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BACKGROUND: Platelet (PLT) count is one of the most important parameters of automated hematology, as spurious PLT reports could affect medical judgement and bring significant risks. In most cases, spurious PLT will not be reported for review criteria, which will be triggered by abnormal PLT histograms and PLT flag(s). Here, we present a case of severe aplastic anemia after hematopoietic stem cell transplantation with spurious high platelet count with normal histogram and no PLT flag(s). METHODS: The electrical impedance channel (PLT-I) and the fluorescence channel (PLT-F) of Sysmex XN-series hematology analyzer was used to obtain PLT results. Then, the sample was retested by another hematology analyzer MINDRAY BC-7500 [NR] CRP, and incubation was performed to rule out cryoglobulin interference. Furthermore, a microscope was used to estimate the PLT count by the ratio of platelets to red blood cells and observe the morphology of cells. RESULTS: Both PLT-I and PLT-F test results were spuriously high, and microscopically assessed platelet counts were relatively reliable. The observed spiny cells and ghost cells caused by hemolysis may have contributed to the inaccuracy of instrumental counting in this case. CONCLUSIONS: For special hematologic patients, PLT-I with flags may not be sufficient for screening purposes and PLT-F is not always accurate. Multiple testing methods including manual microscopy are needed.
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Agmatina/análogos & derivados , Anemia Aplásica , Ácido Oxámico/análogos & derivados , Humanos , Recuento de Plaquetas/métodos , Anemia Aplásica/diagnóstico , Reproducibilidad de los Resultados , PlaquetasRESUMEN
OBJECTIVES: Automated hematology analysis is expected to improve the performance of platelet counting. We evaluated the performance of a new platelet counting, hybrid (PLT-H) and also impedance (PLT-I) and optical (PLT-O) on the BC-780 automated hematology analyzer compared to the international reference method (IRM) in blood samples with thrombocytopenic and platelet interference. METHODS: The basic platelet count performance of the BC-780 automated hematology analyzer was evaluated according to the requirements of the Clinical Laboratory and Standards Institute (CLSI) Document H26-A2. Additionally, the thrombocytopenic (low PLT count) blood samples and the platelet interference blood samples including fragmented red blood cells (RBCs), microcytes or small RBCs, and giant platelets were determined with the BC-780 hematology analyzer compared to the IRM. RESULTS: Blank counting and the carry-over contamination rate of platelet count using the BC-780 both met the manufacturers' claim. For both 123 thrombocytopenic and 232 platelet interference blood samples (72 fragmented RBCs, 91 microcytes and 51 giant platelets), all three platelet counting methods exhibited high comparability with the IRM (the lowest correlation (r)=0.916). Interestingly, the comparability of PLT-H (r=0.928-0.986) with the IRM was better than that of PLT-I (r=0.916-0.979). CONCLUSIONS: The performance of PLT-H in the BC-780 met the manufacturer's specifications. PLT-H exhibits better reproducibility than did PLT-I, correlates well with the PLT-O for thrombocytopenic samples and demonstrates good anti-interference ability. PLT-H counting is therefore recommended as a zero-cost alternative platelet counting method for platelet interference samples in clinical settings.
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Agmatina/análogos & derivados , Hematología , Ácido Oxámico/análogos & derivados , Humanos , Recuento de Plaquetas/métodos , Reproducibilidad de los Resultados , Hematología/métodos , PlaquetasRESUMEN
INTRODUCTION: Activated platelets exert a key role in the pathogenesis of preeclampsia (PE). There is evidence of distinctive patterns of platelet indices in PE in comparison to healthy pregnancies, therefore these indices can be potential tools for PE detection, risk stratification, and management. Considering the vascular aspects of its pathophysiology, PE is characterized by the increased levels of soluble FMS-like tyrosine kinase-1 (sFlt-1) an antiangiogenic factor, and reduced placental growth factor (PlGF), a proangiogenic factor. This study aimed to assess the platelet indices in hypertensive disorders of pregnancy (HDP) and its correlation with angiogenesis-related biomarkers. METHODS: The groups for the study were: control (n = 114); gestational hypertension; (n = 112), and PE (n = 42). The platelet indices included were platelet counts (PLT-I and PLT-F), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR), and immature platelet fraction (IPF# and IPF%). Serum levels of sFlt-1 and PlGF were assessed. RESULTS: PLT-I, PLT-F, and PCT% were lower in PE, while MPV, PDW, P-LCR, IPF%, and IPF# were increased. The parameter MPV presented the best performance for the discrimination of PE. There was a moderate positive correlation between sFlt-1 levels and MPV, PDW, and P-LCR. CONCLUSION: Platelet indices can be potentially applied as additional tools for the diagnosis and management of HDP. Activated platelets may act as an extra source of sFlt-1 in PE.
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Agmatina/análogos & derivados , Hipertensión Inducida en el Embarazo , Ácido Oxámico/análogos & derivados , Preeclampsia , Embarazo , Humanos , Femenino , Preeclampsia/diagnóstico , Hipertensión Inducida en el Embarazo/diagnóstico , Factor de Crecimiento Placentario/metabolismo , Angiogénesis , Biomarcadores , Volúmen Plaquetario MedioRESUMEN
The G protein-coupled receptor 35 (GPR35) has been identified as a potential target in the treatment of inflammatory bowel disease (IBD). However, the lack of high and equipotent agonists on both human and mouse GPR35 has limited the in vivo study of GPR35 agonists in mouse models of IBD. In this study, structural modifications to lodoxamide provides a series of high and equivalent agonists on human, mouse, and rat GPR35. These molecules eliminate the species selectivity of human to mouse and rat orthologs that have been prevalent with GPR35 agonists including lodoxamide. The cLogP properties are also optimized to make the compounds more obedient to drug-like rules, yielding compound 4b (cLogP = 2.41), which activates human, mouse or rat GPR35 with EC50 values of 76.0, 63.7 and 77.8 nM, respectively. Oral administration of compound 4b at 20 mg/kg alleviates clinical symptoms of DSS-induced IBD in mice, and is slightly more effective than 5-ASA at 200 mg/kg. In summary, it can serve as a new start point for exploiting more potent GPR35 agonists without species differences for the treatment of IBD, and warrants further study.
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Enfermedades Inflamatorias del Intestino , Receptores Acoplados a Proteínas G , Ratas , Ratones , Humanos , Animales , Receptores Acoplados a Proteínas G/agonistas , Ácido Oxámico/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Administración OralRESUMEN
In this study, expanded graphite (EG) was prepared by the oxidation and intercalation of the natural flake graphite using perchloric acid and potassium permanganate at different expansion temperatures (300, 400, 500, and 600°C), and were characterized by scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). EG prepared at 500°C was found to be highly effective for the mineralization of oxalic acid aqueous solution during ozonation at pH 3, which was ascribed to the formation of hydroxyl radicals from the surface reaction of surface hydroxyl groups on EG with ozone. The performance of expanded graphite in this catalytic system was basically unchanged after three repeated use. The presence of Cl-, SO42-, HPO42-/H2PO4- and NO3- could inhibit the degradation of oxalic acid in catalytic ozonation with EG. Degradations of oxamic acid and pyruvic acid in catalytic ozonation with EG were pH-dependent, which were lower than that of oxalic acid. The degradations of oxalic acid and oxamic acid were identified as mineralization process by the determination of TOC, while pyruvic acid may transform into organic products such as acetic acid by O3/EG. Manganese ion (Mn2+) could promote the degradation of oxalic acid by O3/EG at pH 3 because permanganate was produced by O3/EG in oxalic acid solution and then reacted with oxalic acid readily at acidic pH. Catalytic ozonation by EG exhibited great application potential for the destruction of refractory organic compounds.
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Grafito , Ozono , Contaminantes Químicos del Agua , Grafito/química , Ácido Oxámico , Ácido Pirúvico , Agua , Ácido Oxálico/química , Catálisis , Ozono/química , Contaminantes Químicos del Agua/químicaRESUMEN
An efficient and straightforward approach for the synthesis of carbamoylated chroman-4-ones has been well-developed. The reaction is triggered through the generation of carbamoyl radicals from oxamic acids under metal-free conditions, which subsequently undergoes decarboxylative radical cascade cyclization on 2-(allyloxy)arylaldehydes to afford various amide-containing chroman-4-one scaffolds with high functional group tolerance and a broad substrate scope.
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Cromanos , Ácido Oxámico , Ciclización , AmidasRESUMEN
Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1ß and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.
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Lipopolisacáridos , Metformina , Animales , Citocinas/metabolismo , Glucosa/metabolismo , Glutamatos/metabolismo , Hipocampo/metabolismo , Inflamasomas/metabolismo , Inflamación/metabolismo , Lactatos/efectos adversos , Lactatos/metabolismo , Lipopolisacáridos/toxicidad , Metformina/farmacología , Microglía/metabolismo , Minociclina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias , Ácido Oxámico/efectos adversos , Ácido Oxámico/metabolismo , Proteínas Quinasas/metabolismo , RatasRESUMEN
This review article describes the recent development in the chemistry of carbamoyl radicals generated from oxamic acids. This mild and efficient method compares well with previous methods of generation of these nucleophilic radicals. The oxidative decarboxylation of oxamic acids can be mediated through thermal, photochemical, electrochemical or photoelectrochemical means, generating carbamoyl radicals, which may further add to unsaturated systems to provide a broad range of important amides. Oxidative decarboxylation of oxamic acids also offers a straightforward entry for the preparation of urethanes, ureas, and thioureas.
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Amidas , Ácido Oxámico , Oxidación-Reducción , UreaRESUMEN
Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
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Neoplasias Encefálicas/patología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Ácido Oxámico/farmacología , Animales , Línea Celular Tumoral , Glucólisis/fisiología , Humanos , L-Lactato Deshidrogenasa/metabolismo , Mitocondrias/metabolismo , Neoplasias/patología , Fenformina/farmacología , Tolerancia a Radiación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Temozolomida/farmacologíaRESUMEN
Aortic dissection (AD) is a disease with high mortality and lacks effective drug treatment. Recent studies have shown that the development of AD is closely related to glucose metabolism. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme and plays an important role in cardiovascular disease. However, the role of LDHA in the progression of AD remains to be elucidated. Here, we found that the level of LDHA was significantly elevated in AD patients and the mouse model established by BAPN combined with Ang II. In vitro, the knockdown of LDHA reduced the growth of human aortic vascular smooth muscle cells (HAVSMCs), glucose consumption, and lactate production induced by PDGF-BB. The overexpression of LDHA in HAVSMCs promoted the transformation of HAVSMCs from contractile phenotype to synthetic phenotype, and increased the expression of MMP2/9. Mechanistically, LDHA promoted MMP2/9 expression through the LDHA-NDRG3-ERK1/2-MMP2/9 pathway. In vivo, Oxamate, LDH and lactate inhibitor, reduced the degradation of elastic fibers and collagen deposition, inhibited the phenotypic transformation of HAVSMCs from contractile phenotype to synthetic phenotype, reduced the expression of NDRG3, p-ERK1/2, and MMP2/9, and delayed the progression of AD. To sum up, the increase of LDHA promotes the production of MMP2/9, stimulates the degradation of extracellular matrix (ECM), and promoted the transformation of HAVSMCs from contractile phenotype to synthetic phenotype. Oxamate reduced the progression of AD in mice. LDHA may be a therapeutic target for AD.
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Disección Aórtica/tratamiento farmacológico , Lactato Deshidrogenasa 5/antagonistas & inhibidores , Ácido Oxámico/uso terapéutico , Adulto , Anciano , Disección Aórtica/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Lactato Deshidrogenasa 5/genética , Lactato Deshidrogenasa 5/metabolismo , Ácido Láctico/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Ácido Oxámico/farmacologíaRESUMEN
BACKGROUND: Inhibition of aerobic glycolysis of cancer cells is considered a promising therapeutic strategy for the treatment of neoplasms. Some inhibitors of energy metabolism can affect not only tumor cells but also the functional polarization of tumor-associated macrophages, which may either enhance the antitumor effect of such agents or impair their antitumor efficacy. AIM: To investigate the effect of oxamate, a lactate dehydrogenase (LDH) inhibitor, on the polarization of peritoneal macrophages (PMP) in both intact mice and mice with transplanted Lewis lung carcinoma (LLC). MATERIALS AND METHODS: The low-metastatic LLC variant, LLC/R9, was transplanted to female C57Bl/6 mice. Sodium oxamate was used as the test agent at concentrations of 0.02, 0.2, and 2 mg/ml. Macrophage polarization in tumor-bearing mice was estimated on day 23 after tumor transplantation by assessing nitric oxide (NO) production and arginase activity as functional indices of PMPs polarization. RESULTS: Oxamate can affect the functional polarization of PMPs in both intact mice and animals with transplanted LLC/R9. Oxamate in all studied concentrations changed the markers of PMPs polarization in intact mice (decreasing NO levels and activating arginase activity) that indicated the stimulation of M2 polarization. In tumor-bearing animals, stimulation of M2 polarization is observed at low concentrations of oxamate (0.02 mg/ml), but its high concentrations (2.0 mg/ml) causes M1 polarization, which is characterized by three-fold increase in the level of NO and a decrease in the level of arginase activity. CONCLUSION: Oxamate, an inhibitor of LDH, can stimulate M2 polarization of peritoneal macrophages of mice bearing LLC in a dose-dependent manner.
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Carcinoma Pulmonar de Lewis/inmunología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Activación de Macrófagos/inmunología , Macrófagos Peritoneales/inmunología , Ácido Oxámico/farmacología , Animales , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Metabolismo Energético , Femenino , Activación de Macrófagos/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Óxido Nítrico/metabolismoRESUMEN
Since the advent of antibody checkpoint inhibitors as highly efficient drugs for cancer treatment, the development of immunomodulating small molecules in oncology has gained great attention. Drug candidates targeting IDO1, a key enzyme in tryptophan metabolism, are currently under clinical investigation in combination with PD-1/PD-L1 agents as well as with other established anti-tumor therapeutics. A ligand based design approach from hydroxyamidine 4 that aimed at heme-binding IDO1 inhibitors resulted in new compounds with moderate IDO1 potency. A hybrid structure design that made use of the linrodostat structure (2) led to oxalamide derived, heme-displacing IDO1 inhibitors with high cell-based IDO1 potency and a favorable ADME/PK profile.
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Amidas/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Ácido Oxámico/farmacología , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Estructura Molecular , Ácido Oxámico/síntesis química , Ácido Oxámico/química , Relación Estructura-ActividadRESUMEN
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1).
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Amidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Ácido Oxámico/farmacología , Amidas/síntesis química , Amidas/química , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/antagonistas & inhibidores , Quinurenina/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Ácido Oxámico/síntesis química , Ácido Oxámico/química , Relación Estructura-ActividadRESUMEN
Neuronal activity within the physiologic range stimulates lactate production that, via metabolic pathways or operating through an array of G-protein-coupled receptors, regulates intrinsic excitability and synaptic transmission. The recent discovery that lactate exerts a tight control of ion channels, neurotransmitter release, and synaptic plasticity-related intracellular signaling cascades opens up the possibility that lactate regulates synaptic potentiation at central synapses. Here, we demonstrate that extracellular lactate (1-2 mM) induces glutamatergic potentiation on the recurrent collateral synapses of hippocampal CA3 pyramidal cells. This potentiation is independent of lactate transport and further metabolism, but requires activation of NMDA receptors, postsynaptic calcium accumulation, and activation of a G-protein-coupled receptor sensitive to cholera toxin. Furthermore, perfusion of 3,5- dihydroxybenzoic acid, a lactate receptor agonist, mimics this form of synaptic potentiation. The transduction mechanism underlying this novel form of synaptic plasticity requires G-protein ßγ subunits, inositol-1,4,5-trisphosphate 3-kinase, PKC, and CaMKII. Activation of these signaling cascades is compartmentalized in a synapse-specific manner since lactate does not induce potentiation at the mossy fiber synapses of CA3 pyramidal cells. Consistent with this synapse-specific potentiation, lactate increases the output discharge of CA3 neurons when recurrent collaterals are repeatedly activated during lactate perfusion. This study provides new insights into the cellular mechanisms by which lactate, acting via a membrane receptor, contributes to the memory formation process.
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Región CA3 Hipocampal/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Ácido Láctico/farmacología , Sinapsis/metabolismo , Animales , Región CA3 Hipocampal/efectos de los fármacos , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Toxina del Cólera/farmacología , Masculino , Plasticidad Neuronal , Ácido Oxámico/farmacología , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T-ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targeting LDHA may be a potential strategy to improve T-ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene-targeting treatment on T-ALL and the underlying molecular mechanism. METHODS: Primary T-ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T-ALL cells. Quantitative real-time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluate ROS production after T-ALL cells were treated with oxamate. A T-ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene-editing technology, and then TUNEL, Western blotting, and T-ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T-ALL transgenic zebrafish. RESULTS: Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P < 0.001). Blocking LDHA significantly decreased the gene and protein expression of c-Myc, as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK-3ß) in the phosphatidylinositol 3'-kinase (PI3K) signaling pathway. LDHA gene knockdown delayed disease progression and down-regulated c-Myc mRNA and protein expression in T-ALL transgenic zebrafish. CONCLUSION: Targeting LDHA exerted an antileukemic effect on T-ALL, representing a potential strategy for T-ALL treatment.
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Lactato Deshidrogenasa 5/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Animales , Animales Modificados Genéticamente , Femenino , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3 beta , Humanos , Células Jurkat , Masculino , Ácido Oxámico/farmacología , Fosfatidilinositol 3-Quinasas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-myc , Transducción de Señal , Linfocitos T , Pez CebraRESUMEN
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Mtb protein tyrosine phosphatase B (mPTPB) is a virulence factor required for Mtb survival in host macrophages. Consequently, mPTPB represents an exciting target for tuberculosis treatment. Here, we identified N-phenyl oxamic acid as a highly potent and selective monoacid-based phosphotyrosine mimetic for mPTPB inhibition. SAR studies on the initial hit, compound 4 (IC50 = 257 nM), resulted in several highly potent inhibitors with IC50 values lower than 20 nM for mPTPB. Among them, compound 4t showed a Ki of 2.7 nM for mPTPB with over 4500-fold preference over 25 mammalian PTPs. Kinetic, molecular docking, and site-directed mutagenesis analyses confirmed these compounds as active site-directed reversible inhibitors of mPTPB. These inhibitors can reverse the altered host cell immune responses induced by the bacterial phosphatase. Furthermore, the inhibitors possess molecular weights <400 Da, log D7.4 < 2.5, topological polar surface area < 75, ligand efficiency > 0.43, and good aqueous solubility and metabolic stability, thus offering excellent starting points for further therapeutic development.
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Antituberculosos/química , Proteínas Bacterianas/antagonistas & inhibidores , Mycobacterium tuberculosis/enzimología , Ácido Oxámico/química , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Animales , Antituberculosos/metabolismo , Antituberculosos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Dominio Catalítico , Permeabilidad de la Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Cinética , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Mycobacterium tuberculosis/efectos de los fármacos , Ácido Oxámico/metabolismo , Ácido Oxámico/farmacología , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
Dimensionally stable anodes (DSA) have been widely used to degrade organic compounds because these surfaces promote the electrogeneration of active chlorine species in the bulk of the solution, as well as in the vicinity of the anode when NaCl is used as supporting electrolyte. In this work, the nanoparticles synthesis of IrO2 and RuO2 was performed to obtain two types of DSA electrodes named Class I and II to degrade oxamic acid. For Class I and II DSA, the nanoparticles used were synthesized separately and in the same reaction medium, respectively. Electrolysis were carried out in an open cylindrical cell without division at 25⯰C, DSAs were used as anodes and a stainless-steel electrode as cathode, both elements have a geometric area of 2.8â¯cm2 immersed in 0.05â¯molâ¯L-1 of NaCl or Na2SO4 and a current density of 3â¯mAâ¯cm-2 was applied for 6â¯h. Active chlorine species generated in the absence of oxamic acid in NaCl were also detected and quantified through ion chromatography. In Na2SO4 there was no degradation of the compound, but in NaCl the oxamic acid concentration reaching 85% with Class I DSA. The same tendency is observed in mineralization, in which Class I DSA allowed reaching a CO2 transformation close to 73%. The difference in the results occurs because with Class I DSA, more hypochlorite is generated than with Class II and therefore there is a larger amount of oxidizing species in the solution that enables the degradation and mineralization of oxamic acid.
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Iridio/química , Modelos Químicos , Ácido Oxámico/química , Compuestos de Rutenio/química , Cloro/análisis , Electrodos , Electrólisis/métodos , Nanopartículas , Oxidación-Reducción , Contaminantes Químicos del Agua/análisisRESUMEN
l-glutamate is an excitatory neurotransmitter in the central nervous system (CNS), which can activate ionotropic receptors (iGluRs) and metabotropic (mGluRs) receptors. N-methyl-D-aspartate (NMDA) receptor is a ligand-gated ion channel belonging to the iGluRs family. Among NMDA receptor subtypes, GluN2B subtype plays a crucial role in CNS diseases. In this review, we summarize, classify and discuss the reports on GluN2B antagonists, published from the 1990s to 2020, to provide the therapeutic potential of GluN2B antagonists on various disorders. The GluN2B antagonists are broadly classified into two categories, which are prototypical antagonists and atypical antagonists. And the latter are further divided into amidine derivatives, 4-aminoquinolines, indole derivatives, benzimidazole derivatives, oxamide derivatives, carbamate derivatives, EVT-101 analogues, 1H-pyrrolo[3,2-b]pyridine derivatives, benzazepin derivatives, other heterocyles and radiotracers. This review will provide a comprehensive description including structure, structure-activity relationship (SAR), and pharmacology of novel GluN2B-subtype selective NMDA antagonists to the medicinal chemists, which would be helpful in rational designing effective drugs aimed toward related CNS disease.
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Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Amidinas/química , Amidinas/farmacología , Aminoquinolinas/química , Aminoquinolinas/farmacología , Benzazepinas/química , Benzazepinas/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Humanos , Indoles/química , Indoles/farmacología , Ácido Oxámico/química , Ácido Oxámico/farmacologíaRESUMEN
In this study, a range of oxamide ligands were synthesized by the reaction of amines with oxalyl chloride in basic medium. Spectroscopic and analytical techniques such as IR, 1H-NMR and ESI-MS techniques were used for characterization of the synthesized oxamides. The synthesized oxamides were screened for Lipoxygenase inhibition. Biological screening revealed that the oxamides possessed good lipoxygenase inhibition activities, whereas, the unsubstituted oxamide did not show any distinct lipoxygenase inhibition activity. Molecular docking studies of the oxamides were also carried out for lipoxygenase inhibition. The results obtained from molecular docking were well correlated with the empirical data.
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Araquidonato 5-Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Ácido Oxámico/análogos & derivados , Aminas/química , Araquidonato 5-Lipooxigenasa/metabolismo , Cloruros/química , Evaluación Preclínica de Medicamentos , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Oxalatos/química , Ácido Oxámico/química , Conformación Proteica , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
Docetaxel (DOC) is one of the most effective chemotherapeutic agents against castrationresistant prostate cancer (CRPC). Despite an impressive initial clinical response, the majority of patients eventually develop resistance to DOC. In tumor metabolism, where tumors preferentially utilize anaerobic metabolism, lactate dehydrogenase (LDH) serves an important role. LDH controls the conversion of pyruvate to lactate, with LDHA, one of the predominant isoforms of LDH, controlling this metabolic process. In the present study, the role of LDHA in drug resistance of human prostate cancer (PC) was examined by analyzing 4 PC cell lines, including castrationproviding strains PC3, DU145, LNCaP and LNCSS (which is a hormone refractory cell line established from LNCaP). Sodium oxamate (SO) was used as a specific LDHA inhibitor. Changes in the expression level of LDHA were analyzed by western blotting. Cell growth and survival were evaluated with a WST1 assay. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V staining. LDH expression was strongly associated with DOC sensitivity in PC cells. SO inhibited growth of PC cells, which was considered to be caused by the inhibition of LDHA expression. Synergistic cytotoxicity was observed by combining DOC and SO in LNCSS cells, but not in LNCaP cells. This combination treatment induced additive cytotoxic effects in PC3 and DU145 cells, caused cell cycle arrest in G2M phase and increased the number of cells in the subG1 phase of cell cycle in LNCSS cells. SO promoted DOC induced apoptosis in LNCSS cells, which was partially caused by the inhibition of DOCinduced increase in LDHA expression. The results strongly indicated that LDHA serves an important role in DOC resistance in advanced PC cells and inhibition of LDHA expression promotes susceptibility to DOC, particularly in CRPC cells. The present study may provide valuable information for developing targeted therapies for CRPC in the future.