Evaluación de la acumulación mitocondrial de estrógenos sintéticos mito-dirigidos en un modelo in vitro

Evaluation of mitochondrial accumulation of mito-targeted synthetic estrogens on in vitro model

Magdiel Orozco Valdivia (2023, [Tesis de maestría])

La mitocondria es un organelo que cumple funciones esenciales en el mantenimiento de las células eucariotas y su disfunción está asociada a la progresión de enfermedades neurodegenerativas, metabólicas y cardiovasculares. Por lo anterior es necesario encontrar tratamientos que mejoren la función mitocondrial. Los estrógenos son hormonas que tienen diversos efectos benéficos sobre las células. Entre estos efectos, se ha observado que las hormonas inciden en la función mitocondrial, por lo que son un potencial tratamiento para las enfermedades asociadas a la disfunción mitocondrial. Una alternativa es mediante los compuestos mito-dirigidos, moléculas con actividad biológica que son acoplados a cationes lipofílicos con la capacidad de acumularse a mayor concentración en la mitocondria respecto a las sustancias no mito-dirigidas. Por lo tanto, se plantea conferir la propiedad acumulativa a los estrógenos mediante el acoplamiento de trifenilfosfonio, un catión lipofílico recurrentemente usado para la generación de mito-dirigidos. Para el presente trabajo se sintetizaron dos estrógenos mito-dirigidos. Este proyecto evalúa la acumulación mitocondrial de los estrógenos mito-dirigidos después de una exposición de estos en un modelo in vitro sensible a estrógenos, comparando su acumulación con la del estrógeno no mito-dirigido. Los resultados indican que los estrógenos mito-dirigidos se acumulan más en las mitocondrias que el estrógeno no mito-dirigido y demuestra que los estrógenos mito-dirigidos tienen capacidad acumulativa, esto permite sentar las bases de un tratamiento hormonal dirigido a las mitocondrias que se pueda aplicar a enfermedades asociadas a la disfunción mitocondrial.

Mitochondria are essential organelles of eukaryotic cells, and their dysfunction is associated with the onset and development of neurodegenerative, metabolic, and cardiovascular diseases. Thus, it is important to develop treatments to improve mitochondrial function. One of the options are estrogens, these hormones have a protective role in cellular function by participating in the regulation of mitochondrial function, making estrogens candidates to be a potential treatment for diseases related to mitochondrial dysfunction. One of the alternative treatments are mito-targeted molecules, which are biologically active molecules conjugated with lipophilic cations. These mito-targeted molecules can accumulate inside mitochondria more than non-targeted molecules. This project aims to synthesize mito-targeted estrogens by conjugating a lipophilic cation, triphenylphosphonium, to a parent estrogenic compound. Our hypothesis is that these novel molecules will accumulate in the interior of the mitochondria and will have more biological activity than the non-targeted estrogen. We synthesized two mito-targeted estrogens for this project and evaluated the mitochondrial accumulation in an estrogen-sensitive in vitro model, comparing their accumulation to non-targeted estrogens. The results indicate mito-targeted estrogens accumulate in mitochondria more than the non-targeted estrogens, showing that mito-targeted estrogens have an accumulation capacity. This insight will make new treatments for diseases related to mitochondrial dysfunction.

estrógenos, mito-dirigido, disfunción mitocondrial, acumulación, mitocondria estrogens, mitochondria, mito-targeted, accumulation, mitochondrial dysfunction BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA BIOLOGÍA HUMANA HORMONAS HORMONAS

Chronic toxicity of shrimp feed added with silver nanoparticles (Argovit-4®) in Litopenaeus vannamei and immune response to white spot syndrome virus infection

Carlos Rosendo Romo Quiñonez Píndaro Álvarez Ruiz CLAUDIO HUMBERTO MEJIA RUIZ NINA BOGDANCHIKOVA Alexey Pestryakov CARINA GAMEZ JIMENEZ WENCESLAO VALENZUELA QUIÑONEZ Magnolia Montoya Mejía EUSEBIO NAVA PEREZ (2022, [Artículo])

"In recent years, the application of silver nanoparticles (AgNPs) as antibacterial compounds has been widely used in human and veterinary medicine. In this work, we investigated the effects of AgNPs (Argovit-4 R ) as feed additives (feed-AgNPs) on shrimp (Litopenaeus vannamei) using three different methods: 1) chronic toxicity after 28 days of feeding, 2) Effects against white spot syndrome virus (WSSV) challenged by oral route, and 3) transcriptional responses of immune-related genes (PAP, ProPO, CTL-3, Crustin, PEN3, and PEN4) following WSSV infection. The results showed that the feed-AgNPs did not interfere with the growth and survival of shrimp. Also, mild lesions in the hepatopancreas were recorded, proportional to the frequency of the feed-AgNP supply. Challenge test versus WSSV showed that feeding every 7 days with feed-AgNPs reduced mortality, reaching a survival rate of 53%, compared to the survival rates observed in groups fed every 4 days, daily and control groups of feed-AgNPs for the 30%, 10%, and 7% groups, respectively. Feed-AgNPs negatively regulated the expression of PAP, ProPO, and Crustin genes after 28 days of treatment and altered the transcriptional responses of PAP, ProPO, CTL-3, and Crustin after WSSV exposure. The results showed that weekly feeding-AgNPs could partially prevent WSSV infection in shrimp culture. However, whether or not transcriptional responses against pathogens are advantageous remains to be elucidated."

Silver nanoparticles, Shrimp, Aquaculture, Chronic toxicity, WSSV, AgNP, Argovit, Litopenaeus vannamei , Silver fed, White spot syndrome virus BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA INMUNOLOGÍA INMUNIZACIÓN INMUNIZACIÓN

Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in neurospora crassa

CYNTHIA LIZZETH ARAUJO PALOMARES (2011, [Artículo])

Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa. © 2011 Araujo-Palomares et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

CDC24 protein, guanine nucleotide exchange factor, protein Cdc42, Rac protein, unclassified drug, cell cycle protein, fungal protein, membrane protein, multiprotein complex, protein Cdc42, Rac protein, allele, apical membrane, article, assay, cell me BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA MICROBIOLOGÍA MICROBIOLOGÍA

Coronin is a component of the endocytic collar of hyphae of neurospora crassa and is necessary for normal growth and morphogenesis

RAMON OSVALDO ECHAURI ESPINOSA (2012, [Artículo])

Coronin plays a major role in the organization and dynamics of actin in yeast. To investigate the role of coronin in a filamentous fungus (Neurospora crassa), we examined its subcellular localization using fluorescent proteins and the phenotypic consequences of coronin gene (crn-1) deletion in hyphal morphogenesis, Spitzenkörper behavior and endocytosis. Coronin-GFP was localized in patches, forming a subapical collar near the hyphal apex; significantly, it was absent from the apex. The subapical patches of coronin colocalized with fimbrin, Arp2/3 complex, and actin, altogether comprising the endocytic collar. Deletion of crn-1 resulted in reduced hyphal growth rates, distorted hyphal morphology, uneven wall thickness, and delayed establishment of polarity during germination; it also affected growth directionality and increased branching. The Spitzenkörper of Δcrn-1 mutant was unstable; it appeared and disappeared intermittently giving rise to periods of hyphoid-like and isotropic growth respectively. Uptake of FM4-64 in Δcrn-1 mutant indicated a partial disruption in endocytosis. These observations underscore coronin as an important component of F-actin remodeling in N. crassa. Although coronin is not essential in this fungus, its deletion influenced negatively the operation of the actin cytoskeleton involved in the orderly deployment of the apical growth apparatus, thus preventing normal hyphal growth and morphogenesis. © 2012 Echauri-Espinosa et al.

actin related protein 2-3 complex, F actin, fimbrin protein, fluorescent dye, fungal protein, fungal protein coronin, green fluorescent protein, unclassified drug, actin binding protein, coronin proteins, fungal protein, article, cell polarity, contr BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA MICROBIOLOGÍA MICROBIOLOGÍA