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PURPOSE OF THE STUDY: Our aim was to compare the effects of intraarticular and intravenous (IV) tranexemic acid (TXA) application on bleeding and complication rates in patients who underwent total knee arthroplasty (TKA). MATERIAL AND METHODS: Between 2017 and 2021, 406 patients who underwent TKA with 2 g of IV TXA and retrograde 1.5 g of TXA applied through the drain were included in the study. Of the patients, 206 were in the IV TXA group. Preoperative and postoperative hemoglobin levels, drain output, BMI, ASA score, blood loss, and the number of transfused patients were recorded. Complications such as symptomatic venous thromboembolism were also recorded. RESULTS: There was no significant difference between the two groups in terms of age, sex, American Society of Anesthesiologists (ASA) score, or BMI (p = 0.68, 0.54, 0.28, 0.45). Total drain output and blood loss were significantly higher in the IV TXA group than in the intraarticular TXA group (p < 0.0001, p < 0.0001). Eighteen patients in the IV TXA group and 1 patient in the intraarticular TXA group received a blood transfusion (p < 0.0001). There was no difference between the two groups in terms of preoperative hemoglobin or platelet count (p = 0.24). However, postoperative hemoglobin level was higher in the patients who received intraarticular TXA (p=0.0005). More thromboembolism events were seen in the IV TXA group (p < 0.0001). CONCLUSIONS: Intraarticular TXA application reduces blood loss more than IV application, reduces the blood transfusion rate, and causes fewer complications. KEY WORDS: tranexemic acid, total knee arthroplasty, intraarticular injection, blood loss, blood transfusion.
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Antifibrinolíticos , Artroplastia de Reemplazo de Rodilla , Pérdida de Sangre Quirúrgica , Ácido Tranexámico , Humanos , Artroplastia de Reemplazo de Rodilla/métodos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Femenino , Masculino , Ácido Tranexámico/administración & dosificación , Pérdida de Sangre Quirúrgica/prevención & control , Anciano , Inyecciones Intraarticulares , Antifibrinolíticos/administración & dosificación , Persona de Mediana Edad , Transfusión Sanguínea/estadística & datos numéricos , Administración Intravenosa , Hemorragia Posoperatoria/prevención & control , Hemorragia Posoperatoria/etiología , Constricción , Estudios RetrospectivosRESUMEN
Histone deacetylases (HDAC) represent promising epigenetic targets for several diseases including different cancer types. The HDAC inhibitors approved to date are pan-HDAC inhibitors and most show a poor selectivity profile, side effects, and in particular hydroxamic-acid-based inhibitors lack good pharmacokinetic profiles. Therefore, the development of isoform-selective non-hydroxamic acid HDAC inhibitors is a highly regarded field in medicinal chemistry. In this study, we analyzed different ligand-based and structure-based drug design techniques to predict the binding mode and inhibitory activity of recently developed alkylhydrazide HDAC inhibitors. Alkylhydrazides have recently attracted more attention as they have shown promising effects in various cancer cell lines. In this work, pharmacophore models and atom-based quantitative structure-activity relationship (QSAR) models were generated and evaluated. The binding mode of the studied compounds was determined using molecular docking as well as molecular dynamics simulations and compared with known crystal structures. Calculated free energies of binding were also considered to generate QSAR models. The created models show a good explanation of in vitro data and were used to develop novel HDAC3 inhibitors.
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In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to rationalize the observed structure-activity relationships.
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Amidohidrolasas , Antibacterianos , Inhibidores Enzimáticos , Escherichia coli , Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/química , Antibacterianos/farmacología , Bacterias/metabolismo , Sitios de Unión , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/química , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Histone deacetylases (HDACs) are epigenetic regulators and additionally control the activity of non-histone substrates. We recently demonstrated that inhibition of HDAC8 overexpressed in various of cancers reduces hepatocellular carcinoma tumorigenicity in a T cell-dependent manner. Here, we present alkylated hydrazide-based class I HDAC inhibitors in which the n-hexyl side chain attached to the hydrazide moiety shows HDAC8 selectivity in vitro. Analysis of the mode of inhibition of the most promising compound 7d against HDAC8 revealed a substrate-competitive binding mode. 7d marked induced acetylation of the HDAC8 substrates H3K27 and SMC3 but not tubulin in CD4+ T lymphocytes, and significantly upregulated gene expressions for memory and effector functions. Furthermore, intraperitoneal injection of 7d (10 mg/kg) in C57BL/6 mice increased interleukin-2 expression in CD4+ T cells and CD8+ T cell proportion with no apparent toxicity. This study expands a novel chemotype of HDAC8 inhibitors with T cell modulatory properties for future therapeutic applications.
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Inhibidores de Histona Desacetilasas , Proteínas Represoras , Ratones , Animales , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Ratones Endogámicos C57BL , Histona Desacetilasas/metabolismo , HidrazinasRESUMEN
Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these enzymes remains challenging due to their high sequence and structural similarity. In the current study, we applied a computational approach to predict the selectivity profile of developed inhibitors. Molecular docking followed by MD simulation and calculation of binding free energy was performed for a dataset of 2-aminobenzamides comprising 30 previously developed inhibitors. For each HDAC isoform, a significant correlation was found between the binding free energy values and in vitro inhibitory activities. The predictive accuracy and reliability of the best preforming models were assessed on an external test set of newly designed and synthesized inhibitors. The developed binding free-energy models are cost-effective methods and help to reduce the time required to prioritize compounds for further studies.
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Inhibidores de Histona Desacetilasas , Pirazinas , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Isoformas de Proteínas , Pirazinas/química , Reproducibilidad de los ResultadosRESUMEN
The bacterial deacetylase LpxC is a promising target for the development of novel antibiotics being selectively active against Gram-negative bacteria. In chiral pool syntheses starting from d- and l-ribose, a series regio- and stereoisomeric monohydroxytetrahydrofuran derivatives was synthesized and tested for LpxC inhibitory and antibacterial activities. Molecular docking studies were performed to rationalize the obtained structure-activity relationships. The (2S,3R,5R)-configured 3-hydroxytetrahydrofuran derivative ent-8 ((2S,3R,5R)-N,3-Dihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (Kiâ¯=â¯3.5⯵M) of the synthesized series of monohydroxytetrahydrofuran derivatives and to exhibit the highest antibacterial activity against E. coli BL21(DE3) and the D22 strain.
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Amidohidrolasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicósidos/química , Glicósidos/farmacología , Amidohidrolasas/efectos de los fármacos , Amidohidrolasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Inhibidores Enzimáticos/síntesis química , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Infecciones por Escherichia coli/tratamiento farmacológico , Glicósidos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Simulación del Acoplamiento MolecularRESUMEN
OBJECTIVES: To evaluate the incidence of numerical chromosomal abnormalities in the patients with early pregnancy loss (EPL) following in vitro fertilization, and evaluate the role of different confounders of the risk of chromosomal abnormality-related pregnancy loss. MATERIAL AND METHODS: A retrospective chart review of all patients from our in vitro fertilization (IVF) center who conceived using assisted reproduction techniques between April 2017 and 2019, who experienced a subsequent early pregnancy loss, and whose abortus materials were successfully karyotyped were included. RESULTS: Of the 243 patients experienced an early loss, the overall rate of chromosomal abnormality was 46.75%. The overall rate of aneuploidy in our patient group was 88.8% (64/72), whereas 6.94% (5/72) of the abnormal karyotypes were polyploid. The most common type of trisomy was Trisomy 16 (20.0%; 11/55) followed by Trisomy 15 (14.5%; 8/55). Univariate and multivariate analyses showed that maternal age (< 35 years) and the total number of retrieved oocytes per cycle (≥ 5) were risk factors for a chromosomal abnormality (< 0.001; < 0.05, respectively). The adjusted OR of karyotypic abnormalities was 0.45 for the antagonist cycle type (p < 0.05), and 0.58 for frozen embryo transfer (p < 0.05). CONCLUSIONS: Karyotypic abnormality is one of the main reasons for pregnancy loss following an IVF procedure. Although the pregnancy rates increased as a result of novel technologies, the ratio of EPL is still high. The implementation of preimplantation genetic screening techniques might lower the incidence of EPL due to chromosomal abnormalities, thus decreasing the burden on the physicians and the patients.
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Aborto Espontáneo , Inyecciones de Esperma Intracitoplasmáticas , Aborto Espontáneo/epidemiología , Femenino , Fertilización In Vitro/efectos adversos , Fertilización In Vitro/métodos , Humanos , Cariotipificación , Embarazo , Índice de Embarazo , Estudios Retrospectivos , Inyecciones de Esperma Intracitoplasmáticas/efectos adversosRESUMEN
This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.
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Diseño de Fármacos , Inhibidores de Histona Desacetilasas/química , Sitios de Unión , Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Relación Estructura-Actividad , Zinc/química , Zinc/metabolismoRESUMEN
Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
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Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Simulación del Acoplamiento Molecular , Pirazinas/química , ortoaminobenzoatos/química , ortoaminobenzoatos/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Línea Celular Tumoral , Células HEK293 , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Espectroscopía de Protones por Resonancia Magnética , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacologíaRESUMEN
The bacterial deacetylase LpxC is a promising target for the development of antibiotics selectively combating Gram-negative bacteria. To improve the biological activity of the reported benzyloxyacetohydroxamic acid 9 ((S)-N-hydroxy-2-{2-hydroxy-1-[4-(phenylethynyl)phenyl]ethoxy}acetamide), its hydroxy group was replaced by a triazole ring. Therefore, in divergent syntheses, triazole derivatives exhibiting rigid and flexible lipophilic side chains, different configurations at their stereocenter, and various substitution patterns at the triazole ring were synthesized, tested for antibacterial and LpxC inhibitory activity, and structure-activity relationships were deduced based on docking and binding energy calculations.
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Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Triazoles/química , Antibacterianos/farmacología , Reacción de Cicloadición , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/farmacología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. In addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. In this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, 1 H NMR, 13 C NMR, mass spectroscopy, and elemental analysis. The IC50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. The cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. The compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. The complex formation was shown qualitatively. The ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques.
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Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Ribonucleótido Reductasas/antagonistas & inhibidores , Tiazoles/farmacología , Tiosemicarbazonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Ligandos , Células MCF-7 , Estructura Molecular , Ribonucleótido Reductasas/metabolismo , Relación Estructura-Actividad , Tiazoles/química , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/químicaRESUMEN
Inhibitors of the bacterial deacetylase LpxC are a promising class of novel antibiotics, being selectively active against Gram-negative bacteria. To improve the biological activity of reported C-furanosidic LpxC inhibitors, the stereochemistry at positionsâ 3 and 4 of the tetrahydrofuran ring was varied. In chiral pool syntheses starting from d-gulono-γ-lactone and d-ribose, a series of (3S,4R)-configured dihydroxytetrahydrofuran derivatives was obtained, of which the (2S,5S)-configured hydroxamic acid 15 ((2S,3S,4R,5S)-N,3,4-trihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (Ki =0.4â µm), exhibiting the highest antibacterial activity against E.â coli BL21 (DE3) and the D22 strain. Additionally, molecular docking studies were performed to rationalize the obtained structure-activity relationships.
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Amidohidrolasas/antagonistas & inhibidores , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Furanos/química , Simulación del Acoplamiento Molecular , Amidohidrolasas/metabolismo , Proteínas Bacterianas/metabolismo , Sitios de Unión , Dominio Catalítico , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Furanos/metabolismo , Furanos/farmacología , Ácidos Hidroxámicos/química , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Mortality and remaining bedridden following the hip fracture surgery are not rare. We tried to measure the levels of inflammatory markers tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) following the hip fracture surgery and compare their levels with controls. We aimed to show a relationship between the levels of these markers and post-operative mortality and walking capability. INTRODUCTION: Osteoporosis is a condition, causing the hip fractures in the elderly. Hip fractures have a high rate of overall mortality up to 30% following the incident. Cytokines such as IL-6 and TNF-α are suggested to play a role in bone resorption and, thus, in the etiology of osteoporosis. METHODS: Plasma levels of IL-6 and TNF-α were measured pre-operatively and on the first and second days after the surgery in 40 Turkish hip fracture patients. The levels of these cytokines were compared with 40 Turkish age-matched healthy controls. The levels of these cytokines were compared between the deceased and surviving patients, as well as the existence of walking capability following the surgery. RESULTS: Significantly higher IL-6 levels were shown on the first and second days after the surgery (p = 0.005; p = 0.01, respectively). The overall death rate of our study group within the 2-year follow-up time was found to be 35%. No statistical significance was found in the means of 2-year follow-up mortality between the patients. Presence of walking capability did not differ between the patients, as well. CONCLUSION: We demonstrated an association between IL-6 levels and hip fracture in our study group following the surgery. We also suggest that TNF-α and IL-6 levels are not related to the occurrence of death and walking capability after the surgery. However, these findings need further functional and clinical confirmation.
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Fracturas de Cadera/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-6/sangre , Fracturas Osteoporóticas/inmunología , Factor de Necrosis Tumoral alfa/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Fracturas de Cadera/mortalidad , Fracturas de Cadera/cirugía , Humanos , Masculino , Persona de Mediana Edad , Fracturas Osteoporóticas/mortalidad , Fracturas Osteoporóticas/cirugía , Periodo Posoperatorio , Periodo Preoperatorio , Pronóstico , Turquía/epidemiología , CaminataRESUMEN
Objective: This study aimed to determine the ratio of seasonal vitamin D deficiency and insufficiency in elementary school children aged between 6-9 years old, living in one of the largest metropols of Europe, Istanbul. Methods: Serum 25(OH)D levels of 640 children aged 6-9 years old were scanned retrospectively from the hospital information system records between September 2017-August 2018 period. Vitamin D deficiency was defined as a serum 25(OH)D level less than 12 ng/mL (30 nmol/L) and insufficiency as levels between 12 and 20 ng/mL (30-50 nmol/L). Results: Serum 25(OH)D levels ranged from 3.90 to 64.60 ng/mL, the median value was 25.95 ng/mL for all subjects. Of all the primary school children, 485 (75.78%) had adequate levels of 25(OH)D. Vitamin D deficiency was observed in 36 of children (5.62%), whereas insufficient levels of 25(OH)D were found in 119 children (18.60%). The ratio of vitamin D insufficiency and deficiency together was highest in spring (31.87%) and lowest in summer (13.12%). Conclusion: Vitamin D deficiency is a widely observed and preventable public health problem among children of different ages. It is necessary to increase the awareness among health professionals, and providing 25(OH)D supplements will yield generations with healthy bone structure and well growth.
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Biomarcadores/sangre , Estaciones del Año , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Vitamina D/sangre , Vitaminas/sangre , Niño , Suplementos Dietéticos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Prevalencia , Pronóstico , Estudios Retrospectivos , Turquía/epidemiología , Deficiencia de Vitamina D/diagnósticoRESUMEN
Hit, Lead & Candidate Discovery After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetylcholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid-20th century proved that cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine, rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However, these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase activity of various heterocyclic-framed compounds, including piperazine derivatives, has been investigated, and compounds with similar effects to known drugs have been identified. The aim of this study was to design new donepezil analogs. In this study, 66 original piperazinyl thiazole derivatives were synthesized by the reaction of piperazine N'-benzoyl thioamides and bromoacetophenones to inhibit AChE. Biological activity was measured by the Ellman method. Compounds 35, 38, 40, 45, 57, and 61 showed a high inhibitory effect among the series (80.36%-83.94% inhibition), and donepezil had a 96.42% inhibitory effect. The IC50 values of compounds 35, 38, and 40, were calculated as 0.9767 µM, 0.9493 µM, and 0.8023 µM, respectively. Compound 45 (IC50 = 1.122), Compound 57 (IC50 = 1.2130) and 61 (IC50 = 0.9193) also exhibited good activity on AChE. Molecular modeling studies were in agreement with the predictions. Trp286, Arg296, and Tyr341 were the key amino acids at the active site. Both donepezil and synthesized compounds seemed to interact with these residues.
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Inhibidores de la Colinesterasa/química , Donepezilo/química , Modelos Moleculares , Piperazina/química , Tiazoles/química , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Donepezilo/farmacología , Humanos , Simulación del Acoplamiento Molecular/métodos , Piperazina/farmacología , Tiazoles/farmacologíaRESUMEN
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a multisystemic, chronic disease accompanied by microvascular complications involving various complicated mechanisms. Intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and cluster of differentiation-146 (CD146) are mainly expressed by endothelial cells, and facilitate the adhesion and transmigration of immune cells, leading to inflammation. In the present study, we evaluated the levels of soluble adhesion molecules in patients with microvascular complications of T2DM. METHODS: Serum and whole blood samples were collected from 58 T2DM patients with microvascular complications and 20 age-matched healthy subjects. Levels of soluble ICAM-1 (sICAM-1) and soluble VCAM-1 (sVCAM-1) were assessed using enzyme-linked immunosorbent assay, while flow cytometry was used to determine CD146 levels. RESULTS: Serum sICAM-1 levels were lower in T2DM patients with microvascular complications than in healthy controls (P<0.05). No significant differences were found in sVCAM-1 and CD146 levels between the study and the control group. Although patients were subdivided into groups according to the type of microvascular complications that they experienced, cell adhesion molecule levels were not correlated with the complication type. CONCLUSION: In the study group, most of the patients were on insulin therapy (76%), and 95% of them were receiving angiotensin-converting enzyme (ACE)-inhibitor agents. Insulin and ACE-inhibitors have been shown to decrease soluble adhesion molecule levels via various mechanisms, so we suggest that the decreased or unchanged levels of soluble forms of cellular adhesion molecules in our study group may have resulted from insulin and ACE-inhibitor therapy, as well as tissue-localized inflammation in patients with T2DM.
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The integrins are a family of heterodimeric transmembrane signaling receptors that mediate the adhesive properties of epithelial cells affecting cell growth and differentiation. In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis. However, only few studies have investigated the role of integrin expression in esophageal squamous cell carcinoma (ESCC). Using a novel quantifying immunofluorescence-staining assay, we investigated the expression of the integrins α2ß1, α3ß1, α6ß1, and α6ß4 in primary ESCC of 36 patients who underwent surgical resection. Magnitude and distribution of expression were analyzed in primary tumor samples and autologous esophageal squamous epithelium. The persistence of the physiologically polarized expression of the subunits α6, ß1, and ß4 in the tumor tissue was significantly associated with prolonged relapse-free survival (pâ=â0.028, pâ=â0.034, pâ=â0.006). In contrast, patients with reduced focal α6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong α6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (pâ=â0.001). Multivariate regression analysis identified the maintenance of strong α6 immunoreactivity at the invasion front as an independent prognostic factor for increased relapse-free and disease-specific survival (pâ=â0.003; pâ=â0.003). Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients. Particularly, the distinct expression of the integrins α6ß4 and α6ß1 at the invasion front as well as the maintenance of a polarized integrin expression pattern in the tumor tissue may serve as valuable new markers to assess the aggressiveness of ESCC.
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Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Integrinas/metabolismo , Análisis por Conglomerados , Supervivencia sin Enfermedad , Epitelio/metabolismo , Epitelio/patología , Carcinoma de Células Escamosas de Esófago , Técnica del Anticuerpo Fluorescente , Humanos , Estimación de Kaplan-Meier , Análisis Multivariante , Invasividad Neoplásica , Subunidades de Proteína/metabolismo , RecurrenciaRESUMEN
Basal transcription regulation of the epidermal growth factor receptor is dependent upon a CA simple sequence repeat polymorphism in the intron-1 (CA-SSR-1). Here, we evaluate the role of CA-SSR-1 in complete resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Genomic DNA was extracted from peripheral blood leukocytes of 241 patients. To determine the number of the CA repeats in the CA-SSR-1, DNA was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters and clinical outcome. Three genotypes were defined based on cut-off points for short allele (S) with ≤18 and long allele (L) >18 CA repeats. A steadily increasing risk was evident between LL, SL, and SS genotype for larger tumor size, presence of lymph node metastases, and disseminated tumor cells in bone marrow as well as tumor recurrence (P < 0.001, chi-square test). A gradual decrease in disease-free and overall survival (OS) was present among LL, SL, and SS patients (P < 0.001, log-rank test). The different outcomes were also evident in nodal status and histological type adjusted subgroup analyses. CA-SSR-1 was identified as the strongest independent prognosticator of tumor recurrence and OS (P < 0.001, Cox regression analysis). CA-SSR-1 is a strong predictive factor for tumor recurrence and overall survival in patients with complete resected esophageal cancer without neoadjuvant or adjuvant therapy.