RESUMEN

The aim of this study was to evaluate the sensitivity of the prawn Palaemon argentinus to the pyrethroid cypermethrin (CYP) and the tetramic acid spirotetramat (STM). These treatments were compared with prawns collected at a reference site to define their basal physiological state. Initially, physicochemical parameters and several pollutants at the selected site were analyzed. The LC50-96 h was determined in adult prawns. Then, prawns were exposed for 96 h to sublethal concentrations of CYP (0.0005 µg/l) and STM (0.44 mg/l) to evaluate the effects on some biochemical endpoints. A treatment combining both pesticides was also added at 5 % of these values. Controls with and without solvent (acetone) were included. The LC50-96 h values were 0.005 µg/l and 4.43 mg/l for CYP and STM, respectively. Moreover, some biomarkers linked to oxidative and energy metabolism were analyzed in the hepatopancreas and muscle of both essayed prawns and those at the basal state. The STM caused a significant decrease in total protein content (32 %) in contrast to the increase of protein carbonyl content (71 %) (p < 0.05). Also, glutathione S-transferase (52 %) and catalase (61 %) activities in the hepatopancreas of exposed prawns were higher compared to both the control and state basal groups (p < 0.05). In muscle, only a significant decrease in the lactate content (69 %) was caused by STM (p < 0.05). In addition, CYP caused a significant increase in the lactate dehydrogenase activity (110 %) in muscle and triacylglycerol content (73 %) in the hepatopancreas (p < 0.05). The integrated biomarker index (IBRv2) analysis showed that STM caused greater damage than CYP. Besides, the combined treatment showed an antagonistic interaction between both insecticides. The differential response of biomarkers to both CYP and STM exposure with respect to their basal levels shows a high sensitivity of P. argentinus demonstrating its potential role as a bioindicator organism.

Asunto(s)

Biomarcadores , Insecticidas , Palaemonidae , Piretrinas , Compuestos de Espiro , Contaminantes Químicos del Agua , Animales , Palaemonidae/efectos de los fármacos , Insecticidas/toxicidad , Piretrinas/toxicidad , Compuestos de Espiro/toxicidad , Contaminantes Químicos del Agua/toxicidad , Biomarcadores/metabolismo , Compuestos Aza/toxicidad , Hepatopáncreas/efectos de los fármacos , Hepatopáncreas/metabolismo

RESUMEN

BACKGROUND: Compatibility studies of insecticides and natural enemies usually focus on short-term lethal effects, without considering the long-term sublethal effects (including progeny). Even less-explored are the effects of commercial insecticides formulated with more than one active product. Short- and long-term lethal and sublethal effects were studied for the first time on the progeny of commercial formulations of spirotetramat, imidacloprid and a commercial mixture of these active ingredients on pupae of Diaeretiella rapae (M'ntosh) (Hymenoptera: Braconidae), an endoparasitoid of aphids considered to be a potential biological control agent. Insecticides were exposed topically on aphid mummies in which the parasitoid was in the pupal stage. RESULTS: Imidacloprid reduced adult emergence by more than 30% and prolonged intra-host development time with respect to control from half the maximum recommended field dose (MFRD). Spirotetramat and commercial mixture only showed significant effects on these endpoints at doses above the MFRD. The tested formulations did not affect adult longevity, sex ratio, and percentage of parasitism in the exposed generation. At low concentrations the active ingredients in the commercial mixture behave synergistically, whereas at medium and high concentrations they behave antagonistically. Considering the 10% lethal dose (LD10), imidacloprid showed the highest hazard coefficient, whereas the commercial mixture was more hazardous when considering the LD50 and LD90. The commercial mixture and imidacloprid induced higher adult emergence and altered the sex ratio in the progeny. CONCLUSIONS: The following order of toxicity on D. rapae can be established: imidacloprid > commercial mixture > spirotetramat. Joint use of this species with imidacloprid and commercial mixture should be avoided in integrated pest management programs. © 2024 Society of Chemical Industry.

Asunto(s)

Compuestos Aza , Insecticidas , Neonicotinoides , Nitrocompuestos , Pupa , Compuestos de Espiro , Avispas , Animales , Compuestos de Espiro/toxicidad , Pupa/efectos de los fármacos , Pupa/crecimiento & desarrollo , Avispas/efectos de los fármacos , Avispas/fisiología , Avispas/crecimiento & desarrollo , Áfidos/efectos de los fármacos , Áfidos/parasitología , Femenino , Imidazoles/toxicidad

RESUMEN

In this article, Density Functional Theory based calculations, including dispersion corrections, PBE0(D3BJ)/Def2-TZVP(-f), were performed to elucidate the photophysics of the [Ru(bpy)2(HAT)]2+ complex in water. In addition, the thermodynamics of the charge and electron transfer excited state reactions of this complex with oxygen, nitric oxide and Guanosine-5'-monophosphate nucleotide (GMP) were investigated. The first singlet excite state, S1, strongly couples with the second and third triplet excited states (T2 and T3) giving rise to a high intersystem crossing rate of 6.26 × 1011 s-1 which is ∼106 greater than the fluorescence rate decay. The thermodynamics of the excited reactions revealed that all electron transfer reactions investigated are highly favorable, due mainly to the high stability of the triply charged radical cation 2PS•3+ species formed after the electron has been transferred. Excited state electron transfer from the GMP nucleotide to the complex is also highly favorable (ΔGsol = -92.6 kcal/mol), showing that this complex can be involved in the photooxidation of DNA, in line with experimental findings. Therefore, the calculations allow to conclude that the [Ru(bpy)2(HAT)]2+ complex can act in Photodynamic therapy through both mechanisms type I and II, through electron transfer from and to the complex and triplet-triplet energy transfer, generating ROS, RNOS and through DNA photooxidation. In addition, the work also opens a perspective of using this complex for the in-situ generation of the singlet nitroxyl (1NO-) species, which can have important applications for the generation of HNO and may have, therefore, important impact for physiological studies involving HNO.

Asunto(s)

Compuestos Organometálicos , Rutenio , 2,2'-Dipiridil , Compuestos Aza , Crisenos , Electrones

RESUMEN

Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 Å X ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases.

Asunto(s)

Compuestos Aza/farmacología , Catepsina B/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Leishmania mexicana/efectos de los fármacos , Tripanocidas/farmacología , Compuestos Aza/síntesis química , Compuestos Aza/química , Catepsina B/metabolismo , Cristalografía por Rayos X , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/química , Dipéptidos/síntesis química , Dipéptidos/química , Dipéptidos/farmacología , Relación Dosis-Respuesta a Droga , Leishmania mexicana/enzimología , Simulación de Dinámica Molecular , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/química , Nitrilos/farmacología , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismo , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química

RESUMEN

In this study, we report for the first time the use of four aza-dipyrromethenes (ADPMs) as photosensitizers for cancer PDT. The synthesis and characterization of the ADPMs and their photodynamic action against B16F10 melanoma cells were assessed. ADPM 2 is the best singlet oxygen generator and the most phototoxic (at 2.5 µM) towards B16F10 cells.

Asunto(s)

Antineoplásicos/farmacología , Compuestos Aza/farmacología , Melanoma/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfobilinógeno/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Melanoma/patología , Ratones , Estructura Molecular , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfobilinógeno/síntesis química , Porfobilinógeno/química , Porfobilinógeno/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

Covering: 2006 to 2018 The application of the 6π-azaelectrocyclization of azatrienes as a key strategy for the synthesis of natural products, their analogs and related bioactive or biomedically-relevant compounds (from 2006 to date) is comprehensively reviewed. Details about reaction optimization studies, relevant reaction mechanisms and conditions are also discussed.

Asunto(s)

Alcaloides/síntesis química , Productos Biológicos/síntesis química , Técnicas de Química Sintética/métodos , Compuestos Aza/química , Ciclización , Agonistas de los Receptores Histamínicos/síntesis química , Piperidinas/química , Piridinas/química , Pirroles/síntesis química , Quinazolinas/síntesis química , Quinolizinas/química , Sesquiterpenos/síntesis química

RESUMEN

Since 1929, several researchers have conducted studies in relation to the nucleoside of adenosine (1) mainly distribution identifying, characterizing their biological importance and synthetic chemistry to which this type of molecule has been subjected to obtain multiple of its derivatives. The receptors that interact with adenosine and its derivatives, called purinergic receptors, are classified as A1, A2A, A2B and A3. In the presence of agonists and antagonists, these receptors are involved in various physiological processes and diseases. This review describes and compares some of the synthetic methods that have been developed over the last 30 years for obtaining some adenosine derivatives, classified according to substitution processes, complexation, mating and conjugation. Finally, we mention that although the concentrations of these nucleosides are low in normal tissues, they can increase rapidly in pathophysiological conditions such as hypoxia, ischemia, inflammation, trauma and cancer. In particular, the evaluation of adenosine derivatives as adjunctive therapy promises to have a significant impact on the treatment of certain cancers, although the transfer of these results to clinical practice requires a deeper understanding of how adenosine regulates the process of tumorigenesis.

Asunto(s)

Adenosina/análogos & derivados , Antineoplásicos/síntesis química , Adenosina/metabolismo , Adenosina/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Compuestos Aza/química , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/metabolismo , Ácidos Sulfónicos/química

RESUMEN

The negative impact of conventional pesticides on the environment is already extensively discussed worldwide. Although the use of chemical agents for controlling agricultural pests remains as first-line strategy for pest control, novel biorational active insecticides, such as spirotetramat, have appeared in the pesticide market during recent years in Argentina. The aim of this study was to assess the toxicity of spirotetramat on two developmental stages of a Neotropical strain of Eretmocerus mundus, with the conventional insecticide cypermethrin as a positive control, and to determine spirotetramat's side effects on parasitoid demographic parameters. Lethal effects of both insecticides on pupae and adults were evaluated by adult emergency and survival, respectively; whereas sublethal effects on both development stages were assessed by adult longevity, reproduction capacity, sex ratio, and longevity of the first progeny. Spirotetramat proved less harmful than cypermethrin at both developmental stages studied, corroborating once more the high toxicity of this pyrethroid to natural enemies. Although spirotetramat did not affect the emergence and reproductive capacity of adults surviving pupal exposure, the longevity of the first progeny was reduced as was adult survival and longevity after exposure to residues. Spirotetramat also reduced all demographic parameters in the population evaluation. This work is the first report of spirotetramat toxicity at the population level and demonstrates the need to assess the total effect of pesticides on natural enemies.

Asunto(s)

Compuestos Aza/toxicidad , Himenópteros , Insecticidas/toxicidad , Compuestos de Espiro/toxicidad , Animales , Argentina , Demografía , Pupa , Reproducción

RESUMEN

BACKGROUND: The metabolic inhibitor 3-bromopyruvate (3-BrPA) is a promising anti-cancer alkylating agent, shown to inhibit growth of some colorectal carcinoma with KRAS mutation. Recently, we demonstrated increased resistance to 3-BrPA in wt p53 tumor cells compared to those with p53 silencing or mutation. Since hypoxic microenvironments select for tumor cells with diminished therapeutic response, we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring (Q61L)-mutant NRAS and wt BRAF, C8161 melanoma with (G12D)-mutant KRAS (G464E)-mutant BRAF, and A549 lung carcinoma with a KRAS (G12S)-mutation. Since hypoxia increases the toxicity of the p53 activator, Prima-1 against breast cancer cells irrespective of their p53 status, we also investigated whether Prima-1 reversed hypoxic resistance to 3-BrPA. RESULTS: In contrast to the high susceptibility of hypoxic mutant NRAS MelJuso cells to 3-BrPA or Prima-1, KRAS mutant C8161 and A549 cells revealed hypoxic resistance to 3-BrPA counteracted by Prima-1. In A549 cells, Prima-1 increased p21CDKN1mRNA, and reciprocally inhibited mRNA expression of the SLC2A1-GLUT1 glucose transporter-1 and ALDH1A1, gene linked to detoxification and stem cell properties. 3-BrPA lowered CAIX and VEGF mRNA expression. Death from joint Prima-1 and 3-BrPA treatment in KRAS mutant A549 and C8161 cells seemed mediated by potentiating oxidative stress, since it was antagonized by the anti-oxidant and glutathione precursor N-acetylcysteine. CONCLUSIONS: This report is the first to show that Prima-1 kills hypoxic wt p53 KRAS-mutant cells resistant to 3-BrPA, partly by decreasing GLUT-1 expression and exacerbating pro-oxidant stress.

Asunto(s)

Acetilcisteína/farmacología , Compuestos Aza/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Piruvatos/farmacología , Células A549 , Hipoxia de la Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Resistencia a Antineoplásicos/genética , Depuradores de Radicales Libres/farmacología , GTP Fosfohidrolasas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 1/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Melanoma/genética , Melanoma/patología , Proteínas de la Membrana/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína p53 Supresora de Tumor/genética

RESUMEN

Clavulanic acid (CA), a potent inhibitor of ß-lactamase enzymes, is produced by Streptomyces clavuligerus (Sc) cultivation processes, for which low yields are commonly obtained. Improved knowledge of the clavam biosynthetic pathway, especially the steps involved in the inversion of 3S-5S into 3R-5R stereochemical configuration, would help to eventually identify bottlenecks in the pathway. In this work, we studied the role of acetate in CA biosynthesis by a combined continuous culture and computational simulation approach. From this we derived a new model for the synthesis of N-acetyl-glycyl-clavaminic acid (NAG-clavam) by Sc. Acetylated compounds, such as NAG-clavam and N-acetyl-clavaminic acid, have been reported in the clavam pathway. Although the acetyl group is present in the ß-lactam intermediate NAG-clavam, it is unknown how this group is incorporated. Hence, under the consideration of the experimentally proven accumulation of acetate during CA biosynthesis, and the fact that an acetyl group is present in the NAG-clavam structure, a computational evaluation of the tentative formation of NAG-clavam was performed for the purpose of providing further understanding. The proposed reaction mechanism consists of two steps: first, acetate reacts with ATP to produce a reactive acylphosphate intermediate; second, a direct nucleophilic attack of the terminal amino group of N-glycyl-clavaminic on the carbonyl carbon of the acylphosphate intermediate leads to a tetrahydral intermediate, which collapses and produces ADP and N-acetyl-glycyl-clavaminic acid. The calculations suggest that for the proposed reaction mechanism, the reaction proceeds until completion of the first step, without the direct action of an enzyme, where acetate and ATP are involved. For this step, the computed activation energy was ≅2.82kcal/mol while the reaction energy was ≅2.38kcal/mol. As this is an endothermic chemical process with a relatively small activation energy, the reaction rate should be considerably high. The calculations offered in this work should not be considered as a definite characterization of the potential energy surface for the reaction between acetate and ATP, but rather as a first approximation that provides valuable insight about the reaction mechanism. Finally, a complete route for the inversion of the stereochemical configuration from (3S, 5S)-clavaminic acid into (3R, 5R)-clavulanic acid is proposed, including a novel alternative for the double epimerization using proline racemase and NAG-clavam formation.

Asunto(s)

Compuestos Aza/química , Modelos Químicos , Estructura Molecular , Estereoisomerismo

RESUMEN

Natural phytotoxins and their synthetic analogs are a potential source of new bioactive compounds for agriculture. Analogs of rubrolides, a class of γ-alkylidene-γ-lactones isolated from different ascidians, have been shown to interfere with the photosynthetic electron-transport chain, yet their activity needs to be improved. With this aim, ten 5-aryl-6-benzyl-4-bromopyridazin-3(2H)-ones were prepared in yields ranging from 44 to 88% by reaction of their correspondent γ-alkylidene-γ-lactones with NH2 NH2 . The structures of these rubrolide analogs were determined by (1) H- and (13) C-NMR, 2D-NMR (COSY and HETCOR), NOE difference, and MS techniques. These compounds were evaluated for their abilities of interfering with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Lactones with electron-withdrawing substituents in the para-position of the benzylidene ring were the most effective inhibitors. Characterization of the activity of 11b/11b' suggested a mechanism based on the interaction with the plastoquinone binding site of photosystem II. Addition of several compounds to the culture medium of a cyanobacterial model strain was found to inhibit algal growth. However, the relative effectiveness was not consistent with their activity in vitro, suggesting the occurrence of multiple targets and/or detoxyfication mechanisms. Indeed, the compounds showed differential effects on the heterotrophic growth of some crop species, Cucumis sativus and Sorghum bicolor. Pyridazin-3(2H)-ones 12e, 12i, and 12j, which have been found poorly active against the photosynthetic electron transport, were the most effective in inhibiting the growth of some weeds, Ipomoea grandifolia and Brachiaria decumbens, under greenhouse conditions.

Asunto(s)

Compuestos Aza/farmacología , Lactonas/farmacología , Fotosíntesis/efectos de los fármacos , Compuestos Aza/química , Brachiaria/efectos de los fármacos , Brachiaria/crecimiento & desarrollo , Cucumis sativus/efectos de los fármacos , Cucumis sativus/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Ipomoea/efectos de los fármacos , Ipomoea/crecimiento & desarrollo , Lactonas/química , Modelos Moleculares , Estructura Molecular , Sorghum/efectos de los fármacos , Sorghum/crecimiento & desarrollo

RESUMEN

There is an increasing number of compounds developed to target one or more pathways involved in vasodilation. Some studies conducted with azaindole and indazole derivatives showed cardiovascular activity associated with these compounds. Fast and easy structural modification of these organic molecules can be achieved using metal complexes promoting a much larger spatial change than organic strategies, potentially leading to novel drugs. Here, we have prepared a series of complexes with a formula cis-[RuCl(L)(bpy)(2)]PF(6), where L = 7-azaindole (ain), 5-azaindole (5-ain), 4-azaindole (4-ain), indazole (indz), benzimidazole (bzim) or quinoline (qui), which were characterized by spectroscopic and electrochemical techniques (CV, DPV). These compounds showed reasonable stability exhibiting photoreactivity only at low wavelength along with superoxide scavenger activity. Cytotoxicity assays indicated their low activity preliminarily supporting in vivo application. Interestingly, vasodilation assays conducted in rat aorta exhibited great activity that largely improved compared to free ligands and even better than the well-studied organic compound (BAY 41-42272), with IC(50) reaching 55 nM. These results have validated this strategy opening new opportunities to further develop cardiovascular agents based on metallo-bicyclic rings.

Asunto(s)

2,2'-Dipiridil/análogos & derivados , Bencimidazoles/química , Indazoles/química , Indoles/química , Compuestos Organometálicos/química , Quinolinas/química , Rutenio/química , Vasodilatadores/química , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Compuestos Aza/química , Compuestos Aza/farmacología , Bencimidazoles/farmacología , Línea Celular , Humanos , Indazoles/farmacología , Indoles/farmacología , Compuestos Organometálicos/farmacología , Quinolinas/farmacología , Ratas , Rutenio/farmacología , Superóxidos/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología

RESUMEN

In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 µM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 µM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.

Asunto(s)

Compuestos Aza/química , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Pancreáticas/patología , Pironas/farmacología , Transducción de Señal/efectos de los fármacos , Acilación , Animales , Línea Celular , Neoplasias Pancreáticas/metabolismo , Pironas/química

RESUMEN

Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.

Asunto(s)

Antiinflamatorios/farmacología , Compuestos Aza/farmacología , Corticosterona/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Hipocampo/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/fisiología , Neuropéptidos/fisiología , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Western Blotting , Células Cultivadas , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Femenino , Técnica del Anticuerpo Fluorescente , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/anomalías , Hipocampo/metabolismo , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Mutantes Neurológicos , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Glucocorticoides/metabolismo

RESUMEN

PURPOSE: To determine species of staphylococci in chronic conjunctivitis, their antibiotic susceptibility pattern, patient treatments, clinical course, and clinical conditions. METHODS: In this prospective study, 243 conjunctival cultures were taken from 191 patients with chronic conjunctivitis, we obtained staphylococci susceptibility patterns with E-test, and they were analyzed in coagulase-positive and negative. The minimum inhibitory concentration for 90% of isolates (MIC90) was determined for Staphylococcus aureus and Staphylococcus epidermidis. Additionally, clinical follow-up and associated factors of all patients were analyzed depending on methicillin resistance (MR) or susceptibility (MS) bacterial state. RESULTS: One hundred and eight (44%) cultures were positive; 81 positive cultures were Gram-positive of which, 77 were staphylococci, 29 coagulase-positive with S. aureus as the most prevalent, 89% MS, and 11% MR. And 48 were coagulase-negative with S. epidermidis as the most isolated with 36% of MS and 64% of MR. Poor susceptibility was found in the staphylococcus coagulase-negative/MR group. Moxifloxacin and vancomycin show the best in vitro activity for all isolates. The MIC90 of moxifloxacin and vancomycin were 0.064/1.5, 0.64/3.0, and 1/3.0 for S. aureus-MS, S. epidermidis-MS, and S. epidermidis-MR, respectively. The most frequently associated factors found in patients with positive culture for staphylococcus were exposure to the health care system 23 (29.87%) of 77 patients and dry eye 23 (29.87%) of 77 patients. Both with a proportion of 3 in 10. CONCLUSION: Coagulase-negative staphylococci were the most frequently isolated from the conjunctiva with 58.33% of MR; even though multiresistance was detected, their susceptibility to a fourth-generation fluoroquinolone, commonly used, such as moxifloxacin, was preserved.

Asunto(s)

Antibacterianos/farmacología , Conjuntivitis Bacteriana/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus/efectos de los fármacos , Adulto , Compuestos Aza/farmacología , Enfermedad Crónica , Conjuntivitis Bacteriana/tratamiento farmacológico , Farmacorresistencia Bacteriana , Fluoroquinolonas , Estudios de Seguimiento , Humanos , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Moxifloxacino , Quinolinas/farmacología , Infecciones Estafilocócicas/microbiología , Staphylococcus/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/aislamiento & purificación , Resultado del Tratamiento , Vancomicina/farmacología

Asunto(s)

Antibacterianos/efectos adversos , Compuestos Aza/efectos adversos , Enfermedades del Iris/inducido químicamente , Trastornos de la Pigmentación/inducido químicamente , Quinolinas/efectos adversos , Enfermedad Aguda , Adulto , Anciano , Femenino , Fluoroquinolonas , Humanos , Enfermedades del Iris/diagnóstico , Masculino , Moxifloxacino , Trastornos de la Pigmentación/diagnóstico

RESUMEN

A simple procedure is proposed for the determination of the antibiotic moxifloxacin in urine using nanostructured gold as surface-enhanced Raman scattering signal enhancer. The standard addition method in conjunction to multivariate curve resolution-alternating least squares was applied to eliminate the matrix effect and to isolate the spectral contribution of the analyte. Even in the presence of unexpected interferences in the urinary media, it was possible to extract and quantify the analyte response, reaching, in this way, the so-called second-order advantage from first-order data. Moreover, although a saturation phenomenon of the metallic surface was observed, the results of the proposed methodology presented important advantages such as high sensitivity and simpler experimental procedures. The moxifloxacin was determined at levels of 0.70 and 1.50 µg mL(-1) in urine diluted to 1.0% (corresponding to 70.0 and 150 µg mL(-1) in the original samples) with relative errors of 4.23 and 8.70%, respectively. The limit of detection (0.085 µg mL(-1)) and limit of quantification (0.26 µg mL(-1)) values indicated that the quantification can be accomplished in urine up to 24 h after the administration of a single 400-mg dose.

Asunto(s)

Compuestos Aza/orina , Oro/química , Nanopartículas del Metal/química , Quinolinas/orina , Espectrometría Raman , Fluoroquinolonas , Humanos , Límite de Detección , Moxifloxacino , Análisis Multivariante

Asunto(s)

Adulto , Anciano , Femenino , Humanos , Masculino , Antibacterianos/efectos adversos , Compuestos Aza/efectos adversos , Enfermedades del Iris/inducido químicamente , Trastornos de la Pigmentación/inducido químicamente , Quinolinas/efectos adversos , Enfermedad Aguda , Enfermedades del Iris/diagnóstico , Trastornos de la Pigmentación/diagnóstico

RESUMEN

The activity of a family scorpiand-like azamacrocycles against Leishmania infantum and Leishmania braziliensis was studied using promastigotes, axenic and intracellular amastigotes forms. All the compounds are more active and less toxic than meglumine antimoniate (Glucantime). Moreover, the data on infection rates and amastigotes showed that compounds P2Py, PN and P3Py are the most active against both species of Leishmania. On the other hand, studies on the inhibitory effect of these compounds on SOD enzymes showed that while the inhibition of the Fe-SOD enzyme of the promastigote forms of the parasites is remarkable, the inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli is negligible. The ultrastructural alterations observed in treated promastigote forms confirmed that the compounds having the highest activity were those causing the largest cell damage. The modifications observed by (1)H NMR, and the amounts of catabolites excreted by the parasites after treatment with the compounds, suggested that the catabolic mechanism could depend on the structure of the side chains linked to the aza-scorpiand macrocycles.

Asunto(s)

Antiprotozoarios/farmacología , Compuestos Aza/farmacología , Leishmania braziliensis/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Compuestos Macrocíclicos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Relación Dosis-Respuesta a Droga , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad

RESUMEN

Nitric oxide (NO) is an important chemical compound involved in many physiological and pathological processes in living organisms. However, nitric oxide is a very reactive radical that needs to be carried through organisms to reach the desired biological target. With the aim of developing new compounds that can be used as biomedical NO carrier agents we carried out a theoretical investigation at B3LYP/6-31+G(d)/LANL2DZ level on the interaction of NO with RuTAP (Ruthenium tetraazaporphyrin) and Ru(L)TAP, where L=Cl-, NH3, and Pyridine (Py)) and the oxidation state of Ru ranging from +1 to +3. The theoretical calculation results show that the geometric and electronic parameters of the Ru-NO bond are highly dependent on the oxidation state of Ru and of the chemical nature of ligand L at axial position. The results also show clearly that RuTAP and Ru(L)TAP are good potential candidates to be used as NO carriers in living organisms.

Asunto(s)

Compuestos Aza/química , Complejos de Coordinación/química , Óxido Nítrico/química , Porfirinas/química , Piridinas/química , Rutenio/química , Animales , Transporte Biológico , Materiales Biomiméticos , Humanos , Ligandos , Modelos Moleculares , Oxidación-Reducción