BACKGROUNDAyurdvedic derived medicines are most promising and effective in the treatment of several cardiovascular diseases. Cocculus hirsutus (CH) has been reported for broad spectrum of activities like anticancer, antidiabetic, antioxidant, cardiotonic and hypotensive etc. OBJECTIVES: The present study aimed to find the cardio-protective effect of CH in experimental hypertension in rats.MATERIALS AND METHODSFor acute renal hypertension, CH animals were pre-treated with CH-1 (250 mg/kg) and CH-2 (500 mg/kg) p. o. for 14 days. On the 15th day, hypertension was induced by renal occlusion and the mean arterial blood pressure (MABP) was recorded. For CAL pretreatment of CH-1 and CH-2 was given for 7 days on the 8th day animals were operated on for ligation. The MABP and the time of onset of ventricular tachycardia (VT), premature ventricular systole (PVS) were recorded. For induction of hypercholesterolemia, animals were fed with a high cholesterol diet (CD) with CH-1 and CH-2 for 21 days. The antioxidant potential of CH was done using the assay of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx).RESULTSCH treatment significantly decreases the MABP, the onset of VT and PVS. The histology show intact cardiac muscle with minimum necrosis and inflammation. CH treatment shows significant decrease in cholesterol, triglycerides, and glucose while HDL levels are significantly increased. The aortic section of CH-treated animals shows the intact layers of the artery, normal thickness and restoration of antioxidant enzymatic activity.CONCLUSIONThe study shows significant cardio protective effect of CH in experimental animals.

2019-02-01·Journal of Food Science3区 · 农林科学

Ultrasound‐Assisted Extraction of Chitosan from Squid Pen: Molecular Characterization and Fat Binding Capacity

3区 · 农林科学

Article

作者: Benjakul, Soottawat ; Prodpran, Thummanoon ; Singh, Avtar

AbstractChitosan from squid (Loligo formosana) pens were prepared and characterized. First, ultrasonication condition was optimized for deproteinization of squid pens using central composite design (CCD) of response surface methodology (RSM). Squid pens were ultrasonicated at amplitude 69% for 41.46 min at the solid/solvent ratio of 1:18 yielded 34% (w/w) chitin with the lowest remaining protein. Therefore, ultrasonication effectively reduced the extraction time for chitin production from squid pens as compared to traditional method (5 hr). When the resultant chitin was subjected to deacetylation at different temperatures and times, yield and degree of deacetylation (DDA) of chitosan were in the range of 50% to 65% (w/w) and 78% to 90%. Intrinsic viscosity and molecular weight (MW) of chitosan were in the range of 3.2 to 6.52 dL/g and 1.2 × 105 to 3.2 × 105 Da, respectively. All the chitosans with different DDA were able to bind oil droplets under the mimicked pH condition of gastrointestinal tract. Chitosan produced by deacetylation at 130 °C for 2 hr (CH130‐2) showed the optimum yield (54%) and had medium MW (1.5 × 105 Da). DDA of CH130‐2 determined using 1H‐NMR was 89%, which was similar to that (87%) obtained from FTIR. XRD results showed destruction of chitin structure and decreased crystallinity index from 55% to 27% after deacetylation. CH130‐2 stabilized the emulsion under the simulated gastrointestinal conditions. Therefore, it could be used as dietary fiber to control the adsorption of fat/oil in the human digestive tract.Practical ApplicationChitin and chitosan are marketable products manufactured from crustacean shells. However, extraction of chitin is time consuming. Ultrasonication has been used for extraction of various biomolecules from different sources. It effectively lowers the processing time and enhances extraction yield. Therefore, application of ultrasonication with optimized condition using RSM could reduce extraction time and enhance yield of chitin from squid pen. Chitin from squid pen could be further converted to chitosan with high DDA. Chitosan was able to act as a dietary fiber and reduce fat absorption in gastrointestinal tract. Thus, this information is of benefit for squid processing industry to exploit squid pen, a processing byproduct.

2017-05-17·Current Cancer Drug Targets4区 · 医学

Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer

4区 · 医学

Article

作者: Sondag, Gregory R ; Geldenhuys, Werner J ; Griffith, Jessica I G ; Terell-Hall, Tori B ; Safadi, Fayez F ; Lockman, Paul R ; Venishetty, Vinay K

BACKGROUNDBrain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases.METHODIn this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma.RESULTSFrom our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB).CONCLUSIONThe results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.

项与 CHIP-2 相关的新闻（医药）

2024-09-13

·精准药物

生物电子等排体不对称合成研究及在药物研发中应用

芳香环广泛存在于天然产物与生物活性化合物中，具有的限制分子构象，通过非共价相互作用增强对受体结合能力，通过交叉偶联反应构建丰富化合物库的特点。但同时富含π电子的芳环易氧化，严重降低代谢稳定性。此外，与C( sp3 )分子相比，芳香族分子的水溶性降低，log D增加 (导致脱靶概率增加)，阻碍了药物研发。基于 C( sp3 ) 的双环烃骨架作为芳香环的等排体，可以作为芳环的替代品。经过适当设计，这些分子骨架可以保留苯环的构象限制和生物活性，并增强生物物理性质。这种等排体取代方法具有两个重要特点。第一是保留现代催化交叉偶联方法所伴随的高效、可靠、模块化和可扩展的合成技术。第二是给予配体立体化学性质。由于大多数生物相关受体是手性的，非对称电子等排体的可能通过锁钥原理增强与其同源受体的结合。如MK-5108 与有丝分裂激酶 Aurora A 的非活性 DFG-out 状态结合时，如果它在受体上部区域占据的体积比下部区域更大，则预计结合效果更好。此外已证实随着化合物中手性中心数量的增加，配体混杂性会降低。目前缺乏从易得前体合成这种等排体的简单、可扩展以及催化对映选择性好的方法。来自美国波士顿大学的研究人员通过合成化学与计算技术交叉研究，描述了一种反应，它保留了当代交叉偶联的优势，并允许将简单的起始材料转化为对映体富集的3,5-二取代三环庚烷骨架，具有与间位二取代苯环相似的空间构象。该反应在低负载的手性钯配合物下发生，并产生可塑的含硼电子等排体，具有进一步改性的巨大潜力。双环庚二烯1在添加合适的亲电试剂后很容易转化为三环庚烷骨架2。双环有机金属化合物3的类似亲电活化可以导致闭环 C-C 键形成，从而转化为三环庚烷骨架。在此基础上，他们证明将合成2和4中的汞盐替换为钯配合物并与有机亲电试剂结合时，可以进行三环庚烷的催化合成，同时亲电试剂被添加到骨架中。在催化量的 Pd(OAc) 2和手性配体L1存在下，二硼底物5和有机亲电试剂参与催化对映选择性环合生成三环庚烷，具有高产率和对映选择性。缺电子和富电子亲电试剂都可以轻松获得产物，并可以扩展到杂环和非芳香族亲电试剂，未保护的苯胺和苯酚也不会干扰反应。化合物5可以直接由廉价的市售降双环庚二烯和B2(pin)2以多克规模制备。5的反应可以在5 mmol的规模上进行，仅需0.5 mol％的钯配合物，经过24小时的反应就可以以良好的产率完成。产物7中的硼酸酯可以通过交叉偶联进行烯丙基化、羧化、胺化和转化为衍生醇等，便于构建丰富的间位二取代苯等排体化合物库。接下来他们对反应的机理进行了研究，密度泛函理论计算用于确定GS0的反应路径的自由能曲线。在路径A中，TS1a的carbopalladation产生中间体GS1a，接下来有机硼作为亲核试剂同时排出和还原金属。在路径B中，TS1b通过nucleopalladation生成GS1b，然后直接进行还原消除得到产物。计算表明，carbopalladation的能量较低，烯烃迁移插入生成GS1a所需的能垒比nucleopalladation低得多 (0.7 kcal mol−1对18.7 kcal mol−1）。计算TS1a产生的13C动力学同位素效应 (KIE) 与通过 Singleton 方法实验确定的结果非常吻合。最值得注意的是5在C2处表现出可忽略不计的 KIE，这与carbopalladation机理一致。此外进行了计算研究以阐明对映体诱导的起源。计算出的导致次要产物立体异构体的过渡态结构将 CH 2双环庚烷结构单元的桥直接位于空间受阻的蒽环体系之下，而主要异构体的过渡态构象避免了这种相互作用。为了确定三环庚烷骨架是否适合用于生物活性分子，研究人员将33的两种对映体制备为脂肪酸酰胺水解酶(FAAH)抑制剂URB597的手性等排类似物，并进行分析。等排类似物具有与URB597相似的分子量，在水缓冲液中的溶解度增加10倍，同时保持了相当的亲脂性。此外，通过小鼠肝微粒体测定发现等排类似物相对URB597表现出明显增加的代谢稳定性。研究人员还通过定量基于活性的蛋白质分析实验比较了化合物 (R,S)-33和(S,R)-33。用不同浓度的每种化合物处理小鼠脑匀浆。标记的蛋白质在链霉亲和素珠上富集，并通过基于定量串联质谱标记的质谱法进行分析。等排类似物的效力不如URB597，但保留了抑制FAAH的能力。此外，电子等排体的加入不会改变URB597的蛋白质组范围选择性，这两种电子等排体对FAAH都保持了比其他23种检测到的丝氨酸水解酶更高的选择性。在第二个比较分析中，对映体三环烷(S,R)-34和(R,S)-34被制备为Hedgehog通路抑制剂sonidegib的类似物。等排体的溶解度具有较大的提升，尽管其代谢稳定性有所下降。他们使用双荧光素酶测定法在Shh-LIGHT2细胞中通过三次独立的 IC50测定对立体异构体等排体进行了比较，发现对映体 sonidegib 类似物以亚微摩尔效力抑制信号传导。总的来说，该研究提供了一种合成代替间位二取代苯的非芳香等排体的不对称催化反应。该反应在钯催化下将二环庚二烯转化为一种含有手性硼酸脂的三环庚烷，并且可以进一步利用硼基团发生交叉偶联生成更加丰富的化合物。反应路线简单廉价，具有很好的对映异构选择性和产率，也能够适应于多种类型的基团，同时具有改善物化性质的潜力，为药物开发提供新的策略。参考文献 1. Zhang, M., Chapman, M., Sarode, B.R. et al. Catalytic asymmetric synthesis of meta benzene isosteres. Nature (2024). 2. Wiesenfeldt, M.P., Rossi-Ashton, J.A., Perry, I.B. et al. General access to cubanes as benzene bioisosteres. Nature 618, 513–518 (2023). 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

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