Suppression of <i>N</i>-Methyl-<i>N</i>-Nitrosourea-Induced Retinal Damage in Mice by Oligonol, an Oligomerized Polyphenol Formulation

Oligonol is a lychee fruit-derived functional food that contains oligomerized polyphenol compounds. Oligonol exhibits a number of beneficial biological effects, primarily due to its antioxidant activity. Retinitis pigmentosa (RP) is an inherited chronic degenerative disease affecting retinal photoreceptor cells. There is currently no effective therapy capable of stopping or reversing the progression of the disease. In RP, apoptosis of photoreceptor cells resulting from oxidative damage is considered to be the final common pathway. In this report, we present an evaluation of the suppressive activity of Oligonol against N-methyl-N-nitrosourea (MNU)-induced retinal damage in mice, which is a commonly used animal model of RP. Both intraperitoneal and oral administration of Oligonol reduced the loss of photoreceptor cells 7 days after MNU injection, as evaluated by histological staining. Photoreceptor cells derived from MNU-treated mice exhibited increased TUNEL-positive staining, suggesting increased DNA fragmentation, a hallmark of apoptosis. Oligonol treatment reduced the number of TUNEL-positive cells. Additionally, Oligonol suppressed MNU-induced retinal production of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress. Moreover, Oligonol attenuated the MNU-induced decrease in the visual activity of mice, as evaluated by the visual cliff test. Oligonol, therefore, effectively suppresses NMU-induced retinal degeneration.

Protective effects of naringenin eye drops on N-methylN-nitrosourea-induced photoreceptor cell death in rats

AIM:To investigate the effects of naringenin eye drops on N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell death in rats.METHODS:Photoreceptor cell death was induced by single intraperitoneal injection of MNU(60 mg/kg)in rats.Both eyes of all animals were instilled with one drop of vehicle,0.5% or 1.0% naringenin eye drops three times per day from 7d before to 17d after MNU injection.Effects of naringenin on MNU-induced photoreceptor cell death were evaluated by electrophysiological and histological analysis.RESULTS:Flash electroretinography (FERG)and oscillatory potentials (OPs) recordings showed that the vehicle control group had remarkable reduction of amplitudes and prolongation of latency times.FERG and OPs responses were significantly reversed in MNUinduced rats treated with 0.5%or 1.0% naringenin eye drops compared with the vehicle control.The retinal morphological results showed that naringenin dosedependently preserved the outer nuclear layer,outer retina and total retina.CONCLUSION:These results indicate that topical treatment with naringenin eye drops prevented retinal neurons from MNU-induced structural and functional damages.

Synthesis and Crystal Structure of Lanthanum Nitrate with Methyl-2-pyridyl Ketone Benzoyl Hydrazone

A novel La complex with methyl-2-pyridyl ketone benzoyl hydrazone has been synthesized and determined by single crystal X-ray diffraction. The crystal is monoclinic with space group C2/c, a =1 7081(3) nm, b =1 5660(3) nm, c =1 3512(3) nm, α=90 00°, β=94 39(1)°, γ=90 00°, V =3 6037(12) nm 3, Z =4 . The complex is a ten-coordinated one with a lanthanum ion surrounded by a N 4O 6 set. The crystal structure is stabilized by hydrogen bonds between water molecules and NO - 3 anions.

Confirmation of N-(Nitrosomethyl) urea as a Nitrosourea Derived by Nitrosation of Fish Sauce

N-(nitrosomethyl ) urea (NMU ) was characterized in the carcinogenic nitrosated fish sauce (NFS) with high performance liquid chromatography (HPLC )- pholohydrolysis-pyrolysis-thermal en -ergy analysis recently. We used HPLC-electronic spray ionization-mass spectrometry and HPLC-diode array detection to confirm NMU in NFS furiher. It was observed that the corresponding chro-matographic fraction of NMU of NFS showed the same mass spectrum (m/z 64, 102, and 145) andultraviolet-absorbance (λ max = 230 nm) as those of authentic NMU. These results confirmed that thecomponent of NFS was NMU

1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/resistant colon cancer cells

AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resistance(5-FU-R)cell line derived from continuous exposure(25μmol/L)to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells.The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting,respectively,after treatment with Resveratrol(Res)and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea(BCNU).Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis,respectively.The extent of DNA damage was measured by the Comet assay.We measured the visible changes in the DNA damage/repair cascade by Western blotting.RESULTS:The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner.Combined application of BCNU and Res caused more apoptosis in5-FU sensitive cells in comparison to individual treatment.In addition,the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells.We established a 5-FU resistance cell line(5-FU-R)from 5-FU-sensitive HCT-116(mismatch repair deficient)cells that was not resistant to other chemotherapeutic agents(e.g.,BCNU,Res)except 5-FU.The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay.There was no significant cell death noted in5-FU-R cells in comparison to 5-FU sensitive cells after5-FU treatment.This resistant cell line overexpressed anti-apoptotic[e.g.,AKT,nuclear factorκB,FLICE-like inhibitory protein),DNA repair(e.g.,DNA polymerase beta(POL-β),DNA polymerase eta(POLH),protein Flap endonuclease 1(FEN1),DNA damage-binding protein 2(DDB2)]and 5-FU-resistance proteins(thymidylate synthase)but under expressed pro-apoptotic proteins(e.g.,DAB2,CK1)in comparison to the parental cells.Increased genotoxicity and apoptosis were observed in resistant cells after combined application of BCNU and Res in comparison to untreated or parental cells.BCNU increased the sensitivity to Res of 5-FU resistant cells compared with parental cells.Fifty percent cell death were noted in parental cells when 18μmol/L of Res was associated with fixed concentration(20μmol/L)of BCNU,but a much lower concentration of Res(8μmol/L)was needed to achieve the same effect in 5-FU resistant cells.Interestingly,increased levels of adenomatous polyposis coli and decreased levels POL-β,POLH,FEN1 and DDB2 were noted after the same combined treatment in resistant cells.CONCLUSION:BCNU combined with Res exerts a synergistic effect that may prove useful for the treatment of colon cancer and to overcome drug resistance.

Meclizine Chloridrate and Methyl-β-Cyclodextrin Associated with Monophosphoester Synthetic Phosphoethanolamine Modulating Proliferative Potential in Triple-Negative Breast Cancer Cells

Synthetic phosphoethanolamine(Pho-s)is a monophosphoester ester with anti-inflammatory and pro-apoptotic properties.Meclizine chloridrate(MC)is a histamine H1 receptor blocker that is also able to inhibit cellular respiration.However,MC does not inhibit cellular respiration in isolated mitochondria such as antimycin and rotenone.Methyl-β-cyclodextrin(MβCD)belongs to theβ-cyclodextrin family,which is capable of removing cholesterol from the plasma membrane.The aim of this study was to evaluate the proliferative effects of meclizine chloridrate and methyl-β-cyclodextrin compounds associated with synthetic phosphoethanolamine in a triple-negative human breast tumor line,MDA-MB-231 Cell viability of the tumor line and normal cells FN1 was evaluated by MTT colorimetric test;the production of free radicals was determined by lipoperoxidation(LPO)test;and the percentage of cell cycle phases and proliferative index was evaluated by flow cytometry.Cell viability demonstrated a significant decrease with the treatments of MβCD,MC and Pho-s associated with MC.The production of free radicals decreases significantly in all treatments.In addition,a significant increase of DNA fragment and decrease in G0/G1 cell cycle phase were observed in cellular percentage with concentrations of 20 and 30 mM of Pho-s in association with MC and MβCD,respectively.

Auxiliary Ligands Mediated One- and Two-dimensional Cd(Ⅱ) Coordination Polymers Incorporating Methyl-3- hydroxy-5-carboxy-2-Thiophenecarboxylate Ligand

Two N-donor ligands mediated Cd（Ⅱ） coordination polymers, namely,[Cd（L）（dmpz）2]n （1） and {[Cd（L）（atr）05（H20）]（H2O）}n （2） （H2L = methyl-3-hydroxy-5-carboxy-2-thiophenecarboxylate, dmpz = 3,5-dimethylpyrazole, and atr= 4-amino-l,2,4-triazole）, havebeen produced. Their structures were characterized by single-crystal X-ray diffraction analysis,elemental analyses and infrared spectra. Compound 1 possesses a one-dimensional （1D） chainstructure and is finally extended into a three-dimensional （3D） supramolecular architecturethough hydrogen bonding interactions. Compound 2 features a two-dimensional （2D） networkwith 4-connected sql topology based on dinuclear Cd（Ⅱ） clusters as nodes, which is alsoassembled into a 3D supramolecular architecture through hydrogen bonding interactions.Furthermore, compounds 1 and 2 exhibit high thermal stabilities and intense fluorescent emissionin the solid, and can be explored as potential luminescent materials.

SYNTHESES OF N- METHYL-^(14)C BENZYL AMINE AND N- METHYL-^(14)C BENZYL NITROSAMINE

The syntheses of N-Methyl-14C benzyl amine and N-Methyl-14C benzyl nitrosamine are reported. Specific activities were approximately 920 MBq/mmol. Chemical and radiochemical purity checked by HPLC were more than 95%.

An Efficient Process for Preparing 4-Methyl-2-phenyl Piperazine Hydrochloride and its Derivatives

An improved method for preparation of 4-methyl-2-phenyl piperazine and its derivatives with higher yield and inexpensive reagents was developed, the products were characterized by 1H-NMR and MS.

Synthesis and Transesterification of the Complexes of Methyl 2-Methyl-3-trichlorostannylpropoinate with Benzylmethylsulfoxide

The title complex, Cl3SnCH2CH(CH3)CO2CH3L (1), was synthesized by the reaction of methyl 2-methyl-3-trichlorostannylpropionate with benzylmethylsulfoxide (L) in solid state at room temperature and readily underwent transesterification into the corresponding analogues Cl3SnCH2CH(CH3)CO2RL when reacted with an alcohol ROH. The structural features of these compounds were described, and the possible mechanism of transesterification was suggested.

A Hydrogen-bonded Tubular Structure of Zinc(Ⅱ) and Methyl-3-pyridylcarbamate

A zinc（Ⅱ） compound [ZnCl2（mpcm）2]（1,mpcm = methyl-3-pyridylcarbamate） was prepared by solvothermal reaction and characterized by elemental analysis,IR spectroscopy,TGA and single-crystal X-ray diffraction.The crystal is of monoclinic system,space group P21/n,C14H16ZnCl2N4O4,Mr = 440.58,a = 8.7893（7）,b = 24.978（2）,c = 9.2510（8）,β = 109.318（1）°,V = 1916.6（3）3,Z = 4,θ = 1.63～25.20°,Dc = 1.527 g/cm3,μ = 1.585 mm-1,F（000） = 896,the final R = 0.0255 and wR = 0.0654 for 3080 observed reflections with Ⅰ 〉 2σ（Ⅰ）.The zinc atom is four-coordinated by the pyridyl groups of two mpcm ligands and two chloride ions with a tetrahedral geometry.Two [ZnCl2（mpcm）2] subunits are held together by a pair of hydrogen bonds,forming a 32-membered macrocyclic dimer,which is further extended into a 3D tubular structure via hydrogen bonding.

In vitro release of 1,3-bis(2-chloroethyl)-1-nitrosourea sustained-release microspheres and the distribution in rat brain tissues

BACKGROUND: The implantation of released chemotherapeutic drugs, which takes biodegradable polymer as vector, into the tumor site can get high concentration and release the drug for a long time, it can directly act on the tumor cells, and reduce the general toxicity. OBJECTIVE: To explore the in vitro and in vivo course of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) sustained-release from BCNU-loaded polylactide (PLA) microspheres (MS) and location in rat brain tissue. DESIGN: A repetitive measurement. SETTING:Central Pharmacy, General Hospital of Chinese People’s Armed Police Forces. MATERIALS: Thirty male SD rats were used. PLA (Mr5000, batch number: KSL8377) was produced by Wako Pure Chemical Inc.,Ltd. (Japan); BCNU (batch number: 021121) by Tianjin Jinyao Amino Acid Co., Ltd.; BCNU-PLA-MS was prepared by the method of solvent evaporation and pressed into tablets (10 mg/tablet). High-performance liquid chromatography (HPLC) Agilent 1100 (USA); LS9800 liquid-scintillation radiometric apparatus (Beckman). Chromatographic conditions: Elite Hypersil ODS2 C18 chromatographic column (5 μm, 4.6 mm×150 mm); Mobile phase: methanol: water (50:50), flow rate was 1.0 mL per minute, wave length of ultraviolet detection was 237 nm, and the inlet amount of samples was 10 μL. METHODS: The experiments were carried out in the experimental animal center of the General Hospital of Chinese Armed Police from May 2004 to July 2005. ① In vitro BCNU-PLA-MS release test: BCNU-PLA-MS was prepared by the method of solvent evaporation, then placed in 0.1 mol/L phosphate buffered solution (PBS, pH 7.4, 37 ℃), part of MS were taken out at 1, 2, 3, 7, 10 and 15 days respectively, and the rest amount of BCNU in MS was determined by HPLC, then the curve of BCNU-PLA-MS release was drawn. ②In vivo BCNU-PLA-MS release and distribution test: The rats were anesthetized, then BCNU-PLA-MS were implanted to the site 1 mm inferior to the cortex of frontal lobe. Five rats were killed postoperatively at 4 hours, 1, 2, 3, 7 and 15 days, the residual MS was removed from the brain tissue. The rest amount of BCNU was determined with HLPC, and the curve of BCNU-PLA-MS release was drawn as compared with the amount of BCNU in the implanted tablets. Besides, brain tissues (1 g) at the implanted side and the contralateral one were obtained respectively, blood sample (0.5 mL) was also collected, 3H-BCNU was counted radioactively in radioactive liquid flash solution. The distributions of BCNU-PLA-MS in normal rat brain tissue and serum were detected. The analysis of variance was applied to compare the intergroup differences of the measurement data. MAIN OUTCOME MEASURES: ① Characteristics of BCNU-PLA-MS release in phosphate buffered solution (PBS) and rat brain tissue; ② Distributions of BCNU-PLA-MS in normal rat brain tissue and serum. RESULTS: ① Release of BCNU-PLA-MS in PBS and rat brain tissue: The BCNU released from BCNU-PLA-MS could be sustained for over 2 weeks both in PBS and brain tissue. In PBS, the released rate of BCNU was over 15% at 24 hours, nearly 50% at 72 hours and over 90% at 15 days. In brain tissue, the released rate was 8% at 4 hours, 16% at 24 hours, 60% at 72 hours, respectively, and BCNU could be sustained released for over 15 days. ② Distributions of BCNU-PLA-MS in normal rat brain tissue and serum: The concentrations of BCNU in the ipsilateral brain tissue were 6 to 70 times higher than those in the contralateral one. The concentrations of BCNU in the ipsilateral brain tissue were obviously higher than those in serum and contralateral brain tissue (F =103.47, P < 0.01). CONCLUSION: BCNU-PLA-MS can increase the drug concentration in targeted brain tissue, decrease that in the non-targeted brain tissue, reduce general toxic and side effects, and have good releasing function.

Synthesis of Methyl-(γ-chloropropyl)dichlorosilane Catalyzed by Silica-supported Karstedt-type Catalyst

Methyl-（γ-chloropropyl）dichlorosilane was synthesized under the catalysis of a silicasupported Karstedt-type catalyst. By orthogonal experimental design method, the optimum reaction parameters such as reactants ratio, reaction temperature and time, and the dosage of catalyst, were determined. At the optimum reaction condition the product yield reached 78.42%, which is higher than that reported in the literatures.

Spectrofluorimetric Determination of Trace Terbium(III) Using 2,6-Bis-(1'-phenyl-3'-methyl-5'-oxopyrazole-4')pyridinediacyl and N-Cetylpyridium Bromide

A new spectrofluorimetric method for determination of trace terbium based on its reaction with 2.6-his-(1'-phenyl-3'-methyl-5'- pyridinediacyl (H_2PMBPP) and N- cetylpyridium bromide (CPB). at an apparent pH=5.0 provided by a hexamethylenetetramine (5% w/w)-hydrochloric acid buffer,is propesed. The calibration graph is linear in the ran ge from

Studies on Semisynthesis and Anibacterial Activity of 7 β-(5-Methyl-1-Aryl-1H-1,2,3-Triazoly-4-Carboxamido) Cephalosporins

Nine new derivatives of 7 β - (5- methyl- 1- aryl- 1H-1, 2, 3- triazoly- 4- carboxamido) cephalosporins were synthesized by acylction of 7 β -amino group of 7-ACA, 7-ADCA and 7-ACT with 5 -methsyl- 1 -aryl- 1 H- 1,2,3-triazoly-4-formyl chloride. The structure of the compounds were confirmed by elementray analysis IR, HNMR and FAB-MS. Some of them showed significant antibacterial activity

An experimental study on N-ethyl-N-nitrosourea-induced rat brain gliomas

Rat brain gliomas were induced by transplacental and subcutaneous administration of synthesized Nethyl-N-nitrosourea(EVU, 60 mg/kg body weight) in the late gestational and 3-day Wistar rats respectively, observed until the end of 12th month after administration.The incidences of tumor formation were 73. 2% and 68.3% (those of gliomas were 65. 9% and 63. 4%) respectively. Histologically, the main types were mixed oligodendro-astrocytomas and oligodendrogliomas, with the characteristics of being microfocal, multifocal and mixed, in presence with focal and/or diffuse proliferation of glial cells. The results showed that these glioma models induced by the synthesized ENU were successful and stable, serving a fine approach to further study of the initiation,growth and differentiation of gliomas. The significance of proliferation of glioblasts in the oncogenesis of ENU-induced gliomas was discussed in this report.

Synthesis Characterization Non-isothermal Kinetics of the Thermal Decomposition and Redox Properties Derived from Copper(Ⅱ) Binuclear Coordination Compound of 1,4-Bis-(1'-Phenyl-3'-Methyl-5'-Pyrazolone-4')-1,4-Butanedione

The paper reports the synthetic procedure and character of Copper(II) binuclearcoordination compound of 1,4-bis-(1'-phenyl-3'-methyl-5'-pyrazolone Thenon-isothermal kinetics of thermal decomposition of the complex has been stUdied from the TG-DTGcurves by means of the Achar et al. and Coats-Redfern methods,the most probab1e kinetic equation canbe expressed as dofdtrAe -E / RT * l /(2Q).The corresponding kinetic compensation effect expressions arefound to be lnuA=0. 1794E+0. 1689.The non-isothermal thermal decomposition process of the complex isone-dimensional diffusion.But electrochemical studies of the complex(Cu2L'2)from cyclic voltamrnetriccurves by means of powder microelectrodes technique'',shows one two-electron irreversible process.

N-甲基-N-亚硝脲诱导的视网膜变性大鼠模型的形态学和功能改变

目的:观察N-甲基-N-亚硝脲(N-m ethyl-N-n itrosourea,MNU)对SD大鼠视网膜光感受器细胞的毒性作用。方法:出生后50 d的SD大鼠84只,随机抽取4只作为正常对照组,余下80只分为4组,每组20只,分别按体质量一次性腹腔注射MNU 80、60、40和30 mg/kg。各组每次4只分别于12 h、24 h、48 h、72 h、120 h行右眼闪光视网膜电图检查(ERG),并于造模后1 d、2 d、3 d、5 d、7 d处死动物,取眼球做组织学检查。结果:1)显示正常对照组的大鼠ERG波形清晰,a、b波振幅正常。MNU 80、60、40和30 mg/kg剂量组a波消失时间分别为3 h、12 h、24 h、120 h;b波消失时间分别为12 h、24 h、72 h、168 h。2)形态学检查测到正常组大鼠中心视网膜的外视网膜厚度为(98.4±1.8)μm。MNU处理后5 d和7 d,80、60、40和30 mg/kg剂量组外视网膜厚度分别为0μm、(9.5±2.3)μm、(42.8±2.7)μm、(71.3±2.4)μm和0μm、0μm、(20.8±2.5)μm、(62.9±2.0)μm,其损伤程度和剂量及时间成正比。结论:MNU可选择性地诱导视网膜光感受器细胞发生凋亡,该作用呈剂量和时间依赖性。