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61.
Nadine Kretschmer Antje Hufner Christin Durchschein Katrin Popodi Beate Rinner Birgit Lohberger Rudolf Bauer 《International journal of molecular sciences》2021,22(5)
Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGloTM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma. 相似文献
62.
Dora Szabo Zsolt Sarszegi Beata Polgar Eva Saghy Adam Nemeth Dora Reglodi Andras Makkos Aniko Gorbe Zsuzsanna Helyes Peter Ferdinandy Robert Herczeg Attila Gyenesei Attila Cziraki Andrea Tamas 《International journal of molecular sciences》2021,22(6)
Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI. 相似文献
63.
Rosa Maria Paragliola Andrea Corsello Giampaolo Papi Alfredo Pontecorvi Salvatore Maria Corsello 《International journal of molecular sciences》2021,22(6)
The most known effects of endogenous Cushing’s syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus–pituitary–thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the “central hypothyroidism”. These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus–pituitary–thyroid axis activity. During active Cushing’s syndrome, the “immunological tolerance” guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing’s syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing’s syndrome patients, both during the active disease and after its remission. 相似文献
64.
We investigate the thermodynamics, kinetics, and capacity of the hydrogen storage reaction: Li2Mg(NH)2 + 2H2 Mg(NH2)2 + 2LiH. Starting with LiNH2 and MgH2, two distinct procedures have been previously proposed for activating samples to induce the reversible storage reaction. We clarify here the impact of these two activation procedures on the resulting capacity for the Li–Mg–N–H reaction. Additionally, we measure the temperature-dependent kinetic absorption data for this hydrogen storage system. Finally, our experiments confirm the previously reported formation enthalpy (ΔH), hydrogen capacity, and pressure–composition–isotherm (PCI) data, and suggest that this system represents a kinetically (but not thermodynamically) limited system for vehicular on-board storage applications. 相似文献
65.
Andrea Kunova Luca Palazzolo Fabio Forlani Giorgia Catinella Loana Musso Paolo Cortesi Ivano Eberini Andrea Pinto Sabrina Dallavalle 《International journal of molecular sciences》2021,22(7)
The increasing emergence of fungicide-resistant pathogens requires urgent solutions for crop disease management. Here, we describe a structural investigation of new fungicides obtained by combining strobilurin and succinate dehydrogenase inhibitor pharmacophores. We identified compounds endowed with very good activity against wild-type Pyricularia oryzae, combined in some cases with promising activity against strobilurin-resistant strains. The first three-dimensional model of P. oryzae cytochrome bc1 complex containing azoxystrobin as a ligand was developed. The model was validated with a set of commercially available strobilurins, and it well explains both the resistance mechanism to strobilurins mediated by the mutation G143A and the activity of metyltetraprole against strobilurin-resistant strains. The obtained results shed light on the key recognition determinants of strobilurin-like derivatives in the cytochrome bc1 active site and will guide the further rational design of new fungicides able to overcome resistance caused by G143A mutation in the rice blast pathogen. 相似文献
66.
Mootaz M. Salman Zaid Al-Obaidi Philip Kitchen Andrea Loreto Roslyn M. Bill Richard Wade-Martins 《International journal of molecular sciences》2021,22(9)
Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools. 相似文献
67.
Iris Ribitsch Andrea Bileck Alexander D. Aldoshin Maciej M. Kadua Rupert L. Mayer Monika Egerbacher Simone Gabner Ulrike Auer Sinan Gültekin Johann Huber David P. Kreil Christopher Gerner Florien Jenner 《International journal of molecular sciences》2021,22(11)
Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies. 相似文献
68.
Rudolf Rothen 《特种铸造及有色合金》2005,(Z1):140
全新的工艺数据永久记录,对压铸过程进行最优化控制满足适用并易于使用的市场需求.布勒公司新的dat@net控制系统(见图1和图2),综合了传统技术,实时操作,工业耐用性和稳定性,以及当今最先进的PCj技术的优点.精心的硬、软件匹配允许使自动化方案不受约束.也是首次,这种控制系统使压铸设备能够按照客户需求完全协调. 相似文献
69.
Summary The effect of tert-butyl chloride in the polymerizations of isobutylene carried out in the presence of SnCl4 in dichloromethane at temperatures-20°C and-78°C was investigated. Synthesized polyisobutylene samples showed a bimodal molecular
weight distribution (MWD) and it was found that the weight content of the lowermolecular weight (LMW) fraction increased with
increasing t-BuCl concentration in the polymerization mixture. The effect of ageing of the initiation mixture t-BuCl/SnCl4 in CH2Cl2 prepared in advance on MWD of the PIB samples was also studied. Ageing of the initiation system supports the formation of
the LMW fraction and this oily PIB is the only product of the polymerization at-20°C,
. 相似文献
70.
Smokers Richard Gense Raymond Rijkeboer Rudolf Dijkhuizen Arjan 《Topics in Catalysis》2004,30(1-4):439-443
Topics in Catalysis - This paper presents the results of a quantitatively substantiated “expert judgement” concerning the potential for further reduction of the exhaust emissions of... 相似文献