响应面法优化头孢菌素C发酵条件

目的 研究顶头孢霉发酵制备头孢菌素C的过程，确定关键影响因素，优化发酵条件，提高发酵水平。 方法 采用Plackett-Burman方法对影响头孢菌素C发酵水平的11个因素进行考察，评估各因素的影响程度，筛查影响发酵水平的关键因素，再采用响应面方法建立这些因素与发酵水平间的数学模型，为发酵条件的优化提供指导。 结果 Plackett-Burman实验发现，金枪鱼浸膏浓度和蛋氨酸浓度是对头孢菌素C发酵产量影响最显著的2个因素，经响应面方法优化后头孢菌素C的产量从32.59g/L提高到了35.99g/L，提高了10.4%。 结论 合适浓度的金枪鱼浸膏和蛋氨酸可提高头孢菌素C发酵产量，通过统计优化方法，可有效提高头孢菌素C发酵水平。     

顶头孢霉菌的内源性蛋氨酸对头孢菌素 C 产生的调节作用

顶头孢霉菌在蛋氨酸特别是 D~-异构体型蛋氨酸存在的情况下,较硫酸盐能更有效地促进头孢菌素 C 的合成。Caltrider 和 Niss 提出蛋氨酸的硫原子作为头孢菌素 C 硫原子的有效来源可能是通过逆硫转化途径而实现的。不管这是不是蛋氨酸的唯一作用,还是提出了许多理由。第一,蛋氨酸的非硫同系物,正白氨酸能代替蛋氨酸刺激头孢菌素 C 的产生。第二,在代谢上更接近于头孢菌素 C的假定中间体高半胱氨酸、胱硫醚、半胱氨酸,却难于提高抗生素产量。第三,当蛋氨酸加到生长物中时,即抗生素合成开     

头孢菌素类产品的市场情况及头孢菌素C发酵工艺

简要的分析了头孢菌素类抗生素目前的市场发展状况，结果表明头抱菌素的研究开发速度减缓，开发广谱、高效、长效的新头孢菌素已成为当务之急。分别从发酵培养基的组成、发酵操作条件以及发酵过程控制三个层面分析了发酵工艺对头孢菌素C产量的影响，为发酵生产头孢菌素C提供了理论和现实意义。     

作为头孢菌素C硫原子的S—磺基半胱氨酸

青霉素和头孢菌素分子结构中所含的硫原子都来源于半胱氨酸。已有报导,产黄青霉所产生青霉素,其中的硫是直接从硫酸盐经硫酸盐还原途径获得,而顶孢头孢霉(C.acremoniurn)产生的头孢菌素中的硫是优先从蛋氨酸经逆转硫化作用途经获得的。作者用头孢菌素 C 类、(包括头孢菌素 C、脱乙酰头孢菌素和其它对头孢菌素酶敏感的     

联机的HPLC法测定头孢菌素C及其发酵副产物

头孢菌素C(CPC)为β-内酰胺类抗生素,其生物合成类似于青霉素,用顶头孢霉的分批投料发酵工艺生产。为了准确和可靠地确定发酵终点、合理补料以便最佳控制发酵过程,必须有效地监测发酵过程中培养基成份、早期杂质及发酵产物与副产物比例。用全自动联机的HPLC测定头孢菌素或青霉素V方法已有报道,但均不能同时测定头孢菌素C发酵过程中主要组份CPC、脱乙酰头孢菌素C(DAC)、脱乙酰氧头孢菌素C     

含硫化合物对头孢菌素生物合成的调节作用

本文研究了国内生产用头孢菌素产生菌(Cephalosporium acremonium)C—82—123对DL-蛋氨酸等十种含硫化合物的利用。在不含任何含硫化合物的合成培养基中分别添加DL-蛋氨酸、硫酸钠、硫代硫酸钠、     

顶头孢霉菌M8650及其高产变株中乙酰羟酸的反馈调节

头孢菌素C(CPC)的结构可划分成四个残基:D-a-氨基已二酸、L-半胱氨酸、D-缬氨酸与乙酰氧基。对于CPC生产与三种组成氨基酸生物合成之间的关系已引起更多注意。有关a-氨基己二酸生物合成与CPC生产之间的关系已有数篇报道。半胱氨酸与其它硫化合物如:蛋氨酸、无机硫酸盐等对CPC生产的影响亦有报道。Warren等报道了缬氨酸及其前体对CPC生产的影响。然而,缬氨酸生物合成与CPC生产之间的关系全未述及。     

发酵液中头孢菌素C的效价测定

为了提高头孢菌素C的生产水平,从事菌种选育工作和发酵工艺研究,掌握稳定而专一的检定方法是必不可少的条件。在顶头孢霉菌的发酵过程中,除产生头孢菌素C外,还同时形成去乙酰头孢菌素C、去乙酰氧头孢菌素C、头孢菌素P和青霉素N等化合物。它们的结构如下:     

顶头孢霉的去代谢产物反馈调节选育模型的建立与应用

目的建立头孢菌素C产生菌———顶头孢霉的去代谢产物反馈调节的高效筛选模型,筛选解除代谢产物反馈调节的突变菌株,提高头孢菌素C的发酵单位。方法使用NTG、UV、60Co连续诱变,结合使用终产物头孢菌素C梯度平板耐受及琼脂柱预筛选的方法进行筛选。结果应用此模型筛选出的高产菌株NUC—118,经摇瓶发酵及30L发酵罐发酵,与出发菌株MNSA851相比,头孢菌素C的发酵单位提高了25%。结论解除代谢产物头孢菌素C反馈调节的筛选模型是一种高效的筛选高产头孢菌素C突变菌株的筛选模型。     

蛋氨酸干扰产黄顶孢霉对缬氨酸的摄取

产黄顶孢霉的头孢菌素C生物合成是一种多步代谢途径.通过该途径,由3种氨基酸经非核糖体缩合而成的线型分子δ-(L-α-氨基已二酰)-L-半胱氨酰-D-缬氨酸(ACV)被环化为异青霉素N,随后扩环成为脱乙酰氧基头孢菌素.在此种抗生素的生物合成中,第4种氨基酸——蛋氨酸起着重要调节作用.把蛋氨酸加入发酵液可刺激头孢菌素C的产生.然而,在头孢菌素C的生物合成中,还不清楚究竟是哪一步受到此种氨基酸的特殊     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.