Mitochondrial control of cell bioenergetics in Parkinson's disease

PMCID: PMC5065935Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra. The earliest biochemical signs of the disease involve failure in mitochondrial-endoplasmic reticulum cross talk and lysosomal function, mitochondrial electron chain impairment, mitochondrial dynamics alterations, and calcium and iron homeostasis abnormalities. These changes are associated with increased mitochondrial reactive oxygen species (mROS) and energy deficiency. Recently, it has been reported that, as an attempt to compensate for the mitochondrial dysfunction, neurons invoke glycolysis as a low-efficient mode of energy production in models of PD. Here, we review how mitochondria orchestrate the maintenance of cellular energetic status in PD, with special focus on the switch from oxidative phosphorylation to glycolysis, as well as the implication of endoplasmic reticulum and lysosomes in the control of bioenergetics.J.P.B. is funded by the MINECO (SAF2013-41177-R; RTC-2015-3237-1), the ISCIII (RD12/0043/0021), the EU SP3-People-MC-ITN program (608381), the EU BATCure grant (666918), the NIH/NIDA (1R21DA037678-01).Peer Reviewe

Deficiency of Parkinson’s Related Protein DJ-1 Alters Cdk5 Signalling and Induces Neuronal Death by Aberrant Cell Cycle Re-entry

DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase, and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson’s disease remains elusive. Here, using a comparative proteomic analysis between wild-type cortical neurons and neurons lacking DJ-1 (data available via ProteomeXchange, identifier PXD029351), we show that this protein is involved in cell cycle checkpoints disruption. We detect increased amount of p-tau and α-synuclein proteins, altered phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signalling pathways, and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation, and the establishment of synapses, but can also contribute to cell cycle progression in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1-associated PD. Therefore, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies

Aplicación del plan ergonómico para mejorar el desempeño laboral de los trabajadores en la empresa Yema de Oro S.R.L. - Huanchaco, 2022

La presente investigación tuvo como objetivo aplicar el plan ergonómico para mejorar el desempeño laboral de los trabajadores en la empresa Yema de Oro S.R.L., Huanchaco - 2022. La metodología utilizada fue de tipo aplicada y de diseño pre – experimental, el estudio tuvo como población y muestra a los 22 trabajadores del área de producción. También, se utilizaron las técnicas de recolección de datos como la observación directa, análisis documental y encuesta. Asimismo, se identificó los principales factores de riesgos disergonómicos, además se evaluó el nivel desempeño laboral inicial alcanzando el 18.2% de los trabajadores manifestando un nivel bueno y se evaluó la eficiencia de los galponeros promedio logrando un 85.54%. Por otro lado, se evaluó los niveles de riesgos ergonómicos con la guía de evaluación rápida, método REBA, método OCRA y método NIOSH. Se aplicó el plan ergonómico a través de controles y capacitaciones ejecutadas. Por último, se evaluó el nivel de desempeño laboral final alcanzando el 45.5% de los trabajadores manifestando un nivel bueno y se evaluó la eficiencia de los galponeros promedio logrando un 96.06%. Se concluyó que la aplicación del plan ergonómico mejora significativamente el desempeño laboral de los trabajadores (p = 0.000 < 0.05)

Loss of PRDX6 aborts proliferative and migratory signaling in hepatocarcinoma cell lines

Peroxiredoxin 6 (PRDX6), the only mammalian 1-Cys member of the peroxiredoxin family, has peroxidase, phospholipase A2 (PLA2), and lysophosphatidylcholine (LPC) acyltransferase (LPCAT) activities. It has been associated with tumor progression and cancer metastasis, but the mechanisms involved are not clear. We constructed an SNU475 hepatocarcinoma cell line knockout for PRDX6 to study the processes of migration and invasiveness in these mesenchymal cells. They showed lipid peroxidation but inhibition of the NRF2 transcriptional regulator, mitochondrial dysfunction, metabolic reprogramming, an altered cytoskeleton, down-regulation of PCNA, and a diminished growth rate. LPC regulatory action was inhibited, indicating that loss of both the peroxidase and PLA2 activities of PRDX6 are involved. Upstream regulators MYC, ATF4, HNF4A, and HNF4G were activated. Despite AKT activation and GSK3β inhibition, the prosurvival pathway and the SNAI1-induced EMT program were aborted in the absence of PRDX6, as indicated by diminished migration and invasiveness, down-regulation of bottom-line markers of the EMT program, MMP2, cytoskeletal proteins, and triggering of the “cadherin switch”. These changes point to a role for PRDX6 in tumor development and metastasis, so it can be considered a candidate for antitumoral therapies

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells

Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the roles and mechanisms of multifunctional Prdx6 in several pathologies and on its sensitivity to, and influence on, the redox environment. We have down-regulated Prdx6 with specific siRNA in hepatoblastoma HepG2 cells to study its role in cell proliferation, redox homeostasis, and metabolic programming. Cell proliferation and cell number decreased while cell volume increased; import of glucose and nucleotide biosynthesis also diminished while polyamines, phospholipids, and most glycolipids increased. A proteomic quantitative analysis suggested changes in membrane arrangement and vesicle trafficking as well as redox changes in enzymes of carbon and glutathione metabolism, pentose-phosphate pathway, citrate cycle, fatty acid metabolism, biosynthesis of aminoacids, and Glycolysis/Gluconeogenesis. Specific redox changes in Hexokinase-2 (HK2), Prdx6, intracellular chloride ion channel-1 (CLIC1), PEP-carboxykinase-2 (PCK2), and 3-phosphoglycerate dehydrogenase (PHGDH) are compatible with the metabolic remodeling toward a predominant gluconeogenic flow from aminoacids with diversion at 3-phospohglycerate toward serine and other biosynthetic pathways thereon and with cell cycle arrest at G1/S transition

Plan de negocios para implementar una empresa productora y comercializadora de galletas con harina de ca?ihua

La Ca?ihua (Chenopodium pallidicaule), es uno de los granos andinos con mayores propiedades nutricionales que existen en nuestro pa?s, cuenta con un nivel elevado de prote?nas 18,8g/100g, muy superior a otros granos como la Kiwicha y Quinua que si est?n muy bien cotizados en el mercado. Actualmente las tendencias alimenticias est?n cambiando, podemos ver c?mo est?n proliferando las tiendas de comidas saludables (Biomarkets) y la preocupaci?n de las personas en su salud es un detalle importante que est? marcando el perfil del consumidor. Tomando como referencia lo antes mencionado, este plan de negocio busca desarrollar una opci?n alimenticia r?pida y saludable para el p?blico de Lima Metropolitana a trav?s de la venta de galletas con harina de Ca?ihua, y satisfacer un nicho de mercado que se encuentra dispuesto a pagar un precio superior por un producto saludable y con contenido nutricional superior al promedio. El plan de negocio para implementar una empresa productora y comercializadora de galletas con harina de Ca?ihua demuestra que el mercado de Lima Metropolitana cuenta con una demanda insatisfecha que el presente proyecto busca solucionar y demuestra la viabilidad de establecer este modelo de negocio

Análisis de marketing en Abbott

Abbott es una empresa estadounidense altamente conocida perteneciente al rubro farmacéutico adaptando sus productos a la facilitación médica y mejoramiento nutricional para distintas necesidades fisiológicas del cuerpo humano en cada etapa fundamental de la vida del ser humano, desde recién nacidos hasta ancianos. En el presente trabajo de investigación se ha analizado y estudiado la empresa Abbott bajo un enfoque de gestión empresarial enfatizando los temas fundamentales del curso Fundamentos de Marketing. Así, los conocimientos teóricos aprendidos en clase se respaldan exitosamente en el análisis de esta empresa y específicamente a Ensure, su producto más conocido. De este modo, el objetivo principal es implementar los conocimientos aprendidos en clase al analizar y evaluar información fundamental que evoque la habilidad de análisis crítico. Para ello, la investigación se divide en cinco capítulos. Además del análisis de los puntos mencionados, se realizó una entrevista a Luciana Rodríguez Gerente de Producto - marca Ensure de Abbott Laboratories Perú, misma que se anexará al finalizar la investigación, con el propósito de obtener información con mayor detalle y que destaque en el presente informe

νμ\nu_\mu disappearance at the SPL, T2K-I, NOν\nuA and the Neutrino Factory

We study the measurement of the atmospheric neutrino oscillation parameters, $\theta_{23}$ and $\Delta m^2_{23}$, at the $\nu_\mu$ disappearance channel at three conventional beam facilities, the SPL, T2K-phase I and NO$\nu$A. These two parameters have been shown to be of crucial importance in the measurement of two of the unknowns of the PMNS mixing matrix, $\theta_{13}$ and the leptonic CP-violating phase $\delta$. In our analyis, the effect of the two discrete ambiguities, ${\rm sign}(\Delta m^2_{23})$ and ${\rm sign}(\tan 2 \theta_{23})$, is explicitly taken into account. We analyse also the $\nu_\mu$ disappearance channel at the Neutrino Factory, and combine it with the ``golden'' $\nu_e \to \nu_\mu$ and ``silver'' $\nu_e \to \nu_\tau$ appearance channels to study its impact on the measurement of $\theta_{13}$ and $\delta$. Eventually, we present the sensitivity of the four facilities to different observables: $\theta_{13}$, $\delta$, maximal $\theta_{23}$, the sign of the atmospheric mass difference, $s_{atm}$, and the $\theta_{23}$-octant, $s_{oct}$.Comment: 40 pages using epsfig; bibliography modifie

Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages. There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.This study was funded by Institute of Health Carlos III (ISCiii) (PI16/00090, PI19/00838 and PI19/01266), Spanish Ministry of Economy and Competitiveness (BFU2016-80006-P), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264), Andalusian Ministry of Equality, Health and Social Policies (PI-0198-2016) and Valencian Ministry of Education, Culture and Sports (PROMETEO/2019/027). P de la C-O was supported by FPU predoctoral fellowship (FPU17/00026) from Spanish Ministry of Education, Culture and Sports. E N-V was supported by the the predoctoral i-PFIS IIS-enterprise contract in science and technologies in health (IFI18/00014) from ISCiii. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERcv), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCiii and co-financed by European Regional Development Fund (ERDF) "A way to achieve Europe" for their financial support

Bioquímica y proteómica vegetal y agrícola

En la presente comunicación se resume lo que ha sido la actividad investigadora del grupo “Bioquímica y Proteómica Vegetal y Agrícola” (PAI AGR-164) en los últimos tres años (2005-2007). Nuestro interés y objetivo científico se ha centrando en el estudio de los cambios adaptativos y reacciones de defensa y de resistencia/tolerancia de las plantas a estreses de tipo biótico (hongos fitopatógenos y plantas parásitas) y abiótico (metales pesados, sequía). Dichos estudios se han llevado a cabo tanto con sistemas modelo (Arabidopsis thaliana y Medicago truncatula), como con especies de interés agronómico (garbanzo, girasol, guisante, maíz) o forestal (encina, alcornoque y pino). En los proyectos de investigación abordados se ha utilizado, en gran medida, una aproximación de proteómica, y también técnicas de bioquímica clásica y transcriptómica. La proteómica constituye, hoy en día, una línea prioritaria en cualquier investigación biológica, suministrando, en el área de la biología vegetal, y en combinación con las técnicas clásicas de bioquímica y las de transcriptómica, información relevante sobre diferentes aspectos básicos y aplicados relacionados con especies de interés agronómico y forestal, como es el de la respuesta a estreses, y la caracterización de genotipos (poblaciones, mutantes, líneas transgénicas). Además, hay aspectos, como el de las modificaciones postraduccionales, que sólo pueden ser abordados experimentalmente mediante una estrategia de proteómica. Nuestro grupo ha iniciado recientemente una nueva línea, dirigida a estudiar el proteoma redox en Arabidopsis y su implicación en la respuesta a patógeno