In Vitro and In Vivo Antitumor Activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy. There is an urgent need for effective therapy inasmuch as resistance, intrinsic and acquired, to conventional therapies is common. Among Pt(II) antitumor drugs, [Pt(O,O′-acac)(γ-acac)(DMS)] (Ptac2S) has recently attracted considerable attention due to its strong in vitro and in vivo antiproliferative activity and reduced toxicity. The purpose of this study was to examine the efficacy of Ptac2S treatment in MPM. We employed the ZL55 human mesothelioma cell line in vitro and in a murine xenograft model in vivo, to test the antitumor activity of Ptac2S. Cytotoxicity assays and Western blottings of different apoptosis and survival proteins were thus performed. Ptac2S increases MPM cell death in vitro and in vivo compared with cisplatin. Ptac2S was more efficacious than cisplatin also in inducing apoptosis characterized by: (a) mitochondria depolarization, (b) increase of bax expression and its cytosol-to-mitochondria translocation and decrease of Bcl-2 expression, (c) activation of caspase-7 and -9. Ptac2S activated full-length PKC-δ and generated a PKC-δ fragment. Full-length PKC-δ translocated to the nucleus and membrane, whilst PKC-δ fragment concentrated to mitochondria. Ptac2S was also responsible for the PKC-ε activation that provoked phosphorylation of p38. Both PKC-δ and PKC-ε inhibition (by PKC–siRNA) reduced the apoptotic death of ZL55 cells. Altogether, our results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, providing a solid starting point for its validation as a suitable candidate for further pharmacological testing.     

Antitumor activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in mouse xenograft model of breast cancer

The higher and selective cytotoxicity of [Pt(O,O′-acac)(γ-acac)(DMS)] toward cancer cell in both immortalized cell lines and in breast cancer cells in primary cultures, stimulated a pre-clinical study so as to evaluate its therapeutic potential in vivo. The efficacy of [Pt(O,O′-acac)(γ-acac)(DMS)] was assessed using a xenograft model of breast cancer developed by injection of MCF-7 cells in the flank of BALB/c nude mice. Treatment of solid tumor-bearing mice with [Pt(O,O′-acac)(γ-acac)(DMS)] induced up to 50% reduction of tumor mass compared with an average 10% inhibition recorded in cisplatin-treated animals. Thus, chemotherapy with [Pt(O,O′-acac)(γ-acac)(DMS)] was much more effective than cisplatin. We also demonstrated enhanced in vivo pharmacokinetics, biodistribution and tolerability of [Pt(O,O′-acac)(γ-acac)(DMS)] when compared with cisplatin administered in Wistar rats. Pharmacokinetics studies with [Pt(O,O′-acac)(γ-acac)(DMS)] revealed prolonged Pt persistence in systemic blood circulation and decreased nefrotoxicity and hepatotoxicity, major target sites of cisplatin toxicity. Overall, [Pt(O,O′-acac)(γ-acac)(DMS)] turned out to be extremely promising in terms of greater in vivo anticancer activity, reduced nephrotoxicity and acute toxicity compared with cisplatin.     

[Pt(O,O’-acac)(γ-acac)(DMS)] Alters SH-SY5Y Cell Migration and Invasion by the Inhibition of Na+/H+ Exchanger Isoform 1 Occurring through a PKC-ε/ERK/mTOR Pathway

We previously showed that [Pt(O,O’-acac)(γ-acac)(DMS)] ([Pt(acac)₂(DMS)]) exerted substantial cytotoxic effects in SH-SY5Y neuroblastoma cells, and decreased metalloproteases (MMPs) production and cells migration in MCF-7 breast cancer cells. The ubiquitously distributed sodium-hydrogen antiporter 1 (NHE1) is involved in motility and invasion of many solid tumours. The present study focuses on the effects of [Pt(acac)₂(DMS)] in SH-SY5Y cell migration and also on the possibility that NHE1 may be involved in such effect. After sublethal [Pt(acac)₂(DMS)] treatment cell migration was examined by wounding assay and cell invasion by transwell assay. NHE1 activity was measured in BCECF-loaded SH-SY5Y as the rate of Na⁺-dependent intracellular pH recovery in response to an acute acid pulse. Gelatin zymography for MMP-2/9 activities, Western blottings of MMPs, MAPKs, mTOR, S6 and PKCs and small interfering RNAs to PKC-ε/-δ mRNA were performed. Sublethal concentrations of [Pt(acac)₂(DMS)] decreases NHE1 activity, inhibites cell migration and invasion and decreases expression and activity of MMP-2 and -9. [Pt(acac)₂(DMS)] administered to SH-SY5Y cells provokes the increment of ROS, generated by NADPH oxidase, responsible for the PKC-ε and PKC-δ activation. Whilst PKC-δ activates p38/MAPK, responsible for the inhibition of MMP-2 and -9 secretion, PKC-ε activates a pathway made of ERK1/2, mTOR and S6K responsible for the inhibition of NHE1 activity and cell migration. In conclusion, we have shown a drastic impairment in tumour cell metastatization in response to inhibition of NHE1 and MMPs activities by [Pt(acac)₂(DMS)] occurring through a novel mechanism mediated by PKC-δ/-ε activation.     

[Zn(phen)(O,N,O)(H2O)] and [Zn(phen)(O,N)(H2O)] with O,N,O?is?2,6-dipicolinate and N,O?is?l-threoninate: synthesis, characterization, and biomedical properties

Two ternary Zn(II) complexes, with 1,10-phenanthroline (phen) as the main ligand and a carboxylate-containing ligand [dipicolinate (dipico) or L-threoninate (L-Thr)] as the subsidiary ligand, were prepared and characterized by elemental analysis, Fourier transform IR, UV, and fluorescence spectroscopy, X-ray diffraction, molar conductivity, and electrospray ionization mass spectrometry. X-ray structure analysis shows that both [Zn(phen)(dipico)(H(2)O)]·H(2)O (1) and [Zn(phen)(L-Thr)(H(2)O)Cl]·2H(2)O (2) have octahedral geometry about the Zn(II) atom. Both complexes can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with concentrations causing 50?% inhibition of cell proliferation (IC(50)) in the low micromolar range. Complex 2 has the highest therapeutic index for HK1. Both Zn(II) complexes can induce cell death by apoptosis. Changing the subsidiary ligand in the Zn(II) complexes affects the UV-fluorescence spectral properties of the coordinated phen ligand, the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells, and their therapeutic index.     

《遗传学原理》(第3版)(中文版)(彩色版)

D.P.Snustad M.J.Simmons等著赵寿元乔守怡等译(复旦大学)书号:978-7-04-017147-1出版日期:2011年4月定价:260.00插图:1000幅字数:180万这是北美较流行的一本优秀的遗传学入门教材。     

Synthesis and Characterization of a Ditriflate-Bridged, Diiron(II) Complex with Syn-N-Donor Ligands: [Fe(2)(μ-OTf)(2)(PIC(2)DET)(2)](BARF)(2)

The synthesis and characterization of the diiron(II) complex [Fe(2)(μ-OTf)(2)-(PIC(2)DET)(2)](BARF)(2) (2), where PIC(2)DET is a 2,3-diethynyltriptycene-linked dipicolinic methyl ester ligand, are described. The dication in 2, contains, [Fe(2)(μ-OTf)(2)(PIC(2)DET)(2)](2+) two symmetry-equivalent iron atoms with octahedral coordination geometries. Each metal ion has a N(2)O(4) atom donor set that includes four atoms from two picolinic ester N,O chelate rings, as well as two oxygen atoms from the bridging trifluoromethanesulfonate groups. The Fe(2)(μ-OTf)(2) core of 2 is stabilized by two PIC(2)DET ligands that bind the two metal ions in a head-to-head fashion, leading to an Fe···Fe distance of 5.173(1)?. Molar conductivity data for 2 are consistent with Fe(2)(μ-OTf)(2)(PIC(2)DET)(2)](2+) retaining its identity in acetone solutions, where it behaves as a 2:1 electrolyte. (1)H NMR spectroscopic, solution (d(6)-acetone) and solid-state magnetic susceptibility data all indicate that the iron atoms of 2 are high-spin (S = 2). A fit of the magnetic data (2 - 300K) to a spin-only isotropic exchange Hamiltonian H = -2JS(1)·S(2) are consistent with weak antiferromagnetic coupling between the two iron atoms with J ~ -0.99(2) cm(-1) and g = 2.10(1).     

天然药物信息(医学期刊扫描:文摘和评论)(三)(英文)

Short- Term GinkgoBiloba SupplementationImproves Cognitive FunctionMix JA,Crews WD Jr.An examination of the efficacyof Ginkgo biloba axtract EGb 76 1on the neuropsychologicfunctioning of cognitively intact older adults.Journal of Al-ternative and Complementary Medicine,2 0 0 0 ;6 (3) :2 19～2 2 9.Forty healthy subjects age 5 5 and older were given 180mg daily of Ginkgo biloba extract or placebo for6 weeks.Ginkgo- supplem ented subjects had improved speed of pro-cessing abilities in ne…     

天然药物信息(医学期刊扫描:文摘和评论)(一)(英文)

Beta- Carotene SupplementationBenefits Cystic Fibrosis PatientsRust P,Eichler I,et al.L ong- term oral beta- carotenesupplementation in patients with cystic fibrosis.Effects onantioxidative status and pulmonary function.Annals of N u-trition and Metabolism,2 0 0 0 ;44 (1) :30～ 37.Patients with cystic fibrosis who were given daily beta-carotene supplements for 2 4weeks had increased plasmalevels of beta- carotene.Since peolpe with cystic fibrosis tendto have lower than norm al levels of …     

天然药物信息(医学期刊扫描:文摘和评论)(二)(英文)

Pycnogenol Improves ChronicVenous Insufficiency SymptomsArcangeli P.Pycnogenol R○ in chronic venous insufficiency.F itoterapia,2 0 0 0 ;71(3 ) :2 3 6～ 2 44.Patients with chronic venous insufficiency who were experienc-ing leg pain and edema had a significant improvement in pain andswelling after supplem entation with Pycnogenol R○ French maritimepine bark extract for 2 months.Sixty percent of treated patients hadcomplete disapperance of pain and edem a at the study' s completion.■N P…     

Dynamic aggregation of the mid-sized gadolinium complex {Ph4[Gd(DTTA)(H2O)2]− 3}

A compound binding three Gd³⁺ ions, {Ph₄[Gd(DTTA)(H₂O)₂]^? ₃} (where H₅DTTA is diethylenetriaminetetraacetic acid), has been synthesized around a hydrophobic center made up of four phenyl rings. In aqueous solution the molecules start to self-aggregate at concentrations well below 1 mM as shown by the increase of rotational correlation times and by the decrease of the translational self-diffusion constant. NMR spectra recorded in aqueous solution of the diamagnetic analogue {Ph₄[Y(DTTA)(H₂O)₂]^? ₃} show that the aggregation is dynamic and due to intermolecular π-stacking interactions between the hydrophobic aromatic centers. From estimations of effective radii, it can be concluded that the aggregates are composed of two to three monomers. The paramagnetic {Ph₄[Gd(DTTA)(H₂O)₂]^? ₃} exhibits concentration-dependent ¹H NMR relaxivities with high values of approximately 50 mM^?1 s^?1 (30 MHz, 25 °C) at gadolinium concentrations above 20 mM. A combined analysis of ¹H NMR dispersion profiles measured at different concentrations of the compound and ¹⁷O NMR data measured at various temperatures was performed using different theoretical approaches. The fitted parameters showed that the increase in relaxivity with increasing concentration of the compound is due to slower global rotational motion and an increase of the Lipari–Szabo order parameter S ².     

原生动物门(Profozoa)(一)

原生动物属于动物界中最原始、最低等的单细胞动物。由于它们的核与细胞质之间存在有明显的核膜,因此这类动物应归属于真核动物。除生活在海洋的放射虫和有孔虫等,原生动物在形态上虽然是一个体形微小(一般在300微米以下)的单细胞动物,但它们又区别于高等动物的体细胞,而是一个完整的,能够独立生活的有机体;它们除具有一般细胞共有的细胞膜、细胞质和细胞核外,还具有一般多细胞动物的运动,消化、呼吸、排泄、生殖和感应性等生理功能。因此,原生动物是一个结构复杂功能奇特的单细胞动物。     

新型O—连接糖基化—O—GlcNAc

一种新型糖基化,单糖Ｎ－乙酰葡萄糖胺通过Ｏ－连接与蛋白质共价相连,随着研究的不断深入,这种新型糖基化受到愈来愈多的重视,本主要论述它的发现,存在部位及可能的功能。     

O）代谢

土壤生物是重要的基因库,土壤生物多样性是全球生物多样性的重要组成部分。土壤生物是C、N地球化学过程（土壤库）的驱动者,调控微量气体代谢。在微量气体代谢中,土壤微生物具有直接的作用。真菌、CH₄生成菌、CH₄氧化菌、硝化菌以及反硝化菌等是调控微量气体代谢的关键生态功能类群。由于相对大的体积和强大的酶化学分解作用,真菌通常主导枯枝落叶的分解活动。“通气—厌气”界面是微生物群落的活跃区域,易发生微量气体代谢。“有机—无机”过渡层、水生植物根际区、土壤动物肠道系统是典型的微量气体代谢界面。土壤动物对微量气体代谢的作用通常为前期的和间接的,并且又是重要的。节肢动物（白蚁）和环节动物（蚯蚓）是分别代谢CH₄和N₂O的两个关键性生态功能类群。在研究土壤生物多样性及其对微量气体代谢的作用方面,由于土壤生态系统的复杂性,需综合传统微生物实验技术与现代同位素技术和分子生物学技术。我国缺乏研究土壤生物多样性及其对微量气体代谢影响的实质性工作,有必要开展这方面的研究。     

非O1群O139群霍乱的研究进展

１９９２年９月首次分离到Ｏ１３９群霍乱菌株以来,亚洲多个国家和地区发生了Ｏ１３９群霍乱弧菌所致霍乱的流行,本文对Ｏ１３９群霍乱的微生物学、免疫学、分子生物学、诊断方法及流行病学等方面的研究作一简述。     

西藏蕨类植物增补(II)(英文)

报道了 8种蕨类植物为西藏新记录 ,并讨论了西藏蕨类植物的区系特点和分类问题     

生理卫生教学参考资料(下册)(续)

第三节脑本节主要闡述脑的构造和它的机能,从量力性的观点出发,教材仅介紹延髓、小脑和大脑三个部分,这是适合实际情况的。延髓的机能着重的介紹了几个神經中枢的机能——呼吸中枢、心搏中枢、血管舒縮中枢和唾液分泌中枢。这几种中枢的机能在上冊各章部已敍述了一些感性知識,例如講到血的流动时就举出肌肉活动加强时,它里面毛細血管舒张的数目就多一些。这一段內就把这些感性知識提高到理論來認識,进一步加深和巩固反射的概念。同时还为講高級神經活动打下基础。例如唾液分泌中枢的位置等。     

Fe–O versus O–O bond cleavage in reactive iron peroxide intermediates of superoxide reductase

It is generally accepted that the catalytic cycles of superoxide reductases (SORs) and cytochromes P450 involve a ferric hydroperoxo intermediate at a mononuclear iron center with a coordination sphere consisting of four equatorial nitrogen ligands and one axial cysteine thiolate trans to the hydroperoxide. However, although SORs and P450s have similar intermediates, SORs selectively cleave the Fe–O bond and liberate peroxide, whereas P450s cleave the O–O bond to yield a high-valent iron center. This difference has attracted the interest of researchers, and is further explored here. Meta hybrid DFT (M06-2X) results for the reactivity of the putative peroxo/hydroperoxo reaction intermediates in the catalytic cycle of SORs were found to indicate a high-spin preference in all cases. An exploration of the energy profiles for Fe–O and O–O bond cleavage in all spin states in both ferric and ferrous models revealed that Fe–O bond cleavage always occurs more easily than O–O bond cleavage. While O–O bond cleavage appears to be thermodynamically and kinetically unfeasible in ferric hydrogen peroxide complexes, it could occur as a minor (significantly disfavored) side reaction in the interaction of ferrous SOR with hydrogen peroxide.     

大肠杆菌O157研究进展

大肠杆菌Ｏ１５７：Ｈ７原来被认为与人类疾病无关，自Ｒｉｌｅｙ等报告此菌与出血性结肠炎流行有关以来，欧、美等国家出现了朋起大肠杆菌Ｏ１５７：Ｈ７感染疾病暴发事件，引起了各国学者的关注。本文将有关此菌在病原学、免疫学和致病机制等方面的研究新进展作一综述。     

Altered replication in human cells promotes DMPK (CTG)(n) · (CAG)(n) repeat instability

Myotonic dystrophy type 1 (DM1) is associated with expansion of (CTG)(n) · (CAG)(n) trinucleotide repeats (TNRs) in the 3' untranslated region (UTR) of the DMPK gene. Replication origins are cis-acting elements that potentiate TNR instability; therefore, we mapped replication initiation sites and prereplication complex protein binding within the ~10-kb DMPK/SIX5 locus in non-DM1 and DM1 cells. Two origins, IS(DMPK) and IS(SIX5), flanked the (CTG)(n) · (CAG)(n) TNRs in control cells and in DM1 cells. Orc2 and Mcm4 bound near each of the replication initiation sites, but a dramatic change in (CTG)(n) · (CAG)(n) replication polarity was not correlated with TNR expansion. To test whether (CTG)(n) · (CAG)(n) TNRs are cis-acting elements of instability in human cells, model cell lines were created by integration of cassettes containing the c-myc replication origin and (CTG)(n) · (CAG)(n) TNRs in HeLa cells. Replication forks were slowed by (CTG)(n) · (CAG)(n) TNRs in a length-dependent manner independent of replication polarity, implying that expanded (CTG)(n) · (CAG)(n) TNRs lead to replication stress. Consistent with this prediction, TNR instability increased in the HeLa model cells and DM1 cells upon small interfering RNA (siRNA) knockdown of the fork stabilization protein Claspin, Timeless, or Tipin. These results suggest that aberrant DNA replication and TNR instability are linked in DM1 cells.