世界生物药品工业的现状与展望（一）

2002年是生物药品工业加速发展的一年,有大量新产品在研发当中,投资更为理性。世界生物药品研发管线充满生机和希望,市场正在稳步发展和上升,但整个生物药品工业存在着机会和风险。     

Absorption of Dietary Cholesterol Oxidation Products and Their Downstream Metabolic Effects Are Reduced by Dietary Apple Polyphenols

Exogenous and endogenous cholesterol oxidation products (COPs) perturb various metabolic processes, and thereby they may induce various homeostasis-related disorders. Here, we observed that procyanidin-rich dietary apple polyphenol (APP) from unripe apples alleviates the perturbation of lipid metabolism by decreasing the exogenous COP levels in rats. Dietary COPs may be the greatest source of COPs found in the human body. Rats (4 weeks of age) were fed AIN-purified diets containing 0.3% COPs supplemented with 0.5 or 2.5% APP for 3 weeks. Dietary APP alleviated the growth inhibition action of the exogenous COPs. The modulations of the liver lipid profile by COPs remained unchanged. However, serum total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels increased following the intake of dietary APP. Further, dietary APP inhibited the increase in lipid peroxide levels in the liver and serum by COPs. The activity of hepatic Δ6 desaturase was lowered by dietary APP in a dose-dependent manner, although exogenous COPs generally increased the activity of this enzyme. In keeping with this observation, Δ6 desaturation indices in the phospholipids and cholesteryl esters of the liver and serum lipids were lower in the APP-fed groups than those in the control group. Dietary APP also promoted the excretion of exogenous COPs, cholesterol, and acidic steroids in feces. Therefore, the inhibition of intestinal absorption of COPs may partly contribute to the alleviation of the perturbation of lipid metabolism and lipid peroxidation levels. Thus, APP may be an important removal agent of exogenous toxic material such as COPs contained in processed or fast foods.     

Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P_eff) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10⁻⁴ mg·min⁻¹·cm⁻². The P_eff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.     

浅析管道系统阀门分类及选用

着重对阀门的分类进行了介绍，按工业管道系统的技术参数，归纳了阀门选用的一般方法及应注意的问题，以便工程技术人员对不同类型阀门的性质与选用有全面的认识。     

Matrix Metalloproteinases (MMPs) and Inhibitors of MMPs in the Avian Reproductive System: An Overview

Many matrix metalloproteinases (MMPs) are produced in the mammalian reproductive system and participate in the regulation of its functions. In birds, the limited information available thus far indicates that MMPs are significant regulators of avian ovarian and oviductal functions, too. Some MMPs and inhibitors of MMPs are present in the hen reproductive tissues and their abundances and/or activities change according to the physiological state. The intraovarian role of MMPs likely includes the remodeling of the extracellular matrix (ECM) during folliculogenesis, follicle atresia, and postovulatory regression. In the oviduct, MMPs are also involved in ECM turnover during oviduct development and regression. This study provides a review of the current knowledge on the presence, activity, and regulation of MMPs in the female reproductive system of birds.     

黑果枸杞多酚的糖析萃取及其抑制糖基化终产物

采用糖析萃取体系提取黑果枸杞中多酚类物质,通过单因素和正交实验考察了有机溶剂质量分数、糖质量分数和粗提物质量分数对多酚类物质糖析萃取效果的影响。得到优化的工艺条件为:叔丁醇质量分数36%、葡萄糖质量分数26%的糖析体系中,粗提物质量分数2%,补足水至100%,在此条件下,总酚、总黄酮和花色苷平均回收率分别为94.15%、94.08%、94.30%。将黑果枸杞多酚用于葡萄糖和甘氨酸体系,考察了加热反应时间、多酚浓度对糖基化终产物(AGEs)的抑制效果,结果表明,在80℃反应2 h,1.0 g/L黑果枸杞多酚对AGEs相对抑制率可达71.93%±1.32%。     

An Overview on the Synthetic Routes and Properties of Ammonium Dinitramide (ADN) and other Dinitramide Salts

In recent years, there has been a considerable interest in the development of novel type of high performance propellants for use in solid rocket motors. Ammonium salt of dinitramidic acid NH₄N(NO₂)₂ (ADN) has attracted wide interest as a potentially useful energetic oxidizer for rocket propellants because of its clean and environment‐friendly exhaust products during burning. ADN contains one N (NO₂)₂ group and its synthesis requires new type of N‐nitration. The present paper reviews the general synthetic methods used for the synthesis of inorganic, organic and metal dinitramide salts and their properties, with a special emphasis on ammonium dinitramide. The salient features with reference to the extent of conversion and ease of separation of the products of the various synthetic methodologies are also addressed.     

雨水排水体系构建和技术发展重点的综述

该文介绍了国际通行的雨水排水体系构架,阐述了“小排水系统”和“大排水系统”的定义,分析了两者在防汛除涝方面的关系。     

粉粒状物料性能与其气力输送特性(待续)

迄今气力输送仍然主要依靠在全尺度试验台上进行气力输送试验，以此来判定给定的散料是否可以密相输送和何种流动模式。然而，正是粉粒状物料的性能对它的气力输送特性有决定性影响，因此．研究散料处理最有前途的课题之一，就是要能事先通过对料性试验数据分析来预测该散料的气力输送特性，从而为选择(设计)装置(系统)作好准备。气力输送特性由粒子特性和散料特性两部分组成，全面阐述了较新的对这两类特性的细节，以及它们对散料的相属和流动模式的影响和分类。     

Effect of Dried Apple Pomace (DAP) as a Feed Additive on Antioxidant System in the Rumen Fluid

The study aimed to evaluate the effect of dried apple pomace (DAP) as a feed additive on the enzymatic activity and non-enzymatic compounds belonging to the antioxidant system in cattle rumen fluid. The experiment included 4 Polish Holstein–Friesian cannulated dairy cows and lasted 52 days. The control group was fed with the standard diet, while in the experimental group, 6% of the feedstuff was replaced by dried apple pomace. After the feeding period, ruminal fluid was collected. The spectrophotometric technique for the activity of lysosomal enzymes, the content of vitamin C, polyphenols, and the potential to scavenge the free DPPH radical was used. The enzyme immunoassay tests (ELISA) were used to establish the activity of antioxidants enzymes and MDA. Among the rumen aminopeptidases, a significant reduction (p < 0.01) from 164.00 to 142.00 was observed for leucyl-aminopeptidase. The activity of glycosidases was decreased for HEX (from 231.00 to 194.00) and β-Glu (from 1294.00 to 1136.00), while a significant statistically increase was noticed for BGRD (from 31.10 to 42.40), α-Glu (from 245.00 to 327.00), and MAN (from 29.70 to 36.70). Furthermore, the activity of catalase and GSH (p < 0.01) was inhibited. In turn, the level of vitamin C (from 22.90 to 24.10) and MDA (from 0.36 to 0.45) was statistically higher (p < 0.01). The most positive correlations were observed between AlaAP and LeuAP (r = 0.897) in the aminopeptidases group and between β-Gal and MAN (r = 0.880) in the glycosidases group. Furthermore, one of the most significant correlations were perceived between SOD and AlaAP (r = 0.505) and AcP (r = 0.450). The most negative correlation was noticed between α-Gal and DPPH (r = −0.533) based on these observations. Apple pomace as a feed additive has an influence on lysosomal degradation processes and modifies oxidation–reduction potential in the rumen fluid. Polyphenols and other low-weight antioxidant compounds are sufficient to maintain redox balance in the rumen.     

Dietary Linseed Oil Reduces Growth While Differentially Impacting LC-PUFA Synthesis and Accretion into Tissues in Eurasian Perch (Perca fluviatilis)

The aim of this study was to evaluate the impact of replacing dietary fish oil (FO) with linseed oil (LO) on growth, fatty acid composition and regulation of lipid metabolism in Eurasian perch (Perca fluviatilis) juveniles. Fish (17.5 g initial body weight) were fed isoproteic and isoenergetic diets containing 116 g/kg of lipid for 10 weeks. Fish fed the LO diet displayed lower growth rates and lower levels of DHA in the liver and muscle than fish fed the FO diet, while mortality was not affected by dietary treatment. However, DHA content recorded in the liver and muscle of fish fed the LO diet remained relatively high, despite a weight gain of 134 % and a reduced dietary level of long‐chain polyunsaturated fatty acids (LC‐PUFA), suggesting endogenous LC‐PUFA biosynthesis. This was supported by the higher amounts of pathway intermediates, including 18:4n‐3, 20:3n‐3, 20:4n‐3, 18:3n‐6 and 20:3n‐6, recorded in the liver of fish fed the LO diet in comparison with those fed the FO diet. However, fads2 and elovl5 gene expression and FADS2 enzyme activity were comparable between the two groups. Similarly, the expression of genes involved in eicosanoid synthesis was not modulated by dietary LO. Thus, the present study demonstrated that in fish fed LO for 10 weeks, growth was reduced but DHA levels in tissues were largely maintained compared to fish fed FO, suggesting a physiologically relevant rate of endogenous LC‐PUFA biosynthesis capacity.     

An Overview into Polyethylene Terephthalate (PET) Hydrolases and Efforts in Tailoring Enzymes for Improved Plastic Degradation

Plastic or microplastic pollution is a global threat affecting ecosystems, with the current generation reaching as much as 400 metric tons per/year. Soil ecosystems comprising agricultural lands act as microplastics sinks, though the impact could be unexpectedly more far-reaching. This is troubling as most plastic forms, such as polyethylene terephthalate (PET), formed from polymerized terephthalic acid (TPA) and ethylene glycol (EG) monomers, are non-biodegradable environmental pollutants. The current approach to use mechanical, thermal, and chemical-based treatments to reduce PET waste remains cost-prohibitive and could potentially produce toxic secondary pollutants. Thus, better remediation methods must be developed to deal with plastic pollutants in marine and terrestrial environments. Enzymatic treatments could be a plausible avenue to overcome plastic pollutants, given the near-ambient conditions under which enzymes function without the need for chemicals. The discovery of several PET hydrolases, along with further modification of the enzymes, has considerably aided efforts to improve their ability to degrade the ester bond of PET. Hence, this review emphasizes PET-degrading microbial hydrolases and their contribution to alleviating environmental microplastics. Information on the molecular and degradation mechanisms of PET is also highlighted in this review, which might be useful in the future rational engineering of PET-hydrolyzing enzymes.     

Enhanced Solubility and Oral Bioavailability of γ-Tocotrienol Using a Self-Emulsifying Drug Delivery System (SEDDS)

The aim of this study was to evaluate the in vitro and in vivo performance of γ‐tocotrienol (γ‐T3) incorporated in a self‐emulsifying drug delivery system (SEDDS) and to compare its enhanced performance to a commercially available product, namely Tocovid Suprabio? (hereafter Tocovid), containing tocotrienols. The solubilization of γ‐T3 was tested in a dynamic in vitro lipolysis model followed by in vitro cellular uptake study for the lipolysis products. In addition, in vitro uptake studies using Caco₂ cells were conducted at different concentrations of γ‐T3 prepared as SEDDS, Tocovid, or mixed micelles. γ‐T3 incorporated in SEDDS or Tocovid was orally administered to rats at different doses and absolute oral bioavailability from both formulations were determined. The dynamic in vitro lipolysis experiment showed about two fold increase in the solubilization of γ‐T3 prepared as SEDDS compared to Tocovid, which correlated with higher cellular uptake in the subsequent uptake studies. In vitro cellular uptake and in vivo oral bioavailability studies have shown a twofold increase in the cellular uptake and oral bioavailability of γ‐T3 incorporated in SEDDS compared to Tocovid as a result of improvement in its solubility and passive uptake as confirmed by in vitro studies. In conclusion, incorporation of γ‐T3 in SEDDS formulation enhanced γ‐T3 solubilization and passive permeability, thus its cellular uptake and oral bioavailability when compared to Tocovid.     

Date Palm Fruit (Phoenix dactylifera): Effects on Vascular Health and Future Research Directions

Cardiovascular disease is a leading cause of death globally, presenting an immense public and economic burden. Studies on cardioprotective foods and their bioactive components are needed to address both personal and public health needs. Date fruit is rich in polyphenols, particularly flavonoids, certain micronutrients, and dietary fiber, which can impact vascular health, and have the potential to attenuate vascular disease in humans. Data from in vitro and animal studies report that consumption of date fruit or extracts can modulate select markers of vascular health, particularly plasma lipid levels including triglycerides and cholesterol, indices of oxidative stress and inflammation, but human data is scant. More investigation is needed to better characterize date polyphenols and unique bioactive compounds or fractions, establish safe and effective levels of intake, and delineate underlying mechanisms of action. Implementing scientific rigor in clinical trials and assessment of functional markers of vascular disease, such as flow-mediated dilation and peripheral arterial tonometry, along with gut microbiome profiles would provide useful information with respect to human health. Emerging data supports the notion that intake of date fruit and extracts can be a useful component of a healthy lifestyle for those seeking beneficial effects on vascular health.     

Development of Classification Models for Identifying "True" P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as "true" P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function.     

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III–IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal–plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.     

随机出、入水双容水箱液位控制实验及被控对象的数学模型

首先介绍双容水箱液位控制实验仪的实物系统装置,随后,设计了随机出入水的双容水箱供排液系统液位控制实验,并用机理分析法建立被控对象的数学模型,最后分析上述系统的能控性和能观性.     

Synthesis and Characterization of Biocompatible Poly(ethylene glycol)-b-Poly(L-lactide) and Study on Their Electrospun Scaffolds

A series of multiblock copolymer, Poly(L-lactide)-b-Poly(ethylene glycol) (PLLA-b-PEG) were synthesized and characterized by Fourier transform infrared spectra, differential scanning calorimetry and wide angle X-ray diffraction. PLLA-b-PEG fibrous scaffolds were prepared by electrospinning. The morphology of the fibers was affected by the solution concentration and different weight ratio of PLLA/PEG. In comparison with the electrospun PLLA membrane, the electrospun fibrous membranes of PLLA-b-PEG demonstrated an enhanced water absorption percentage and reductive water contact angle. The electrospun PLLA-b-PEG with weight ratio 90/10 and 75/25 fibrous membranes exhibited good flexibility and deformability to be beneficial for tissue engineering scaffolds.     

非线性观测器及其应用(上)一类高阶非线性系统的观测器

针对子系统的不可测状态之间呈下三角阵式关联的一类主阶非线性系统,本文给出了其观测器型式和反馈增益阵的设计方法,同时进一步讲座了存在不可测输入时系统的观测,这种观测器设计简单,便于实施和调变量进行的处理,对于化工生产过程中经常遇到的这类高阶非线性系统,这种观测器设计简单,便于实施和调整。     

Study on the Performance of Diglycidyl Ether of Bisphenol-A/Hyperbranched Aromatic Polyester Epoxy Resin (HTME) System and Their Toughness Mechanism

This paper reports on the use of liquid hyperbranched aromatic polyester epoxy resin (HTME) as an additive to an epoxy resin/amine system. Four kinds of different molecular weight and epoxy equivalent weight HTME as modifiers in the diglycidyl ether of bisphenol-A (DGEBA) amine systems are discussed in detail. It was shown that the content and molecular weight of HTME have important effect on the performance of the cured system, and the performance of the HTME/DGEBA blends has maximum with the increase of content and molecular weight or generation of HTME. The impact strength and fracture toughness of the cured system with 9 wt.% second or three generation of HTME are almost 2.77 and 1.71 times, respectively, DGEBA performance; furthermore, the tensile and flexural strength can be enhanced about 17% and 20%, respectively. The glass transition temperature and Vicat temperature, however, are found to decrease to some extent. The scanning electron microscopy (SEM), dynamic mechanical analysis (DMA), and molecular simulation technology are used to study the situ reinforcing and toughening mechanism. The three-dimensional size and structure shape of HTME-2 are displayed by molecular simulation technology.