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Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively, the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.
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Inflamación/complicaciones , Placenta/metabolismo , Nacimiento Prematuro/etiología , Nacimiento Prematuro/metabolismo , Transcriptoma , Triptófano/metabolismo , Biomarcadores , Biología Computacional/métodos , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inflamación/etiología , Redes y Vías Metabólicas , Embarazo , Resultado del Embarazo , Nacimiento Prematuro/diagnóstico , Factores de RiesgoRESUMEN
The pregnane X receptor (PXR) is a ligand-activated nuclear receptor controlling hepatocyte expression of numerous genes. Although expression changes in xenobiotic-metabolizing, lipogenic, gluconeogenic and bile acid synthetic genes have been described after PXR activation, the temporal dynamics of their expression is largely unknown. Recently, 3D spheroids of primary human hepatocytes (PHHs) have been characterized as the most phenotypically relevant hepatocyte model. We used 3D PHHs to assess time-dependent expression profiles of 12 prototypic PXR-controlled genes in the time course of 168 h of rifampicin treatment (1 or 10 µM). We observed a similar bell-shaped time-induction pattern for xenobiotic-handling genes (CYP3A4, CYP2C9, CYP2B6, and MDR1). However, we observed either biphasic profiles for genes involved in endogenous metabolism (FASN, GLUT2, G6PC, PCK1, and CYP7A1), a decrease for SHP or oscillation for PDK4 and PXR. The rifampicin concentration determined the expression profiles for some genes. Moreover, we calculated half-lives of CYP3A4 and CYP2C9 mRNA under induced or basal conditions and we used a mathematical model to describe PXR-mediated regulation of CYP3A4 expression employing 3D PHHs. The study shows the importance of long-term time-expression profiling of PXR target genes in phenotypically stable 3D PHHs and provides insight into PXR function in liver beyond our knowledge from conventional 2D in vitro models.
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Receptores de Esteroides , Citocromo P-450 CYP3A/metabolismo , Hepatocitos/metabolismo , Humanos , Receptor X de Pregnano/genética , Receptor X de Pregnano/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismoRESUMEN
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drugâ»drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.
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Sistema Enzimático del Citocromo P-450/genética , Redes Reguladoras de Genes , Modelos Teóricos , Receptores de Esteroides/genética , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Retroalimentación Fisiológica , Humanos , Receptor X de Pregnano , Receptores de Esteroides/metabolismoRESUMEN
BACKGROUND: Early diagnosis and prompt effective therapy are crucial for the prevention of tuberculosis (TB) transmission, particularly in regions with high levels of multi-drug resistant TB. This study aimed to evaluate the extent of delay in diagnosis and treatment of TB in Uzbekistan and identify associated risk factors. METHODS: A cross-sectional study was performed on hospital patients with newly diagnosed TB. The time between the onset of respiratory symptoms and initiation of anti-TB treatment was assessed and delays were divided into patient, health system and total delays. Univariable and multivariable logistic regression analysis was used to evaluate determinants of diagnostic and treatment delay. RESULTS: Among 538 patients enrolled, the median delay from onset of symptoms until treatment with anti-TB drugs was 50 days. Analysis of the factors affecting health-seeking behaviour and timely treatment showed the presence of the patient factor. Self-medication was the first health-seeking action for 231 (43%) patients and proved to be a significant predictor of delay (p = 0.005), as well as coughing (p = 0.009), loss of weight (p = 0.001), and visiting private and primary healthcare facilities (p = 0.03 and p = 0.02, respectively). CONCLUSION: TB diagnostic and treatment delay was mainly contributed to by patient delay and should be reduced through increasing public awareness of TB symptoms and improving public health-seeking behaviour for timely initiation of anti-TB treatment. Efforts should be made to minimise irrational use of antibiotics and support interventions to restrict over-the-counter availability of antibiotics.
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Diagnóstico Tardío/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Automedicación/estadística & datos numéricos , Tiempo de Tratamiento/estadística & datos numéricos , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Pulmonar/diagnóstico , Adolescente , Adulto , Antibacterianos/uso terapéutico , Estudios Transversales , Diagnóstico Precoz , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Factores de Riesgo , Factores de Tiempo , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Uzbekistán/epidemiología , Adulto JovenRESUMEN
Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC50s ranging from â¼10 to 24 µM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.
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Flowability is among the most important properties of powders, especially when fine particle size fractions need to be processed. In this study, our goal was to find a possibly simple but accurate mathematical model for predicting the mass flow rate for different fractions of the pharmaceutical excipient sorbitol for direct compression. Various regression models derived from the Jones-Pilpel equation for the prediction of the mass flow rate were investigated. Using validation with experimental data for various particle and hopper orifice sizes, we focused on the prediction accuracy of the respective models, i.e., on the relative difference between measured and model-predicted values. Classical indicators of regression quality from statistics were addressed as well, but we consider high prediction accuracy to be particularly important for industrial processing in practice. For individual particle size fractions, the best results (an average prediction accuracy of 3.8%) were obtained using simple regression on orifice size. However, for higher accuracy (3.1%) in a unifying model, valid in the broad particle size range 0.100-0.346 mm, a fully quadratic model, incorporating interaction between particle and orifice size, appears to be most appropriate.
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Albeit the preparation of liquisolid systems represents an innovative approach to enhance the dissolution of poorly soluble drugs, their broader utilization is still limited mainly due to the problematic conversion of the liquid into freely flowing and readily compressible powder. Accordingly, the presented study aims to determine the optimal carrier/coating material ratio (R value) for formulations based on magnesium aluminometasilicate (NUS2) loaded with polyethylene glycol 400. Four commercially available colloidal silica were used as coating materials in nine different R values (range of 5 - 100). The obtained results suggested that the higher R value leads to the superior properties of powder mixtures, such as better flowability, as well as compacts with higher tensile strength and lower friability. Moreover, it was observed that the type of coating material impacts the properties of liquisolid systems due to the different arrangement of particles in the liquisolid mixture. To confirm the noted dependency of R value and coating material type, the one- and two-way ANOVA, linear regression and principal component analysis (PCA) techniques were performed. In addition, a comparison of results with the properties of loaded NUS2 itself revealed that LSS with sufficient properties may be prepared even without the coating material.
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Magnesio , Dióxido de Silicio , Composición de Medicamentos , Polvos , Solubilidad , ComprimidosRESUMEN
Aim: We studied the influence of coffee consumption on the therapeutic effect of methotrexate (MTX) in patients with rheumatoid arthritis (RA) sorted according to ADORA2A genotypes. Patients & methods: 82 RA patients were dichotomized according to caffeine intake with a threshold of 700 mg/week. Disease activity score 28 (DAS28) was applied (>3.2: high; <3.2: low or remission). Patients were genotyped using quantitative PCR allelic discrimination. Results: We found significantly higher risk of RA in patients with higher caffeine intake and the CT genotype of ADOARA2A rs2298383, rs3761422 and rs2267076 SNPs. The CC genotype of ADORA2A rs2236624 SNP in patients with lower caffeine intake treated with MTX is significantly protective. Conclusion:ADORA2A genotypes and coffee intake influence risk of RA and efficacy of it MTX treatment.
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Adenosina/genética , Adenosina/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Café/metabolismo , Receptor de Adenosina A2A/genética , Adulto , Antirreumáticos/metabolismo , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Café/efectos adversos , Estudios Transversales , Femenino , Humanos , Masculino , Metotrexato/metabolismo , Metotrexato/uso terapéutico , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND AND AIMS: Increased plasma levels of soluble endoglin (sEng) were detected in patients with endothelial dysfunction-related disorders and hypercholesterolemia. In this study, we hypothesized that high levels of sEng accompanied by mild hypercholesterolemia could aggravate endothelial and vessel wall dysfunction and affect endoglin/eNOS signaling in mouse aorta. METHODS: Three-month-old female transgenic mice on CBAxC57BL/6J background, with high levels of sEng (Sol-Eng+high HFD), and their littermates with low levels of sEng (Sol-Eng+low HFD), were fed a high fat diet for six months. Plasma samples were used for biochemical, ELISA and Luminex analyses of total cholesterol, sEng and inflammatory markers. Functional parameters of aorta were assessed with wire myograph 620M. Western blot analyses of membrane endoglin/eNOS signaling and endothelial dysfunction/inflammation markers in aorta were performed. RESULTS: Functional analysis of aorta showed impaired KCl induced vasoconstriction, endothelial-dependent relaxation after the administration of acetylcholine as well as endothelial-independent relaxation induced by sodium nitroprusside in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. Ach-induced vasodilation after administration of l-NAME was significantly higher in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. The expression of endoglin, p-eNOS/eNOS, pSmad2/3/Smad2/3 signaling pathway was significantly lower in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. CONCLUSIONS: The results indicate that long-term hypercholesterolemia combined with high levels of sEng leads to the aggravation of endothelial and vessel wall dysfunction in aorta, with possible alterations of the membrane endoglin/eNOS signaling, suggesting that high levels of soluble endoglin might be considered as a risk factor of cardiovascular diseases.
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Aorta/metabolismo , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Endoglina/metabolismo , Endotelio Vascular/metabolismo , Hipercolesterolemia/complicaciones , Animales , Aorta/patología , Aorta/fisiopatología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/fisiopatología , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Endoglina/genética , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Femenino , Humanos , Hipercolesterolemia/etiología , Mediadores de Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Transducción de Señal , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Regulación hacia Arriba , Vasoconstricción , VasodilataciónRESUMEN
BACKGROUND: Non-prescription access to antimicrobials is common, and self-prescribing is increasingly popular in Russian society. The aim of this study was to assess the attitudes of community pharmacists regarding antibiotic use and self-medication. METHODS: We conducted a cross-sectional study from September-December 2015 of community pharmacists in the Saint-Petersburg and Leningrad region, Russia. A self-administered questionnaire was used to assess antibiotic use and self-medication practices. The data were analysed using logistic regression and Pearson chi-squared tests. RESULTS: Of the 316 pharmacists (77.07%) who completed the questionnaire, 230 (72.8%) self-medicated with antibiotics. Antibiotics were mostly used to self-treat upper (53.3%) and lower respiratory tract infections (19.3%), relying on their own knowledge (81.5%), previous treatment experience (49%) and patients' prescriptions (17%). The most commonly used antibiotics were macrolides (33.2%). Characteristics such as age, education and experience were related to antibiotic use and self-medication. CONCLUSIONS: The study confirmed that self-prescription of antibiotics is a common practice amongst pharmacists in Saint Petersburg and also identified personal and professional characteristics of pharmacists strongly associated with self-medication.
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Antibacterianos/administración & dosificación , Actitud del Personal de Salud , Farmacias/normas , Farmacéuticos/normas , Automedicación/normas , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Farmacias/tendencias , Farmacéuticos/psicología , Farmacéuticos/tendencias , Federación de Rusia/epidemiología , Automedicación/psicología , Automedicación/tendencias , Autoinforme , Adulto JovenRESUMEN
Background Inappropriate use of antibiotics is a public health problem of great concern. Objective To evaluate knowledge of antibiotics, race, gender and age as independent risk factors for self-medication. Setting Residents and population from different regions of Saudi Arabia. Methods We conducted a cross sectional survey study among residents. Data were collected between June 2014 to May, 2015 from 1310 participants and data were recorded anonymously. The questionnaire was randomly distributed by interview of participants and included sociodemographic characteristics, antibiotics knowledge, attitudes and behavior with respect to antibiotics usage. Main outcome measure Population aggregate scores on questions and data were analyzed using univariate logistic regression to evaluate the influence of variables on self-prescription of antibiotics. Results The response rate was 87.7 %. A cumulative 63.6 % of participants reported to have purchased antibiotics without a prescription from pharmacies; 71.1 % reported that they did not finish the antibiotic course as they felt better. The availability of antibiotics without prescription was found to be positively associated with self-medication (OR 0.238, 95 % CI 0.17-0.33). Of those who used prescribed or non-prescribed antibiotics, 44.7 % reported that they kept left-over antibiotics from the incomplete course of treatment for future need. Interestingly, 62 % of respondents who used drugs without prescription agreed with the statement that antibiotics should be access-controlled prescribed by a physician. We also found significant association between storage, knowledge/attitudes and education. Conclusions The overall level of awareness on antibiotics use among residents in Saudi Arabia is low. This mandates public health awareness intervention programs to be implemented on the use of antibiotics.