Monoliths with chiral surface functionalization for enantioselective capillary electrochromatography

The state-of-the-art in CEC enantiomer separations with monolithic capillary columns is comprehensively reviewed. The various types of monolithic columns comprising in situ organic polymer monoliths, molecularly imprinted polymer (MIP) monoliths, silica monoliths and monoliths made from particles are discussed with a focus on materials’ synthesis, chemistry and properties as well as column aspects. Monolithic MIP-type porous layer open-tubular (PLOT) columns are treated herein as well. From this survey of the literature, the authors come to the conclusion that monolithic silica capillaries appear to become the preferred column type for CEC enantiomer separations of low-molecular drugs and other chiral pharmaceuticals or chemicals.     

Synthesis of four diastereomeric enkephalins incorporating cyclopropyl phenylalanine

Four diastereomeric D-Ala²,Leu⁵-enkephalins have been synthesized and their CD spectra and rat brain binding affinities determined. Only the peptides containing Z-cyclopropyl phenylalanine residues showed strong binding affinity. No correlation between CD spectra and bioactivity could be made.     

EFFECTIVE INVERSION OF LEFT HEART REMODELING BY PHENYLALANINE IN ESSENTIAL HYPERTENSION

R68umeObjectifConlrmerl,actiondePhenylalanineime)d'inverserleremodeiageducorurgauchechezleshyPertendus.MfthodesLeschangementsd,dchocardiOgraPhiesontcomParesopres3,6et9moisd,ObservationentrelegrouPetemoin(Placebo1g/j amiloridecombine1comPrime/j)etlegrouPePhe(Phe1g/j amiloridecombin61comPrime/j),lecritered,inclusiondesmaladesetanthyPertrOPhieduventriculegauche.l'dPaisseurdusoptuminterventriculaire(IVST)oupost-parietaleduventriculegauchePWT>12mm.NousavonsadOPtdlarandomi2ation,mdthodeau…     

Tetrahydrobiopterin and Parkinson''s disease

Two patients with Parkinson's disease were treated with 1 g tetrahydrobiopterin (BH4) for 5 days. Clinical improvement was not observed. In the cerebrospinal fluid (CSF) a 4-8 fold increase in the concentration of homovanillic acid (HVA), and a 3-fold increase in the concentration of 5-hydroxyindole acetic acid (5-HIAA) was measured. However, the concentration of HVA reached, was only approximately half as high, as that of patients treated with madopar (DOPA + benserazid). In urine, the excretion of HVA increased 13-37 fold, when the patients were treated with madopar, whereas no increase in the HVA excretion was measured after the BH4 administration. Additionally, 2 patients with Parkinson's disease were treated with 1 g BH4 in combination with 15 g tyrosine for 3 days, and 1 parkinsonian patient was treated with 15 g tyrosine daily for 7 weeks. No increase in the CSF concentrations of HVA or 5-HIAA was observed. The results suggest, the BH4 in the dosage used, is not effective in the treatment of Parkinson's disease.     

Preparations,solution conformations and molecular structures of N,N′-ethylene-bridged dipeptides and their derivatives

The solution conformations of novel dipeptides, methyl (2S, 3′S)-3-methyl-2-(2′-oxo-3′-isopropyl-1′-piperazinyl)-butanoate (EVV-OCH₃), methyl (2S, 3′S)-3-phenyl-2-(2′-oxo-3′-benzyl-1′-piperazinyl) propionate (EFF-OCH₃), and their derivatives (Boc-Gly-EW-OH, Boc-Gly-EVV-Gly-OH, and Boc-Gly-EFF-OH), were studied by ‘H NMR measurements and molecular mechanics calculations (1). The molecular structures of Boc-Gly-EVV-OH, Boc-Gly-EFF-OH, and the hydrochloride of EVV-OCH₃ were determined by X-ray analyses. The conformations of the piperazinone rings and the side chains of these oligopeptides were clarified.     

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Abstract: The initial goal of this study was to analyze, using photolabeling, the interactions between Substance P and its tachykinin NK‐1 receptor. Therefore, the photoreactive amino acid para‐benzoyl‐phenylalanine (pBzl)Phe was incorporated into the Substance P sequence from position 4 to 11 leading to Bapa⁰[(pBzl)Phe^x]SP analogs. Biotinyl sulfone‐5‐aminopentanoic acid (Bapa) was introduced in order to purify the covalent complex. These photoreactive SP analogs were first assayed for their affinity for the two binding sites associated with the NK‐1 receptor, as well as for their potency in activating the phospholipase C and adenylate cyclase pathways. All analogs photoreactive from position 4 to 11 have moderate to high affinity for the two NK‐1 receptor‐binding sites, except for the analog modified at position 7. This affinity could be correlated to their potency to activate the phospholipase C and adenylate cyclase pathways, except for the analog photoreactive at position 11. Bapa⁰[(pBzl)Phe¹¹]SP was found to be an agonist in the phospholipase C pathway and an antagonist in the adenylate cyclase pathway, other analogs modified at position 11 were therefore analyzed. Among these, Bapa⁰[Pro⁹, (pBzl)Hcy(O₂)¹¹]SP is a partial agonist, whereas Bapa⁰[Hcy(ethylaminodansyl)¹¹]SP is a full agonist in the phospholipase C pathway, the two analogs being antagonist in the adenylate cyclase pathway. These results show that analogs of SP can be simultaneously agonist at one binding site and antagonist at the other binding site associated with the NK‐1 receptor.     

Control of racemization in peptide chain elongation with an unprotected amino acid

The racemization of the penultimate residue of the tripeptide prepared from Boc-d -Phe-d -Phe and free glycine in an aqueous mixed solvent system was examined. An HPLC method was developed to quantitate the amount of product with inverted stereochemistry, starting material, and other biproducts of the reaction. Depending on coupling conditions, the amount of inversion varied from less than 0.5 to nearly 25%. Using near optimal conditions (20% aqueous dioxane, 0.05 m reactants, 5°) two peptides were successfully synthesized in good yield with an acceptable extent of racemization. After recrystallization these peptides contained 0.1-0.2% diastereomer and were recovered in 70-74% yield. Such a prodedure could be useful for the incorporation of radiolabeled amino acids at the carboxyterminus of a peptide where minimal handling of radiolabeled intermediates is desirable.     

我国2015年新生儿遗传代谢病筛查指标切值的调查

摘要：目的: 调查我国新生儿遗传代谢病筛查检验指标的切值情况,为新生儿遗传代谢病筛查工作提供建议。 方法：调取国家卫生计生委临床检验中心2015年全国新生儿遗传代谢病筛查指标苯丙氨酸（Phe）、促甲状腺激素（TSH）、葡萄糖-6-磷酸脱氢酶（G6PD）和17-羟孕酮（17-OHP）室间质量评价回报结果中切值相关信息,包括实验室编码、单位名称、所在地区、指标切值、切值来源、方法学原理、仪器、试剂和校准品。分析不同地区、方法学原理和切值来源对4个指标切值大小的影响。 结果：220家实验室中,切值来源中所占比例最高的3项依次为：试剂厂家说明书（48.2%~69.8%）、实验室自行确定（27.7%~35.2%）和新生儿疾病筛查技术规范（0.0%~20.0%）。参加研究的机构数量最多的3个省份分别为广东（25家）、山东（17家）和江苏（16家）。对切值情况调查显示：Phe切值分布在1.60~5.00 mg/dL;TSH切值分布在4.82~18.00 mIU/L;G6PD切值在2.00~10.00 U/gHb;17-OHP切值在23.20~60.00 nmol/L范围内。对于Phe指标,各来源组和方法组切值差异均有统计学意义（P均＜0.05）;对于TSH指标,各来源组间切值差异有统计学意义（P＜0.05）,但方法组间差异无统计学意义（P＞0.05）;对于G6PD和17-OHP指标,不同来源和方法组的切值差异均无统计学意义（P均＞0.05）。 结论：各个检验指标切值较为一致,有个别实验室切值差异较大,建议各实验室对现有不同方法的切值进行评审。     

Effects of high doses of glucocorticoids on free amino acids,ribosomes and protein turnover in human muscle

BACKGROUND: Treatment with glucocorticosteroids causes a negative nitrogen balance, but the kinetic mechanisms responsible for this catabolic effect are controversial. We investigated the effects of 60 mg day(-1) prednisolone on protein synthesis and degradation in human skeletal muscle. MATERIALS AND METHODS: Healthy adults (n = 9) were studied in the postabsorptive state, before and after 3 days of prednisolone treatment. The L-[ring 2,6(-3)H(5)]-phenylalanine tracer technique, concentration and size distribution of the ribosomes, mRNA content of the ubiquitin-proteasome pathway components in muscle, phenylalanine flux across the leg, and the free amino acid concentrations in skeletal muscle were used to study muscle protein metabolism. RESULTS: The concentrations of most amino acids in arterial blood increased after prednisolone. There were also increased effluxes of phenylalanine, asparagine, arginine, alanine, methionine and isoleucine from the leg. The rate of protein degradation, as measured by the appearance rate (Ra) of phenylalanine, increased by 67% (P = 0.023) which, together with a doubling of the net release of phenylalanine from the leg (P = 0.007), indicated accelerated protein degradation. The pathway was not identified but there was no significant increase in mRNAs' encoding components of the ubiquitin-proteasome pathway. There was a 6% reduction in polyribosomes (P = 0.007), suggesting a decrease in the capacity for protein synthesis, although there was no measured decrease in the rate of protein synthesis. CONCLUSIONS: These findings indicate that high doses of prednisolone lead to a sharp increase in net protein catabolism, which depends more on enhanced protein breakdown, and an uncertain effect on protein synthesis. The mechanisms stimulating proteolysis and the pathway stimulated to increase muscle protein degradation should be explored.     

苯丙氨酸二肽类化合物Y101对刀豆蛋白A致小鼠免疫性肝损伤的保护作用

目的:观察苯丙氨酸二肽类化合物Y101(简称Y101)对刀豆蛋白A(CnoA)致小鼠免疫性肝损伤的保护作用,并探讨其可能的作用机制。方法:将昆明种小鼠随机分为生理盐水组、CnoA模型组、Y101低、中、高(25,50,100 mg.kg-1)剂量组和联苯双酯组(LB,150 mg.kg-1)。除生理盐水组外,CnoA模型组和各给药组均于d 5和d 7给药1 h后尾静脉注射20 mg.kg-1 CnoA溶液使之中毒(按0.1 mL/10 g体重)。末次中毒后禁食不禁水,8 h后眼球取血,并迅速取肝脏备检。检测其血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)含量。取肝脏,称重,检测肝脏中丙二醛(MDA)、一氧化氮(NO)、超氧化物歧化酶(SOD)、谷胱甘肽(GSH)的含量;另取肝脏做病理组织学检查。结果:与正常组比较,模型组小鼠血清中ALT、AST活性,肝内MDA、NO含量及肝脾指数显著升高(P<0.01),肝内SOD、GSH水平及胸腺指数明显降低(P<0.01)。低、中、高剂量Y101对肝损伤大鼠上述指标均有不同程度的改变,且呈良好的剂量关系。给予Y101治疗后,中、高剂量组的肝组织病理变化均明显轻于模型组。结论:Y101对CnoA致小鼠免疫性肝损伤具有保护作用,其作用机制可能与其抗氧化作用有关。