IBGM - Artículos de revista https://uvadoc.uva.es/handle/10324/32523 2026-04-17T11:48:00Z 2026-04-17T11:48:00Z Garrido Moraga, Rocío Serrano Lorenzo, Pablo Esteban Amo, María J. Bellusci, Marcello Fuente García, Miguel Ángel de la Arenas, Joaquín González Quintana, Adrián Ugalde, Cristina Simarro Grande, María Martín Casanueva, Miguel Ángel https://uvadoc.uva.es/handle/10324/83787 2026-03-24T20:07:19Z 2026-01-01T00:00:00Z

This study examines two rare compound heterozygous missense variants in the SDHA gene, c.1535G > A (p. R512Q) and c.1753C > T (p.R585W), identified in a pediatric patient presenting with neurological manifesta- tions, including epilepsy, developmental delay, and optic atrophy. The SDHA gene encodes a key component of succinate dehydrogenase (SDH), an essential enzyme complex at the intersection of two fundamental metabolic pathways: the Krebs cycle, and the mitochondrial respiratory chain (MRC). Patient-derived fibroblasts were used to evaluate the impact of the mutations on SDH activity and MRC as- sembly and function. The analysis revealed significant decreases in SDH activity and subunit levels, as well as impaired assembly. Additionally, complex I (CI) activity and CI-containing supercomplexes formation were also impaired, indicating more widespread mitochondrial dysfunction. Unexpectedly, basal and maximal respiration rates remained unchanged, though spare respiratory capacity was significantly reduced. These findings demonstrate the deleterious effects of the c.1535G > A and c.1753C > T variants, which had previously been associated with primary mitochondrial disorder (PMD) and tumors but had not been functionally validated until now

2026-01-01T00:00:00Z Arribas Rodríguez, Elisa González de Castro, Carolina Fiz López, Aida Prado Moura, Ángel de Martín Muñoz, Álvaro Fernández Salazar, Luis Ignacio Barrio, Jesús Izquierdo, Sandra García Alonso, Francisco Javier Andrés Asenjo, Beatriz de García Abril, José María Romero de Diego, Alejandro Iván Sánchez González, Javier Santander, Cecilio Arranz Sanz, Eduardo Chaparro, María Garrote Adrados, José Antonio Gisbert, Javier P. Bernardo Ordiz, David https://uvadoc.uva.es/handle/10324/83733 2026-03-20T20:01:36Z 2026-01-01T00:00:00Z

This study aimed to characterize human intestinal conventional dendritic cells (cDCs) in health and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). Three cDC subsets (CD103− cDC2, CD103+ cDC2, and cDC1) were identified from lamina propria mononuclear cells. Their phenotype and function were analyzed in healthy and IBD-inflamed gut tissues. In the healthy gut, cDC2 predominated over cDC1, with CD103+ cDC2 dominating the duodenum and CD103− cDC2 prevalent in the ileum and colon. CD103+ cDC2 expressed higher PD-L1 and produced more IL-10. In culture, CD103+ cDC2 increased proportionally unless inhibited by LPS. All subsets induced IL-10+ helper T-cell differentiation, with ileal cDCs being more stimulatory than colonic ones. In IBD, cDCs showed constitutively lower SIRPα expression across conditions. Notably, UC-inflamed colon exhibited reduced cDC1 and CD103+ cDC2, while CD-inflamed colon maintained these subsets but showed increased T-cell stimulation and IL-17+ T-cell priming. Intestinal cDC subsets prime IL-10+ helper T-cells in health. In UC, reduced cDC1 and CD103+ cDC2 in inflamed mucosa contrast with CD, suggesting distinct pathogenic mechanisms that could inform targeted therapies.

2026-01-01T00:00:00Z Portillo de la Fuente, Ana María Prado Santos, Ángel de Soares, Ana J. https://uvadoc.uva.es/handle/10324/82745 2026-02-13T20:00:50Z 2026-01-01T00:00:00Z

Inflammatory bowel disease (IBD), including Crohn s disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation driven by elevated tumor necrosis factor-alpha (TNF-α). Infliximab, an anti-TNF-α monoclonal antibody, is widely used in the treatment of inflammatory bowel disease but shows variable effectiveness due to interindividual pharmacokinetic diversity. We develop a low-dimensional mathematical model of ordinary differential equations to describe TNF-α dynamics, its interactions with receptors and infliximab, and the influence of drug clearance on treatment outcomes in CD and UC. This model is combined with a pharmacokinetic framework that enables the estimation of the infliximab clearance coefficient, which can then be used to guide dosage adjustments in the treatment. The model balances biological realism with analytical tractability, enabling rigorous mathematical analysis and numerical simulations. The parameters are adapted for CD and UC. The study investigates how drug clearance influences treatment efficacy, initially using constant clearance values and later incorporating values that vary with the level of inflammation. Simulations are performed across a range of clearance rates and dosing regimens, providing detailed insights into infliximab and TNF-α dynamics, as well as therapeutic drug monitoring parameters. Our results highlight the critical role of clearance and therapeutic drug monitoring in optimizing infliximab therapy. This approach offers valuable insights to support personalized treatment strategies in IBD.

2026-01-01T00:00:00Z Santo-Domingo, Jaime Caldero Escudero, Elena Romero Sanz, Silvia Alvarez-Illera, Pilar Fuente Pérez, Sergio De La García Casas, Paloma Fonteriz García, Rosalba Inés Montero, Mayte Álvarez Martín, Javier https://uvadoc.uva.es/handle/10324/77016 2025-12-11T12:46:53Z 2025-01-01T00:00:00Z

Accumulation of aggregated β-amyloid peptide is a key histopathological feature of Alzheimer's Disease (AD). Experimental models of AD based on β-amyloid peptide display calcium (Ca2+) signaling alterations, and targeting key components of the cellular Ca2+ signaling system has been postulated to modulate AD onset and progression. Here we have taken advantage of a C. elegans strain that over-expresses the most toxic human ß-amyloid peptide (Aß1–42) in body-wall muscle cells, to study the impact of calreticulin (crt-1) silencing on body-wall muscle performance. Crt-1 knockdown reduced the percentage of paralyzed worms in a dose-dependent manner and improved locomotion parameters in free-mobility assays in Aß1–42-overexpressing worms. At the cellular level, crt-1 silencing prevented Aß1–42-induced exacerbated mitochondrial respiration and mitochondrial ROS production without impacting mitochondrial sarcomere organization. Crt-1 knockdown reduced the number and size of Aß1–42 aggregates in body-wall muscle cells and prevented the formation of Aß1–42 oligomers. We propose that crt-1 depletion reduces the number of Aß1–42 aggregates, precluding Aß1–42-induced mitochondrial toxicity and improving muscle function. We identify C. elegans crt-1 as a gene involved in the toxicity associated with the expression of human Aß1–42, and thus a potential new target for treatment.

2025-01-01T00:00:00Z Gil Bernabé, Sara Feás Rodríguez, Noa Pérez Riesgo, Enrique Corraliza Gómez, Miriam Fra Rodríguez, Joaquín García-Rostán y Pérez, Ginesa María https://uvadoc.uva.es/handle/10324/75937 2025-06-11T19:01:53Z 2025-01-01T00:00:00Z

Few studies have analyzed the prevalence of TERT amplification in thyroid cancer, showing discrepancies in various top- ics. The impact on tumor recurrence and patient survival in papillary thyroid carcinoma (PTC) remains unknown. Thirteen cancer cell lines and 215 tumor samples from 91 patients, who underwent surgery for PTC (41), poorly differentiated thyroid carcinoma (PDC = 15), or anaplastic thyroid carcinoma (ATC = 35), were analyzed. Clonality, spread with tumor dediffer- entiation or metastatic PTC cells, and coexistence with TERTp, BRAF, RAS, and PIK3CA mutations were also investigated. TERT amplification was found in 17%, 20%, and 17% of the PTC, PDC, and ATC, respectively. It was more frequent in follicular variant PTC and PTC with distant metastases (86%, P = 0.0448). The cell lines HTh74, SW1736, and T242 had amplification. In PTC, TERT amplification was a subclonal event. The increase in TERT copy number spread in all cases with metastatic PTC cells. In 67% of the PDC and 100% of the ATC, TERT activation segregated with tumor dedifferentiation. TERT amplification correlated with TERTp mutations in PTC (P = 0.0313) and PIK3CA mutations in ATC (P = 0.0272). TERT amplification significantly correlated with vascular invasion (P = 0.03637), distant metastases at diagnosis and/or follow-up (P = 0.04482), metachronous distant metastases (P = 0.03131), death patient status (P = 0.000829), stage at diag- nosis (P = 0.01995), and stage III/IV at last follow-up (P = 0.01552). TERT amplification associated independently with tumor-related recurrence and death. Our study shows that PTC can be stratified into clinically prognostic relevant categories based on the presence or not of TERT amplification in the cells.

2025-01-01T00:00:00Z Sánchez Sánchez, Laura Fernández, Roberto Ganfornina Álvarez, María Dolores Astigarraga, Egoitz Barreda Gómez, Gabriel https://uvadoc.uva.es/handle/10324/69615 2024-09-10T06:13:35Z 2022-01-01T00:00:00Z

Cellular senescence is one of the main contributors to some neurodegenerative disorders. The early detection of senescent cells or their related effects is a key aspect in treating disease progression. In this functional deterioration, oxidative stress and lipid peroxidation play an important role. Endogenous antioxidant compounds, such as α-tocopherol (vitamin E), can mitigate these undesirable effects, particularly lipid peroxidation, by blocking the reaction between free radicals and unsaturated fatty acid. While the antioxidant actions of α-tocopherol have been studied in various systems, monitoring the specific effects on cell membrane lipids at scales compatible with large screenings has not yet been accomplished. Understanding the changes responsible for this protection against one of the consequences of senescence is therefore necessary. Thus, the goal of this study was to determinate the changes in the lipid environment of a Paraquat-treated human astrocytic cell line, as a cellular oxidative stress model, and the specific actions of the antioxidant, α-tocopherol, using cell membrane microarray technology, MALDI-MS and lipidomic analysis. The stress induced by Paraquat exposure significantly decreased cell viability and triggered membrane lipid changes, such as an increase in certain species of ceramides that are lipid mediators of apoptotic pathways. The pre-treatment of cells with α-tocopherol mitigated these effects, enhancing cell viability and modulating the lipid profile in Paraquat-treated astrocytes. These results demonstrate the lipid modulation effects of α-tocopherol against Paraquat-promoted oxidative stress and validate a novel analytical high-throughput method combining cell cultures, microarray technology, MALDI-MS and multivariate analysis to study antioxidant compounds against cellular senescence.

2022-01-01T00:00:00Z Sánchez Sánchez, Laura García, Javier Fernández, Roberto Noskova, Ekaterina Egiguren Ortiz, June Gulak, Marina Ochoa, Eneko Laso, Antonio Oiarbide, Mikel Santos, José Ignacio Andrés, María Fe González Coloma, Azucena Adell, Albert Astigarraga, Egoitz Barreda Gómez, Gabriel https://uvadoc.uva.es/handle/10324/69397 2024-08-21T19:00:49Z 2023-01-01T00:00:00Z

Cannabis has been used for decades as a palliative therapy in the treatment of cancer. This is because of its beneficial effects on the pain and nausea that patients can experience as a result of chemo/radiotherapy. Tetrahydrocannabinol and cannabidiol are the main compounds present in Cannabis sativa, and both exert their actions through a receptor-mediated mechanism and through a non-receptor-mediated mechanism, which modulates the formation of reactive oxygen species. These oxidative stress conditions might trigger lipidic changes, which would compromise cell membrane stability and viability. In this sense, numerous pieces of evidence describe a potential antitumor effect of cannabinoid compounds in different types of cancer, although controversial results limit their implementation. In order to further investigate the possible mechanism involved in the antitumoral effects of cannabinoids, three extracts isolated from Cannabis sativa strains with high cannabidiol content were analyzed. Cell mortality, cytochrome c oxidase activity and the lipid composition of SH-SY5Y cells were determined in the absence and presence of specific cannabinoid ligands, with and without antioxidant pre-treatment. The cell mortality induced by the extracts in this study appeared to be related to the inhibition of the cytochrome c oxidase activity and to the THC concentration. This effect on cell viability was similar to that observed with the cannabinoid agonist WIN55,212-2. The effect was partially blocked by the selective CB1 antagonist AM281, and the antioxidant α-tocopherol. Moreover, certain membrane lipids were affected by the extracts, which demonstrated the importance of oxidative stress in the potential antitumoral effects of cannabinoids.

2023-01-01T00:00:00Z García Casas, Paloma Arias del Val, Jessica Álvarez Illera, María Pilar Fonteriz García, Rosalba Inés Montero Zoccola, María Teresa Álvarez Martín, Javier https://uvadoc.uva.es/handle/10324/66092 2024-12-17T10:58:00Z 2018-01-01T00:00:00Z

The sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca2+ up to the millimolar range and is therefore the main controller of the ER [Ca2+] level ([Ca2+]ER), which has a key role in the modulation of cytosolic Ca2+ signaling and ER-mitochondria Ca2+ transfer. Given that both cytosolic and mitochondrial Ca2+ dynamics strongly interplay with energy metabolism and nutrient sensitive pathways, both of them involved in the aging process, we have studied the effect of SERCA inhibitors on lifespan in C. elegans. We have used thapsigargin and 2,5-Di-tert-butylhydroquinone (2,5-BHQ) as SERCA inhibitors, and the inactive analog 2,6-Di-tert-butylhydroquinone (2,6-BHQ) as a control for 2,5-BHQ. Every drug was administered to the worms either directly in the agar or via an inclusion compound with g-cyclodextrin. The results show that 2,6-BHQ produced a small but significant increase in survival, perhaps because of its antioxidant properties. However, 2,5-BHQ produced in all the conditions a much higher increase in lifespan, and the potent and specific SERCA inhibitor thapsigargin also extended the lifespan. The effects of 2,5-BHQ and thapsigargin had a bell-shaped concentration dependence, with a maximum effect at a certain dose and smaller or even toxic effects at higher concentrations. Our data show therefore that submaximal inhibition of SERCA pumps has a pro-longevity effect, suggesting that Ca2+ signaling plays an important role in the aging process and that it could be a promising novel target pathway to act on aging.

2018-01-01T00:00:00Z García Casas, Paloma Arias del Val, Jessica Álvarez Illera, María Pilar Wojnicz, Aneta Ríos, Cristobal de los Fonteriz García, Rosalba Inés Montero Zoccola, María Teresa Álvarez Martín, Javier https://uvadoc.uva.es/handle/10324/66090 2024-12-17T10:55:06Z 2019-01-01T00:00:00Z

The benzothiazepine CGP37157 has shown neuroprotective effects in several in vitro models of excitotoxicity involving dysregulation of intracellular Ca2+ homeostasis. Although its mechanism of neuroprotection is unclear, it is probably related with some of its effects on Ca2+ homeostasis. CGP37157 is a well-known inhibitor of the mitochondrial Na+/Ca2+ exchanger (mNCX). However, it is not very specific and also blocks several other Ca2+ channels and transporters, including voltage gated Ca2+ channels, plasma membrane Na+/Ca2+ exchanger and the Ca2+ homeostasis modulator 1 channel (CALHM1). In the present work, we have studied if CGP37157 could also induce changes in life expectancy. We now report that CGP37157 extends C. elegans lifespan by 10%–15% with a bell-shaped concentration response, with high concentrations producing no effect. The effect was even larger (25% increase in life expectancy) in worms fed with heat-inactivated bacteria. The worm CGP37157 concentration producing maximum effect was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and was close to the IC50 for inhibition of the Na+/Ca2+ exchanger. CGP37157 also extended the lifespan in eat-2 mutants (a model for caloric restriction), suggesting that caloric restriction is not involved in the mechanism of lifespan extension. Actually, CGP37157 produced no effect in mutants of the TOR pathway (daf15/unc24) or the insulin/insulin-like growth factor-1 (IGF-1) pathway (daf-2), indicating that the effect involves these pathways. Moreover, CGP37157 was also ineffective in nuo-6 mutants, which have a defect in the mitochondrial respiratory chain complex I. Since it has been described that neuroprotection by this compound in cell cultures is abolished by mitochondrial inhibitors, this suggests that life extension in C. elegans and neuroprotection in cell cultures may share a similar mechanism involving mitochondria.

2019-01-01T00:00:00Z García Casas, Paloma Álvarez Illera, María Pilar Gómez Orte, Eva Cabello, Juan Fonteriz García, Rosalba Inés Montero Zoccola, María Teresa Álvarez Martín, Javier https://uvadoc.uva.es/handle/10324/66082 2024-12-17T10:55:43Z 2021-01-01T00:00:00Z

We have reported recently that the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 extends lifespan in Caenorhabditis elegans by a mechanism involving mitochondria, the TOR pathway and the insulin/IGF1 pathway. Here we show that CGP37157 significantly improved the evolution with age of the sarcomeric regular structure, delaying development of sarcopenia in C. elegans body wall muscle and increasing the average and maximum speed of the worms. Similarly, CGP37157 favored the maintenance of a regular mitochondrial structure during aging. We have also investigated further the mechanism of the effect of CGP37157 by studying its effect in mutants of aak-1;aak-2/AMP-activated kinase, sir-2.1/sirtuin, rsks-1/S6 kinase and daf-16/FOXO. We found that this compound was still effective increasing lifespan in all these mutants, indicating that these pathways are not involved in the effect. We have then monitored pharynx cytosolic and mitochondrial Ca2+ signalling and our results suggest that CGP37157 is probably inhibiting not only the mitochondrial Na+/Ca2+ exchanger, but also Ca2+ entry through the plasma membrane. Finally, a transcriptomic study detected that CGP37157 induced changes in lipid metabolism enzymes and a four-fold increase in the expression of ncx-6, one of the C. elegans mitochondrial Na+/Ca2+ exchangers. In summary, CGP37157 increases both lifespan and healthspan by a mechanism involving changes in cytosolic and mitochondrial Ca2+ homeostasis. Thus, Ca2+ signalling could be a promising target to act on aging.

2021-01-01T00:00:00Z Álvarez Martín, Javier Álvarez Illera, María Pilar Santo Domingo Mayoral, Jaime Fonteriz García, Rosalba Inés Montero Zoccola, María Teresa https://uvadoc.uva.es/handle/10324/66080 2024-12-17T10:56:59Z 2022-01-01T00:00:00Z

Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as -amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing A peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

2022-01-01T00:00:00Z Srinivasan, Sumithra Yasaswini Álvarez Illera, María Pilar Kukhtar, Dmytro Benseny-Cases, Núria Cerón, Julián Álvarez Martín, Javier Fonteriz García, Rosalba Inés Montero Zoccola, María Teresa Laromaine, Anna https://uvadoc.uva.es/handle/10324/66078 2024-12-17T10:58:32Z 2023-01-01T00:00:00Z

Experimental studies and clinical trials of nanoparticles for treating diseases are increasing continuously. However, the reach to the market does not correlate with these efforts due to the enormous cost, several years of development, and off-target effects like cardiotoxicity. Multicellular organisms such as the Caenorhabditis elegans (C. elegans) can bridge the gap between in vitro and vertebrate testing as they can provide extensive information on systemic toxicity and specific harmful effects through facile experimentation following 3R EU directives on animal use. Since the nematodes’ pharynx shares similarities with the human heart, we assessed the general and pharyngeal effects of drugs and polypyrrole nanoparticles (Ppy NPs) using C. elegans. The evaluation of FDA-approved drugs, such as Propranolol and Racepinephrine reproduced the arrhythmic behavior reported in humans and supported the use of this small animal model. Consequently, Ppy NPs were evaluated due to their research interest in cardiac arrhythmia treatments. The NPs’ biocompatibility was confirmed by assessing survival, growth and development, reproduction, and transgenerational toxicity in C. elegans. Interestingly, the NPs increased the pharyngeal pumping rate of C. elegans in two slow-pumping mutant strains, JD21 and DA464. Moreover, the NPs increased the pumping rate over time, which sustained up to a day post-excretion. By measuring pharyngeal calcium levels, we found that the impact of Ppy NPs on the pumping rate could be mediated through calcium signaling. Thus, evaluating arrhythmic effects in C. elegans offers a simple system to test drugs and nanoparticles, as elucidated through Ppy NPs.

2023-01-01T00:00:00Z Romero Sanz, Silvia Caldero Escudero, Elena Álvarez Illera, María Pilar Santo Domingo Mayoral, Jaime Fonteriz García, Rosalba Inés Montero Zoccola, María Teresa Álvarez Martín, Javier https://uvadoc.uva.es/handle/10324/66076 2025-01-10T13:45:24Z 2023-01-01T00:00:00Z

Introduction: The high prevalence of neurodegenerative diseases in our population and the lack of effective treatments encourage the search for new therapeutic targets for these pathologies. We have recently described that submaximal inhibition of the Sarco-Endoplasmic Reticulum Ca2+ ATPase (SERCA), the main responsible for ER calcium storage, is able to increase lifespan in Caenorhabditis elegans worms by mechanisms involving mitochondrial metabolism and nutrient-sensitive pathways. Methods: We have studied here the effects of submaximal SERCA inhibition in a chemicalmodel of Parkinson’s disease (PD) induced in C. elegansworms by treatment with themitochondrial complex I inhibitor rotenone. For specific SERCA inhibition,we treated worms with RNAi against sca-1, the sole orthologue of SERCA in C. elegans. Results and Discussion: Our results show that rotenone produces alterations in worms that include decreased lifespan, smaller size, reduced fertility, decreased motility, defecation and pumping rate, increased mitochondrial ROS production, reduced mitochondrial membrane potential and oxygen consumption rate, altered mitochondrial structure, and altered ethanol preference in behavioral studies. Most of these alterations were either fully or partially reversed in worms treated with sca-1 RNAi, suggesting that SERCA inhibition could be a novel pharmacological target in the prevention or treatment of neurodegeneration.

2023-01-01T00:00:00Z Corraliza Gómez, Miriam Lillo, Concepción Cózar Castellano, Irene Arranz Sanz, Eduardo Sánchez Romero, Diego Ganfornina Álvarez, María Dolores https://uvadoc.uva.es/handle/10324/62942 2023-11-14T20:01:00Z 2022-01-01T00:00:00Z

The insulin-degrading enzyme (IDE) is a zinc-dependent metalloendopeptidase that belongs to the M16A metalloprotease family. IDE is markedly expressed in the brain, where it is particularly relevant due to its in vitro amyloid beta (Aβ)-degrading activity. The subcellular localization of IDE, a paramount aspect to understand how this enzyme can perform its proteolytic functions in vivo, remains highly controversial. In this work, we addressed IDE subcellular localization from an evolutionary perspective. Phylogenetic analyses based on protein sequence and gene and protein structure were performed. An in silico analysis of IDE signal peptide suggests an evolutionary shift in IDE exportation at the prokaryote/eukaryote divide. Subcellular localization experiments in microglia revealed that IDE is mostly cytosolic. Furthermore, IDE associates to membranes by their cytoplasmatic side and further partitions between raft and non-raft domains. When stimulated, microglia change into a secretory active state, produces numerous multivesicular bodies and IDE associates with their membranes. The subsequent inward budding of such membranes internalizes IDE in intraluminal vesicles, which later allows IDE to be exported outside the cells in small extracellular vesicles. We further demonstrate that such an IDE exportation mechanism is regulated by stimuli relevant for microglia in physiological conditions and upon aging and neurodegeneration.

2022-01-01T00:00:00Z Elexpe, Ane Sánchez Sánchez, Laura Tolentino Cortez, Tarson Astigarraga, Egoitz Torrecilla, María Barreda Gómez, Gabriel https://uvadoc.uva.es/handle/10324/62573 2023-11-02T20:01:13Z 2022-01-01T00:00:00Z

Drug side effects are one of the main reasons for treatment withdrawal during clinical trials. Reactive oxygen species formation is involved in many of the drug side effects, mainly by interacting with the components of the cellular respiration. Thus, the early detection of these effects in the drug discovery process is a key aspect for the optimization of pharmacological research. To this end, the superoxide formation of a series of drugs and compounds with antidepressant, antipsychotic, anticholinergic, narcotic, and analgesic properties was evaluated in isolated bovine heart membranes and on cell membrane microarrays from a collection of human tissues, together with specific inhibitors of the mitochondrial electron transport chain. Fluphenazine and PB28 promoted similar effects to those of rotenone, but with lower potency, indicating a direct action on mitochondrial complex I. Moreover, nefazodone, a drug withdrawn from the market due to its mitochondrial hepatotoxic effects, evoked the highest superoxide formation in human liver cell membranes, suggesting the potential of this technology to anticipate adverse effects in preclinical phases.

2022-01-01T00:00:00Z Abascal Saiz, Alejandra Duque Alcorta, Marta Fioravantti, Victoria Antolín, Eugenia Fuente Luelmo, Eva Haro, María Ramos Álvarez, María Pilar Perdomo Hernández, Germán Bartha, José Luis https://uvadoc.uva.es/handle/10324/61798 2023-09-25T19:00:44Z 2022-01-01T00:00:00Z

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset). We compared antiangiogenic factors soluble Fms-like Tyrosine Kinase-1 (sfLt-1), placental growth factor (PlGF), and soluble endoglin (sEng)), lipid and carbohydrate metabolism in maternal plasma, and lipid metabolism in the placenta from assays of fatty acid oxidation, fatty acid esterification, and triglyceride levels in all groups. Antiangiogenic factors sFlt-1, sFlt-1/PlGF ratio, and sEng showed a positive correlation with triglyceride, free fatty acid, and C-peptide maternal serum levels. However, there was no relationship between angiogenic factors and placental lipid metabolism parameters. Free fatty acids were predictive of elevated sFlt-1 and sEng, while C-peptide was predictive of an elevated sFlt1/PlGF ratio. The findings in this study generate a model to predict elevated antiangiogenic factor values and the relationship between them with different products of lipid and carbohydrate metabolism in maternal serum and placenta in preeclampsia.

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