Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile,Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC₅₀^(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.     

A Review on Current Strategies for Extraction and Purification of Hyaluronic Acid

Since it is known that hyaluronic acid contributes to soft tissue growth, elasticity, and scar reduction, different strategies of producing HA have been explored in order to satisfy the current demand of HA in pharmaceutical products and formulations. The current interest deals with production via bacterial and yeast fermentation and extraction from animal sources; however, the main challenge is the right extraction technique and strategy since the original sources (e.g., fermentation broth) represent a complex system containing a number of components and solutes, which complicates the achievement of high extraction rates and purity. This review sheds light on the main pathways for the production of HA, advantages, and disadvantages, along with the current efforts in extracting and purifying this high-added-value molecule from different sources. Particular emphasis has been placed on specific case studies attempting production and successful recovery. For such works, full details are given together with their relevant outcomes.     

Autotaxin Has a Negative Role in Systemic Inflammation

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.     

羧酸和乙酸酐合成甲基酮的研究

酮是化学化工行业应用广泛的重要中间体,其常见的合成方法这些年来不断有新的报道。文章研究了以常见的羧酸和乙酸酐为起始原料合成甲基酮的方法。该方法实施简单,产物收率62%～89%,为酮提供了一种未见文献报道的合成新方法。     

木薯发酵制备酒精后剩余残渣的综合利用

木薯发酵制备乙醇会产生大量以淀粉和纤维素为主要成分的残渣。经实验证明,在浓硫酸(60%)、浓硝酸和催化剂共同作用下,经水解-氧化-水解可成功地将木薯渣制备成草酸。实验确定了用木薯渣制备草酸的较优条件,测定了产品的熔点,分析了剩余残渣、废水,结果表明剩余残渣和废水不会对环境造成污染,既为草酸的生产提供了新思路,又为农产品的残渣综合利用找到途径,发展前景广阔。     

CALMODULIN1 and WRKY53 Function in Plant Defense by Negatively Regulating the Jasmonic Acid Biosynthesis Pathway in Arabidopsis

Jasmonic acid (JA) is an important hormone that functions in plant defense. cam1 and wrky53 mutants were more resistant to Spodoptera littoralis than in the wild-type (WT) Arabidopsis group. In addition, JA concentration in cam1 and wrky53 mutants was higher compared with the WT group. To explore how these two proteins affect the resistance of Arabidopsis plants, we used a yeast two-hybrid assay, firefly luciferase complementation imaging assay and in vitro pull-down assay confirming that calmodulin 1 (CAM1) interacted with WRKY53. However, these two proteins separate when calcium concentration increases in Arabidopsis leaf cells. Then, electrophoretic mobility shift assay and luciferase activation assay were used to verify that WRKY53 could bind to lipoxygenases 3 (LOX3) and lipoxygenases 4 (LOX4) gene promoters and negatively regulate gene expression. This study reveals that CAM1 and WRKY53 negatively regulate plant resistance to herbivory by regulating the JA biosynthesis pathway via the dissociation of CAM1-WRKY53, then the released WRKY53 binds to the LOXs promoters to negatively regulate LOXs gene expression. This study reveals WRKY53′s mechanism in insect resistance, a new light on the function of WRKY53.     

湿法磷酸生产中管道结垢物二氧化硅含量的测定

介绍采用氟硅酸钾容量法测定湿法磷酸生产中管道结垢物二氧化硅含量的方法及注意事项。该法较常用的高氯酸脱水重量法操作简单、快速,具有较好的准确度。     

进口硫磺对我国磷复肥工业发展战略的影响

根据近几年我国进口硫磺量的迅速增长,2005年进口量达830万t,占全球硫磺产量的1/5,导致国际硫磺价格猛涨,1997年硫磺到岸价在35~45美元/t,2005年已达94.4美元/t以上,分析国际硫磺价格猛涨对我国磷复肥发展的巨大影响,而我国2006~2007年还将增加硫磺制酸能力540万t。为此,提出几点应对策略,新建硫酸装置应采取一炉两用的原料路线,并提出必须大力挖掘国内硫资源。     

Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate,Fenofibric Acid,and Pemafibrate

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays—a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ–bezafibrate, PPARγ–fenofibric acid, and PPARδ/γ–pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.     

影响一级油质量的因素及控制方法

介绍了在实际生产过程中影响一级油质量的因素,并提出了相应的控制方法。