The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

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Aplicación de la imagen tridimensional a la cirugía laparoscópica del colon: análisis morfométrico a partir de reconstrucciones de TAC, estudio en cadáver y en vivo

El objetivo de este trabajo ha sido analizar las modificaciones que sufre el colon en su anatomía y su disposición, en relación con la posición, el sexo, la edad y el índice de masa corporal, y describirlas a través de reconstrucciones tridimensionales obtenidas a partir de imágenes de TAC. Se dividió el trabajo en un Estudio radiológico en cadáveres, y un Estudio radiológico en pacientes. En el primero, se emplearon tres cadáveres humanos conservados con la técnica de Thiel, en los que fueron reproducidas las condiciones reales de una colectomía laparoscópica en cuanto a neumoperitoneo, con 15 mmHg, y decúbitos posturales, con 15 º de decúbito lateral derecho, izquierdo, o Trendelenburg, en diez series según el protocolo establecido, realizándoles un TAC abdominal una vez obtenidas las mencionadas condiciones. En el segundo estudio, se seleccionaron 130 pacientes del Hospital Royo Villanova de Zaragoza con un TAC abdominal con contraste intravenoso y sin patología a nivel del colon. Se realizó una reconstrucción tridimensional de las imágenes de TAC obtenidas con el software OsiriX ®, y se localizaron en ésta los puntos anatómicos definidos (PUBIS, ESPINA, AH, AE, UIC, UDS, AMS y AMI), para posteriormente realizar con el software ImageJ ® la medida de las variables morfométricas establecidas entre los puntos (longitudes ESPINA - ESPINA, PUBIS - AMS, PUBIS - AMI, AMS - AMI, PUBIS - AH, PUBIS - AE, PUBIS - UIC, PUBIS - UDS, AMS - AH, AMS - AE, AMI - AH y AMI - AE, y ángulos AH - PUBIS - AE, AH - AMS - AE y AH - AMI - AE). De las 450 medidas realizadas en el Estudio radiológico en cadáveres, 202 sufrieron modificaciones entre el 5 % y el 9,99 %, y 112 por encima del 10 %, en las diferentes series que modificaron la presión de neumoperitoneo y el grado de decúbito lateral y de Trendelenburg. Las mayores diferencias se observaron en las medidas que relacionaban el pubis con ambas arterias mesentéricas y las arterias mesentéricas con los ángulos del colon, siendo éstas todavía mayores en las tres últimas series del estudio, en las que se realizó una manipulación en la posición del colon transverso al elevar el epiplon mayor. En el Estudio radiológico en pacientes, se observó una importante variabilidad anatómica en la morfología del colon con las reconstrucciones tridimensionales obtenidas, y se evidenciaron diferencias significativas en las medidas planteadas al estudiar los sujetos del estudio por grupos de sexo (hombres y mujeres), edad (65 años y menores, y mayores de 65 años) e índice de masa corporal (normopeso, sobrepeso y obesidad). Como conclusión, se considera que el colon se puede estudiar en cuanto a su variabilidad anatómica y su diferente disposición, con reconstrucciones tridimensionales obtenidas a partir de imágenes de TAC, y que éste sufre modificaciones que se pueden relacionar con la posición, el sexo, la edad y el índice de masa corporal

On the dynamics of the adenylate energy system: homeorhesis vs homeostasis.

Biochemical energy is the fundamental element that maintains both the adequate turnover of the biomolecular structures and the functional metabolic viability of unicellular organisms. The levels of ATP, ADP and AMP reflect roughly the energetic status of the cell, and a precise ratio relating them was proposed by Atkinson as the adenylate energy charge (AEC). Under growth-phase conditions, cells maintain the AEC within narrow physiological values, despite extremely large fluctuations in the adenine nucleotides concentration. Intensive experimental studies have shown that these AEC values are preserved in a wide variety of organisms, both eukaryotes and prokaryotes. Here, to understand some of the functional elements involved in the cellular energy status, we present a computational model conformed by some key essential parts of the adenylate energy system. Specifically, we have considered (I) the main synthesis process of ATP from ADP, (II) the main catalyzed phosphotransfer reaction for interconversion of ATP, ADP and AMP, (III) the enzymatic hydrolysis of ATP yielding ADP, and (IV) the enzymatic hydrolysis of ATP providing AMP. This leads to a dynamic metabolic model (with the form of a delayed differential system) in which the enzymatic rate equations and all the physiological kinetic parameters have been explicitly considered and experimentally tested in vitro. Our central hypothesis is that cells are characterized by changing energy dynamics (homeorhesis). The results show that the AEC presents stable transitions between steady states and periodic oscillations and, in agreement with experimental data these oscillations range within the narrow AEC window. Furthermore, the model shows sustained oscillations in the Gibbs free energy and in the total nucleotide pool. The present study provides a step forward towards the understanding of the fundamental principles and quantitative laws governing the adenylate energy system, which is a fundamental element for unveiling the dynamics of cellular life

An Update of Kaempferol Protection against Brain Damage Induced by Ischemia-Reperfusion and by 3-Nitropropionic Acid

Kaempferol, a flavonoid present in many food products, has chemical and cellular antioxidant properties that are beneficial for protection against the oxidative stress caused by reactive oxygen and nitrogen species. Kaempferol administration to model experimental animals can provide extensive protection against brain damage of the striatum and proximal cortical areas induced by transient brain cerebral ischemic stroke and by 3-nitropropionic acid. This article is an updated review of the molecular and cellular mechanisms of protection by kaempferol administration against brain damage induced by these insults, integrated with an overview of the contributions of the work performed in our laboratories during the past years. Kaempferol administration at doses that prevent neurological dysfunctions inhibit the critical molecular events that underlie the initial and delayed brain damage induced by ischemic stroke and by 3-nitropropionic acid. It is highlighted that the protection afforded by kaempferol against the initial mitochondrial dysfunction can largely account for its protection against the reported delayed spreading of brain damage, which can develop from many hours to several days. This allows us to conclude that kaempferol administration can be beneficial not only in preventive treatments, but also in post-insult therapeutic treatments

Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

Deep whole genome and transcriptome sequencing have highlighted the importance of an emerging class of non-coding RNA longer than 200 nucleotides (i.e., long non-coding RNAs (lncRNAs)) that are involved in multiple cellular processes such as cell differentiation, embryonic development, and tissue homeostasis. Cancer is a prime example derived from a loss of homeostasis, primarily caused by genetic alterations both in the genomic and epigenetic landscape, which results in deregulation of the gene networks. Deregulation of the expression of many lncRNAs in samples, tissues or patients has been pointed out as a molecular regulator in carcinogenesis, with them acting as oncogenes or tumor suppressor genes. Herein, we summarize the distinct molecular regulatory mechanisms described in literature in which lncRNAs modulate carcinogenesis, emphasizing epigenetic and genetic alterations in particular. Furthermore, we also reviewed the current strategies used to block lncRNA oncogenic functions and their usefulness as potential therapeutic targets in several carcinomas

Kaempferol prevents the activation of complement C3 protein and the generation of reactive A1 astrocytes that mediate rat brain degeneration induced by 3-nitropropionic acid

El kaempferol es un antioxidante natural presente en verduras y frutas utilizadas en la alimentación humana. En trabajos anteriores, demostramos que la administración intraperitoneal (i.p.) de kaempferol protege fuertemente contra la neurodegeneración del cuerpo estriado inducida por inyecciones i.p. de ácido 3-nitropropiónico (NPA), un modelo animal de la enfermedad de Huntington. Recientemente, hemos demostrado que la generación de astrocitos reactivos A1 es un evento temprano en la neurodegeneración inducida por inyecciones i.p. de NPA. En el presente trabajo, hemos evaluado experimentalmente la hipótesis de que el kaempferol protege tanto frente a la activación de la proteína C3 del complemento como frente a la generación de astrocitos reactivos A1 en estriado e hipocampo de cerebro de rata. Para ello, hemos administrado inyecciones i.p. de NPA y kaempferol a ratas Wistar adultas. a ratas Wistar adultas siguiendo el protocolo descrito en trabajos anteriores. La administración de kaempferol previene la activación proteolítica de la proteína C3 del complemento y la generación de astrocitos reactivos A1 inducida por NPA en el cuerpo estriado y el hipocampo. Además, bloqueó el aumento de la expresión de NF-κB inducido por la NPA y la mayor secreción de citoquinas IL-κB. secreción de citocinas IL-1α, TNFα y C1q, que se han relacionado con la generación de astrocitos reactivos A1. Además, la administración de kaempferol previno el aumento de la producción de péptidos β amiloides en el estriado y el hipocampo, un hallazgo novedoso en la degeneración cerebral inducida por NPA encontrado en este trabajo.Kaempferol is a natural antioxidant present in vegetables and fruits used in human nutrition. In previous work, we showed that intraperitoneal (i.p.) kaempferol administration strongly protects against striatum neurodegeneration induced by i.p. injections of 3-nitropropionic acid (NPA), an animal model of Huntington’s disease. Recently, we have shown that reactive A1 astrocytes generation is an early event in the neurodegeneration induced by NPA i.p. injections. In the present work, we have experimentally evaluated the hypothesis that kaempferol protects both against the activation of complement C3 protein and the generation of reactive A1 astrocytes in rat brain striatum and hippocampus. To this end, we have administered NPA and kaempferol i.p. injections to adult Wistar rats following the protocol described in previous work. Kaempferol administration prevents proteolytic activation of complement C3 protein and generation of reactive A1 astrocytes NPA-induced in the striatum and hippocampus. Also, it blocked the NPA-induced increase of NF-κB expression and enhanced secretion of cytokines IL-1α, TNFα, and C1q, which have been linked to the generation of reactive A1 astrocytes. In addition, kaempferol administration prevented the enhanced production of amyloid β peptides in the striatum and hippocampus, a novel finding in NPA-induced brain degeneration found in this work.• Ministerio de Economía y Competitividad y Fondos FEDER. Subvenciones: BFU2014-53641-P y BFU2017-85723-P (I + D + i) • Junta de Extremadura. Ayudas GR21174 e IDA1-19-0055-3 • Fundación Cafés Delta. Financiación para Joana Poejo • Fundación Carolina. Beca predoctoral para Jairo SalazarpeerReviewe

Tyrosine hydroxylase is expressed during early heart development and is required for cardiac chamber formation

47 p.-5 fig.-6 supl.tab.-5 supl.fig.AimsTyrosine hydroxylase (TH) is the first and rate-limiting enzyme in catecholamine biosynthesis. Whereas the neuroendocrine roles of cathecolamines postnatally are well known, the presence and function of TH in organogenesis is unclear. The aim of this study was to define the expression of TH during cardiac development and to unravel the role it may play in heart formation. Methods and results: We studied TH expression in chick embryos by whole mount in situ hybridization and by quantitative reverse transcription-polymerase chain reaction and analysed TH activity by high-performance liquid chromatography. We used gain-and loss-of-function models to characterize the role of TH in early cardiogenesis. We found that TH expression was enriched in the cardiac field of gastrulating chick embryos. By stage 8, TH mRNA was restricted to the splanchnic mesoderm of both endocardial tubes and was subsequently expressed predominantly in the myocardial layer of the atrial segment. Overexpression of TH led to increased atrial myosin heavy chain (AMHC1) and T-box 5 gene (Tbx5) expression in the ventricular region and induced bradyarrhythmia. Similarly, addition of l-3,4-dihydroxyphenylalanine (l-DOPA) or dopamine induced ectopic expression of cardiac transcription factors (cNkx2.5, Tbx5) and AMHC1 as well as sarcomere formation. Conversely, blockage of dopamine biosynthesis and loss of TH activity decreased AMHC1 and Tbx5 expression, whereas exposure to retinoic acid (RA) induced TH expression in parallel to that of AMHC1 and Tbx5. Concordantly, inhibition of endogenous RA synthesis decreased TH expression as well as that of AMHC1 and Tbx5. Conclusion: TH is expressed in a dynamic pattern during the primitive heart tube formation. TH induces cardiac differentiation in vivo and it is a key regulator of the heart patterning, conferring atriogenic identity. © The Author 2010.This work was supported by the Spanish Ministry of Science and Innovation (MICINN) [BFU2007-61055 to C.H.-S., BFU2007-66350/BFI to C.L.-S.]; and the Junta de Extremadura [PRI07A005 to V.G.-M.]Peer Reviewe

Biochemical and anatomical basis of brain dysfunctions caused by cytochrome b5 reductase deficiency or dysregulation

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How to target neurodegenerative diseases with flavonoid-rich food or extracts?

Comunicação oralN/