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791.
Amandine Grimm Imane Lejri Franois Hall Martine Schmitt Jürgen Gtz Frederic Bihel Anne Eckert 《Journal of neuroendocrinology》2020,32(1)
Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD. 相似文献
792.
Gonglu Tian Baiquan Wang Shansheng Xu Xiuzhong Zhou Bo Liang Liang Zhao Fenglou Zou Yang Li 《Macromolecular chemistry and physics.》2002,203(1):31-36
A series of sila‐bridged dinuclear zirconocenes [E(C5H4)2][Cp′ZrCl2]2 (Cp′=C5H5, E = Me2Si ( 1 ), Me2SiSiMe2 ( 2 ), Me2SiOSiMe2 ( 3 ), Me2SiOSiMe2OSiMe2 ( 4 ); Cp′=C5HMe4, E = Me2SiOSiMe2 ( 5 ), Me2SiOSiMe2OSiMe2 ( 6 )) have been synthesized. These complexes have been studied as catalysts for ethylene polymerization in the presence of MAO. Polymerization results indicated that the polymerization activity of the zirconocenes increased as the bridging ligand became longer for the same type of bridging ligands. Complex 4 , holding trisiloxane bridging, exhibited greater activity than the mononuclear zirconocene [Cp2ZrCl2]. All the siloxane‐bridged dinuclear zirconocenes showed the highest activity at higher temperature (60 or 70°C) in contrast to the corresponding siloxane‐bridged dinuclear cyclopentadienyl and indenyl zirconocenes which showed a maximum activity at 40°C. The molecular weight of polyethylene with 4 was very high at low temperature (13.43×105 g·mol–1 at 20°C) but decreased significantly with increasing temperature. The molecular weight distributions obtained for polyethylene were similar with the mononuclear metallocene catalysts at low temperatures and slightly broad at higher temperatures. The tetramethylcyclopentadienyl complexes 5 and 6 showed lower polymerization activities than the corresponding cyclopentadienyl complexes 3 and 4 as a result of steric effects. The relationship between structures and catalytic properties of catalysts has been discussed. 相似文献
793.
Maria J. Mokrosz Beata Duszyska Stanisaw Misztal Aleksandra Kodziska Ewa Tatarczyska Ewa Chojnacka-Wjcik Marta Dziedzicka-Wasylewska 《Archiv der Pharmazie》1998,331(10):325-330
A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT1A/5-HT2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT1A (Ki = 2 – 44 nM) and/or 5-HT2A affinity (Ki = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT1A receptors. The 5-HT2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT1A/5-HT2A affinity and an in vivo antagonistic activity towards both receptor subtypes. 相似文献
794.
黄酮类成分广泛存在于植物、中草药中,具有多种药理学活性,近年来的研究表明,它可以通过调控多种信号通路发挥其抗炎、抗氧化、化学预防等作用。笔者聚焦在药物代谢、免疫调节、化学预防中具有重要作用的芳香烃受体,在系统综述芳香烃受体功能及调控模式基础上,总结了不同黄酮类化合物对芳香烃受体的激动或拮抗作用,并对常见黄酮成分通过芳香烃受体发挥其抗肿瘤、抗溃疡性结肠炎、抗特异性皮炎的独特作用机制进行了介绍,并展望了黄酮类化合物在上述疾病治疗中潜在前景和局限性。 相似文献
795.
796.
核酸适体技术研究进展 总被引:8,自引:0,他引:8
核酸适体(aptamer)指的是经体外筛选技术SELEX(指数富集配体系统进化)筛选出的能特异结合蛋白质或其他小分子物质的寡聚核苷酸片段,对可结合的配体有严格的识别能力和高度的亲和力。核酸适体在生物传感器、新药开发以及纳米技术等方面有着广泛的用途,本文对核酸适体近两年的研究进展进行综述。 相似文献
797.
《Clinical Lymphoma, Myeloma & Leukemia》2023,23(6):438-445
IntroductionNon-Hodgkin lymphoma (NHL) is a heterogeneous disease, with each subtype associated with different risk factors. Within this group, diffuse large B-cell lymphoma (DLBCL) can be highlighted, the most common type of NHL.NK cells are key components of the innate immune response and may play an important antitumor role.ObjectiveThe objective of the present work was to determine the polymorphism of KIR genes in Brazilian patients with DLBCL.Materials and MethodsFurthermore, we evaluated the association between the polymorphism of these genes and their ligands with the clinical course of the disease. For the study, 112 patients with DLBCL and 222 voluntary blood and bone marrow donors. The genetic material of these samples were extracted for KIR and HLA typing, determination of HLA ligands, determination of the KIR haplotype and search for the deletion of 22 bp in the KIR2DS4 gene. KIR genotype distributions were made by direct counting using 2 × 2 contingency tables using Fisher's exact test. The magnitude of the association was measured by odds ratio (OR) and 95% confidence interval. P values <.05 were considered significant. Overall survival and progression-free survival were assessed with a Kaplan-Meier estimator.ResultsIn the present study, an association of HLA-Bw4 and HLA-Bw480I ligand was found with more advanced stages of the disease. Also, an association of the KIR2DL3 gene with a better response to treatment was found.ConclusionWith this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment was found. With this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment.Non-Hodgkin lymphoma (NHL) is a heterogeneous disease, with each subtype associated with different risk factors. Within this group, diffuse large B-cell lymphoma (DLBCL) can be highlighted, the most common type of NHL.NK cells are key components of the innate immune response and may play an important antitumor role. The objective of the present work was to determine the polymorphism of KIR genes in Brazilian patients with DLBCL. Furthermore, we evaluated the association between the polymorphism of these genes and their ligands with the clinical course of the disease. For the study, 112 patients with DLBCL and 222 voluntary blood and bone marrow donors. The genetic material of these samples were extracted for KIR and HLA typing, determination of HLA ligands, determination of the KIR haplotype and search for the deletion of 22 bp in the KIR2DS4 gene. KIR genotype distributions were made by direct counting using 2 × 2 contingency tables using Fisher's exact test. The magnitude of the association was measured by odds ratio (OR) and 95% confidence interval. P values <.05 were considered significant. Overall survival and progression-free survival were assessed with a Kaplan-Meier estimator. In the present study, an association of HLA-Bw4 and HLA-Bw480I ligand was found with more advanced stages of the disease. Also, an association of the KIR2DL3 gene with a better response to treatment was found. With this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment was found. With this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment. 相似文献
798.
目的 基于SHAP法观察以临床、病理、MRI特征及体素内不相干运动(IVIM)成像定量参数联合模型预测宫颈癌细胞程序性死亡蛋白1(PD-1)及其配体(PD-L1)表达的价值。方法 采集63例治疗前初诊宫颈癌盆腔MRI,并对病理标本行PD-1/PD-L1免疫组织化学染色;比较PD-1表达阳性与阴性组、PD-L1表达阳性与阴性组临床、病理、MRI表现及IVIM参数(真实弥散系数D、灌注相关弥散系数D*及灌注分数f)的差异,并以logistic回归分析筛选宫颈癌PD-1及PD-L1表达阳性的独立影响因素,建立预测宫颈癌PD-1及PD-L1表达阳性联合模型;以受试者工作特征(ROC)曲线评估模型诊断效能,以SHAP法解释其中各变量的贡献价值。结果 PD-1阳性组与阴性组、PD-L1阳性组与阴性组之间肿瘤病理分级、宫旁浸润、淋巴结转移及D值差异均有统计学意义(P均<0.05)。FIGO分期、肿瘤病理分级、宫旁浸润、淋巴结转移和D值均为宫颈癌PD-1/PD-L1表达阳性的独立影响因素(P均<0.05);以之建立的联合模型的曲线下面积分别为0.85及0.89。根据SHAP值,联合模型中FIGO分期和肿瘤病理分级的贡献最大。结论 以宫颈癌临床、病理、MRI特征及IVIM参数D值构建的联合模型可有效预测其PD-1/PD-L1表达。 相似文献
799.
800.
《药学学报(英文版)》2023,13(5):2152-2175
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase–hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 μmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood–brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19. 相似文献