Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K-562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC 50-9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC 50-28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC 50-104.2 μM) and human fibroblasts (HS27) (CC 50-105.0 μM). Thus, among this novel series of TZD *
SUMMARY:This work investigates the role of oleanolic acid (OA), isolated from the olive (Olea europaea L.) leaf, as a radical scavenger and inhibitor of the hydrolyzing enzymes of dietary carbohydrates. New evidence is provided showing that OA may capture 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) and peroxyl radicals, and also exert a strong and non-competitive inhibition of α-glucosidase (IC 50 10.11 ± 0.30 µM). The kinetic and spectrometric analyses performed indicate that OA interacts with this enzyme inside a hydrophobic pocket, through an endothermic and non spontaneous process of a hydrophobic nature. These are two possible mechanisms by which OA may facilitate a better control of post-prandial hyperglycaemia and oxidative stress, so contributing to preserving insulin signalling. Obesity, insulin resistance and Type 2 Diabetes Mellitus are considered the first pandemics of the 21st century. In this sense, OA might be used in future preventive and therapeutic strategies, as an ingredient in new drugs and functional foods.KEYWORDS: Anti-diabetic activity; Antioxidant; α-glucosidase inhibitor; Olea europaea; Oleanolic acid RESUMEN: La Captación de radicales libres y la inhibición de α-glucosidasa, dos posibles mecanismos involucrados en la actividad antidiabética del ácido oleanólico. Este trabajo estudia el papel del ácido oleanólico (OA), aislado de la hoja de olivo, como secuestrador de radicales libres e inhibidor de enzimas implicados en la hidrolisis de los carbohidratos de la dieta, dos mecanismos por los que el triterpeno podría mitigar la hiperglicemia postprandial y el estrés oxidativo. Se aportan nuevas evidencias que muestran que el OA puede capturar radicales ácido 2,2'-azino-bis-(3-etilbenzotiazolín)-6-sulfónico y peroxilo, y que ejerce una potente inhibición nocompetitiva de α-glucosidasa (IC 50 10.11±0.30 µM). El análisis cinético y espectrométrico llevado a cabo indica que OA interacciona con este enzima en el interior de un bolsillo hidrofóbico, mediante un proceso endotér-mico no espontáneo, de naturaleza hidrofóbica. Estos son dos posibles mecanismos por los cuales el OA puede facilitar un mejor control de la hiperglucemia postprandial y el estrés oxidativo, lo que contribuye a preservar la señalización de la insulina. La obesidad, la resistencia a la insulina y la diabetes mellitus tipo 2 se consideran la primera pandemia del siglo XXI. En este sentido, el OA podría ser utilizado en futuras estrategias preventivas y terapéuticas, como ingrediente de nuevos fármacos y alimentos funcionales. Free radical scavenging and α-glucosidase inhibition, two potential mechanisms involved in the anti-diabetic activity of oleanolic acid. Grasas Aceites 67 (3): e142. doi: http://dx
Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital role in tumor cell survival and are overexpressed in various cancers. GLUT1, the most overexpressed GLUT in many cancers, is emerging as a promising anticancer target. To develop GLUT1 inhibitors, we rationally designed, synthesized, structurally characterized, and biologically evaluated in-vitro and in-vivo a novel series of furyl-2-methylene thiazolidinediones (TZDs). Among 25 TZDs tested, F18 and F19 inhibited GLUT1 most potently (IC 50 11.4 and 14.7 μM, respectively). F18 was equally selective for GLUT4 (IC 50 6.8 μM), while F19 was specific for GLUT1 (IC 50 152 μM in GLUT4). In-silico ligand docking studies showed that F18 interacted with conserved residues in GLUT1 and GLUT4, while F19 had slightly different interactions with the transporters.
How is fuzzy logic usually formalized? There are many seemingly reasonable requirements that a logic should satisfy: e.g., since A&B and B&A are the same, the corresponding and-operation should be commutative. Similarly, since A&A means the same as A, we should expect that the and-operation should also satisfy this property, etc. It turns out to be impossible to satisfy all these seemingly natural requirements, so usually, some requirements are picked as absolutely true (like commutativity or associativity), and others are ignored if they contradict to the picked ones. This idea leads to a neat mathematical theory, but the analysis of real-life expert reasoning shows that all the requirements are only approximately satisfied. we should require all of these requirements to be satisfied to some extent. In this paper, we show the preliminary results of analyzing such operations. In particular, we show that non-associative operations explain the empirical 7 AE 2 law in psychology according to which a person can normally distinguish between no more than 7 plus minus 2 classes.
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