pro‐inflammatory cytokine production. Conclusions These results indicated that rBPTI exerted a protective effect on CCl₄‐induced liver injury in mice. Thus, rBPTI may have potential application for prevention of liver injury induced by metabolism of drugs and toxic substances.     

In vivo administration of hydroxylated phenobarbital metabolites: effect on rat hepatic cytochromes P-450, epoxide hydrolase and UDP-glucuronosyltransferase

p-Hydroxyphenobarbital and m-hydroxyphenobarbital injected intraperitoneally to rats at the dose of 80 mg/kg induced a small increase of cytochrome P-450 in crude liver homogenate (expressed as nmoles/g liver) but a decrease of cytochrome P-450 concentration in isolated microsomes (expressed as nmoles/mg microsomal protein). A similar decrease of NADPH-cyt c reductase and epoxide hydrolase specific activities was observed. Pretreatment of animals with phenobarbital metabolites did not alter the native UDP-glucuronosyltransferase, but depressed the specific activity of digitonin-treated UDP-glucuronosyltransferase towards p-nitrophenol. Gel electrophoresis of microsomes showed that p-hydroxyphenobarbital and m-hydroxyphenobarbital did not induce a net biosynthesis of proteins with molecular weight near 50,000. Qualitative examination of monooxygenase activities indicated that the administration of hydroxylated phenobarbital did not modify the catalytic characteristics of microsomes, as compared with those of control microsomes. When phenobarbital and its p-hydroxyderivative were simultaneously injected to rats, specific enzyme activities of microsomes were increased as compared with controls but remained lower than with phenobarbital alone. The qualitative characteristics of the monooxygenase system were similar to those of microsomes from phenobarbital-induced rats. It may be concluded that phenobarbital produces both a proliferation of endoplasmic reticulum and an induction of drug-metabolizing activities, whereas its hydroxylated metabolites only retain the prolifer-ative activity: thus, these two effects of phenobarbital might depend on two different molecular mechanisms.     

p38丝裂原激活蛋白激酶抑制剂对脓毒症鼠心肌损伤的保护作用

目的探讨脓毒症时心肌损害的原因及p38丝裂原激活蛋白激酶（MAPK）抑制剂的保护作用。方法健康清洁级雄性SD大鼠66只,采用随机数字表法分为空白组6只,对照组30只,治疗组30只。空白组仅行麻醉,对照组和治疗组采用盲肠结扎并穿刺术制作脓毒症模型,在不同时间点观察大鼠心肌酶（CK—MB）、血清肿瘤坏死因子-α（TNF—α）、白细胞介素-1β（IL-1β）的浓度及其mRNA在心肌的表达。结果术后血清TNF-α、IL-1β进行性升高,CK—MB也显著升高。正常心肌组织微量表达IL-1β mRNA,不表达TNF-α mRNA,脓毒症时两者大量表达。血清TNF-α、IL-1β浓度及其mRNA在心肌中的表达与心肌损害程度呈显著正相关（相关系数分别为0．918、0．795、0．905、0．768）。应用p38MAPK抑制剂SB203580后,血清TNF-α、IL-1浓度显著降低,其mRNA在心肌中的表达减少,同时血CK-MB减低。结论TNF-α、IL-1的大量释放及其在心肌中的表达是脓毒症心肌损害的原因之一,通过调控p38MAPK信号通路可对脓毒症鼠心肌损害起保护作用。     

Mechanism of sphingosine‐1‐phosphate induced cardioprotection against I/R injury in diabetic rat heart: Possible involvement of glycogen synthase kinase 3β and mitochondrial permeability transition pore

There is growing evidence that diabetes mellitus causes attenuation of the bioactive metabolite of membrane sphingolipids, sphingosine‐1‐phosphate, and this may be a key mechanism in the decreased cardioprotective effect of ischaemic preconditioning (IPC) in the diabetic heart. Thus, this study has been designed to investigate the role and pharmacological potential of sphingosine‐1‐phosphate in diabetic rat heart. Diabetes was produced in Wistar rats by administration of a low dose of streptozotocin (STZ) (35 mg/kg, i.p., once) and feeding a high fat diet (HFD) for 6 weeks. Isolated rat heart was subjected to 30 min ischaemia followed by 120 min of reperfusion (I/R). The heart was subjected to pre‐ischaemic treatment (before ischaemia for 20 min) and pharmacological preconditioning with the S1P agonist FTY720 (0.6 μmol/L) with and without atractyloside (an mPTP opener; in the last episode of reperfusion before I/R). Myocardial infarction was assessed in terms of increase in lactate dehydrogenase (LDH), creatinine kinase‐MB (CK‐MB), myeloperoxidase (MPO) level and infarct size (triphenyltetrazolium chloride staining). Immunohistochemistry analysis was done for assessment of tumour necrosis factor (TNF)‐α and glycogen synthase kinase (GSK)‐3β level in cardiac tissue. Pre‐ischaemic treatment and pharmacological preconditioning with FTY720 significantly decreased I/R‐induced myocardial infarction, TNF‐alpha, GSK‐3β level and release of LDH and CK‐MB as compared to control group. The cardioprotective effect of S1P agonist was significantly attenuated by atractyloside. It may be concluded that S1P agonist FTY720 prevents the diabetic heart from ischaemic reperfusion injury, possibly through inhibition of GSK‐3β and regulation of opening of mitochondrial permeability transition pore.     

Activities of hepatic epoxide hydrolase and glutathione S-transferase in rats under the influence of tetramethyl thiuramdisulfide, tetramethyl thiurammonosulfide or dimethyl dithiocarbamate

The epoxide hydrolase (EH) activity in the liver of adult female Wistar rats significantly increased 18 h after the administration by gavage of tetramethyl thiuramdisulfide (TMTD, 1 mmol/kg) or tetramethyl thiurammonosulfide (TMTM, 2 mmol/kg). No increase was observed 5 h after administration of Na-dimethyl dithiocarbamate (Na-DMDTC, 4 mmol/kg). The glutathione S-transferase (GST) activity in the cytosol and microsomes of the liver was slightly enhanced after oral (gavage) administration of TMTD, TMTM or Na-DMDTC (doses up to 4 mmol/kg). In vitro, TMTD, TMTM, and Na-DMDTC significantly enhanced the hepatic activity of EH prepared from adult female Wistar rats. Cytosolic and microsomal GST activities from the liver were significantly raised in vitro by Na-DMDTC. The results have a bearing on the evaluation of the risk to health of these chemicals in the workplace.