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1.
Pharmaceut Med ; 38(3): 241-250, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38512636

RESUMEN

INTRODUCTION: Medical departments have evolved from a position of support to one of strategic leadership. The number of tasks and the complexity of interactions in which they are involved is increasing. However, the spectrum of their activity in the sector differs significantly from one company to another. Therefore, the aim of this study was to describe their situation within the pharmaceutical industry, analyzing the positions, functions, and profiles of their professionals. METHODS: This study consisted of an online survey containing 25 questions grouped into four blocks (structure, medical direction, training, and activities and responsibilities). Medical departments in the Spanish pharmaceutical industry of different sizes and scope were invited to participate. The survey took place in 2021, with a designated response period of three months. It is important to note that all responses collected during this time were treated as anonymous. RESULTS: Thirty companies participated. A total of 93.3% of respondents worked for an international laboratory, with a size of 0-5 or 11-20 people (20.7%). For 27.6% of the companies, the number of medical advisors per medical department was 1 or 4, with varying numbers of medical scientific liaisons (1, 6-10, and > 20). A total of 56.7%, 33.3%, and 6.7% indicated that the country manager, head of regional medical affairs, and head of global medical affairs, respectively, had a solid-line reporting relationship with the medical directorate. Medical directors were mostly graduates in medicine (86.2%) with a doctorate (34.5%), and medical managers were mainly graduates in medicine (77.8%) and pharmacy (66.7%). CONCLUSIONS: This study reveals that respondents predominantly work in internationally focused laboratories, with professionals ranging from experienced medical directors to managers with 6-20 years of experience, each with distinct roles.


Asunto(s)
Industria Farmacéutica , España , Humanos , Encuestas y Cuestionarios , Liderazgo , Femenino , Masculino
2.
bioRxiv ; 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-37790458

RESUMEN

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all of the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Glut2 knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in body's defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Glut2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria, but are met with a compensatory increase in endogenous glucose production.

3.
Diabetologia ; 67(1): 170-189, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37712955

RESUMEN

AIMS/HYPOTHESIS: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus. METHODS: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. RESULTS: Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis. CONCLUSIONS/INTERPRETATION: Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.


Asunto(s)
Diabetes Mellitus Tipo 2 , Animales , Cricetinae , Femenino , Humanos , Ratones , Cricetulus , Diabetes Mellitus Tipo 2/complicaciones , Metabolismo Energético/genética , Glucosa/metabolismo , Homeostasis/fisiología , Ratones Noqueados , Obesidad/metabolismo , Proteómica
4.
Front Mol Biosci ; 10: 1206074, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37818099

RESUMEN

Chagas disease (ChD), caused by Trypanosoma cruzi, is endemic in American countries and an estimated 8 million people worldwide are chronically infected. Currently, only two drugs are available for therapeutic use against T. cruzi and their use is controversial due to several disadvantages associated with side effects and low compliance with treatment. Therefore, there is a need to search for new tripanocidal agents. Natural products have been considered a potential innovative source of effective and selective agents for drug development to treat T. cruzi infection. Recently, our research group showed that hexanic extract from Clethra fimbriata (CFHEX) exhibits anti-parasitic activity against all stages of T. cruzi parasite, being apoptosis the main cell death mechanism in both epimastigotes and trypomastigotes stages. With the aim of deepening the understanding of the mechanisms of death induced by CFHEX, the metabolic alterations elicited after treatment using a multiplatform metabolomics analysis (RP/HILIC-LC-QTOF-MS and GC-QTOF-MS) were performed. A total of 154 altered compounds were found significant in the treated parasites corresponding to amino acids (Arginine, threonine, cysteine, methionine, glycine, valine, proline, isoleucine, alanine, leucine, glutamic acid, and serine), fatty acids (stearic acid), glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine), sulfur compounds (trypanothione) and carboxylic acids (pyruvate and phosphoenolpyruvate). The most affected metabolic pathways were mainly related to energy metabolism, which was found to be decrease during the evaluated treatment time. Further, exogenous compounds of the triterpene type (betulinic, ursolic and pomolic acid) previously described in C. fimbriata were found inside the treated parasites. Our findings suggest that triterpene-type compounds may contribute to the activity of CFHEX by altering essential processes in the parasite.

5.
Cell Signal ; 111: 110857, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37604243

RESUMEN

Calcium sensing receptor (CaSR), a class C GPCR, regulates essential secretory pathways, involving communication between endocytic and secretory Rab GTPases, via still to be fully defined molecular mechanisms. To address how communication between endocytic and secretory vesicles occurs, we hypothesized that CaSR activates endocytic Rab11A-dependent effector pathways acting upstream of Rab27B-regulated secretion. We found that Rab11A is critical to promote Rab27B-dependent secretion of chemotactic and inflammatory factors, including IL-8, CCL2/MCP-1, and IL1-ß, in response to CaSR stimulation. It also attenuates secretion of IL-6. The process is mediated by endosomal PI3-kinases, Vps34 and PI3KC2α, which promote Rab27B activation. Rab11A interacts with and activates MADD, a guanine exchange factor for Rab3, and Rab27A/B. Mechanistically, CaSR drives Rab11A-dependent coupling of recycling endosomes to secretory-vesicles via endosomal PI3K-mediated activation of a MADD/Rab27B pathway.

6.
Trop Med Infect Dis ; 8(5)2023 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-37235311

RESUMEN

BACKGROUND: Chagas disease is a potentially fatal disease caused by the parasite Trypanosoma cruzi. There is growing scientific interest in finding new and better therapeutic alternatives for this disease's treatment. METHODS: A total of 81 terpene compounds with potential trypanocidal activity were screened and found to have potential T. cruzi cysteine synthase (TcCS) inhibition using molecular docking, molecular dynamics, ADME and PAIN property analyses and in vitro susceptibility assays. RESULTS: Molecular docking analyses revealed energy ranges from -10.5 to -4.9 kcal/mol in the 81 tested compounds, where pentacyclic triterpenes were the best. Six compounds were selected to assess the stability of the TcCS-ligand complexes, of which lupeol acetate (ACLUPE) and α-amyrin (AMIR) exhibited the highest stability during 200 ns of molecular dynamics analysis. Such stability was primarily due to their hydrophobic interactions with the amino acids located in the enzyme's active site. In addition, ACLUPE and AMIR exhibited lipophilic characteristics, low intestinal absorption and no structural interferences or toxicity. Finally, selective index for ACLUPE was >5.94, with moderate potency in the trypomastigote stage (EC50 = 15.82 ± 3.7 µg/mL). AMIR's selective index was >9.36 and it was moderately potent in the amastigote stage (IC50 = 9.08 ± 23.85 µg/mL). CONCLUSIONS: The present study proposes a rational approach for exploring lupeol acetate and α-amyrin terpene compounds to design new drugs candidates for Chagas disease.

7.
ChemistryOpen ; 12(5): e202200241, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37226371

RESUMEN

Copper oxide nanoparticles (CuO-NPs) were functionalized with specific antibodies to target their antibacterial activity against Gram-positive or Gram-negative bacteria. The CuO-NPs were covalently functionalized to cover their surface with specific antibodies. The differently prepared CuO-NPs were characterized by X-ray diffraction, transmission electron microscopy and dynamic light scattering. The antibacterial activities of the unmodified CuO-NPs and the antibody-functionalized nanoparticles (CuO-NP-AbGram- and CuO-NP-AbGram+ ) were determined for both Gram-negative Escherichia coli and Gram-positive Bacillus subtilis bacteria. The antibody-functionalized NPs showed a differential increase of their antibacterial activity according to the specific antibody. The CuO-NP-AbGram- in E. coli showed reduced half maximal inhibitory concentration (IC50 ) and minimum inhibitory concentration (MIC) values when compared with unfunctionalized CuO-NPs. On the other hand, the CuO-NP-AbGram+ also showed reduced IC50 and MIC values in B. subtilis, when compared with non-functionalized CuO-NPs. Thus, the functionalized CuO nanoparticles with specific antibodies showed enhanced specificity of their antibacterial activity. The advantages of "smart" antibiotic nanoparticles are discussed.


Asunto(s)
Cobre , Nanopartículas , Escherichia coli , Anticuerpos , Antibacterianos/farmacología , Óxidos
9.
Bol. latinoam. Caribe plantas med. aromát ; 21(4): 455-463, jul. 2022. ilus, tab, graf
Artículo en Español | LILACS | ID: biblio-1526702

RESUMEN

Abstract: This article describes the chemical composition, physical properties and acetylcholinesterase (A ChE) and butyrylcholinesterase (BuChE) activity of stem - distilled essential oil (E O ) from Bursera graveolens wood chips, Burseraceae. The plant material was acquired in Quimis (Bosque de Sancán), city of Jipijapa in the province of Manabí, coastal region o f Ecuador. Thirty - six components were identified by CG - MS, which represented 98.54% of the volatile oil. The main components were limonene (68.52%) and mentofuran (20.37%). The hydrocarbon monoterpenes constituted the most abundant fractions. The average y ield of the E O was 1.26%. Regarding the physical properties of E O , the following values were obtained: relative density (1,029 g/mL), refractive index (1,477) and specific rotation (+4,567). The E O presented IC 50 inhibition values of 47.2 and 51.9 µg/mL fo r the enzymes AChE and BuChE, respectively.


Resumen: Este artículo describe la composición química, propiedades físicas y actividad acetilcolinesterasa (AChE) y butirilcolinesterasa (BuChE) del aceite esencial (AE) destilado a vapor de astillas de madera de Bursera graveolens , Burseraceae. La materia vegetal fue adquirida en Quimis (Bosque de Sancán), ciudad de Jipijapa en la provincia de Manabí, región costera d e Ecuador. Treinta y seis componentes fueron identificados por CG - MS, que representaron al 98.54 % del aceite volátil. Los componentes principales fueron limoneno (68.52%) y mentofurano (20.37%). Los monoterpenos hidrocarburos constituyeron las fracciones m ás abundantes. El rendimiento medio del AE fue de 1.26%. Con respecto a las propiedades físicas del AE se obtuvo los siguientes valores, densidad relativa (1.029 g/mL), índice de refracción (1.477) y rotación específica (+4.567). El AE presentó valores de inhibición IC 50 de 47.2 y 51.9 µg/mL para las enzimas AChE y BuChE, respectivamente.


Asunto(s)
Aceites Volátiles/química , Bursera/metabolismo , Bursera/química , Acetilcolinesterasa/farmacología , Acetilcolinesterasa/química , Butirilcolinesterasa/farmacología , Butirilcolinesterasa/química , Aceites Volátiles/farmacología , Ecuador
10.
Heliyon ; 8(3): e09182, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35368545

RESUMEN

Chagas disease, a worldwide public health concern, is a chronic infection caused by Trypanosoma cruzi. Considering T. cruzi chronic persistence correlates with CD4+ and CD8+ T cell dysfunction and the safety and efficacy profiles of Benznidazol and Nifurtimox, the two drugs currently used for its etiological treatment, are far from ideal, the search of new trypanocidal treatment options is a highly relevant issue. Therefore, the objective of this work was to evaluate the trypanocidal effect and cytokine production induction of three extracts (hexane, dichloromethane and hydroalcoholic) obtained from Clethra fimbriata, a plant traditionally used as a febrifuge in Colombia. Additionally, the extracts' major components with the highest trypanocidal activity were determined. It was evidenced C. fimbriata hexane extract exhibited the highest activity capable of inhibiting the three parasite developmental stages with an IC50/EC50 of 153.9 ± 29.5 (epimastigotes), 39.3 ± 7.2 (trypomastigotes), and 45.6 ± 10.5 (amastigotes) µg/mL, presenting a low cytotoxicity in VERO cells with a selectivity index ranging from 6.49 to 25.4. Moreover, this extract induced trypomastigote apoptotic death and inhibited parasite cell infection. The extract also induced IFN-γ and TNF production in CD4+ and CD8+ T cells, as well as de novo production of the cytotoxic molecules granzyme B and perforin in CD8+ T cells from healthy donors. Fatty acids and terpenes represented C. fimbriata key compounds. Thus, the trypanocidal activity and cytokine production induction of the hexane extract may be associated with terpene presence, particularly, triterpenes.

11.
J Cell Commun Signal ; 16(2): 239-252, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34854057

RESUMEN

Calcium sensing receptor, a pleiotropic G protein coupled receptor, activates secretory pathways in cancer cells and putatively exacerbates their metastatic behavior. Here, we show that various CaSR mutants, identified in breast cancer patients, differ in their ability to stimulate Rac, a small Rho GTPase linked to cytoskeletal reorganization and cell protrusion, but are similarly active on the mitogenic ERK pathway. To investigate how CaSR activates Rac and drives cell migration, we used invasive MDA-MB-231 breast cancer cells. We revealed, by pharmacological and knockdown strategies, that CaSR activates Rac and cell migration via the Gßγ-PI3K-mTORC2 pathway. These findings further support current efforts to validate CaSR as a relevant therapeutic target in metastatic cancer.

12.
J Biol Chem ; 298(1): 101440, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34808208

RESUMEN

Metastatic lung cancer is a major cause of death worldwide. Dissemination of cancer cells can be facilitated by various agonists within the tumor microenvironment, including by lysophosphatidic acid (LPA). We postulate that Rho guanine nucleotide exchange factors (RhoGEFs), which integrate signaling cues driving cell migration, are critical effectors in metastatic cancer. Specifically, we addressed the hypothetical role of ARHGEF17, a RhoGEF, as a potential effector of Gßγ in metastatic lung cancer cells responding to LPA. Here, we show that ARHGEF17, originally identified as a tumor endothelial marker, is involved in tumor growth and metastatic dissemination of lung cancer cells in an immunocompetent murine model. Gene expression-based analysis of lung cancer datasets showed that increased levels of ARHGEF17 correlated with reduced survival of patients with advanced-stage tumors. Cellular assays also revealed that this RhoGEF participates in the invasive and migratory responses elicited by Gi protein-coupled LPA receptors via the Gßγ subunit complex. We demonstrate that this signaling heterodimer promoted ARHGEF17 recruitment to the cell periphery and actin fibers. Moreover, Gßγ allosterically activates ARHGEF17 by the removal of inhibitory intramolecular restrictions. Taken together, our results indicate that ARHGEF17 may be a valid potential target in the treatment of metastatic lung cancer.


Asunto(s)
Subunidades beta de la Proteína de Unión al GTP , Subunidades gamma de la Proteína de Unión al GTP , Neoplasias Pulmonares , Factores de Intercambio de Guanina Nucleótido Rho , Transducción de Señal , Animales , Movimiento Celular , Progresión de la Enfermedad , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Metástasis de la Neoplasia , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/genética , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Transducción de Señal/fisiología , Microambiente Tumoral
13.
Medicina (Kaunas) ; 57(9)2021 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-34577877

RESUMEN

Background: Alzheimer's disease (AD) is characterized by the presence of ß-amyloid plaques and neurofibrillary tangles, while Lewy body dementia (LBD) is characterized by α-synuclein (α-syn) inclusions. Some authors examine α-syn protein in the neurodegeneration process of AD and propose to consider cerebrospinal fluid (CSF) α-syn as a possible additional biomarker to the so-called "core" of AD. Objective: To determine whether there is a correlation between α-syn levels and "core" AD biomarkers in patients with mild cognitive impairment (MCI). Materials and methods: In total, 81 patients in the early stages of MCI were selected from the outpatient dementia consultation in Alicante General Hospital. Using a cross-sectional case-control design, patients were analyzed in four groups: stable MCI (MCIs; n = 25), MCI due to AD (MCI-AD; n = 32), MCI due to LBD (MCI-LBD; n = 24) and a control group of patients with acute or chronic headache (Ctrl; n = 18). Correlation between CSF protein levels in the different groups was assessed by the Rho Spearman test. Results: We found positive correlations between T-tau protein and α-syn (ρ = 0.418; p value < 0.05) and p-tau181p and α-syn (ρ = 0.571; p value < 0.05) exclusively in the MCI-AD group. Conclusion: The correlation found between α-syn and tau proteins in the first stages of AD support the involvement of α-syn in the pathogenesis of AD. This result may have clinical and diagnostic implications, as well as help to apply the new concept of "precision medicine" in patients with MCI.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Enfermedad de Alzheimer/diagnóstico , Biomarcadores , Estudios Transversales , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , alfa-Sinucleína
14.
Biochim Biophys Acta Mol Cell Res ; 1868(7): 119026, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33845096

RESUMEN

Chemotactic and angiogenic factors secreted within the tumor microenvironment eventually facilitate the metastatic dissemination of cancer cells. Calcium-sensing receptor (CaSR) activates secretory pathways in breast cancer cells via a mechanism driven by vesicular trafficking of this receptor. However, it remains to be elucidated how endosomal proteins in secretory vesicles are controlled by CaSR. In the present study, we demonstrate that CaSR promotes expression of Rab27B and activates this secretory small GTPase via PI3K, PKA, mTOR and MADD, a guanine nucleotide exchange factor, also known as DENN/Rab3GEP. Active Rab27B leads secretion of various cytokines and chemokines, including IL-6, IL-1ß, IL-8, IP-10 and RANTES. Expression of Rab27B is stimulated by CaSR in MDA-MB-231 and MCF-7 breast epithelial cancer cells, but not in non-cancerous MCF-10A cells. This regulatory mechanism also occurs in HeLa and PC3 cells. Our findings provide insightful information regarding how CaSR activates a Rab27B-dependent mechanism to control secretion of factors known to intervene in paracrine communication circuits within the tumor microenvironment.


Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores Sensibles al Calcio/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Calcio/metabolismo , Línea Celular Tumoral , Quimiocinas/metabolismo , Quimiotaxis , Proteínas Quinasas Dependientes de AMP Cíclico , Citocinas/metabolismo , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Femenino , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Fosfatidilinositol 3-Quinasa , Receptores Sensibles al Calcio/fisiología , Vías Secretoras/fisiología , Serina-Treonina Quinasas TOR , Microambiente Tumoral , Proteínas de Unión al GTP rab/fisiología
15.
Exp Parasitol ; 223: 108079, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524381

RESUMEN

Chagas disease is caused by Trypanosoma cruzi, and it is an important cause of morbidity and mortality in Latin America. There are no vaccines, and the chemotherapy available to treat this infection has serious side effects. In a search for alternative treatments, we determined the in vitro susceptibility of epimastigote and trypomastigote forms of T. cruzi and the cytotoxic effects on peripheral blood mononuclear cells (PBMCs) of ethanolic extracts obtained from six different plant species. The ethanolic extracts of Ageratina vacciniaefolia, Clethra fimbriata and Siparuna sessiliflora showed antiprotozoal activity against epimastigotes and low cytotoxicity in mammalian cells. However, only the ethanolic extract of C. fimbriata showed activity against T. cruzi trypomastigotes, and it had low cytotoxicity in PBMCs. An analysis on the phytochemical composition of C. fimbriata extract showed that its metabolites were primarily represented by two families of compounds: flavonoids and terpenoids. Lastly, we analyzed whether the A. vacciniaefolia, C. fimbriata, or S. sessiliflora ethanolic extracts induced IFN-γ or TNF-α production. Significantly, ethanolic extracts of C. fimbriata induced TNF-α production and S. sessiliflora induced both cytokines. In addition, C. fimbriata and S. sessiliflora induced the simultaneous secretion of IFN-γ and TNF-α in CD8+ T cells. The antiprotozoal and immunomodulatory activity of C. fimbriata may be related to the presence of flavonoid and triterpene compounds in the extract. Thus, these findings suggest that C. fimbriata may represent a valuable source of new bioactive compounds for the therapeutic treatment of Chagas disease that combines trypanocidal activity with the capacity to boost the immune response.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Trypanosoma cruzi/efectos de los fármacos , Adulto , Ageratina/química , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Cromatografía Líquida de Alta Presión , Clethraceae/química , Colombia , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Interferón gamma/metabolismo , Laurales/química , Masculino , Medicina Tradicional , Extractos Vegetales/toxicidad , Espectrometría de Masa por Ionización de Electrospray , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
16.
Future Cardiol ; 16(5): 469-480, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32228182

RESUMEN

Aim: To ascertain the clinical profile and management of edoxaban in clinical practice. Materials & methods: Prospective, noninterventional postauthorization study of nonselected patients with atrial fibrillation treated with edoxaban from 12 European countries. Patients' baseline characteristics are presented. Results: A total of 13,638 patients (73.6 ± 9.5 years; 76.6/23.4% edoxaban 60/30 mg; CHA2DS2-VASc 3.1; 838 [6.1%] from Spain) were included. In Spain, the percentage of very elderly and fragile patients was greater and the risk of thromboembolism (CHA2DS2-VASc ≥2, 98.0 vs 87.3%; p < 0.001) and bleeding (HAS-BLED, 3.2 vs 2.7; p < 0.001) was greater in patients treated with edoxaban 30 mg. The proportion of patients taking edoxaban 30 mg was similar than in ENGAGE AF-TIMI 48. Conclusion: In Spain, patients treated with edoxaban were older and fragile.


Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular , Anciano , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Europa (Continente)/epidemiología , Inhibidores del Factor Xa/uso terapéutico , Humanos , Estudios Prospectivos , Piridinas , Sistema de Registros , Tiazoles
17.
Zebrafish ; 16(6): 505-507, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31408407

RESUMEN

Characterization of a protein of interest during development is essential for functional studies. A general strategy for understanding the function of a particular protein involves the generation of null mutations, or treatment with drugs, that interfere with its activity. To demonstrate that the synthesis, stability, or activity of a protein has been affected, accurate and efficient detection of low amounts of protein is essential. This can be achieved by immunohistochemistry or by western blot. Here we describe a method for the detection of proteins from single de-yolked zebrafish embryos. This procedure includes a fixation step and the concomitant elimination of lipids from the yolk cell. We show that this approach allows the rapid analysis of proteins in embryos without having to manually remove the yolk. This method provides a convenient alternative for genotyping of mutant embryos as early as the 128 cell stage. In addition, in drug- or morpholino-treated embryos, the correlation between the penetrance of a phenotype and the concentration of a protein present may be established.


Asunto(s)
Western Blotting/métodos , Embrión no Mamífero/química , Proteínas de Peces/aislamiento & purificación , Técnicas de Genotipaje/métodos , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo
18.
Sci Rep ; 8(1): 15369, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30337622

RESUMEN

SWI/SNF or BAF chromatin-remodeling complexes are polymorphic assemblies of homologous subunit families that remodel nucleosomes and facilitate tissue-specific gene regulation during development. BAF57/SMARCE1 is a BAF complex subunit encoded in animals by a single gene and is a component of all mammalian BAF complexes. In vivo, the loss of SMARCE1 would lead to the formation of deficient combinations of the complex which might present limited remodeling activities. To address the specific contribution of SMARCE1 to the function of the BAF complex, we generated CRISPR/Cas9 mutations of smarce1 in zebrafish. Smarce1 mutants showed visible defects at 72 hpf, including smaller eyes, abnormal body curvature and heart abnormalities. Gene expression analysis revealed that the mutant embryos displayed defects in endocardial development since early stages, which led to the formation of a misshapen heart tube. The severe morphological and functional cardiac problems observed at 4 dpf were correlated with the substantially increased expression of different cardiac transcription factors. Additionally, we showed that Smarce1 binds to cis-regulatory regions of the gata5 gene and is necessary for the recruitment of the BAF complex to these regions.


Asunto(s)
Proteínas Cromosómicas no Histona , Endocardio/embriología , Regulación del Desarrollo de la Expresión Génica , Mutación , Factores de Transcripción , Proteínas de Pez Cebra , Pez Cebra , Animales , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Embrión no Mamífero/embriología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
19.
Front Chem ; 6: 276, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30175092

RESUMEN

The use of medicinal plants to counteract the oxidative damage in neurodegenerative diseases has steadily increased over the last few years. However, the rationale for using these natural compounds and their therapeutic benefit are not well explored. In this study, we evaluated the effect of different Physalis peruviana extracts on astrocytic cells (T98G) subjected to oxidative damage induced by rotenone. Extracts of fresh and dehydrated fruits of the plant with different polarities were prepared and tested in vitro. Our results demonstrated that the ethanolic extract of fresh fruits (EF) and acetone-dehydrated fruit extract (AD) increased cell viability, reduced the formation of reactive oxygen species (ROS) and preserved mitochondrial membrane potential. In contrast, we observed a significant reduction in mitochondrial mass when rotenone-treated cells were co-treated with EF and AD. These effects were accompanied by a reduction in the percentage of cells with fragmented/condensed nuclei and increased expression of endogenous antioxidant defense survival proteins such as ERK1/2. In conclusion, our findings suggest that ethanolic and acetone extracts from P. peruviana are potential medicinal plant extracts to overcome oxidative damage induced by neurotoxic compounds.

20.
AMB Express ; 8(1): 35, 2018 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-29523979

RESUMEN

The original version of this article (Diaz-Cardenas et al. 2017) unfortunately contained a mistake in Fig. 1. The pie chart of Fig. 1 should explain the distribution of the relative abundance of the Bacteria and Archaea strains isolated at Zipaquirá salt mine: Proteobacteria 39%; Actinobacteria 9%, Bacteroidetes 1%, Archaea 3% and Firmicutes 48% instead of NOMBRE DE CATEGORIA [PORCENTAJE]. The corrected Fig. 1 and caption are given below.

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