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1.
Curcumin (diferuloylmethane), the major yellow pigment isolated from the turmeric (Curcuma longa), has received much attention due to several biological properties. Curcumin exhibits a variety of pharmacological effects including antitumor, anti-inflammatory, and anti-infectious activities. In the present study, the effects of curcumin on apoptosis in the acute promyelocytic human leukemia (HL-60) cells was evaluated. Cytotoxic effects of curcumin on HL-60 cells were determined by MTT. HL-60 cells underwent apoptosis on treatment with curcumin, as indicated by increased annexin V-binding capacity and caspase-3 activation with flow cytometric analysis. Concentrations of 15, 20, and 40?μM curcumin significantly reduced cell proliferations. When HL-60 cells were treated with 10, 15, 20, and 40?μM concentration of curcumin, apoptotic rates were determined as 1.2, 81.1, 84.5, and 88.6%, respectively. On the incubations with the concentrations of curcumin, caspase-3 expressions (+) were found to be elevated by 8.5, 18.6, 91.2, and 92.4%, respectively. It was shown that curcumin had significant cytotoxic and apoptotic effects on HL-60 cells. It was suggested that curcumin may have a potential therapeutic role for human leukemia. 相似文献
2.
Stefan Gahbauer Galen J. Correy Marion Schuller Matteo P. Ferla Yagmur Umay Doruk Moira Rachman Taiasean Wu Morgan Diolaiti Siyi Wang R. Jeffrey Neitz Daren Fearon Dmytro S. Radchenko Yurii S. Moroz John J. Irwin Adam R. Renslo Jenny C. Taylor Jason E. Gestwicki Frank von Delft Alan Ashworth Ivan Ahel Brian K. Shoichet James S. Fraser 《Proceedings of the National Academy of Sciences of the United States of America》2023,120(2)
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.The macrodomain of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nonstructural protein 3 (NSP3) (Mac1) presents an intriguing target for drug discovery (1–5). Upon viral infection, host cells initiate an innate interferon-mediated immune response leading to the expression of poly-(ADP-ribose)-polymerases (PARPs), which catalyze the antiviral posttranslational addition of ADP-ribose (ADPr) to a large range of target proteins (6). Mac1 enzymatically reverses this mono-ADP-ribosylation, counteracting immune signaling (7). Promisingly, inactivation of Mac1 by single-point mutations in the ADPr-binding site significantly reduced lethality and pathogenicity in mice after SARS-CoV infection (8). Small-molecule inhibitors of SARS-CoV-2 Mac1 should therefore offer novel therapeutics to mitigate COVID-19 (9, 10).A challenge for the development of such inhibitors has been the lack of small-molecule modulators of macrodomain activity, other than ADPr; indeed, only recently have quantitative assays been developed (10, 11). This is true not only for Mac1 from SARS-CoV-2, but also for the overall family of enzymes, which lack good chemical matter by which their activity can be probed, despite their importance in several areas of health and diseases. Accordingly, to map the recognition determinants of Mac1, we adopted a biophysical approach, screening for fragment ligands using protein crystallography, molecular docking, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), and a binding assay based on homogeneous time-resolved fluorescence (HTRF) (12). Mac1 proved to be unusually amenable to structure determination, enabling us to determine the structures of over 230 fragment complexes, typically to ultra-high resolution (often better than 1.1 Å), affording us a detailed map of enzyme hot spots with chemical matter of sufficient potency with which to optimize a quantitative assay (12, 13).Nevertheless, our best fragments remained of modest potency, with none more potent than 180 µM. Here, we describe the discovery and optimization of potent macrodomain ligands using two strategies (Fig. 1). In the first, we sought to link and merge pairs of fragments to create larger molecules that exploited multiple hot spots, so reaching higher affinities. This used a fragment-linking method (12), adapted to explore a virtual library of 22 billion readily synthesizable molecules (14). In the second approach, we exploited the hot spots revealed by the initial fragments to guide computational docking of ultra-large chemical libraries of lead-like molecules, potentially more potent than the fragments docked in our original study (12). Both approaches ultimately led to compounds with IC50 values as low as 0.4 µM for the merged fragments and as low as 1.7 µM for the docking hits (Fig. 1). These represent the most potent inhibitors reported for any member of the broad family of macrodomains. Furthermore, the many X-ray crystal structures determined here provide an extensive resource for drug development campaigns against this promising antiviral target.Open in a separate windowFig. 1.Overview of the structure-based strategies used to discover ligands that bind to the NSP3 macrodomain of SARS-CoV-2 (Mac1). 相似文献
3.
Kaptan Yagmur Suner Asli Taş Mehmet Nedim Oksel Fahrettin Aksu Kenan Sayiner Abdullah 《Clinical rheumatology》2021,40(9):3783-3788
Clinical Rheumatology - Although latent tuberculosis infection (LTBI) treatment is given before anti-tumor necrosis factor (TNF) treatment, tuberculosis (TB) still develops in these patients and... 相似文献
4.
Julide Yagmur Mehmet Cansel Nusret Acikgoz Murat Yagmur Ferhat Eyupkoca Necip Ermis Erdal Akturk 《Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital》2012,39(6):881-883
A 49-year-old woman who had idiopathic thrombocytopenic purpura was admitted to our hospital with severe chest pain. Electrocardiography revealed inferolateral myocardial infarction. The patient underwent immediate coronary angiography, which revealed thrombi in the left coronary system. Percutaneous intervention was not indicated, because the thrombi had occluded the distal segments of multiple coronary arteries. Administration of tirofiban satisfactorily dissolved the thrombi.Key words: Coronary thrombosis, multivessel; myocardial infarction; platelet aggregation inhibitors/therapeutic use; purpura, thrombocytopenic, idiopathic/therapy; tirofibanIdiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which autoantibodies bind platelets, leading to their sequestration by the reticuloendothelial system.1 Patients with ITP typically have mucocutaneous bleeding. Although such reports are rare, thrombotic complications such as acute myocardial infarction (MI) and stroke also occur in patients with ITP.2–4 We present the case of a middle-aged woman with ITP who sustained an acute MI caused by multivessel coronary thrombosis. 相似文献
5.
Meckel's diverticulum(MD) results from incomplete involution of the proximal portion of the vitelline(also known as the omphalomesenteric) duct during weeks 5-7 of foetal development. Although MD is the most commonly diagnosed congenital gastrointestinal anom-aly, it is estimated to affect only 2% of the population worldwide. Most cases are asymptomatic, and diagno-sis is often made following investigation of unexplained gastrointestinal bleeding, perforation, inflammation or obstruction that prompt clinic presentation. While MD range in size from 1-10 cm, cases of giant MD(≥ 5 cm) are relatively rare and associated with more severe forms of the complications, especially for obstruction. Herein, we report a case of giant MD with secondary small bowel obstruction in an adult male that was suc-cessfully managed by surgical resection and anasto-mosis created with endoscopic stapler device(80 mm, endo-GIA stapler). Patient was discharged on post-operative day 6 without any complications. Histopatho-logic examination indicated Meckel's diverticulitis with-out gastric or pancreatic metaplasia. 相似文献
6.
Beyza Ozcan Dilek Ulubas Isik Ozge Aydemir Yusuf Kale Nazile Erturk Ahmet Yagmur Bas Nihal Demirel 《European journal of pediatrics》2014,173(2):257-258
Congenital megalourethra is a rare urogenital malformation characterized by severe dilatation and elongation of the penile urethra. It causes functional obstruction of the lower urinary system. Herein, we present a newborn with congenital megalourethra with single umbilical artery. 相似文献
7.
Mustafa Altunsoy Murat Selim Botsali Emre Korkut Ebru Kucukyilmaz Yagmur Sener 《Acta odontologica Scandinavica》2014,72(8):874-879
Objective. The aim of this study was to evaluate the effect of different surface treatments on the microtensile bond strength (μTBS) and shear bond strength (SBS) of resin-modified glass ionomer cement (RMGIC) to dentin. Materials and methods. Fifty-two extracted human molars were flattened to obtain dentin surfaces. For SBS assessment 40 teeth were divided into four groups according to their surface treatments (acid etching, Er:YAG laser QSP mode, Er:YAG laser MSP mode and control-SiC) (n = 10). A plastic cylinder was placed over the differently treated dentin surfaces and RMGIC was placed into the rings and polymerized. Twelve teeth were used for the μTBS test. The treated dentin surfaces described above were restored with 4 mm high RMGIC and light cured; then, the specimens were sectioned into serial sticks (n = 15) and μTBS and SBS were tested for failure in a testing machine with a 1 mm/min crosshead speed. The data were analyzed by one-way ANOVA and Tukey HSD tests (α = 0.05). Results. Acid etching showed significantly higher SBS than the other groups (p < 0.05). Er:YAG QSP and MSP-treated groups showed higher SBS values than the control group, but the difference was not statistically significant (p > 0.05). Er:YAG MSP showed the highest μTBS value followed by acid etching, whereas the control group exhibited the lowest value (p < 0.05) and the differences between the control group and Er:YAG QSP were not significant (p > 0.05). Conclusions. The application of Er:YAG MSP mode and acid etching to dentin can be used for improving the bond strength of RMGIC. 相似文献
8.
Low serum transferrin correlates with acute‐on‐chronic organ failure and indicates short‐term mortality in decompensated cirrhosis 下载免费PDF全文
9.
10.
The concept of crosstalk‐directed embryological target mining and its application to essential hypertension treatment failures 下载免费PDF全文
Alan Alper Sag MD Oguzhan Sal MD Yagmur Kilic MD Emine Meltem Onal MD Mehmet Kanbay MD 《Journal of clinical hypertension (Greenwich, Conn.)》2017,19(5):530-533
This review aims to introduce the novel concept of embryological target mining applied to interorgan crosstalk network genesis, and applies embryological target mining to multidrug‐resistant essential hypertension (a prototype, complex, undertreated, multiorgan systemic syndrome) to uncover new treatment targets and critique why existing strategies fail. Briefly, interorgan crosstalk pathways represent the next frontier for target mining in molecular medicine. This is because stereotyped stepwise organogenesis presents a unique opportunity to infer interorgan crosstalk pathways that may be crucial to discovering novel treatment targets. Insights gained from this review will be applied to patient management in a clinician‐directed fashion. 相似文献