Alkaloids from Juglans Mandshurica maxim induce distinctive cell death in hepatocellular carcinoma cells

The aim of this work was to further investigate the anticancer potential of Juglans mandshurica Maxim, including the separation of active constituents and their anti-proliferative effects with underlying mechanism of action. Five alkaloids (1–5) were isolated from the bark of J. mandshurica. Among them, 1 showed the highest cytotoxic activities against Hep3B and HepG2 cells with an IC50 values of 61.80 and 56.24 μM, respectively. Therefore, the cellular mechanism involved 1 was subsequently studied. Our results showed that 1 markedly caused apoptosis and autophagy, but without cell cycle arrest in HepG2 cells. Interestingly, only autophagic cell death was induced in 1-treated Hep3B cells. It is concluded that the isolated alkaloids exerted a certain anti-hepatoma potential, and our results may provide a basis for the further investigation of the alkaloids extracted from J. mandshurica.     

Synthesis,characterization, and biological studies of lanthanide complexes with 2,6-pyridine dicarboxylic acid and α-picolinic acid

Four new solid ternary complexes of lanthanide with 2,6-pyridine dicarboxylic acid and α-picolinic acid [Ln(DPA)(L^α)(H₂O)] · 2H₂O (Ln = La³⁺, Ce³⁺, Eu³⁺, or Gd³⁺; DPA = 2,6-pyridine dicarboxylic acid; HL^α = α-picolinic acid) have been synthesized and characterized by elemental analysis, molar conductance, FT-IR, UV–Vis, and TG–DTA. The antibacterial activities indicate that all the complexes exhibit antibacterial ability against Escherichia coli and Staphylococcus aureus with broad antimicrobial spectra. The anticancer activity of the La complex against K562 tumor cell in vitro is measured using methyl thiazolyl tetrazolium (MTT) colorimetry and flow cytometry. The La complex can induce K562 tumor cell apoptosis, presenting the best apoptosis effect by acting on the S period after inducing K562 tumor cell for 72 h.     

Syntheses,characterizations and bioactivities on HeLa cells and KB cells of two dinuclear manganese complexes with carboxylate bridges

To explore anti-tumor activities of manganese complexes, two complexes have been synthesized and characterized. Complex 1 is bridged by 1,10-phenanthroline and 2,4-biphenyl dicarboxylate. The two complexes have strong fluorescent emission and interact with DNA in an intercalative mode. The complexes also exhibit significant cytotoxic specificity and cancer cell inhibition.     

2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: synthesis and in vitro antitumour activity

Tiazofurin analogues bearing a 5-hydroxymethyl-2-methyl-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (2 and 3), and two novel thiazole-based acyclo-C-nucleosides 4 and 16 have been synthesized in multistep sequences starting from d-xylose (compounds 2 and 3) or from d-arabinose (compounds 4 and 16). All synthesized analogues showed potent in vitro antitumour activities against a panel of human tumour cell lines. Flow cytometry data suggest that cytotoxic effects of analogues 2–4 and 16 in the culture of K562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of K562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bcl-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2–4 and 16) in K562 cells induced apoptosis in a caspase-dependent way.     

Morphological and ultrastructural examination of senescence in Morchella elata

In recent years, the artificial cultivation of Morchella mushrooms that belong to Elata Clade, including Morchella elata, has been developed rapidly in China. However, the prominent problem of spawn aging has been frustrating the morel farming. In this paper, aging in M. elata was achieved from 12 to 17 subcultures and lifespan of 1536–2256 h by successive subculturing. The lifespan can be roughly divided into juvenile phase and senescent phase with respect to the mycelia linear growth rate. After a certain period of rapid growth with almost constant rate at the juvenile phase, the isolate entered the senescent phase characterized by slow down of mycelia growth, producing pigments ahead of time and final death of the apical hyphae. The period of the senescent phase was definitely 240–288 h; while that of the juvenile phase was diverse relying on different isolates. Moreover, microscopic study showed that angles between the leading and primary hyphae increased constantly with aging. In senesced hyphal cells of M. elata, the typical characteristics of autophagy (enlargement of vacuoles and existence of organelles sequestrated lysosomes) and apoptosis (condensation of the cytoplasm and nuclear and plasmolysis) were observed. In addition, in the final stage of senescence, the apical hyphae collapsed with the plasma membrane and all the cellular organelles disrupted, indicated a necrotic mode of cell death. Taken together, these data revealed the involvement of autophagy, apoptosis and necrosis in senescence of M. elata. The characterization and molecular mechanism of autophagy, apoptosis and necrosis need further study and the systematic study of morel aging will be beneficial for the healthy development of morel farming.     

去甲斑蝥素对人胰腺癌PANC-1 细胞凋亡作用的研究

目的 探讨去甲斑蝥素对人胰腺癌PANC-1细胞凋亡的作用及其机制。方法 将PANC-1 细胞株随机分为处理组 和对照组,处理组加入不同浓度的去甲斑蝥素培养24h后,CCK-8 法检测细胞增殖情况;流式细胞术分析细胞的凋亡情况;免疫印迹法检测细胞内质网应激和凋亡相关蛋白的表达;荧光定量PCR 技术检测细胞内质网应激和凋亡相关蛋白mRNA表达。结果 不同浓度去甲斑蝥素处理PANC-1细胞24h后,与对照组相比,能降低细胞的存活率并诱导其凋亡。与对照组相比,处理组中内质网应激和凋亡相关蛋白的表达水平均上调（均P＜0.05）,同时其mRNA 的表达水平亦均上调（均P＜0.05）。结论 去甲斑蝥素能明显抑制人胰腺癌PANC-1 细胞的生长并诱导其凋亡,并且具有浓度依赖性,这一作用可能是通过内质网应激介导的凋亡途径实现的。     

藤黄酸诱导肺癌细胞H1975凋亡的机制研究

目的 研究藤黄酸（GA）诱导人肺癌细胞H1975凋亡的分子机制,探讨氧自由基（ROS）和JNK信号通路在GA杀伤 肺癌细胞中的作用。方法 以人肺癌细胞H1975为研究对象,MTT法测定GA抑制细胞增殖的作用,Annexin V/PI 双染法测定细胞凋亡率,DCFH-DA 法测定ROS 含量,JC-1探针染色分析线粒体膜电位（MMP）,Western blot检测JNK 信号通路的激活和线粒体凋亡途径相关蛋白表达的变化。结果 GA 呈剂量依赖性抑制H1975细胞的增殖,各实验组细胞存活率与空白对照组比较,均有统计学差异（P＜0.05 或0.01）。1、2.5 和5滋mol/L GA 作用24h 后,细胞凋亡率分别为25.2%、51.8%和75.1%,剪切型凋亡相关蛋白cleaved caspase-9、cleaved caspase-3 和cleaved PARP 的表达随GA 浓度增高而显著增加,与空白对照组比较,均有统计学差异（P＜0.05或0.01）。GA 作用2h 后H1975细胞ROS 含量显著升高,磷酸化JNK（p-JNK）表达上调（P＜0.05或0.01）。GA 作用16h后各实验组细胞MMP 均明显降低（均P＜0.05）。GA 作用24h后实验组细胞线粒体凋亡途径相关蛋白Bax、Bak、Bik表达增加,而抗凋亡蛋白Bcl-2表达与空白对照组相比明显下降（P＜0.05 或0.01）。结论 GA 具有诱导H1975 细胞凋亡的作用,其可能机制是上调细胞内ROS含量,激活JNK 信号通路,进而引起MMP 降低和线粒体凋亡途径激活。     

Active ingredients of Inula helenium L. exhibits similar anti-cancer effects as isoalantolactone in pancreatic cancer cells

Abstract

Isoalantolactone is one of the major active ingredients from Inula helenium L. However, it is low cost-effective to isolate isoalantolactone from Inula helenium L. In this study, we optimized the extraction strategy and obtained a mixture of active ingredients with exact proportion (termed as F35), which were alloalantolactone, alantolactone and isoalantolactone at the ratio of 1/5/4 respectively. The anti-tumor activity of F35 was compared with isoalantolactone on pancreatic cancer cells. As a result, F35 showed nearly the same anti-proliferation activity as isoalantolactone in two cell lines. Both F35 and isoalantolactone could induce mitochondrion-related apoptosis at the concentration of 6?μg/ml. In addition, F35 inhibited colony-formation and migration of PANC-1 and SW1990 cells. To conclude, F35 exhibited similar anti-proliferation and anti-migration effect as isoalantolactone on two pancreatic cancer cell lines, suggesting that alantolactone or alloalantolactone might have comparable anti-tumor effect as isoalantolactone.     

Novel benzimidazole derivatives as anti-cervical cancer agents of potential multi-targeting kinase inhibitory activity

Multi-target EGFR, HER2, VEGFR-2 and PDGFR is an improved strategy for the treatment of solid tumors. This work deals with synthesis of an array of new 6-benzoyl benzimidazole derivatives utlizing1-(6-benzoyl-2-(3,4-dimethoxyphenyl)-1H benzo[d] imidazol-1-yl)propan-2-one (1) as a starting compound. The new compounds were screened as cytotoxic agents against cervical cancer cells (Hela) and Doxorubicin served as a reference drug. Most of the tested compounds showed promising anticancer activity in addition to their safety towards the normal cell line. The most potent candidates were evaluated as EGFR, HER2, PDGFR-β and VEGFR2 inhibitors in comparison to Erlotinib. Compounds 9 and 13 exhibited promising suppression effects. Also, the latter compounds exhibited their ability to induce cellular apoptosis alongside cell cycle arrest at the G2/M phase and accumulation of cells in pre-G1 phase. Molecular docking analysis suggested that compounds 2c, 3f, 9, 12 and 13 tightly interacts with the amino acid residues in the active binding site of HER2 kinase.     

Design,synthesis and docking studies of new hydrazinyl-thiazole derivatives as anticancer and antimicrobial agents

Increase in the number of infections caused by pathogenic microbes in cancer patients has prompted the searcher to invest in the development of agents having dual anticancer and antimicrobial properties. The present study is concerned with synthesis and screening for anticancer and antimicrobial activity of a series of 5-hydrazinyl-2-(2-(1-(thien-2-yl)ethylidene)hydrazinyl)thiazole derivatives. The structure elucidation of the synthesized hydrazinyl thiazole derivatives was illustrated by spectroscopic and elemental analysis. All the newly synthesized compounds 5a-p were evaluated for in-vitro cytotoxic activity against breast carcinoma (MCF-7 cell line), hepatocellular carcinoma (HePG-2) and colorectal cancer (HCT-116) cell lines using MTT assay method. Compounds 5 g, 5h showed broad spectrum activity against three cancer cell lines with IC₅₀ ranged from 3.81 to 11.34 µM in compared to the reference drug Roscovitine (IC₅₀ = 9.32 to 13.82 µM), while compounds 5 l and 5 m were found to be more selective against HePG-2 and HCT-116 cell line (IC₅₀ = 9.29 and 8.93 µM respectively) and compound 5j was more selective against HePG-2 and MCF-7 cell lines (IC₅₀ = 6.73 and 10.87 µM respectively). The inhibitory activity of the most promising compounds was tested against the EGFR and ARO enzymes and were further tested for apoptosis and Annexin V/PI staining. The results of enzyme-based tests revealed that the tested compound 5j has a dual inhibitory effect on the EGFR and ARO enzymes with IC₅₀ = 82.8 and 98.6 nM respectively in compared to the reference drugs Erlotinib and Letrozole (IC₅₀ = 62.4 and 79 nM respectively). Furthermore, the majority of the tested hydrazinyl thiazole derivatives exhibited significant antimicrobial activity against the used pathogenic microbes species. Compounds 4b, 5h, 5j and 5 m exerted a good antibacterial and antifungal activity against all tested pathogenic microbes. Therefore, it was concluded that compounds 5 h, 5j and 5 m proved to possess dual anticancer and antimicrobial agent and may serves as a useful lead compounds in search for further modification or derivatization to give more potent and selective agents.