Cucurbitacins: A Role in Cucumber Beetle Steroid Nutrition?

The conditional role of cucurbitacins as phytosteroid supplements, cholesterol precursors, or ecdysteroid antagonists in the spotted cucumber beetle, Diabrotica undecimpunctata howardi, was investigated in two ways: by comparing larval survival and growth rate on cucurbitacin-rich and cucurbitacin-poor squash cultivars of Cucurbita pepo and by manipulating the presence of cholesterol, phytosteroids, and cucurbitacins in an artificial diet and examining the effects on adult survival and fecundity. Larvae that developed on cucurbitacin-rich roots grew significantly faster and survived as well as larvae on cucurbitacin-poor roots. There was no evidence, however, that adults could substitute cucurbitacins in vital phytosteroid roles. Beetles reared on a cucurbitacin-rich, phytosteroid-poor diet laid significantly fewer eggs and died significantly younger than beetles with a full complement of dietary phytosteroids and also laid fewer eggs than beetles with no access to phytosteroids in their adult diet. The data are consistent with the hypothesis that, when the side chain of dietary cucurbitacins can be successfully hydrogenated, these compounds play a nutritional role as substitutes or precursors for structural steroids. In contrast, when the carbon–carbon double bond cannot be hydrogenated, cucurbitacins may become antagonists at ecdysteroid receptors, negatively affecting beetle fitness.     

提高生防菌对水果采后病害防治能力的研究进展

水果采后病害的生物防治已成为一个研究热点,但微生物防治的效果往往不如化学杀菌剂的效果,这限制了微生物生防菌的应用。近年来,学者们提出了许多措施来提高生防菌对水果采后病害的防治能力,本文对这些措施进行了综述。     

内皮素受体拮抗剂CPU0213对异丙肾上腺素心肌病SERCA2a表达的改善作用

目的 研究异丙肾上腺素心肌病模型心肌细胞肌浆网钙ATP 酶(sarco-endoplasmic reticulumATPase 2a, SERCA2a) 表达的改变, 以及新型内皮素受体拮抗剂CPU0213的治疗作用。方法 雄性SD大鼠皮下给予异丙肾上腺素(2 mg·kg^-1·d^-1)10 d, 治疗组动物在第6 到第10 天皮下给予CPU0213 (30 mg·kg^-1·d^-1)。各组动物颈动脉插管记录心功能指标:左心室收缩压(LVSP), 左心室舒张末期压(LVEDP), 和左心室压力变化最大速率(±dp dtmax)。左心室心肌组织SERCA2a 的mRNA 及蛋白表达分别用逆转录聚合酶链反应(RT-PCR) 和蛋白免疫印迹法(Western blotting) 测定。结果 异丙肾上腺素引起左心室收缩和舒张功能明显下降, 同时SERCA2a 的mRNA 及蛋白表达均显著下调(P<0.05)。CPU0213 显著提高SERCA2a 表达(P<0.05), 明显改善心功能(P<0.05)。结论 CPU0213 可通过逆转肌浆网钙调控蛋白SERCA2a 的表达下调, 使异丙肾上腺素引起的心功能下降得以恢复。本实验证明SERCA2a是β 受体过度激活引发心衰过程中的重要靶点。内皮素受体介导了β 受体过度激活状态下SERCA2a的表达下调, 是内皮素受体拮抗剂治疗心衰的重要依据之一。     

Synthesis of four chiral pharmaceutical intermediates by biocatalysis

Chiral intermediates were prepared by biocatalytic processes for the chemical synthesis of four pharmaceutical drug candidates. These include: (i) the microbial reduction of 3,5-dioxo-6-(benzyloxy) hexanoic ethyl ester to (3S,5R)-dihydroxy-6-(benzyloxy) hexanoic acid ethyl ester, an intermediate for a new anticholesterol drug; (ii) synthesis of (2R,3S)-(-)-N-benzoyl-3-phenyl isoserine ethyl ester, a taxol side-chain synthon; (iii) the microbial oxygenation of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile to the corresponding (3S,4S) epoxide and (3S,4R)-trans diol, intermediates for synthesis of potassium channel opener; (iv) the biotransformation of (exo,exo)-7-oxabicyclo [2.2.1] heptane-2,3-dimethanol to the corresponding chiral lactol and lactone, intermediates for thromboxane A₂ antagonist.     

Novel NK1R-Targeted 68Ga-/177Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure–Activity Relationships

Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with ⁶⁸Ga and ¹⁷⁷Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The ¹⁷⁷Lu-radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the ¹⁷⁷Lu-labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R-targeting vectors.     

Metformin’s Mechanism of Action Is Stimulation of the Biosynthesis of the Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)

Metformin is the leading drug for treating type 2 diabetics, but the mechanism of action of metformin, despite some suggested mechanisms such as the activation of the AMP-kinase, is largely unknown. Among its many positive effects are the reduction of blood glucose levels, the inhibition of cyclic AMP synthesis, gluconeogenesis and an increase in sensitivity to insulin. Recent studies have described the natural antagonist of cyclic AMP, prostaglandylinositol cyclic phosphate. Synthesis of cyclic PIP is stimulated in all organs by hormones such as insulin and also by drugs such as metformin. Its primary action is to trigger the dephosphorylation of proteins/enzymes, phosphorylated on serine/threonine residues. Cyclic PIP triggers many of the regulations requested by insulin. The parallels between the beneficial effects of metformin and the regulations triggered by cyclic PIP suggest that the mechanism of action of this key drug may well be explained by its stimulation of the synthesis of cyclic PIP.     

支持向量机算法用于拮抗药化合物活性的模式识别

试用新近提出的，特别适合于小样本多变量训练集的支持向量机（support vector machine,简称SVM）算法于复杂药物分子设计。对一批26个处理化疗或放疗呕吐拮抗药的候选化合物筛选数据用留一法判别SVM的预报能力。结果表明：与人工神经网络，最近邻法（KNN），Fisher法相比，SVM算法可以提供误报率更低的数学模型。     

4-(2-呋喃基)-2-硫代-1,2,3,4-四氢嘧啶-5-羧酸酯类化合物的合成及其钙拮抗活性

以硫脲、2-呋喃甲醛和乙酰乙酸酯为原料,利用Biginelli反应合成了6个4-(2-呋喃基)-2-硫代-1,2,3,4-四氢嘧啶-5-羧酸酯类化合物,并利用熔点、质谱、红外光谱和核磁共振氢谱进行表征,其中4个是未见文献报道的新化合物。考察了其中4个目标化合物对家兔离体主动脉条血管收缩的抑制作用。药理实验结果表明,部分目标化合物具有一定的钙拮抗活性。     

Multifaceted Functions of TWSG1: From Embryogenesis to Cancer Development

Bone morphogenetic proteins (BMPs) play an important role in development. Twisted gastrulation BMP signaling modulator 1 (TWSG1) was initially identified as a regulator of the dorsoventral axis formation in Drosophila. The mechanism of BMP signaling modulation by TWSG1 is complex. TWSG1 inhibits BMP signaling by binding to BMP ligands including BMP4, whereas it enhances signaling by interacting with Chordin, a BMP antagonist. Therefore, TWSG1 can act as both a BMP agonist and antagonist. TWSG1 has various functions ranging from embryogenesis to cancer progression. TWSG1 knockout mice showed neural, craniofacial, and mammary defects. TWSG1 also regulated erythropoiesis and thymocyte development. Furthermore, the relationship between TWSG1 and cancer has been elucidated. Allelic loss of TWSG1 was detected in colorectal cancer. TWSG1 expression was upregulated in papillary thyroid carcinoma and glioblastoma but downregulated in gastric and endometrial cancers. TWSG1 suppressed BMP7-enhanced sphere formation and migration in endometrial cancer cells, indicating its tumor-suppressive role. Further studies are required to clarify the TWSG1 function and its association with BMP signaling in cancer development. Finally, TWSG1 is abundantly expressed in human and mouse ovaries and sustains follicular growth in rodent ovaries. Thus, TWSG1 has various functions ranging from fertility to cancer. Therefore, TWSG1 signaling modulation may be beneficial in treating specific diseases such as cancer.     

A Novel Aryl Hydrocarbon Receptor Antagonist HBU651 Ameliorates Peripheral and Hypothalamic Inflammation in High-Fat Diet-Induced Obese Mice

Obesity is a chronic peripheral inflammation condition that is strongly correlated with neurodegenerative diseases and associated with exposure to environmental chemicals. The aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear receptor activated by environmental chemical, such as dioxins, and also is a regulator of inflammation through interacting with nuclear factor (NF)-κB. In this study, we evaluated the anti-obesity and anti-inflammatory activity of HBU651, a novel AhR antagonist. In BV2 microglia cells, HBU651 successfully inhibited lipopolysaccharide (LPS)-mediated nuclear localization of NF-κB and production of NF-κB-dependent proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. It also restored LPS-induced mitochondrial dysfunction. While mice being fed a high-fat diet (HFD) induced peripheral and central inflammation and obesity, HBU651 alleviated HFD-induced obesity, insulin resistance, glucose intolerance, dyslipidemia, and liver enzyme activity, without hepatic and renal damage. HBU651 ameliorated the production of inflammatory cytokines and chemokines, proinflammatory Ly6c^high monocytes, and macrophage infiltration in the blood, liver, and adipose tissue. HBU651 also decreased microglial activation in the arcuate nucleus in the hypothalamus. These findings suggest that HBU651 may be a potential candidate for the treatment of obesity-related metabolic diseases.