Compound 3k治疗骨关节炎:调控氧化应激通路改善软骨细胞糖酵解的作用机制

背景:骨关节炎现已被认为是一种代谢性疾病,既往研究表明糖酵解在骨关节炎的发生发展中起重要作用。Compound 3k作为一种新型糖酵解小分子抑制剂,具有抗炎及抗肿瘤等功效,因此可靶向糖酵解,有望为骨关节炎治疗提供新的思路。目的:基于缺氧诱导因子1α/活性氧的氧化应激通路探究Compound 3k在糖酵解过度活跃所导致的骨关节炎中的作用机制。方法:取对数生长期的ATDC5成软骨细胞,用10 ng/mL白细胞介素1β作用24 h诱导骨关节炎体外细胞模型,以CCK-8法检测不同浓度(0.25,0.5,1,2.5,5,10,15μmol/L)Compound 3k的细胞毒性,选出合适浓度进行后续实验。将软骨细胞随机分为对照组、模型组、治疗组,模型组以10 ng/mL的白细胞介素1β诱导,治疗组以Compound 3k预刺激2 h后与白细胞介素1β共培养,用CCK-8法检测各组细胞增殖情况;用ELISA试剂盒检测各组细胞炎症水平;用试剂盒检测各组细胞活性氧、细胞外乳酸脱氢酶及葡萄糖含量;qRT-PCR及Western blot检测相关炎症因子白细胞介素6、肿瘤坏死因子α及糖酵解相关基因葡萄糖转运蛋白1、甘油醛3-磷酸脱氢酶、单羧酸转运蛋白1和缺氧诱导因子1α的表达水平。结果与结论:①与对照组相比,模型组细胞增殖活性下降、糖酵解水平活跃,表现为细胞外乳酸脱氢酶含量增加(P<0.001),葡萄糖含量减少(P<0.001),相关炎症因子白细胞介素6(P<0.0001)及肿瘤坏死因子α(P<0.001),糖酵解相关基因葡萄糖转运蛋白1(P<0.001)、甘油醛3-磷酸脱氢酶(P<0.001)、单羧酸转运蛋白1(P<0.001)及缺氧诱导因子1α(P<0.001)的表达水平均上调,并伴随氧化应激,活性氧过量产生。②与模型组相比,Compound 3k的治疗有效提高细胞增殖活性,抑制过度活跃的糖酵解水平的同时,抑制了骨关节炎软骨细胞炎症(P<0.001)及糖酵解相关基因的表达(P<0.001),且抑制氧化应激,缺氧诱导因子1α的表达水平下调(P<0.0001),活性氧水平下降。③上述结果证实,Compound 3k抑制了白细胞介素1β诱导的软骨细胞炎症,其机制可能与糖酵解及缺氧诱导因子1α/活性氧介导的氧化应激有关。

Two Novel Nitrogen-rich Energetic Coordination Compounds M_2(DAT)_5(H_2O)_3(TNR)_2(M = Zn and Co):Synthesis,Characterization,Thermal Properties and Sensitivity

Two novel energetic coordination compounds Zn2（DAT）5（H2O）3（TNR）2 and Co2（DAT）5（H2O）3（TNR）2 were synthesized and their structures were characterized by elemental analysis and FT-IR spectroscopy.The crystal structures were determined by single-crystal X-ray diffraction.The results reveal that the compounds have similar molecular structures and the crystals belong to the triclinic system,space group P with a = 11.491（3）,b = 13.564（3）,c = 15.496（3） ,V = 2180.4（8） 3,C17H28 Zn2N36O19,Mr = 1203.02 g·mol-1,Dc = 1.832 g·cm-3,μ（MoKα） = 1.221 mm-1,F（000） = 1223,Z = 2,R = 0.0596 and wR = 0.1514 for 11289 observed reflections（I 〉 2σ（I）） for Zn2（DAT）5（H2O）3（TNR）2 and a = 11.5291（13）,b = 13.4894（15）,c = 15.4852（17） ,V = 2164.8（4） 3,C17H28Co2N36O19,Mr = 1190.14 g·mol-1,Dc = 1.826 g·cm-3,μ（MoKα） = 0.888 mm-1,F（000） = 1211,Z = 2,R = 0.0576 and wR = 0.1431 for 11218 observed reflections（I 〉 2σ（I）） for Co2（DAT）5（H2O）3（TNR）2,respectively.The thermal decomposition characteristics of the com-pounds were investigated using differential scanning calorimetry and thermal gravimetry-diffediffer-rential thermal gravimetry.The results of thermal decomposition processes were similar for the two compounds.Both undergo four-step decomposition after the loss of coordinated H2O molecules.The final solid residues for the two DAT complexes were the corresponding metal oxides.The kinetic parameter of the first exothermic process of the compounds was studied by applying the Kissinger and Ozawa-Doyle methods.The thermodynamic parameters of the activation could be calculated.Sensitivity tests revealed that Co2（DAT）5（H2O）3（TNR）2 was more sensitive than Zn2（DAT）5（H2O）3（TNR）2.

Syntheses, Crystal Structures, Magnetic and Luminescent Properties of Ni(Ⅱ), Cd(Ⅱ) and Pb(Ⅱ) Coordination Compounds Constructed from 5-Fluoronicotinic Acid

Five coordination compounds, namely [Ni2(5-Fnic)2(H2 O)4](1), [Ni(5-Fnic)(μ-5-Fnic)(H2 biim)]n(2), {[Cd((μ-5-Fnic)2(H2 O)2]×4,4’-bipy}n(3), [Pb2(μ-5-Fnic)2(μ3-5-Fnic)2(H2 O)2]n(4), and [Pb(5-Fnic)2(4,4’-bipy)(H2 O)](5), have been constructed hydrothermally using 5-FnicH(5-FnicH = 5-fluoronicotinic acid), H2 biim(H2 biim = 2,2’-biimidazole), 4,4’-bipy(4,4’-bipy = 4,4’-bipyridine), NiCl2×6 H2 O, CdCl2×H2 O and PbCl2. The products were isolated as stable crystalline solids and were characterized by IR spectra, elemental analyses, thermogravimetric analyses(TGA), and single-crystal X-ray diffraction analyses. Structures of 1~5 range from discrete 0 D monomers(1 and 5) to 1 D coordination polymers(2 and 4) and 2 D metal-organic network(3). A broad structural diversity of 1~5 is guided by the type of the metal(Ⅱ) node and the introduction of auxiliary ligands. The magnetic(for 2) and luminescent(for 3~5) properties were also investigated and discussed.

Magnetic properties and magnetocaloric effects in(Ho_(1-x)Y_x)_5Pd_2 compounds

The crystal structure, magnetic and magnetocaloric properties of(Ho_(1-x) Y_(0.5))_5 Pd_2 compounds are investigated. All the compounds crystallize in a cubic Dy_5 Pd_2-type structure with the space group Fd3 m and undergo a second order transition from spin glass(SG) state to paramagnetic(PM) state. The spin glass transition temperatures T_g decrease from 26 K for x = 0 to 13 K for x = 0.5. In the PM region, the reciprocal susceptibilities for all the compounds obey the Curie–Weiss law. The paramagnetic Curie temperatures(θp) for Ho_5 Pd_2,(Ho_(0.75) Y_(0.25)_5 Pd_2, and(Ho_(0.5) Y_(0.5))_5 Pd_2 are determined to be 32 K, 30 K, and 22 K, respectively, and the corresponding effective magnetic moments(μeff) are10.8 μB/Ho, 10.3 μB/RE, and 7.5 μB/RE, respectively. Magnetocaloric effect(MCE) is anticipated according to the Maxwell relation, based on the isothermal magnetization curves. For a magnetic field change of 0–5 T, the maximum values of the isothermal magnetic entropy change-?SMof the(Ho_(1-x)Y_x)_5 Pd_2(x = 0, 0.25, and 0.5) compounds are determined to be 11.5 J·kg^(-1)·K^(-1), 11.1 J·kg^(-1)·K^(-1), and 8.9 K J·kg^(-1)·K^(-1), with corresponding refrigerant capacity values of 382.3 J·kg^(-1), 336.2 J·kg^(-1), and 242.5 J·kg^(-1), respectively.

Duration of treatment with 5-aminosalicylic acid compounds

The development of 5-aminosalicylic acid (5-ASA) therapy as a life long treatment for ulcerative colitis is reviewed from its origins in the 1940s to the present day. The drug was designed to treat rheumatoid arthritis,but was found helpful in the management of nine patients with ulcerative colitis. This discovery preceded the emergence of the clinical trial as a tool for assessing a new drug's efficacy; as a result it lacked scientific rigour and was selective in its presentation of results. Nevertheless it identified the future cornerstone of therapy in ulcerative colitis. In 1962,the first double blind controlled trial of sulphasalazine was conducted on 40 patients. Outcome measures were subjective and included symptoms and an assessment of the rectal mucosa. In 1973,the first two papers on the role of sulphasalazine in maintenance of remission were published. Both used placebo controls and had a stratified design. Outcomes were measured using "an intention to treat" approach. The British study of 64 patients used both subjective and objective criteria to assess outcomes. Patients on placebo had a relapse rate four times patients on active treatment and this founded the basis for a life long approach to therapy with 5-ASA compounds in ulcerative colitis. However,in 1985,a small "on demand" study of 32 patients suggested this approach might be as effective as continuous treatment. Some support for this view came from an Italian study which showed no benefit to continued treatment for those in remission for two years or more. The central problem these studies identify is that of adherence to treatment in the long-term. Few studies have considered patients' attitudes to continuous therapy and it is an area that needs further investigation.

ELECTRONIC STRUCTURE OF THE LaNi_(5-x)Ga_x INTERMETALLIC COMPOUNDS

The equilibrium structures and electronic structure of LaNi5-xGax （x=0, 0.5, 1.0） compounds have been investigated by all-electron calculations. Based on the full geometry optimization, the densities of states and electron densities of LaNi5-xGax are plotted and analyzed. It is clear that the substitution of Ga at the Ni site leads to a progressive filling of the Ni-d bands, the ionic interaction between Ni and Ni, with Ga plays a dominant role in the stability of LaNi5-xGax compounds. The smaller the shift of EF toward higher energy region, the more stable the compounds will be. The increased contribution of the Ni-d-Ga-d interactions near EF and the low energy metal-gallium bonding bands indicate that the compounds become more stable. The results are compared with experimental data and discussed in light of previous studies.

Studies on Functionally Substituted n5-Cyclopentadienyl Transition-Metal Compounds --Synthesis and Crystal Structure of η5-CH3COC5H4W(CO)3CH2C5H5

Reaction of benzyl chloride with η5-CH3COC5H4W(CO)2Na formed in situ from η6-CH3CO C6H4Na and W(CO)2 gives η6-CH3COC6H4W(CO)3CH2C5H5.The single crystal structure of the product was determined by X-ray diffraction method. It crystallizes in the triclinlc space group P1 with unit cell parameters a= 10.199(5),b=12.116(7), c=14.207(6)A;a=69.47(5),β=72. 38(3),γ= 85.89(4);V= 1569. 9A3, Dc= 1.98 g/cm2; Z=4. Least-square refinement led to final R value of 0. 0539 and Rw value of 0. 0553, based on 3548 independent observed reflections.

Review on Metal-Acid Tandem Catalysis for Hydrogenative Rearrangement of Furfurals to C_(5) Cyclic Compounds

Hydrogenative rearrangement of biomas s-derived furfurals(furfural and 5-hydroxymethyl furfural) to C_(5) cyclic compounds(such as cyclopentanones and cyclopentanols) offers an expedient reaction route for acquiring O-containing value-added chemicals thereby replacing the traditional petroleum-based approaches.The scope for developing efficient bifunctional catalysts and establishing mild reaction conditions for upgrading furfurals to cyclic compounds has stimulated immense deliberation in recent years.Extensive efforts have been made toward developing catalysts for multiple tandem conversions,including those with various metals and supports.In this scientific review,we aim to summarize the research progress on the synergistic effect of the metal-acid sites,including simple metal-supported acidic supports,adjacent metal acid sites-supported catalysts,and in situ H_(2)-modified bifunctional catalysts.Distinctively,the catalytic performance,catalytic mechanism,and future challenges for the hydrogenative rearrangement are elaborated in detail.The methods highlighted in this review promote the development of C_(5) cyclic compound synthesis and provide insights to regulate bifunctional catalysis for other applications.

Quantum Chemical Studies on Polydecker Sandwich Compounds with C_3B_2H_5 Ligand

The results of SCF CNDO-CO calculation on polymeric [(η5,μ-2,3-dihydro-1 , 3-di-borolyl)M](M= Cr, Mn, Fe, Co, Ni) indicate that polydecker sandwich compounds with odd valence electrons in each stacking unit (C3B2H5)M have Peierls distorted structures, while those with even valence electrons are favorable to the formation of regular structures. The Band structures show that both LU and HO bands are d-bands for all of the polydecker sandwich compounds studied.

STUDIES ON ORGANOPHOSPHORUS COMPOUNDS 69.A NOVEL SYNTHESIS OF 5-SUBSTITUTED 3-(1'-DIETHOXYPHOSPHORYLALKYL)-2-ISOXAZOLINES

Additions of diethyl phosphite to α-nitroalkenes followed by the introduction of trimethylchlorosilane and an activated alkene, gave the corresponding title compounds via regioselective 1,3-dipolar cycloaddition in moderate yield.

Is There any Hexazirconium Cluster in the Compounds [HP(t-Bu)_2Ph_3]_3[Zr_6Cl_(18)H_5] and Zr_6Cl_(14)(PPr_3)_4H_4?

The [Zr6(μ2-Cl)12Cl6H4]3- ion with C4v Symmetry in the title compounds has been calculated by DV-Xα program. The calculated results show that ther is almost no available covalence bonding between zirconium atoms and significant Zr 4d AO compositions in the MOs. but there are much stronger Zr-Cl(bridging) bonding. All analysis results suggest that these compounds would be the cluster with Zr6Cl12 cage linked by Zr-Cl bridging bonding plus six Cl teminal ligands rather than the hexazirconium cluster in view of the chemical bonding.

Cu_(6)Sn_(5)纳米颗粒对SAC3005/Cu焊点形貌和性能的影响

研究了添加Cu_(6)Sn_(5)纳米颗粒对SAC3005焊料焊点金属间化合物的形貌和性能的影响。采用湿化学法制备Cu_(6)Sn_(5)纳米颗粒,将Cu_(6)Sn_(5)纳米颗粒添加到SAC3005焊料中,经回流焊后,制备SAC3005-xCu_(6)Sn_(5)(x=0%,0.12%,0.18%,质量分数)复合焊点。采用金相显微镜对焊点的横断面进行观察,对焊点的横断面金属间化合物(IMCs)进行测量。采用ANSYS有限元软件对界面IMCs模型进行模拟,分析印刷电路板(PCB板)焊点失效机理。结果表明:添加Cu_(6)Sn_(5)纳米颗粒改性SAC3005/Cu焊点后的IMCs层厚度变薄。Cu_(6)Sn_(5)纳米颗粒的加入抑制了回流焊接过程中IMCs的生长,提高了焊点的可靠性。Cu_(6)Sn_(5)纳米颗粒的添加阻碍了Sn原子和Cu原子在界面处的扩散,抑制了Cu_(6)Sn_(5)IMCs的生长。添加质量分数为0.12%的Cu_(6)Sn_(5)纳米颗粒时抑制效果最好。焊点界面Cu_(6)Sn_(5)层和Cu_(3)Sn层是应力应变集中的地方,焊点交界处为焊点服役过程中的薄弱环节。

5-取代-4-氨基-3-巯基-1,2,4-三唑衍生物的应用进展

5-取代-4-氨基-3-巯基-1,2,4-三唑是一类重要的五元杂环化合物,由于分子中含有巯基和伯胺基两个活性基团,既可以单个基团参与反应生成N-或S-取代产物,又可以同时发生反应生成稠杂环化合物。由其衍生而来的化合物具有广泛的生物活性,在抗菌、抗肿瘤、抗结核、抗炎镇痛、酶抑制剂、荧光探针等方面都表现出优异的性能。综述了近年来5-取代-4-氨基-3-巯基-1,2,4-三唑衍生物在医学、农业及材料领域的应用,为今后进一步研究、开发此类化合物提供参考。

Two new phenolic compounds from Ardisia gigantifolia

Two new compounds were isolated from the 60% ethanol extract of the dried rhizome of Ardisia gigantifolia Stapf. The structures were elucidated on the basis of spectroscopic methods as （＋）-5-（1,2-dihydroxypentyl）-benzene- 1,3-diol and （-）-5-（1,2- dihydroxypentyl）benzene- 1,3-diol.

Study on Reaction of Thiophene Compounds and Olefins for Deep Desulfurization of Gasoline

The HY,Hβ,HZSM-5,and SAPO-11 zeolites were investigated in the alkylation reaction of thiophene and olefins.As a result,some sulfur-containing impurities could be converted to higher molecular weight components with their boiling point being in the range of diesel fraction.HZSM-5 had the highest activity and selectivity of desulfurization.At the same time,extensive oligomerization of olefins was not found and coke yield was very low,which could lead to high yield of gasoline products.The main reaction mechanism verifies that the second order alkylation reaction can be carried out on the outer surface and/or pores of the catalyst.The catalytic performance of the HZSM-5 catalyst which is poisoned by 2,4-dimethylquinoline during alkylation to form larger molecules of sulfur compounds is obviously weakened due to the decrease of the acid sites on the outer surface and at the mouth of pores.

碱处理改性ZSM-5分子筛孔结构对VOCs吸附性能的影响

采用氢氧化钠和四丙基氢氧化铵混合碱溶液处理制备一系列改性ZSM-5分子筛,通过X射线衍射(XRD)、扫描电子显微镜(SEM)、N_(2)吸附、水接触角测定等手段对改性样品进行了分析表征,采用固定床吸附器对比评价5A、NaY和不同碱改性ZSM-5分子筛吸附剂对正己烷和乙酸乙酯的动态吸附性能。结果表明:氢氧化钠和四丙基氢氧化铵摩尔浓度均为0.2 mol/L的碱改性ZSM-5-G-3样品的比表面积及总孔体积分别为425 m^(2)/g和0.585 cm^(3)/g,比改性前高硅ZSM-5-G-1样品分别提高了17.7%和174.6%,介孔比表面积增加8.6倍,达到317 m^(2)/g,介孔体积增加12.3倍,达到0.531 cm^(3)/g;随着碱溶液浓度的增加,改性分子筛材料水接触角减小;25℃时,正己烷和乙酸乙酯在ZSM-5-G-3吸附剂床层上的穿透吸附量分别为76.99和101.08 mg/g,比改性前ZSM-5-G-1吸附剂床层分别提高了40.3%和17.4%。改性ZSM-5-G-3样品对挥发性有机化合物(VOCs)吸附性能的显著提高主要归因于碱改性提供了更多的吸附位和介孔结构。

Syntheses, Characterization and Biological Activity of Novel Thiazoylazo Dye and Its Coordination Compounds

The present work describes the synthesis of a novel heterocyclic azo dye by general diazonization of 2-amino-4,5-dimethylthiazole followed by the diazo- coupling of the resulting diazonium ion with 5-methyl-2-(propan-2-yl)phenol to obtain ligand L. This was characterized using Fourier-transformed infrared and electronic spectrophotometry. Ligand L was further coordinated with five metal ions, M:L, 1:2 [M = Cu(II), Mn(II), Zn(II), Ni(II) and Co(II)]. The coordination compounds obtained were characterized by electronic, IR spectrophotometry, magnetic susceptibility and percentage metal analyses. The results obtained suggested that a thiazoylazo dye was obtained as ligand L. It was proposed that two molecules of the solvent coordinated to the metal ion in addition with the ligands to give an octahedral geometry for copper(II), manganese(II) and nickel(II) complexes. On the other hand, square planar geometry was suggested for zinc(II) and cobalt(II) complexes. The anti-infla- mmatory activity of the ligand and coordination compounds was evaluated using four in vitro-based assays viz: xanthine oxidase and lipoxygenase inhibition assay, membrane stability and protein denaturation assay. The synthesized compounds generally exhibited good anti-inflammatory activity in all the assays carried out. However, the reference standards, in this instance, were more effective in the case of xanthine oxidase, lipoxygenase and protein denaturation inhibitory assays. For the membrane stability study, the coordination compounds and ligand L elicited more potent anti-inflammatory activity than the standard drug.

ZSM-5分子筛对典型涂装VOCs的吸附性能及机理研究

通过水热法成功合成了一系列宽硅铝比(50、100、150、300、500、800、1500、3000)的ZSM-5分子筛,旨在研究其对涂装行业典型挥发性有机物(volatile organic compounds,VOCs)的吸附规律。同时,结合分子筛表面的酸性位点,以解析硅铝比对分子筛吸附性能的影响机制。实验结果表明,丙酮的吸附能力主要受自身极性、支链结构和分子筛表面酸位点的影响。而乙酸丁酯、苯乙烯、对二甲苯、苯、甲苯的吸附性能会同时受到自身的分子量、分子直径、极性、分子结构和官能团的影响,分子量和分子直径大、极性强且具有支链结构的VOCs更容易被ZSM-5分子筛吸附。这6种VOCs中,ZSM-5分子筛对丙酮的吸附效果最好,硅铝比对其吸附性能的影响也最大。这是因为丙酮比其他VOCs更容易吸附在Lewis酸位点上,硅铝比的改变会影响酸位点的数量。低硅铝比的分子筛由于具有较多的酸位点,更适用于丙酮的吸附。

ACTIVATION OF TiFe-LaNi_5 COMPOUND PARTICLES

Through controlled mechanical alloying treatment, TiFe and LaNi5 particles combined together on the surface of TiFe. This kind of compound particles can be easily activated at room temperature and an H2-pressure of 4.0 MPa. LaNi5 particles provided 'window' and 'path' for entrance of hydrogen from the surface to the interior of TiFe alloy.

5-氟尿嘧啶长循环脂质体的制备及表征

目的采用复合磷脂制备5-氟尿嘧啶(5-fluorouracil,5-FU)长循环脂质体,进行处方和工艺优化,并建立初步表征评价。方法采用逆向蒸发法制备5-FU复合磷脂长循环脂质体,用聚乙二醇(DSPE-mPEG2000)修饰脂质体,并根据单因素试验考察复合磷脂的比例、磷脂与胆固醇比例、药脂比、外水相pH值、载药温度及时间对5-FU长循环脂质体包封率的影响。采用紫外分光光度法测定包封率,以包封率为指标,分别考察蛋黄卵磷脂(E80)/氢化大豆磷脂(hydrogenated soy phosphatidylcholine,HSPC)质量比、药脂比、磷脂/胆固醇质量比以及外水相缓冲液pH等因素对脂质体质量的影响,在此基础上用正交设计对处方进行优化。考察5-氟尿嘧啶长循环脂质体的制剂学性质以及脂质体在4℃冷藏条件下的30天样品稳定性。结果经逆向蒸发法制备的5-FU长循环脂质体包封率为(68.81±0.22)%,载药量为(5.47±0.02)%。电镜结果及粒径检测显示,平均粒径为107 nm左右,PDI值稳定在0.3以下,粒度分布均匀,且呈单峰分布。于4℃条件放置3 d包封率无明显变化,30 d包封率下降(2.86±0.21)%。结论用复合磷脂制备的5-FU长循环脂质体制备工艺简单可行,性质稳定。