T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematopoietic malignancy prone to relapse and drug resistance. Half of all T-ALL patients exhibit mutations in Notch1, which leads to aberrant Notch1 associated signaling cascades. Notch1 activation is mediated by the γ-secretase cleavage of the Notch1 receptor into the active intracellular domain of Notch1 (NCID). Clinical trials of γ-secretase small molecule inhibitors (GSIs) as single agents for the treatment of T-ALL have been unsuccessful. The present study demonstrated, using immunofluorescence and western blotting, that blocking γ-secretase activity in T-ALL cells with -[(3,5-difluorophenyl) acetyl]-L-alanyl-2-phenyl] glycine-1,1-dimethylethyl ester (DAPT) downregulated NCID and upregulated the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5). Upregulation of DR5 restored the sensitivity of T-ALL cells to TRAIL. Combination index revealed that the combined treatment of DAPT and TRAIL synergistically enhanced apoptosis compared with treatment with either drug alone. TRAIL combined with the clinically evaluated γ-secretase inhibitor 3-[(1r, 4s)-4-(4-chlorophenylsulfonyl)-4-(2, 5-difluorophenyl) cyclohexyl] propanoic acid (MK-0752) also significantly enhanced TRAIL-induced cell death compared with either drug alone. DAPT/TRAIL apoptotic synergy was dependent on the extrinsic apoptotic pathway and was associated with a decrease in BH3 interacting-domain death agonist and x-linked inhibitor of apoptosis. In conclusion, γ-secretase inhibition represents a potential therapeutic strategy to overcome TRAIL resistance for the treatment of T-ALL.
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http://dx.doi.org/10.3892/ol.2016.5011 | DOI Listing |
J Trace Elem Med Biol
January 2025
Department of Pathology, College of Medicine, King Khalid University, Asir 61421, Saudi Arabia; Department of Forensic Medicine and Clinical Toxicology, Mansoura University, Egypt.
Background: Vanadium (VAN) is a significant trace element, but its higher exposure is reported to cause severe organ toxicity. Tectochrysin (TEC) is a naturally derived flavonoid which demonstrates a wide range of pharmacological properties.
Aim: The current study was planned to assess the cardioprotective potential of TEC against VAN induced cardiotoxicity in rats via regulating biochemical, and histological profile.
Sci Total Environ
January 2025
National Engineering Research Center for Efficient Utilization of Soil and Fertilizer Resources, Key Laboratory of Agricultural Environment in Universities of Shandong, College of Resources and Environment, Shandong Agricultural University, Tai'an 271018, China. Electronic address:
Perfluorooctane sulfonate (PFOS) and its new substitute, perfluorobutane sulfonate (PFBS), are increasing in concentration in the environment annually, and their toxicity cannot be ignored. With an increasing amount of PFOS and PFBS entering the environment, especially into farmland soil, it is very likely to pollute tobacco-planting soil. Therefore, we chose tobacco (Nicotiana tabacum L.
View Article and Find Full Text PDFForensic Sci Int Genet
December 2024
Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway.
With the advent of commercial DNA databases, investigative genetic genealogy (IGG) has emerged as a powerful forensic tool, rivalling the impact of STR analyses, introduced four decades ago. IGG has been frequently applied in the US and tested in other countries, but never in Norway. Here, we apply IGG to three cold criminal cases and successfully identify the donor of the DNA in two of these cases.
View Article and Find Full Text PDFAppl Radiat Isot
January 2025
Reactor Design Group, IGCAR, Kalpakkam, 603102, India.
This study examines the impact of the Westcott g-factor on the concentration of elements like In, Ir, Re, Yb, Eu and Lu, measured using neutron capture reactions (n,γ), specifically focusing on those reactions, whose thermal neutron capture cross-sections (σ ) deviate from the conventional '1/v' behaviour. These measurements are quantified using k₀-based neutron activation analysis. The Westcott g-factor for the non-1/v nuclides was calculated using the characterized neutron temperature (T) at PFTS irradiation channel of KAMINI reactor.
View Article and Find Full Text PDFActa Pharm
December 2024
University of Zagreb Faculty of Pharmacy and Biochemistry, Department of Pharmacognosy 10000 Zagreb, Croatia.
Biowaste produced in urban parks is composed of large masses of organic matter that is only occasionally used economically. In this work, extracts of six plants widely distributed in urban parks in Central Europe (, , , , , and ), prepared using 10 % and 50 % ethanol, were screened for their antidiabetic and related properties. HPLC and UV-Vis analysis revealed the presence of caffeic acid, quercetin, luteolin, and apigenin derivatives.
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