Multiple Glycosaminoglycan-binding Epitopes of Monocyte Chemoattractant Protein-3/CCL7 Enable It to Function as a Non-oligomerizing Chemokine

The interaction of chemokines with glycosaminoglycans (GAGs) facilitates the formation of localized chemokine gradients that provide directional signals for migrating cells. In this study, we set out to understand the structural basis and impact of the differing oligomerization propensities of the chemokines monocyte chemoattractant protein (MCP)-1/CCL2 and MCP-3/CCL7 on their ability to bind GAGs. These chemokines provide a unique comparison set because CCL2 oligomerizes and oligomerization is required for its full in vivo activity, whereas CCL7 functions as a monomer. To identify the GAG-binding determinants of CCL7, an unbiased hydroxyl radical footprinting approach was employed, followed by a focused mutagenesis study. Compared with the size of the previously defined GAG-binding epitope of CCL2, CCL7 has a larger binding site, consisting of multiple epitopes distributed along its surface. Furthermore, surface plasmon resonance (SPR) studies indicate that CCL7 is able to bind GAGs with an affinity similar to CCL2 but higher than the non-oligomerizing variant, CCL2(P8A), suggesting that, in contrast to CCL2, the large cluster of GAG-binding residues in CCL7 renders oligomerization unnecessary for high affinity binding. However, the affinity of CCL7 is more sensitive than CCL2 to the density of heparan sulfate on the SPR surfaces; this is likely due to the inability of CCL7 to oligomerize because CCL2(P8A) also binds significantly less tightly to low than high density heparan sulfate surfaces compared with CCL2. Together, the data suggest that CCL7 and CCL2 are non-redundant chemokines and that GAG chain density may provide a mechanism for regulating the accumulation of chemokines on cell surfaces.     

精准营养联合生长抑素对胃癌根治术患者的临床疗效

目的探讨生长抑素联合精准营养疗法对胃癌根治术患者术后营养指标水平和肠道菌群的影响。方法选取我院2017年10月至2019年1月收治并拟行胃癌根治术治疗的92例胃癌患者为研究对象,随机分为对照组(46例)和观察组(46例)。两组患者术后均给予常规处理。对照组患者同时给予生长抑素+常规肠外营养支持,观察组患者同时给予生长抑素+精准营养支持。于营养干预前后统计两组患者营养相关指标[体质量、血清白蛋白(ALB)、前白蛋白(PA)、淋巴细胞计数(LC)、肌酐(Ct)以及尿素氮(UN)]水平;对肠道菌群进行alpha分析,并计算肠杆菌、肠球菌、乳杆菌和双歧杆菌数量。结果营养干预前,两组患者营养相关指标水平以及肠道菌群相关指标水平之间差异无统计学意义(均P>0.05)。营养干预后,(1)观察组患者平均体质量以及血清ALB、PA、LC水平分别为(56.98±5.34)kg、(29.98±6.03)mg/L、(137.14±35.17)g/L、(1.15±0.26)×10⁹,对照组分别为(53.29±5.18)kg、(26.12±5.29)mg/L、(104.53±27.66)g/L、(0.82±0.18)×10⁹,两组之间差异有统计学意义(均P<0.05);(2)观察组患者肠道菌群Chao指数和Ace指数水平分别为(397.84±75.23)、(408.26±78.34),对照组分别为(362.13±66.23)、(371.19±70.09),两组之间差异有统计学意义(均P<0.05);(3)观察组患者肠道肠杆菌、肠球菌数量明显低于对照组,而乳杆菌、双歧杆菌数量明显高于对照组(均P<0.05)。结论胃癌根治术患者术后联合生长抑素和精准营养疗法能够显著改善患者的营养状况,保持肠道菌群丰度,平衡肠道菌群分布,值得临床研究和应用。     

肝癌乙型肝炎病毒感染患者术后恩替卡韦抗病毒治疗的临床疗效及安全性评价

目的:探讨肝癌乙型肝炎病毒(HBV)感染患者根治性切除术后采用恩替卡韦抗病毒治疗的临床疗效及安全性。方法:收集2015年1月-2017年8月在我院行根治性切除术的肝癌HBV感染患者279例为研究对象,以血清HBV-DNA载量10~5 copies/ml为界限,分为高病毒复制组128例,低病毒复制组151例,按照随机数字表法将高病毒复制组分为高-治疗组64例、高-对照组64例,将低病毒复制组分为低-治疗组76例、低-对照组75例。高-治疗组和低-治疗组术后给予恩替卡韦0.5 mg/d,高-对照组和低-对照组未行抗病毒治疗。比较手术前、术后7 d各组的血清HBV-DNA水平,血清白蛋白(ALB)、谷丙转氨酶(ALT)、前白蛋白(PA),以及术后并发症的发生情况。结果:高-治疗组、高-对照组、低-治疗组、低-对照组术后血清ALB、PA均较治疗前降低,血清ALT均较治疗前升高,且高-治疗组或低-治疗组术后血清ALB、PA均高于高-对照组或低-对照组,血清ALT水平均低于高-对照组或低-对照组,差异均有统计学意义(P0.05);高-治疗组或低-治疗组术后血清HBV-DNA水平均低于治疗前,且均低于同期高-对照组或低-对照组,差异均有统计学意义(P0.05)。高-治疗组与高-对照组、低-治疗组与低-对照组患者术后并发症发生率均无统计学差异(P0.05)。结论:恩替卡韦能显著改善肝癌HBV感染患者术后的血清HBV-DNA载量水平和肝功能,安全性高,值得临床推广。     

保乳手术与改良根治术治疗Ⅰ-Ⅱ期乳腺癌患者的疗效及生存状况比较研究

目的:比较分析乳腺癌保乳手术和根治术的临床疗效及患者生存状况。方法:回顾性分析2012年6月至2015年6月在我院乳腺外科行手术治疗的乳腺癌患者92例的临床资料,其中行保乳手术患者24例(保乳组),行根治手术患者68例(根治组),两组患者术后均采用个性化综合治疗巩固疗效,对比观察两组疗效及预后状况;通过乳腺癌生命质量测定量表(FACT-B)检测对比两组患者术后1、2年的生存质量;并对比两组患者术后乳房美容效果。结果:保乳组患者手术时间、术中出血量、引流量以及引流时间均明显较根治组少,差异有统计学意义(P0.05),而淋巴结清扫数则无明显差异(P0.05);两组患者上肢水肿发生率无明显差异(P0.05),而保乳组切缘皮瓣缺血发生率低于根治组(P0.05);两组患者术后2年生存率、复发率以及远处转移率无统计学差异(P0.05)。保乳组患者术后1、2年生理状况、情感状况、社会状况、功能状况、其他因素及生活质量综合评分均显著高于根治组,差异有统计学意义(P0.05);保乳组术后乳房美容效果的优良率显著高于根治组,差异有统计学意义(P0.05)。结论:相比于根治术,保乳手术不仅具有创伤小、术后恢复快的优势,患者预后状况与根治术相当,同时可更好的改善患者生存质量,术后乳房美容效果较好,临床应用价值更高。     

Synthetic construction of sugar-amino acid hybrid polymers involving globotriaose or lactose and evaluation of their biological activities against Shiga toxins produced by Escherichia coli O157:H7

Synthetic assembly of sugar moieties and amino acids in order to create “sugar-amino acid hybrid polymers” was accomplished by means of simple radical polymerization of carbohydrate monomers having an amino acid-modified polymerizable aglycon. Amines derived from globotriaoside and lactoside as glycoepitopes were condensed with known carbobenzyloxy derivatives, including Z-Gly, Z-l-Ala and Z-β-Ala, which had appropriate spacer ability and a chiral center to afford fully protected sugar-amino acid hybrid compounds in good yields. After deprotection followed by acryloylation, the water-soluble glycomonomers were polymerized with or without acrylamide in the presence of a radical initiator in water to give corresponding copolymers and homopolymers, which were shown by SEC analysis to have high molecular weights. Evaluation of the biological activities of the glycopolymers against Shiga toxins (Stxs) was carried out, and the results suggested that glycopolymers having highly clustered globotriaosyl residues had high affinity against Stx2 (K_D?=?2.7～4.0?µM) even though other glycopolymers did not show any affinity or showed very weak binding affinity. When Stx1 was used for the same assay, all of the glycopolymers having globotriaosyl residues showed high affinity (K_D?=?0.30～1.74?µM). Interestingly, couple of glycopolymers having lactosyl moieties had weaker binding affinity against Stx1. In addition, when cytotoxicity assays were carried out for both Stxs, glycopolymers having highly clustered globotriaosyl residues showed higher affinity than that of the copolymers, and only highly clustered-type glycopolymers displayed neutralization potency against Stx2.     

Effect of Brønsted acids on the thiophenol-mediated radical addition–translocation–cyclization process for the preparation of pyrrolidine derivatives

Abstract

A thiophenol-mediated method for the conversion of propargylamines to pyrrolidines under acidic conditions is described. This cascade reaction involves addition of a thiyl radical to the terminal alkyne followed by a 1,5-hydrogen transfer (radical translocation) and a rapid cyclization affording the pyrrolidine ring. Our studies reveal that complete protonation of the tertiary amine with 10 equivalents of trifluoroacetic acid avoids undesired hydrogen atom abstractions by the thiyl radicals.     

Identification of novel allosteric modulators for the G-protein coupled US28 receptor of human cytomegalovirus

The highly constitutively active G-protein coupled receptor US28 of human cytomegalovirus (HCMV) is an interesting pharmacological target because of its implication on viral dissemination, cardiovascular diseases and tumorigenesis. We found that dihydroisoquinolinone and tetrahydroisoquinoline scaffolds may be promising lead structures for novel US28 allosteric inverse agonists. These scaffolds were rapidly synthesized by radical carboamination reactions followed by non-radical transformations. Our novel US28 allosteric modulators provide valuable scaffolds for further ligand optimization and may be helpful chemical tools to investigate molecular mechanisms of US28 constitutive signaling and its role in pathogenesis.     

Thrombin inhibitors with lipid peroxidation and lipoxygenase inhibitory activities

Vascular oxidative stress, endothelial injury, and thrombosis are intertwined processes that display a synergistic pathological effect in many cardiovascular diseases. Antithrombotic therapy with anticoagulant and/or antiplatelet agents, combined with interventions against vascular oxidative stress and/or inflammation, both boosting endothelial antithrombotic potential, could display a synergistic action in the treatment of thrombosis. Of the compounds 10a-h and 11a-d, shown to possess thrombin inhibitory activity, 11a-d were found to display radical scavenging activity, 10a, 10d, and 10f were demonstrated to inhibit lipid peroxidation of linoleic acid, and 10b and 10h inhibited soybean lipoxygenase. The observed combination of thrombin inhibition with lipid peroxidation and/or lipoxygenase inhibitory activity makes compounds 10 and 11 interesting candidates for further investigations towards multiple antithrombotic drugs.     

Structural and spectroscopic characterisation of the holmium double-decker partially oxidised and bi-radical phthalocyanine complexes with iodine

Two crystals of holmium(III) double-decker iodine doped phthalocyanines, HoPc₂I_5/3 (I) and HoPc₂I (II), were grown directly in the reaction of holmium chips with 1,2-dicyanobenzene under versatile quantity of iodine at 180-160 °C. The complex I crystallises in the P4/mcc space group of tetragonal system, while the complex II crystallises in the P2/c space group of monoclinic system. The space group of P4/mcc and z = 1 requires that the Ho(III) atom is statistically disordered in the HoPc₂I_5/3 structure. The iodine atoms form linear symmetrical triiodide ions in I, while the I⁻ ions in II. Assignment of iodine species as in the HoPc₂I_5/3 and I⁻ in HoPc₂I complexes point to the +5/9 and +1 oxidation state of the HoPc₂ unit in these complexes. Thus one Pc macrocycle of the double-decker HoPc₂ units has a non-integer oxidation state of −1.222 in I, while both Pc-rings are one-electron oxidised radical Pc⁻ in II. Magnetic susceptibilities of HoPc₂I_5/3 and HoPcI at room temperature are 4.56 × 10⁻² and 5.12 × 10⁻² emu/mol and the calculated magnetic moments are 10.46 and 11.08 μ_B, respectively. UV-Vis spectroscopic measurement of I and II in benzene solution were carried out and discussed.     

Comparison of antioxidant effectiveness of lipoic acid and dihydrolipoic acid

The abilities of dihydrolipoic acid (DHLA) to scavenge peroxynitrite (ONOO^?), galvinoxyl radical, 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonate) cation radical (ABTS^+?), and 2,2′‐diphenyl‐1‐picrylhydrazyl radical (DPPH) were higher than those of lipoic acid (LA). The effectiveness of DHLA to protect methyl linoleate against 2,2′‐azobis(2‐amidinopropane hydrochloride) (AAPH)‐induced oxidation was about 2.2‐fold higher than that of LA, and DHLA can retard the autoxidation of linoleic acid (LH) in the β‐carotene‐bleaching test. DHLA can also trap ～0.6 radicals in AAPH‐induced oxidation of LH. Moreover, DHLA can scavenge ～2.0 radicals in AAPH‐induced oxidation of DNA and AAPH‐induced hemolysis of erythrocytes, whereas LA can scavenge ～1.5 radicals at the same experimental conditions. DHLA can protect erythrocytes against hemin‐induced hemolysis, but accelerate the degradation of DNA in the presence of Cu²⁺. Therefore, the antioxidant capacity of –SH in DHLA is higher than S‐S in LA. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 25:216–223, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.20378