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Aging is characterized by increased reactive species, leading to redox imbalance, oxidative damage, and senescence. The adverse effects of alcohol consumption potentiate aging-associated alterations, promoting several diseases, including liver diseases. Nucleoredoxin (NXN) is a redox-sensitive enzyme that targets reactive oxygen species and regulates key cellular processes through redox protein-protein interactions. Here, we determine the effect of chronic alcohol consumption on NXN-dependent redox interactions in the liver of aged mice. We found that chronic alcohol consumption preferentially promotes the localization of NXN either into or alongside senescent cells, declines its interacting capability, and worsens the altered interaction ratio of NXN with FLII, MYD88, CAMK2A, and PFK1 proteins induced by aging. In addition, carbonylated protein and cell proliferation increased, and the ratios of collagen I and collagen III were inverted. Thus, we demonstrate an emerging phenomenon associated with altered redox homeostasis during aging, as shown by the declining capability of NXN to interact with partner proteins, which is enhanced by chronic alcohol consumption in the mouse liver. This evidence opens an attractive window to elucidate the consequences of both aging and chronic alcohol consumption on the downstream signaling pathways regulated by NXN-dependent redox-sensitive interactions.

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Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted­in­Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein­coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.

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Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer's disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies.

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The aim of this work was to evaluate the in vitro bacterial inhibition of different types of garlic on Escherichia coli ATCC 25922, Listeria monocytogenes and Staphylococcus aureus. The bacterial strains were molecularly identified using gen 16S rDNA molecular identification. Four different types of garlics were used: 1) white, 2) Japanese, 3) elephant and 3) black, and these were evaluated at two different concentrations (0.25 and 0.125 g/mL) per garlic type. Bioactive compounds present in the garlics were identified using high-performance liquid chromatography coupled to ultraviolet detector (HPLC-UV), and total polyphenols were quantified by the Folin-Ciocalteu technique. The Kirby-Bauber method was used for the bacterial evaluation. Aqueous extract of black garlic had the highest amount of polyphenols 6.26 ± 0.21 mg GAE/mL. The area of inhibition was measured and classified as sensitive, intermediate or resistant. Using the disc diffusion assay, higher concentration (0.25 g/mL) of aqueous extract of white garlic had the highest antibacterial activity area, with 21.46 ± 3.94 mm for L. monocytogenes, 20.61 ± 2.47 mm for S. aureus and 17.83 ± 2.21 mm for E. coli. White garlic had comparable antimicrobial activity as the control (tetracycline at 30 µg) as indicated by the size of the inhibition halos. Based on your results, white garlic can be used as an alternative to synthetic antimicrobials.

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Several factors, including pharmacogenetics, contribute to inter-individual variability in drug response. Many antiepileptic drugs (AEDs) are metabolized by a variety of enzymatic reactions, and the cytochrome P450 (CYP) family has attracted considerable attention. Some of the CYPs exist as genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure. Regarding the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of particular interest. There have been recent advances in discovering factors such as these, especially those underlying the risk of medication toxicity. This review summarizes the evidence about whether such polymorphisms affect the clinical action of AEDs to facilitate future studies on the pharmacogenetics of epilepsy. We performed Key Words searches in the public databases PubMed, Medscape, and Rxlisty, Pharm GKB for genetic polymorphisms and the NCBI website for the nomenclature of alleles of CYP450, finding that CYP2D6, CYP2C9, CYP3A4, and CYP2D19 were involved in the metabolism of most antiepileptic drugs, given the allele frequency in the population and the associated variability in the clinical response.

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BACKGROUND: Vasovagal syncope is a common clinical condition, consequential to reduced cerebral blood flow resulting from a failure in cardiovascular homeostasis during orthostasis. Blood pressure regulation is the basis for syncope development. In this regulation, the α1a-adrenergic receptor plays a major role. Some studies have found a positive correlation between the Arg347Cys polymorphism of the α1a-adrenergic receptor to hypertension and heart autonomic control. The goal of this study is to evaluate the possible association between the Arg347Cys α1a-adrenergic receptor polymorphism and vasovagal syncope in a Mexican population. METHODS/MAJOR FINDINGS: A sample of 89 vasovagal syncope patients and 40 healthy controls were studied. Arg347Cys α1a-adrenergic receptor polymorphism was determined by the PCR-RFLP method. We found an increased frequency of genotype ArgArg in vasovagal syncope patients. In a logistic regression model significant associations were found in two genetic models, in codominant model (OR=13.21: CI 95% 3.69-54.99, p<0.001) and in additive model (OR=12.68: CI 95% 3.5-53.07, p<0.001) for ArgArg genotype with CysCys as reference. CONCLUSIONS: Our data suggests an important participation of Arg347Cys polymorphism as susceptibility factor in patients with vasovagal syncope. ArgArg genotype could be a marker for vasovagal syncope susceptibility in the Mexican population.

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Desde los primeros años de vida, todos los seres humanos recibimos un cúmulo de actitudes, conductas y valores que son aprendidos ya sea como modos de aprendizaje o como modelos de imitación del comportamiento de los sujetos adultos. Estas predeterminaciones sociales se han estructurado históricamente a partir del sistema binario masculinidad/feminidad, cuya reducción cultural propicia inequidades de género que afectan la convivencia social y que se manifiestan en la circulación doméstica o masiva de imágenes que construyen códigos y representaciones culturales que confrontan equívocamente a las identidades sexuales. Bajo esta perspectiva general, en este artículo pretendemos resaltar, a través de un análisis semiótico y multidisciplinario, algunos códigos visuales manifiestos en una selección de fotografías que evidencian la perpetuación de la inequidad de género.

Desde os primeiros anos de vida, todos os seres humanos recebem uma série de atitudes, comportamentos e valores que são aprendidos, seja como modos de aprendizagem ou como modelos de imitação do comportamento dos indivíduos adultos. Estes padrões sociais são historicamente estruturados a partir do sistema binário de masculinidade / feminilidade, e a redução cultural promove desigualdades de gênero que afetam a harmonia social e manifestam-se na circulação interna ou masiva de imagens construídas com códigos e representações culturais que equivocadamente confrontam identidades sexuais. Sob esta perspectiva geral neste artigo destacamos, através duma análise semiótica e multidisciplinar, alguns códigos visuais presentes numa seleção de fotografias que mostram a perpetuação da desigualdade de gênero.

From the first years of life, each human being receives an accumulation of attitudes, conducts and values that are learned and apprehended sometimes like specific learning ideals and some others like imitation models of adult’s behavior. This context has been structured historically from the binary system of masculinity/femininity, whose cultural reduction determines gender inequalities that affect social interactions. The gender inequalities are identified in the domestic and the massive circulation of images that contribute with the configuration of codes and representations that promote confusing gender identities. The aim of this article is to show some visual codes presented in a group of photographs that exhibit the perpetuation of gender inequalities.

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Dog overpopulation is a major health problem in developing countries due to the existence of some zoonotic diseases in which dogs act as reservoirs, besides the aggressive events to humans. Distribution, behavior patterns and combined methodologies are needed aspects in the design of successful dog population control programs. Coumestrol is a phytoestrogen which induces alterations in the reproductive male system, when bind to alpha and beta estrogen receptors acting as an agonist or antagonist fashion. Both receptor types also exist in central nerve regions governing sexual behavior of those animals such as the preoptic area, ventro medial nucleous, the amygdala and the olfactory bulb. In this study, 300 μg/kg coumestrol was orally administered to male dogs, once a week for a 4 week period. Dogs were freed for 5 min in a 9 m² area having a recipient containing vaginal discharges from estrous dog females and other similar vessel containing sterile saline solution. Smelling latency time for each recipient, smelling frequency and territory marking in response to stimulus, was recorded. At the end of the test, semen was collected and evaluated. A significative difference (P < 0.005) in smelling latency time and smelling frequency to the vaginal discharge was found; sperm count decreased from 518.4 ± 215.4 × 10(6) to 57.6 ± 50.4 × 10(6) at week 4 and the abnormal sperm morphology increased from 14.7 ± 3.3% at 0 week to 60.0 ± 20%. In conclusion, 300 μg/kg coumestrol given orally to male dogs for 4 weeks induces alterations in the olfactory behavior along with an oligo and teratospermic effect.

La sobrepoblación canina es un problema importante de salud pública debido a la transmisión de enfermedades zoonóticas y las agresiones hacia el humano. En el diseño de programas para controlar la población canina se requiere del conocimiento de su distribución, comportamiento y metodologías combinadas para tener éxito. El coumestrol es un fitoestrógeno que induce alteraciones en el aparato reproductor de los machos al unirse a los receptores estrogénicos alfa y beta, en donde actúa de manera dosis-dependiente como agonista o antagonista. Estos receptores también existen en las estructuras del sistema nervioso que regulan el comportamiento sexual, como la región preóptica, núcleo ventromedial, la amígdala y el bulbo olfatorio. En este estudio se administró coumestrol (300 μg/kg) por vía oral a perros machos, una vez por semana durante cuatro semanas; los perros se colocaron durante cinco minutos en un área aislada de 9 m² en donde se colocó un frasco conteniendo secreciones vaginales obtenidas de perras en estro y otro con solución salina estéril. Se registró el tiempo de latencia de los perros para olfatear cada frasco, su frecuencia de respuesta y la frecuencia con que se presentó conducta de marcaje en respuesta al estímulo. Una vez concluido el experimento, se obtuvo semen y se evaluó. Se encontró diferencia significativa (P < 0.005) en el periodo de latencia y frecuencia con la que el macho se acercó a oler las secreciones vaginales y el conteo espermático disminuyó de 518.4 ± 215.4 × 10(6) al inicio del estudio a 57.6 ± 50.4 × 10(6) en la semana cuatro y el porcentaje de anormalidades espermáticas aumentó de 14.7 ± 3.3 puntos en la semana 0 a 60.0 ± 20.0% en la semana cuatro. Se concluye que el tratamiento de perros con coumestrol durante cuatro semanas ocasiona alteraciones en la conducta de exploración olfatoria y tiene un efecto oligospérmico y teratospérmico.

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Dog overpopulation is considered a human health risk; they are the terrestrial vector of rabies and reservoirs for other human diseases. Surgical neutering and intratesticular injections have been used in male dogs. Physiological and morphological alterations in reproductive organs can be induced by phytoestrogens. Our goal was to evaluate the effect of oral coumestrol on dog ejaculates and testis histology. Two groups of 5 healthy adult dogs were used. One coumestrolcontaining biscuit was given once a week for a 4 week period to the experimental group. Ejaculates were obtained and evaluated. After treatment, testis were obtained and processed for histology. Compared to controls, treated dogs have reduced tubules (462 +/- 1.4 vs 336 +/- 2 micron(2)), spermatogenic epithelium (49.1 +/- 0.01 vs 13.3 +/- 0.01 micron(2)), and lumen opening (891 +/- 1.4 vs 530 +/- 26.9 micron). Ejaculates from treated animals have increased numbers of abnormal spermatozoa and reduced sperm concentration.

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INTRODUCTION: Estrogens are well recognized as important hormones in male reproduction and act as ligands to alpha and beta estrogen receptors. Both estrogen receptors could interact with estrogen-mimicking compounds such as the fluorescent phytoestrogen coumestrol, which acts both in an agonist or antagonist fashion. OBJECTIVE: To investigate the presence of Coumestrol-Estrogen Receptor complexes by fluorescence in testis and epididymis, its effect in the ER expression by immunostain in the same tissues and the effect of this binding in the testis histological characteristics. DESIGN: Adult healthy and sexually active dogs were assigned to either the experimental or control group .Coumestrol impregnated dog biscuits were given to each animal from the experimental group once a week for a 4 week period. The control group received a biscuit with no Coumestrol, also once a week and for the same period. Testis morphology, ER immunodetection, and coumestrol-receptor binding were evaluated. SETTING: The experiment was done in the facilities of the Mexico City canine shelter. Animals were caged individually with food and water ad libitum and having at least two daily hours for exercise. RESULTS: Morphological alterations in testis after oral administration of coumestrol were detected. The main alterations include decreased germinal epithelium in tubule, and the loss of a continuous proliferation and differentiation gamete layer. Fluorescence signals in testis interstitial Leydig cells and epididymus indicating ER-coumestrol complexes were detected at the same points to those Immunohystochemically detected ER. CONCLUSIONS: Coumestrol administration induces testis alterations and coumestrol-ER complexes can be co-localized by binding-enhanced fluorescence and immunoprecipitation.

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The purpose of this study was to evaluate the correlation between the vasovagal syncope (VVS) and the beta1 adrenergic receptor polymorphism at the 389 position. Seventy individuals with VVS were selected. DNA was extracted from peripheral blood by salting out and subjected to the amplification-restriction test. Genotype identification was made by polyacrylamide gel electrophoresis. A higher frequency in genotype and allele frequencies were found in individuals with positive tilted table test respect individuals with negative test, as well as a marked preference of the GlyGly phenotype in women. Genotype Arg389Gly was the most frequent between individuals with positive response in passive phase with respect to those in the induced phase. When the genotype was analyzed based on the hemodynamic response (VASIS) a gradient is observed in the frequency of Arg389Gly with the highest major frequency in the cardio-inhibitory response followed by the mixed response, and finally the vasodepressor response. These results suggest that the SVV has a genetic component associated with the Arg389Gly polymorphism of the adrenergic receptor. The Gly allele has a high risk association and it is maintained in the population through heterozygosis.

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The purpose of this study was to evaluate the correlation between the vasovagal syncope (VVS) and the beta1 adrenergic receptor polymorphism at the 389 position. Seventy individuals with VVS were selected. DNA was extracted from peripheral blood by salting out and subjected to the amplification-restriction test. Genotype identification was made by polyacrylamide gel electrophoresis. A higher frequency in genotype and allele frequencies were found in individuals with positive tilted table test respect individuals with negative test, as well as a marked preference of the GlyGly phenotype in women. Genotype Arg389Gly was the most frequent between individuals with positive response in passive phase with respect to those in the induced phase. When the genotype was analyzed based on the hemodynamic response (VASIS) a gradient is observed in the frequency of Arg389Gly with the highest major frequency in the cardio-inhibitory response followed by the mixed response, and finally the vasodepressor response. These results suggest that the SVV has a genetic component associated with the Arg389Gly polymorphism of the adrenergic receptor. The Gly allele has a high risk association and it is maintained in the population through heterozygosis.

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Rabies transmission by wild animals has not being controlled satisfactorily. One major rabies vector to humans and cattle is the hematophagous vampire bat Desmodus rotundus whose distribution is still increasing in the Americas. Of all of the strategies currently in place to control this vector, none of them are really specific and some have ecological impacts. In the present study we used a naturally occurring phytoestrogen on a small vampire bat colony. After collection, bats were fed bovine blood containing 200 microg coumestrol for a 30-day period. After treatment, gonads were excised and processed for histological evaluation. Data indicate that coumestrol adversely affects gonad histology and has a possible impact on the fertility of both male and female vampire bats.

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Helminth infections are a medical problem in the world nowadays. In this paper a novel atom-level chemical descriptor has been applied to estimate the anthelmintic activity. Total and local linear indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The discriminant model has an accuracy of 90.11% in the training set, with a high Matthews' correlation coefficient (MCC=0.80). To assess the robustness and predictive power of the obtained model, internal (leave-n-out) and external validation process was performed. The QSAR model correctly classified 88.55% of compounds in this external prediction set, yielding a MCC of 0.77. Another LDA model was carried out to outline some conclusions about the possible modes of action of anthelmintic drugs. It has an accuracy of 93.50% in the training set, and 80.00% in the external prediction set. After that, the developed model was used in the virtual--in silico--screening and several compounds from the Merck Index, Negwer's Handbook and Goodman and Gilman were identified by the model as anthelmintic. Finally, the experimental assay of an organic chemical (a furylethylene derivative) by an in vivo test permits us to carry out an assessment of the model. An accuracy of 100% with the theoretical predictions was observed. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.

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We have developed a classification function that is capable of discriminating between anticoccidial and nonanticoccidial compounds with different structural patterns. For this purpose, we calculated the Markovian electron delocalization negentropies of several compounds. These molecular descriptors, which act as molecular fingerprints, are derived from an electronegativity-weighted stochastic matrix (1Pi). The method attempts to describe the delocalization of electrons with time during the process of molecule formation by considering the 3D environment of the atoms. Accordingly, the entropies of this random process are used as molecular descriptors. The present study involves a stochastic generalization of the original idea described by Kier, which concerned the use of molecular negentropies in QSAR. Linear discriminant analysis allowed us to fit the discriminant function. This function has given rise to a good classification of 82.35% (28 anticoccidials out of 34) and 91.8% of inactive compounds (56/61) in training series. An overall classification of 88.42% (84/95) was achieved. Validation of the model was carried out by means of an external predicting series and this gave a global predictability of 93.1%. Finally, we report the experimental assay (more than 95% of lesion control) of two compounds selected from a large data set through virtual screening. We conclude that the approach described here seems to be a promising 3D-QSAR tool based on the mathematical theory of stochastic processes.

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In this work, the TOMOCOMD-CARDD approach has been applied to estimate the anthelmintic activity. Total and local (both atom and atom-type) quadratic indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The obtained model correctly classified 90.37% of compounds in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. The QSAR model correctly classified 88.18% of compounds in this external prediction set. A second model was performed to outline some conclusions about the possible modes of action of anthelmintic drugs. This model permits the correct classification of 94.52% of compounds in the training set, and 80.00% of good global classification in the external prediction set. After that, the developed model was used in virtual in silico screening and several compounds from the Merck Index, Negwer's handbook and Goodman and Gilman were identified by models as anthelmintic. Finally, the experimental assay of one organic chemical (G-1) by an in vivo test coincides fairly well (100%) with model predictions. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.

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La zona Pelúcida (ZP) es la matriz extracelular que rodea a los ovocitos de los mamíferos y juega un papel primordial en el proceso de la fertilización, básicamente en el reconocimiento del espermatozoide por el ovocito, evitando la polispermia y ayudando a la implantación de óvulo en el útero para el desarrollo del embrión. Actualmente se reconoce que su estructura es reticular y que sus principales componentes moleculares son glicoproteínas de diversos pesos moleculares, los cuales son altamente inmunogénicos. Los anticuerpos producidos contra la ZP se han usado para prevenir los procesos iniciales de la fertilización; además se ha demostrado que en algunas mujeres la causa de esterilidade sea la presencia de auto-anticuerpos en contra de la ZP de sus ovocitos. Los anticuerpos monoclonales (AcM) que se han producido en diferentes especies de mamíferos en contra de los componentes de la ZP han mostrado las siguientes características: son tejido-específicos, tienen reacción cruzada con ovocitos de otras especies de mamíferos, previenen la unión de espermatozoides a los ovocitos y algunos previenen la fertilización in vivo. Se han obtenido AcM que reconocen los antígenos de la ZP tanto en forma conformacional como secuencial. Se concluye que los AcM son una herramienta adecuada para el estudio de las funciones de la ZP durante la fertilización

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