Novel 2-substituted nitronyl nitroxides as free radical scavengers: synthesis, biological evaluation and structure-activity relationship

To develop more potent small molecules with enhanced free radical scavenger properties, we designed and synthesized a series of nitronyl nitroxide derivatives 4a-h. A lead compound 4f was discovered based on Ach-induced vascorelaxation assay. Further chemical modification based on this scaffold provided a new series of 2-substituted phenylnitronyl nitroxide derivatives 6a-s. The newly synthesized compounds 6a-s possess improved radical scavenger's activity based on PC12 cell survival assay. Compounds 6g,n,o, and s are some of the most potent compounds in terms of NO, H(2)O(2), and OH scavenging ability. 2-Substitued phenylnitronyl nitroxides had a higher radical scavenging activity with the electron-donating group (EDG). In contrast, the introduction of electron-withdrawing group (EWG) to the aromatic ring led to a dramatic decrease in its radical scavenging activity. These results suggest that the electron-donating group (EDG) of the aromatic ring may be an important factor influencing the radical scavenging behavior of these compounds, and the potency of free radical scavenging activity largely depended on the position and electronic properties of the phenyl ring substituents. The enhanced radical scavenging capacities of the novel 2-substituted nitronyl nitroxides may be potential drug leads against the deleterious action of ROS (reactive oxygen species)/RNS (reactive nitrogen species).     

Purification and Characterization of Flavonoids from the Leaves of Zanthoxylum bungeanum and Correlation between Their Structure and Antioxidant Activity

Nine flavonoids were isolated and characterized from the leaves of Zanthoxylum bungeanum. Their structures were elucidated by spectroscopic techniques as quercetin (1), afzelin (2), quercitrin (3), trifolin (4), quercetin-3-O-β-D-glucoside (5), isorhamnetin 3-O-α-L-rhamnoside (6), hyperoside (7), vitexin (8) and rutin (9). All compounds were isolated from the leaves of Z. bungeanum for the first time. Five compounds (2, 4, 5, 6 and 8) were found for the first time in the genus Zanthoxylum. To learn the mechanisms underlying its health benefits, in vitro (DPPH, ABTS, FRAP and lipid peroxidation inhibition assays) and in vivo (protective effect on Escherichia coli under peroxide stress) antioxidant activities of the nine flavonoids were measured. Quercetin and quercetin glycosides (compounds 1, 3, 5, 7, 9) showed the highest antioxidant activity. Structure-activity relationships indicated that the -OH in 4′ position on the B ring and the -OH in 7 position on the A ring possessed high antioxidant activity; B ring and/or A ring with adjacent -OH groups could greatly increase their antioxidant ability. Also, due to the different structures of various flavonoids, they will certainly exhibit different antioxidant capacity when the reactions occur in solution or in oil-in-water emulsion. These findings suggest that Z. bungeanum leaves may have health benefits when consumed. It could become a useful supplement for pharmaceutical products and functional food ingredients in both nutraceutical and food industries as a potential source of natural antioxidants.     

Hes-1-targeting siRNA inhibits the maturation of murine myeloid-derived dendritic cells

Activation of Notch by Jagged-1 may plays a pivotal role in maturation of dendritic cells (DCs), but the mechanism has not been completely defined. In the present study, Hes-1 (Hairy/enhancer-of-split)-targeting siRNA was used to confirm a role of Jagged-1-Notch signaling pathway activation in maturation of murine bone marrow-derived DCs and to search for a target that plays a critical role. The results showed that compared with the control, lipopolysaccharide or Zymosan A groups, Jagged-1 (a soluble Jagged 1/Fc chimera protein) effectively increased expression of Hes-1 and Deltex-1 mRNA, which could be reversed by DAPT (2, 4-diamino-5-phenylthiazole), a specific inhibitor of the Notch signaling pathway. Hes-1-targeting siRNA could successfully down-regulate the endogenous Hes-1 expression in the DCs. Concurrently, a significant down-regulation of CD40, CD80, CD86 and MHC-II expressions on the surface of the DCs was found with the reduction of IL-12 yielded by the DCs. Our results demonstrate that Hes-1-targeting siRNA can inhibit the maturation of the DCs induced by Jagged-1, indicating Hes-1 may be an important target of Notch signaling mediating the maturation of DCs.     

PI3K pathway inhibitor LY294002 alters Jurkat T cell biobehaviours via ERK1/2-ICBP90 mediation

Little is known about whether there is a relationshipbetweenPI3K/AKT, ERK1/2 and an inverted CCAAT box binding protein (ICBP90) in biological behaviours of tumour cells. The aim of this study was to determine thisusing Jurkat T cells. Compared to PD98059 (an ERK1/2 signaling inhibitor), DAPT (a Notch signaling inhibitor) or adriamycin (a classical anti-tumour drug), the inhibition of Jurkat T cell growth by LY294002 (a PI3K/Akt signaling inhibitor) was more obvious. LY294002 combined with adriamycin appeared to have a synergistic effect. LY294002 strongly blocked Jurkat T cells at each phase of cell cycle with a decrease of DNA content, superior to adriamycin. Consistent with these changes, the expression of phosphorylated ERK1/2 was markedly decreased in the LY294002-treated Jurkat T cells, leading to the reduction of ICBP90 production, followed by moderate attenuation of TGF-β secretion. The results suggest that deactivation of PI3K/Akt signalling can surpress Jurkat T cell growth through inhibiting cell proliferation and blocking the cell cycle. ICBP90 may mediate the PI3K/AKT-ERK1/2 signalling to regulate leukemia cell growth.     

CircBACH1 (hsa_circ_0061395) promotes hepatocellular carcinoma growth by regulating p27 repression via HuR

In recent years, an increasing number of circular RNAs (circRNAs) have been discovered in hepatocellular carcinoma (HCC). However, the functions of most circRNAs require further investigation. Here, we found that circBACH1 was significantly upregulated in HCC tissues and that high circBACH1 levels were closely associated with poor prognosis. In addition, circBACH1 could promote HCC growth by accelerating cell cycle progression in vitro and in vivo. We next investigated the cellular and molecular mechanisms and discovered that circBACH1 inhibited p27 translation, which influenced cell cycle progression. Moreover, we revealed that circBACH1 could combine directly with HuR using RNA immunoprecipitation assays, pull-down assays, and electrophoretic mobility shift assays. The combination of these molecules facilitated HuR translocation from the nucleus to the cytoplasm according to the fluorescence in situ hybridization and immunofluorescence results. Finally, silencing HuR abrogated circBACH1's inhibition of p27 translation and abolished the circBACH1-induced effect on HCC proliferation. In sum, circBACH1 plays a significant role as an oncogene through the circBACH1/HuR/p27 axis in HCC development.     

凤眼莲入侵程度对金鱼藻和黑藻生长及种间关系的影响

湿地生态系统中凤眼莲（Eichhornia crassipes）入侵造成湿地植物群落结构退化及功能崩溃,直接影响沉水植物的生长繁殖及初级生产力。目前关于凤眼莲的入侵机制有一定的研究,而关于凤眼莲入侵程度对沉水植物金鱼藻（Ceratophyllum demersum）和黑藻（Hydrilla verticillate）生长及种间关系的影响相对缺乏。以外来入侵植物凤眼莲,沉水植物金鱼藻和黑藻为研究对象,设计凤眼莲入侵程度（无入侵,轻度入侵对应盖度25%,重度入侵对应盖度75%）交叉定植方式（黑藻单种模式、金鱼藻单种模式,金鱼藻和黑藻混种模式）的控制实验,探究凤眼莲入侵强度对沉水植物金鱼藻和黑藻生长及种间关系的影响。结果表明,凤眼莲入侵程度显著降低了金鱼藻的生物量、分枝数;黑藻的株高、分枝数和分节数。无凤眼莲入侵时,两种沉水植物生物量均最大,两者种间竞争关系较强;随凤眼莲入侵盖度增加,两种沉水植物的生物量先急剧降低后略微增加,种间关系经过微弱促进后又变为竞争作用,其中黑藻表现出明显的竞争优势。此外,凤眼莲入侵略微降低了水体中的总氮、总磷含量。结构方程模型分析结果表明凤眼莲入侵以及水体总氮、总磷等水体理化性质对沉水植物生长均有显著负向影响（P<0.05）,且水体理化性质对沉水植物生长的影响强于凤眼莲入侵。总之,凤眼莲入侵显著降低了金鱼藻和黑藻生长繁殖,随着凤眼莲入侵程度增加,两种沉水植物种间关系由竞争转变为促进再转变为竞争。研究结果为凤眼莲入侵有效控制及湿地沉水植被的恢复与重建提供了一定的理论依据和技术支撑。     

Synthesis of new class dipeptide analogues with improved permeability and antithrombotic activity

3-(S)-1,2,3,4-Tetrahydro-beta-carboline-3-carboxylic acid isolated from A. Chinese G. Don was found to possess moderate anti-aggregation activity, but with poor bioavailability. To improve its pharmacological property, we designed and synthesized a series of novel dipeptide analogues by incorporating tetrahydro-beta-carboline-3-carboxylic acid skeleton as an amino acid surrogate (*Trp). It turned out these dipeptide analogues exhibited good membrane permeability based on in vitro Caco-2 cell monolayers permeability assay. As a result, the overall biological properties of these molecules were significantly improved depending on the nature of the amino acid residues introduced onto the 3-position of the tetrahydro-beta-carboline moiety. It was very interesting to notice that these dipeptide analogues (5b,c,h,i,n,o,p,q) displayed a remarkable dual antiaggregatory activity in both of ADP- and PAF-induced platelet aggregation assay, and their aggregation response was significantly higher than that of aspirin (p<0.01). In addition, these dipeptide analogues were observed for the dose-dependent antithrombotic effect using in vivo rat arterial thrombosis model. The potency of antithrombotic activity of 5h,i,n,p was significantly higher than that of aspirin (n=12, p<0.01) at equal dose (5 micromol/kg).