Polyphenolic Flavonoid Compound Quercetin Effects in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Flavonoids are ubiquitous groups of polyphenolic compounds present in most natural products and plants. These substances have been shown to have promising chemopreventive and chemotherapeutic properties with multiple target interactions and multiple pathway regulations against various human cancers. Polyphenolic flavonoid compounds can block the initiation or reverse the promotion stage of multistep carcinogenesis. Quercetin is one of the most abundant flavonoids found in fruits and vegetables and has been shown to have multiple properties capable of reducing cell growth in cancer cells. Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) therapy remains a challenge for hematologists worldwide, and the outcomes for patients with both disorders continue to be poor. This scenario indicates the increasing demand for innovative drugs and rational combinative therapies. Herein, we discuss the multitarget effects of the flavonoid quercetin, a naturally occurring flavonol, on AML and MDS.     

STL1, a New AKT Inhibitor,Synergizes with Flavonoid Quercetin in Enhancing Cell Death in A Chronic Lymphocytic Leukemia Cell Line

Using a pharmacophore model based on the experimental structure of AKT-1, we recently identified the compound STL1 (ZINC2429155) as an allosteric inhibitor of AKT-1. STL1, was able to reduce Ser473 phosphorylation, thus inhibiting the PI₃K/AKT pathway. Moreover, we demonstrated that the flavonoid quercetin downregulated the phosphorylated and active form of AKT. However, in this case, quercetin inhibited the PI₃K/AKT pathway by directly binding the kinases CK2 and PI₃K. In the present work, we investigated the antiproliferative effects of the co-treatment quercetin plus STL1 in HG-3 cells, derived from a patient affected by chronic lymphocytic leukemia. Quercetin and STL1 in the mono-treatment maintained the capacity to inhibit AKT phosphorylation on Ser473, but did not significantly reduce cell viability. On the contrary, they activated a protective form of autophagy. When the HG-3 cells were co-treated with quercetin and STL1, their association synergistically (combination index < 1) inhibited cell growth and induced apoptosis. The combined treatment caused the switch from protective to non-protective autophagy. This work demonstrated that cytotoxicity could be enhanced in a drug-resistant cell line by combining the effects of different inhibitors acting in concert on PI₃K and AKT kinases.     

Quercetin enhances vitamin D2 stability and mitigate the degradation influenced by elevated temperature and pH value

Vitamin D₂ (vit. D₂) is a nutraceutical essentially needed for good health. However, it is susceptible to oxygen and high temperature. The use of natural products such as bioflavonoids possessing anti-degradative effect of vit. D₂ degradation has not been described before. A combinational effect of vit. D₂ with quercetin showed a positive effect and inhibited vit. D₂ degradation when exposed to high temperature (50 ℃ and 75 ℃) at different time points. The results obtained revealed vit. D₂ degradation was drastically increased with longer incubation under thermal treatment. However, quercetin and vit. D₂ groups were able to significantly inhibit the degradation of vit. D₂ and stabilize it, evaluated through the retention percentage. We also exposed vit. D₂ at solutions with different pH values (1, 4, 5, 7, 10). Quercetin exerted vit. D₂ anti-degradation at different pH values as well as under thermal pressure at different time points. Conclusively, quercetin can be an effective way to reduce temperature and pH induced degradation of vit. D₂.     

Evaluation of quercetin as a potential β-lactamase CTX-M-15 inhibitor via the molecular docking,dynamics simulations,and MMGBSA

Antimicrobial resistance (AMR) threatens millions of people around the world and has been declared a global risk by the World Economic Forum. One of the important AMR mechanisms in Enterobacteriaceae is the production of extended-spectrum β-lactamases. The most common ESBL, CTX-M β-lactamases, is spread to the world by CTX-M-15 and CTX-M-14. Sulbactam, clavulanic acid, and tazobactam are first-generation β-lactamase inhibitors and avibactam is a new non-β-lactam β-lactamase inhibitor. We studied that avibactam, sulbactam, clavulanic acid, tazobactam, and quercetin natural flavonoids were docked to target protein CTXM-15. Subsequently, the complexes were simulated using the molecular dynamics simulations method during 100 ns for determining the final binding positions of ligands. Clavulanic acid left CTX-M-15 and other ligands remained in the binding site after the simulation. The estimated binding energies were calculated during 100 ns simulation by the MMGBSA-MMPBSA method. The estimated free binding energies of avibactam, sulbactam, quercetin, tazobactam, and clavulanic acid were sorted as –33.61 kcal/mol, –16.04 kcal/mol, –14 kcal/mol, –12.68 kcal/mol, and –2.95 kcal/mol. As a result of both final binding positions and free binding energy calculations, Quercetin may be evaluated an alternative candidate and a more potent β-lactamases inhibitor for new antimicrobial combinations to CTX-M-15. The results obtained in silico studies are predicted to be a preliminary study for in vitro studies for quercetin and similar bioactive natural compounds. These studies are notable for the discovery of natural compounds that can be used in the treatment of infections caused by β-lactamase-producing pathogens.     

液相色谱法同时测定维药蜀葵花中芦丁、槲皮素和山柰酚

维药是祖国医药学不可分割的组成部分。维药现代化,即利用现代技术研究维药的有效成分,是维药科学化、标准化、规范化、商品化和产业化的必经之路。本文建立了维药蜀葵花中有效成分芦丁、槲皮素和山柰酚的选择性提取方法,优化了高效液相色谱法(HPLC)同时测定这3种有效成分的分析条件。采用HC-C₁₈色谱柱(250 mm×4.6 mm, 5 μm)和甲醇-0.4%磷酸(50:50, v/v)流动相,在柱温30 ℃和流速1.00 mL/min的条件下实现了3种物质之间以及和干扰物之间的基线分离。维药蜀葵花中芦丁、槲皮素及山柰酚的线性范围分别为12.5~150 μg/mL (r=0.9998), 12.5~125 μg/mL (r=0.9999)及12.5~125 μg/mL (r=0.9988),加标回收率(n=5)分别为100.3%(RSD=1.1%)、97.60%(RSD=0.47%)、97.75%(RSD=0.71%)。该方法实现了同时测定维药蜀葵花中芦丁、槲皮素及山柰酚,为其他黄酮类物质的开发应用提供了科学依据,同时也可为其他维药分析提供借鉴。     

樟树叶化学成分研究

为研究樟属植物香樟树叶的化学成分,运用正相和反相硅胶柱层析、半制备型高效液相色谱法对樟树叶提取分离纯化,用波谱技术鉴定其结构.结果表明：从该植物中分离得到5个化合物,其中1个为木脂素类化合物,4个为黄酮苷类化合物,分别为（8R,8＇R）-3,3＇,4,4＇-四甲氧基-9-氧代-8-8＇,9-O-9＇-木脂素（I）,槲皮素-3-Ο-α-L-鼠李糖苷（II）,山奈酚-3-Ο-β-D-葡萄糖基（6→1）-α-L-鼠李糖苷（III）,芦丁（IV）,槲皮素-3-Ο-β-D-葡萄糖苷（V）.     

肝肿瘤细胞HepG2代谢指纹及代谢足迹的NMR分析

细胞代谢特征的分析是认识细胞生物化学过程物质基础的一个关键点. 该文使用培养72 h的肝肿瘤细胞HepG2为模型,使用一维与二维核磁共振谱学分析方法, 分析了该细胞本身及其培养液中代谢物的组成,确定了50余种覆盖三羧酸循环、糖酵解、氨基酸合成、脂肪酸与胞膜代谢、嘌呤与嘧啶代谢等多个代谢途径的代谢物,发现细胞本身与培养基中代谢物组成能够分别提供“细胞代谢指纹”与“细胞代谢足迹”等互补性信息. 同时发现此方法可用于研究植物次生代谢物槲皮素对肝肿瘤细胞HepG2代谢的影响. 结果表明,核磁共振波谱技术是分析细胞代谢组特征和研究药物对细胞代谢影响规律的有效手段.     

Photochemical properties of selected flavonol dyes: Effects on their separation using capillary electrophoresis

Flavonols are naturally occurring dyes that can be extracted from plants. Because of their antioxidant properties, they are thought to have health benefits. In this study, the photochemical degradation properties of selected flavonols were investigated. Dilute solutions of dyes were exposed to light from a broadband visible light source, and the rate of photodegradation was determined by measuring the decrease in fluorescence of the dyes with respect to time. At pH 9.24, the first-order rate constants for 10?µg?mL^?1 solutions of myricetin, quercetin, kaempferol, and morin were 0.468, 0.162, 0.108, and 0.126?s^?1, respectively. Interestingly, the stability of these historical dyes was also found to be greatly affected by pH. Awareness of the photochemical properties and stability of flavonol dyes is very important for capillary electrophoresis (CE) separations. Photodegradation of the flavonol dyes under the alkaline conditions (pH 9.2) used in CE can have a profound effect on the reproducibility of repeated separations. Even a modest decrease in pH (pH 8.5) greatly improved the stability of these dyes and enabled the successful separation of these flavonol dyes with minimal degradation over time.     

环氧合酶-2的表达与槲皮素保护作用的研究

为探讨环氧合酶-2(COX-2)的蛋白表达与槲皮素对镉致急性肾损伤保护作用的机制,采用雄性Wistar大鼠随机分成对照组、镉组、治疗(高、中、低剂量)组.测定血尿素氮、尿N-乙酰β-氨基葡萄糖苷酶、尿γ-L-谷氨酰转肽酶、尿蛋白含量评价肾损伤程度,对肾组织进行病理学研究及western-blot检测,观察肾脏COX-2的蛋白表达.结果表明,镉组与对照组相比肾损伤指标明显增高,槲皮素治疗组与镉组相比肾损伤指标降低;电镜下槲皮素治疗组均较镉组肾小管损伤得到不同程度的改善;镉组与对照组相比COX-2蛋白表达明显增加,治疗组与镉组相比COX-2蛋白的表达均降低.提示槲皮素对镉致急性肾损伤的治疗作用可能与槲皮素抑制了镉诱导的炎症反应有关.图2,表2,参9.