羟嘌呤醇对衰竭心肌蛋白氧化和心肌收缩力的长期效果

目的研究黄嘌呤氧化酶（XO）抑制剂——羟嘌呤醇（Oxy）增强缺血后心力衰竭心肌收缩力的长期效果,并初步探讨其作用机制。方技将120只SV120小鼠随机分为心肌梗死（MI）对照组、假手术组和Oxy治疗组。通过结扎冠状动脉左前降支（LAD）建立小鼠缺血后心力衰竭模型。Oxy治疗组口服1mmol／L Oxy。9～11个月后,对三组小鼠进行心脏超声检查;取右心室束状肌分析其心肌兴奋-收缩耦联的变化。应用激光光栅衍射测定肌节长度;应用离子渗透微注射法向样本心肌细胞内注入Fura-2荧光染料,测量心肌细胞质内游离Ca^2＋浓度（[Ca^2＋]．）;通过应用ryanodine和增加刺激频率的方法使心肌达到强直收缩,即心肌纤维与Ca^2＋的相互作用处于稳定状态,分析在稳定状态下心肌收缩力一细胞内钙关系;应用Western blotting测定肌丝蛋白的氧化情况。结果长期口服Oxy能明显改善心力衰竭小鼠的心脏收缩功能,减小室壁厚度;明显改善心肌细胞的兴奋-收缩耦联过程,有效地增强心肌收缩力,显著提高稳态时心肌细胞钙激活的最大收缩力（Fmax）。Western blotting检测显示,与MI对照组心肌肌丝蛋白相比,Oxy治疗组中的肌动蛋白氧化修饰受到明显抑制。结论长期服用Oxy能够有效改善衰竭心肌的工作状态,改善／促进兴奋-收缩耦联过程,增强心肌收缩力。这种长期作用的机制是抑制心肌肌丝中肌动蛋白的氧化修饰,从而增强肌丝对钙的敏感性,增加收缩力。Oxy由于对[Ca^2＋]．的增加较小,能够减轻细胞内Ca^2＋负担及其所带来的负作用,具有更好的临床应用前景。     

Electrospun Micro‐ and Nanostructured Polymer Particles

Electrospinning at relatively low polymer concentrations produces polymer particles rather than fibers. To study the relationship between solvent characteristics and particle morphologies, PMMA was electrospun from seven different solvents and PSVPh random copolymers were electrospun from solutions in MEK. High‐speed photography was used to visualize the particle‐formation process. Based on these studies, a qualitative relationship between the solvent properties and the electrospun particle morphologies is discussed. By tailoring the solution properties and electrospinning conditions, particles with different morphologies (porous polygonal particles, solid polygonal particles, hollow spheres, cups etc) can be produced.

     

Oxidative metabolism of mescaline in the central nervous system. IV. In vivo metabolism of mescaline and 2,3,4-trimethoxy-beta-phenylethylamine

Metabolic rates of mescaline (3,4,5-trimethoxy-β-phenylethylamine) and of its non-hallucinogenic isomer, 2,3,4-trimethoxy-β-phenylethylamine were studied in whole and in different areas of mouse brain in vivo. The effects of Pargyline and of Probenecid on the concentrations of the amines and their corresponding metabolites, together with the results obtained from intraventricular injections of mescaline suggested the formation of the trimethoxyphenylacetic acids in the brain.The metabolic differences between mescaline and 2,3,4-trimethoxy-β-phenylethylamine are discussed in terms of possible implications of metabolic parameters with psychotomimetic activity.     

Oxidative metabolism of mescaline in the central nervous system. 3. Side chain degradation of mescaline and formation of 3,4,5-trimethoxy-benzoic acid in vivo

After intraperitoneal injection of 8-[¹⁴C]mescaline. HCl into mice 0.05 per cent of the injected radioactivity was found within 1 hr in the respiratory gases. This observation prompted us to search for mescaline metabolites with a degraded side chain. 3,4,5-trimethoxy-benzoic acid was identified in brain and liver by derivative formation and mass spectrometry. N-acetyl-mescaline was also identified by mass spectrometry. Some new cationic mescaline metabolites were detected in brain but the available data did not allow us to establish conclusively the structure of these compounds     

De novo terminal deletion of chromosome 7 [46, XX, del(7)(q35)]

Objective : To report a new case of de novo 7q deletion distal to q35.
Methodology : Developmental, cytogenetic and audiological investigations were carried out in the assessment of this rare chromosomal condition.
Results : Moderate developmental delay, mild congenital microcephaly, growth retardation and conductive hearing impairment were found for this case of 46, XX, del(7)(q35).
Conclusions : The phenotype of 7q terminal deletion is highly variable.     

Absorption, distribution and metabolism of propyl anthranilate.

Analysis of the gut contents of rats killed at intervals after dosage with propyl anthranilate or anthranilic acid suggested that both acid and ester were absorbed rapidly; the chief site of absorption was the stomach. Not more than a trace of the ester was hydrolysed in the stomach but of the dosed ester detected in the small intestine (less than 7%) a considerable proportion, increasing with time after dosing was present as anthranilic acid. Measurement of the level of radioactivity in the blood after administration of 14C-labelled propan-1-ol, propyl anthranilate or anthranilic acid showed that the alcohol was absorbed more rapidly than either the ester or acid. Unchanged propyl anthranilate was readily detected in the blood of rats dosed with the ester and some unhydrolysed ester was excreted in the urine. The level of radioactivity of the organs of rats 2 h and 4 h after administration of the 14C-labelled compounds was measured. Velocity constants for the excretion of 14CO2 by rats dosed with 14C-labelled propyl anthranilate were significantly lower than those found for rats dosed with [14C]propan-1-ol indicating a limiting step in the metabolism of the propyl moiety of the ester which did not occur in the metabolism of propan-1-ol. The urinary metabolites of anthranilic acid excreted by rabbits and rats dosed with the acid were qualitatively the same as those excreted by these species after dosing with propyl anthanilate; some quantitative differences were however, observed.     

in vitro metabolism of 1-β-d-arabinofuranosylcytosine and 1-β-2'-fluoro-arabino-5-iodocytosine in normal and herpes simplex type 1 virus-infected cells

Phosphorylation of 1-β-D-2'-F-arabino-5-iodocytosine (FIAC), a newly synthesized pyrimidine nucleoside with potent antiherpesvirus activity, was compared with that of its parent compound, 1-β-D-arabinofuranosylcytosine (ara-C). While ara-C was phosphorylated extensively by homogenates of normal, rapidly proliferating mouse tissues, FIAC was a poor substrate for the nucleoside kinase occurring in such normal tissues. With cell homogenates of noninfected Vero cells, thymidine (TdR) was phosphorylated about fifty and twenty times more efficiently than FIAC and ara-C, while infection of Vero cells with Herpes Simplex Virus Type 1 (HSV-1) resulted in a 23-fold increase of TdR- and a 1270-fold increase of FIAC phosphorylation. In contrast, phosphorylation of ara-C was increased only by a factor of 2.6. While the reaction products obtained with homogenates of normal mouse tissues were 5'-mono-, di- and triphosphates of ara-C and FIAC, the reaction products with noninfected and infected Vero cell homogenates were predominantly monophosphates. In contrast, TdR was efficiently phosphorylated to its 5'-mono-, di- and triphosphates by such homogenates. In intact HSV-1-infected Vero cells, FIAC was rapidly taken up and phosphorylated to FIACMP and to an as yet unidentified metabolite. In contrast, TdR was taken up and phosphorylated to 5'-mono-, di- and triphosphates and ara-C was taken up moderately but metabolized poorly to its 5'-mono-, di- and triphosphates. Thus, in normal tissues, FIAC was a poorer substrate than ara-C for nucleoside kinases, but in intact HSV-1-infected Vero cells FIAC was efficiently phosphorylated and thus behaved like a TdR analog, except that it was phosphorylated only to the 5'-monophosphate and a hitherto unidentified metabolite. The greatly increased phosphorylation of FIAC by HSV-1-infected Vero cells probably accounts, at least in part, for its great selectivity of action.     

2-Methoxy-3,8,9-trihydroxy coumestan: a new synthetic inhibitor of Na+,K+-ATPase with an original mechanism of action

The aim of the present work was to analyse the interaction between Na⁺,K⁺-ATPase and one of our recent synthesized coumestans, namely the original molecule 2-methoxy-3,8,9-trihydroxy coumestan (PCALC36). Rat brain (mainly α2 and α3 Na⁺,K⁺-ATPase isoforms) and kidney (α1 isoform) fractions enriched with Na⁺,K⁺-ATPase were utilized to compare the inhibition promoted by PCALC36 with that of classical inhibitors like ouabain and vanadate. Analysis of inhibition curves revealed that unlike ouabain, which was about a thousand times more potent to inhibit brain isoforms than kidney isoform, PCALC36 had a similar affinity for brain ( μM) and kidney ( μM) isoforms. The inhibitory effect of PCALC36 was not antagonized by 1-10 mM K⁺, as observed with ouabain. Whereas vanadate was more potent in ionic conditions promoting the E2 conformation of the enzyme, the inhibitory effect of PCALC36 was equal in ionic conditions favouring either the E1 or E2 conformations. Equilibrium binding assays with []ouabain revealed that the addition of 2-10 μM PCALC36 did not change the K_d of ouabain but decreased its maximal binding (B_max) in a concentration-dependent manner (from 76.6 to 44.0 pmol/mg protein). This inhibitory effect of PCALC36 was not reverted after an extensive washing procedure indicating that it forms a very stable complex with Na⁺,K⁺-ATPase. We conclude that PCALC36, a new molecule with a non-steroidal skeleton, inhibits the Na⁺,K⁺-ATPase by a mechanism of action different from the cardiac glycosides and could thus serve as a structural paradigm to develop new inotropic drugs.