Artículos (Bioquímica y Biología Molecular)

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Neuroinflammation in Age-Related Neurodegenerative Diseases: Role of Mitochondrial Oxidative Stress
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Abadin, X.; Dios, Cristina de; Zubillaga, M.; Ivars, E.; Puigròs, M.; Marí, M.; Morales, A.; Vizuete Chacón, María Luisa; Vitorica Ferrández, Francisco Javier; Trullas, R.; Colell, A.; Roca Agujetas, Vicente; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Ministerio de Ciencia e Innovación (MICIN). España; Instituto de Salud Carlos III; Generalitat de Catalunya; Junta de Andalucía; Agencia Estatal de Investigación. España; European Union (UE)
A shared hallmark of age-related neurodegenerative diseases is the chronic activation of innate immune cells, which actively contributes to the neurodegenerative process. In Alzheimer’s disease, this inflammatory milieu exacerbates both amyloid and tau pathology. A similar abnormal inflammatory response has been reported in Parkinson’s disease, with elevated levels of cytokines and other inflammatory intermediates derived from activated glial cells, which promote the progressive loss of nigral dopaminergic neurons. Understanding the causes that support this aberrant inflammatory response has become a topic of growing interest and research in neurodegeneration, with high translational potential. It has been postulated that the phenotypic shift of immune cells towards a proinflammatory state combined with the presence of immunogenic cell death fuels a vicious cycle in which mitochondrial dysfunction plays a central role. Mitochondria and mitochondria-generated reactive oxygen species are downstream effectors of different inflammatory signaling pathways, including inflammasomes. Dysfunctional mitochondria are also recognized as important producers of damage-associated molecular patterns, which can amplify the immune response. Here, we review the major findings highlighting the role of mitochondria as a checkpoint of neuroinflammation and immunogenic cell deaths in neurodegenerative diseases. The knowledge of these processes may help to find new druggable targets to modulate the inflammatory response.
Comparing Fermented Food and Vitamin E on Exercise-mediated Nrf2/ARE Activation in Middle-aged/ Elderly: A Randomized, Double-blind Clinical Study
(Functional Food Institute, 2024) Cervi, Joseph; Rastmanesh, Reza; Ahmadi, Amir Moghadam; Ayala Gómez, Antonio; Aperio, Cristiana; Lorenzetti, Aldo; Osato, Maki; Marotta, Francesco; Nardin, Antonio; He, Fang; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
Background: There is a compelling need to emphasize the importance of deepening the rationale behind functional foods research in molecular biology. Indeed, establishing stringent criteria to evaluate functional food interventions in disease prevention and as adjunctive therapeutic strategies offers significant opportunities for health promotion. Objective: This study investigated the effects of fermented papaya preparation (FPP®) and vitamin E on gene expression in middle-aged/elderly individuals, leveraging FPP’s established antioxidant and immune-regulatory benefits. Methods: Graded Exercise Walking Test was administered twice weekly for 6 months. Total Antioxidant capacity (TAC) and gene expression (Nrf2, NQO1, HO-1) in PBMC were measured monthly. Results: Throughout the 6-month study, routine biochemistry and BMI remained stable. Both treatments significantly improved Total Antioxidant Capacity (TAC), Vitamin E exhibiting earlier effects (3 months). Notably, FPP® supplementation led to sustained over-expression of nuclear Nrf2 in all subjects, surpassing Vitamin E’s effects. NQO1 gene expression was rapidly and consistently upregulated in the FPP group, exceeding baseline and Vitamin E levels throughout the study. HO-1 gene expression was upregulated by FPP at 1 month in younger age quartiles (Q1-2) and at 3 and 6 months in all subjects, regardless of age and gender. In contrast Vitamin E did not significantly impact Nrf2, NQO1, or HO-1 gene expression. Conclusion: These findings demonstrate that FPP, unlike Vitamin E, potentiates Nrf2 signaling, triggering a downstream epigenetic cascade. Notably, our clinical data reveal that physical exercise combined with functional food supplementation partially restores impaired Nrf2 signaling in elderly individuals.
Nerve injury triggers time-dependent activation of the locus coeruleus, influencing spontaneous pain-like behavior in rats.
(Lippincott, Williams & Wilkins, 2024-04-10) Suarez Pereira, Irene; Lopez Martin, Carolina; Camarena Delgado, Carmen; Llorca Torralba, Meritxell; Gonzalez Saiz, Francisco; Ruiz Laza, Rocío; Santiago Pavón, Martiniano; Berrocoso, Esther; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
Pain Medicine A nesthesiology, V 141 • NO 1 July 2024 131 ediTOR’S PeRSPecTiVe What We Already Know about This Topic • Increasing evidence suggests the involvement of the noradrenergic locus coeruleus in the dynamic modulation of nociception • The role of neuronal projections from the locus coeruleus to the spi- nal cord and to the rostral anterior cingular cortex in the modulation of neuropathic pain over time is incompletely understood What This Article Tells us That Is New • In an experimental model of chronic constriction nerve injury in rats, a combination of genetic and histologic approaches revealed a biphasic time-dependent role for locus coeruleus neurons in mod- ulating nociceptive responses • After 2 days of nerve injury, activation of locus coeruleus neurons projecting to spinal cord played a role in attenuating pain-like behavior while activation of locus coeruleus neurons projecting to the rostral anterior cingular cortex amplified nociceptive responses • After 30 days of nerve injury, only the projections from locus coe- ruleus neurons to the rostral anterior cingular cortex contributed to the modulation of pain-like behavior in this experimental model The locus coeruleus (LC) noradrenergic system is the main source of noradrenaline in the central nervous system, and it is a key brain area involved in pain plas- ticity.1–3 Numerous studies indicate that the LC is engaged by acute noxious stimuli or inflammation, promoting feed- back inhibition of pain.4–6 However, recent studies suggest that the LC does not fulfill a uniform role in chronic pain, but rather, it changes dynamically through the activation of specific LC projections while others are silenced as pain Nerve Injury Triggers Time-dependent Activation of the Locus Coeruleus, Influencing Spontaneous Pain-like Behavior in Rats Irene Suárez-Pereira, Ph.D., Carolina López-Martín, M.Sc., Carmen Camarena-Delgado, Ph.D., Meritxell Llorca-Torralba, Ph.D., Francisco González-Saiz, M.D., Rocío Ruiz, Ph.D., Martiniano Santiago, Ph.D., Esther Berrocoso, Ph.D. A nesthesiology 2024; 141:131–50 aBSTRacT Background: Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, the authors explored the cellular cFos activ- ity of the LC and its projections in conjunction with spontaneous pain-like behavior in neuropathic rats. Methods: Tyrosine hydroxylase:Cre and wild-type Long–Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short- term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro- Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and after noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacologic approaches, as were its projections, in association with spontaneous pain-like behaviors. Results: CCI-ST enhanced basal cFos expression in the LC and in its pro- jection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not mod- ified by stimulation. No cFos expression was found in the CCI-LT LC ipsilateral (ipsi)/contralateral (contra)→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LC ipsi is blocked, or by selec- tively blocking the LC ipsi→SC projection. Activation of the LC ipsi or LC ipsi/contra→ SC dampened pain-like behavior. Moreover, Designer Receptor Exclusively Activated by Designer Drugs (DREADDs)–mediated inactivation of the CCI-ST LC ipsi→rACC or CCI-LT LC ipsi/contra→rACC pathway, or intra-rACC antagonism of α-adrenoreceptors, also dampens pain-like behavior. conclusions: In the short term, activation of the LC after CCI attenuates spontaneous pain-like behaviors via projections to the SC while increasing nociception via projections to the rACC. In the long term, only the projec- tions from the LC to the rACC contribute to modulate pain-like behaviors in this model.
Analysis of Patient Referrals from Primary Care to Ophthalmology. The Role of the Optometrist
(Elsevier, 2024) Carrasco Solís, Rafael; Rodríguez Griñolo, María Rosario; Ponte Zúñiga, Beatriz; Mataix Albert, Beatriz; Lledó de Villar, María Leticia; Martínez de Pablos, Rocío; Rodríguez de la Rúa Franch, Enrique; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Instituto de Salud Carlos III
Purpose: The aim of this study was to characterize the quality of primary care referrals of patients to ophthalmology at the Virgen Macarena Hospital in Seville. This will enable us to optimize ophthalmologic resources and to evaluate the role of the optometrist in improving referrals. Methods: We performed a retrospective cross-sectional review of 220 ophthalmology consultations referred from primary care to the hospital from March to May 2022. The following data were extracted: age, sex, reason for consultation, diagnosis, priority level, whether it was an initial consultation or a follow-up visit, whether there was a secondary referral and whether the referral was appropriate. Excel (version 2312) was used for the data analysis. Results: The age range of the patients was from 3 years to 91 years. The patients were 41.8 % male and 58.2 % female. The conditions found were grouped as follows: cataracts (27.27 %), refractive errors (20.9 %), anterior segment disease (18.8 %), posterior segment disease (14.07 %), normal examination (18.63 %) and others (0.9 %). The most common reason for consultation was blurred vision or loss of vision (43.63 %). In total, 41.36 % of the consultations were considered inappropriate. The age group requiring the highest number of consultations was over 65 years (38.64 %). Conclusions: With 41.36 percent of referrals deemed unnecessary, it is clear that referrals can be improved. This would reduce strain on the ophthalmology service and improve patient care. The importance of the optometrist in primary care is demonstrated by the fact that 20.9 % of the diagnoses were refractive errors.
Iron Accumulation and Lipid Peroxidation in Cellular Models of Nemaline Myopathies
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-02-08) López-Cabrera, Alejandra; Piñero-Pérez, Rocío; Álvarez-Córdoba, Mónica; Cilleros-Holgado, Paula; Gómez-Fernández, David; Reche-López, Diana; Romero-González, Ana; Romero-Domínguez, José Manuel; de la Mata, Mario; Martínez de Pablos, Rocío; González-Granero, Susana; García-Verdugo, José Manuel; Sánchez-Alcázar, José A.; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Instituto de Salud Carlos III; Junta de Andalucía; Universidad Pablo de Olavide; Generalitat Valenciana
One of the most prevalent types of congenital myopathy is nemaline myopathy (NM), which is recognized by histopathological examination of muscle fibers for the presence of “nemaline bodies” (rods). Mutations in the actin alpha 1 (ACTA1) and nebulin (NEB) genes result in the most prevalent types of NM. Muscle weakness and hypotonia are the main clinical characteristics of this disease. Unfortunately, the pathogenetic mechanisms are still unknown, and there is no cure. In previous work, we showed that actin filament polymerization defects in patient-derived fibroblasts were associated with mitochondrial dysfunction. In this manuscript, we examined the pathophysiological consequences of mitochondrial dysfunction in patient-derived fibroblasts. We analyzed iron and lipofuscin accumulation and lipid peroxidation both at the cellular and mitochondrial level. We found that fibroblasts derived from patients harboring ACTA1 and NEB mutations showed intracellular iron and lipofuscin accumulation, increased lipid peroxidation, and altered expression levels of proteins involved in iron metabolism. Furthermore, we showed that actin polymerization inhibition in control cells recapitulates the main pathological alterations of mutant nemaline cells. Our results indicate that mitochondrial dysfunction is associated with iron metabolism dysregulation, leading to iron/lipofuscin accumulation and increased lipid peroxidation.
Food-derived vesicles as immunomodulatory drivers: Current knowledge, gaps, and perspectives
(Elsevier, 2024-06-20) Rivero Pino, Fernando; Márquez Parada, Elvira; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Gobierno de España
Extracellular vesicles (EVs) are lipid-bound membrane vesicles released from cells, containing active compounds, which can be found in different foods. In this review, the role of food-derived vesicles (FDVs) as immunomodulatory drivers is summarized, with a focus on sources, isolation techniques and yields, as well as bioavailability and potential health implications. In addition, gaps and perspectives detected in this research field have been highlighted. FDVs have been efficiently extracted from different sources, and differential ultracentrifugation seems to be the most adequate isolation technique, with yields ranging from 108 to 1014 EV particles/mL. Animal studies show promising results in how these FDVs might regulate different pathways related to inflammation. Further investigation on the production of stable components in a cost-effective way, as well as human studies demonstrating safety and health-promoting properties, since scarce information has been reported until now, in the context of modulating the immune system are needed.
Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
(MDPI, 2024-12-15) Domínguez Martín, Helena; Gavilán Dorronzoro, Elena; Parrado, Celia; Burguillos García, Miguel Ángel; Daza Navarro, María Paula; Ruano Caballero, Diego; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Junta de Andalucía; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; Unión Europea NextGeneration; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla. CTS257: Envejecimiento y Neurodegeneración.
first_pagesettingsOrder Article Reprints Open AccessArticle Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines by Helena Domínguez-Martín 1,2,†,Elena Gavilán 1,2,†ORCID,Celia Parrado 1,Miguel A. Burguillos 1,2ORCID,Paula Daza 3 andDiego Ruano 1,2,* 1 Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla (US), 41012 Sevilla, Spain 2 Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla (US), 41013 Sevilla, Spain 3 Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla (US), 41012 Sevilla, Spain * Author to whom correspondence should be addressed. † These authors contributed equally to this work and share first authorship. Cells 2024, 13(24), 2069; https://doi.org/10.3390/cells13242069 Submission received: 4 November 2024 / Revised: 10 December 2024 / Accepted: 13 December 2024 / Published: 15 December 2024 (This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a. Proteotoxic stress, induced by proteasome inhibition, produced early apoptosis in BV2 cells, due in part to a predominant activation of the PERK-CHOP pathway. In contrast, N2a cells showcased greater resistance and robust induction of the IRE1α-sXbp1 arm of the UPR. We also demonstrated that proteotoxic stress activated autophagy in both cell lines but with different kinetics and cellular functions. In N2a cells, autophagy restored cellular proteostasis, while in BV2 cells, it participated in regulating phagocytosis. Finally, proteotoxic stress predominantly activated the mTORC2-AKT-FOXO1-β-catenin pathway in BV2 cells, while N2a cells preferentially induced the PDK1-AKT-FOXO3 axis. Collectively, our findings suggest that proteotoxic stress triggers cell-specific responses in microglia and neurons, with different physiological outcomes.
Selective, Rapid and Simultaneous Determination of Ergosterol and Ergocalciferol in Mushrooms by UPLC-Q-TOF-MS
(Elsevier, 2021) Román Hidalgo, Cristina; Villar Navarro, Mercedes; Falcón García, Gonzalo Enrique; Carbonero Aguilar, M. P.; Bautista Palomas, Juan Dionisio; Bello López, Miguel Ángel; Martín Valero, María Jesús; Fernández Torres, Rut; Universidad de Sevilla. Departamento de Química Analítica; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Ministerio de Economía y Competitividad (MINECO). España; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
An ultra-performance liquid chromatography coupled to atmospheric pressure chemical ionization-quadrupole time-of-flight mass spectrometry method has been optimized and validated for the determination of ergosterol and ergocalciferol in mushroom samples, using cholecalciferol as surrogate standard. The separation was carried out with a Synergi Hydro-RP column (100 mm x 3.00 mm i.d, 2.5 μm particle size), (Phenomenex, CA, USA) column, thermostated at 35 °C. The mobile phase was 0.1 % formic acid aqueous solution and methanol in gradient elution mode and it was achieved in 5 min approximately. Detection was achieved by atmospheric pressure chemical ionization in positive mode and quadrupole time-of-flight mass spectrometry. Desolvation and interface temperatures were set at 500 °C and 150 °C, respectively. The recoveries obtained were within 92–105 % for ergosterol, 77–81 % for ergocalciferol and 83–87 % for cholecalciferol. Method limits of detection were 0.4 and 0.5 μg g−1 for ergosterol and ergocalciferol, respectively, and method limits of quantitation were 1.2 and 1.3 μg g−1 for ergosterol and ergocalciferol, respectively. A rapid and simple extraction procedure using small amount of sample (100 mg) with hexane was optimized and the method was applied to the determination of ergosterol and ergocalciferol in white button mushrooms (Agaricus bisporus var. bisporus) exposed to UV irradiation. Results were compared to the corresponding non-irradiated mushrooms.
HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-01-18) Pérez Castro, Miguel Ángel; Hernández Rasco, Francisco; Alonso Bellido, Isabel María; Letrán Sánchez, María S.; Pérez Villegas, Eva María; Vitallé, Joana; Real Navarrete, Luis Miguel; Ruiz Mateos, Ezequiel; Venero Recio, José Luis; Tabares, Lucía; Carrión, Ángel Manuel; Armengol, José Ángel; Bachiller, Sara; Ruiz Laza, Rocío; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España
The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function.
Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of its effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases
(Elsevier, 2019-05) Martínez de Pablos, Rocío; Espinosa Oliva, Ana María; Hornedo Ortega, Ruth; Cano Rodríguez, María Mercedes; Argüelles Castilla, Sandro; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Economía y Competitividad (MINECO). España; European Union (UE)
Aging is a complex process. It is considered a risk factor for several diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes, most of which have an oxidative and inflammatory base. Given that life expectancy is increasing, there is a present interest in the search for anti-aging strategies that allow a healthy aging. Interestingly, in Spain, where the Mediterranean Diet (MD) is the reference food pattern, life expectancy will have the highest average by 2040. This diet is characterized, among other items, by virgin olive oil intake, which contains between 50–200 mg/kg of hydroxytyrosol, a major polyphenolic component of olive oil. Hydroxytyrosol is formed by the hydrolysis of oleuropein during the maturing of olives, storage of olive oil, and preparation of table olives. It is a yield of oleuropein by microbiota action in the organism after virgin olive oil consumption. The daily intake in context of the MD is estimated to be around 0.15 and 30 mg/day. In the last few years, hydroxytyrosol has received increasing attention due to its multiple pharmacological activities, such as antioxidant, anti-inflammatory and pro-apoptotic activities. It has also been the focus of extensive research regarding its bioactivity. In this sense, hydroxytyrosol is under consideration for the development of new anti-aging strategies. In this review we will summarize the potential anti-aging effects of hydroxytyrosol and its protective role in several age-related diseases.
Targeting pro-senescence mitogen activated protein kinase (Mapk) enzymes with bioactive natural compounds
(Elsevier, 2019-09) Cano Rodríguez, María Mercedes; Guerrero Castilla, Angélica; Nabavi, Seyed Mohammad; Ayala Gómez, Antonio; Argüelles Castilla, Sandro; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla
Aging is a multifactorial universal process characterized by a gradual decrease in physiological and biochemical functions. Given that life expectancy is on the rise, a better understanding of molecular mechanisms of the aging process is necessary in order to develop anti-aging interventions. Uncontrolled cellular senescence promotes persistent inflammation and accelerates the aging process by decreasing tissue renewal, repair and regeneration. Senescence of immune cells, immunesenescence, is another hallmark of aging. Targeting pro-senescent enzymes increases survival and therefore the lifespan. Although the upregulation of Mitogen Activated Protein Kinases (MAPK) enzymes in aging is still controversial, increasing evidence shows that dysregulation of those enzymes are associated with biological processes that contribute to aging such as irreversible senescence. In this manuscript components of the MAPK pathway will be summarized, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38, as well as natural flavonoids, phenolic and diterpenoids with anti-senescence activity that shows positive effects on longevity and MAPK inhibition. Although more studies using additional aging models are needed, we suggest that these selected natural bioactive compounds that regulate MAPK enzymes and reduce senescent cells can be potentially used to improve longevity and prevent/treat age-related diseases.
Adipose-derived stem cells decreased microglia activation and protected dopaminergic loss in rat lipopolysaccharide model
(John Wiley & Sons, 2019-08) Muñoz Pinto, Mario Faustino; Argüelles Castilla, Sandro; Medina, Rafael; Cano Rodríguez, María Mercedes; Ayala Gómez, Antonio; Universidad de Sevilla. Departamento de Fisiología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Junta de Andalucía
Adult stem cell therapy is being used extensively to rejuvenate damaged tissue. One important tissue source to obtain these cells is adipose, which contains cells called adipose-derived stem cells (ADSCs). These cells have a great therapeutic potential not only for their multipotent properties as well as for immunomodulatory effects on the immune system. Parkinson's disease is characterized as neurodegenerative disorder which etiology is undoubtedly related to neuroinflammation process. The properties of ADSCs can be used as a new tool in stem cells therapy to treat neurodegenerative disorders. However, their efficacies are still controversial. Some authors have reported neuroprotection effects, while others did not find differences or stem cells increased the damage. Our previous study showed that ADSCs can survive long time after transplantation, suggesting us some biological effects could need more time to be repaired. In this study, we assessed the neuroprotection 6 months after transplantation. Our results suggest ADSCs can protect the dopaminergic loss after lipopolysaccharide (LPS) injection both reducing the microglia activation and differentiating into dopaminergic cells.
Water-soluble rice bran enzymatic extract attenuates dyslipidemia, hypertension and insulin resistance in obese Zucker rats
(Springer, 2013) Justo Gómez, María Luisa; Rodríguez Rodríguez, Rosalía; Claro Cala, Carmen María; Álvarez de Sotomayor Paz, María; Parrado Rubio, Juan; Herrera González, María Dolores; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Instituto de Biomedicina de Sevilla (IBIS); Gobierno de España; Ministerio de Ciencia Y Tecnología (MCYT). España; Universidad de Sevilla. CTS1074: InmunoNutrición e InmunoMetabolismo; Universidad de Sevilla. CTS178: Farmacología Cardiovascular; Universidad de Sevilla. AGR212: Tecnología y Aplicación de Enzimas
Background and purpose: Rice bran enzymatic extract (RBEE) has advantages compared to the original rice bran or its oils including water solubility, lack of rancidity and increased content in high nutritional proteins and nutraceutical compounds, particularly phytosterols, γ-oryzanol and tocols. Our aim was to determine the beneficial effects of RBEE in the pathogenesis of metabolic syndrome in obese Zucker rats. Methods: Obese Zucker rats and their lean littermates were fed a 1 and 5 % RBEE-supplemented diet (O1, O5, L1 and L5). Simultaneously, obese and lean Zucker rats, fed a standard diet, were used as controls (OC and LC, respectively). Body weight, food and water intake, and systolic blood pressure were weekly evaluated. After treatment, biochemical assays of serum glucose, insulin, triglycerides (TG), total cholesterol (TC), non-esterified fatty acids (NEFA), adiponectin and nitrates (NO(x)) were determined. Results: RBEE treatment reduced circulating levels of TG and TC, whereas increased HDL-cholesterol without altering NEFA values in obese rats. The extract also induced a significant dose-dependent reduction of hypertension linked to obesity. RBEE of 5 % improved insulin resistance and subsequently reduced HOMA-IR index without altering serum glucose levels. Obese animals treated with RBEE showed partial restoration of adiponectin levels and a significant attenuation of pro-inflammatory values of NO(x). Conclusion: These findings evidence the nutraceutical properties of RBEE against the pathogenesis of metabolic syndrome by attenuating dyslipidemia, hypertension and insulin resistance as well as by restoring hypoadiponectinemia associated to obesity.
Effects on goal directed behavior and habit in two animal models of Parkinson’s disease
(Elsevier, 2020) Márquez, Inmaculada; Muñoz Pinto, Mario Faustino; Ayala Gómez, Antonio; López García, Juan Carlos; Vargas Romero, Juan Pedro; Díaz Argandoña, Estrella; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Psicología Experimental; Ministerio de Economia, Industria y Competitividad (MINECO). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Instrumental conditioning involves two different processes: Goal-directed behavior, characterized by its dependence on the causal relationship between action and outcome and the sensitivity of actions to changes in the value of the outcome; and habits, characterized for its persistence and insensitivity to changes after conditioning. It is known that the dopaminergic system is involved in both kind of learning. The present experiments analyzed two animal models of Parkinson's disease. The 6-OHDA model causes selective damage of the catecholaminergic neurons, specifically affecting the dopaminergic neurons in nigro-striatal system. This model simulates degenerative process symptomatology of Parkinson's disease. On the other hand, the LPS model generates an inflammation process in the infusion area. This model simulates the early symptoms of this disorder, including neuroinflammation and microglia activation. In order to validate both parkinsonian models, we studied if 6-OHDA and LPS models cause the same behavioral effects. The results showed that the 6-OHDA model interfered with the process involved in habit formation. In contrast, animals treated with LPS showed a goal-directed learning deficit. Differences between these models could be due to the different effects on Substantia Nigra neurons. 6-OHDA model might disrupt the nigrostriatal pathway, while LPS could interfere on efferences and afferences to Substantia Nigra.
Oxidative stress and renal status of farmers exposed to pesticides in Seville (Spain)
(Elsevier, 2024-11-15) Casanova, Alfredo G.; Hinojosa, María G.; Chamorro López, Carmen; Martín Reina, José; Aguilera Velázquez, Raúl; Bautista Palomas, Juan Dionisio; Moreno Navarro, Isabel María; Universidad de Sevilla. Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Fundación Prevent. España; Junta de Andalucía
The aim was to determine whether indirect exposure to pesticides, specifically a copper-based fungicide, induces alterations in oxidative stress and subclinical and early kidney biomarkers in male farmers tasked with olives harvesting. Furthermore, we tested whether sex influences the susceptibility to pesticide-induced renal damage by comparing the results of this study with those obtained previously. The study focused on olive farmers (n = 41) indirectly exposed to copper-based fungicides in Estepa (Sevilla, Spain), comparing them with a control group (n = 32). Blood samples were analyzed for metal concentrations (Cu, Mn, Se, and Zn), lipid peroxidation (MDA), protein oxidation (carbonyl groups), and antioxidant enzyme activities (SOD and CAT) while urine samples were assessed for biomarkers of early kidney damage (NGAL, KIM-1, transferrin, IGFBP7, TIMP-2). Although no significant, a tendency to increase lipid and protein oxidation was observed, together with the activity of antioxidant enzymes SOD and CAT, and a decrease in total antioxidants. Moreover, an increase in urinary NGAL and IGFBP7 among pesticide-exposed farmers suggests potential underdiagnosis of kidney damage. Farmers exhibit a subtle tendency to oxidative stress compared to control, while metal levels are significantly lower in farmers, suggesting potential compensatory responses. Furthermore, biomarkers for early kidney damage are elevated, emphasizing their vulnerability in both sexes. These findings highlight the need for investigations of renal health in pesticide-exposed farmers for preventative measures and regular health monitoring.
A New Biostimulant Derived from Soybean by-products Enhances Plant Tolerance to Abiotic Stress Triggered by Ozone
(Springer Nature, 2024) Orts, A.; Navarro Torre, Salvadora; Macías Benitez, S.; Orts Gómez, José María; Naranjo Fernández, Emilia; Castaño Navarro, Angélica; Parrado Rubio, Juan; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Microbiología y Parasitología; Ministerio de Ciencia e Innovación (MICIN). España
Background: Tropospheric ozone is an air pollutant that causes negative effects on vegetation, leading to significant losses in crop productivity. It is generated by chemical reactions in the presence of sunlight between primary pollutants resulting from human activity, such as nitrogen oxides and volatile organic compounds. Due to the constantly increasing emission of ozone precursors, together with the influence of a warming climate on ozone levels, crop losses may be aggravated in the future. Therefore, the search for solutions to mitigate these losses becomes a priority. Ozone-induced abiotic stress is mainly due to reactive oxygen species generated by the spontaneous decomposition of ozone once it reaches the apoplast. In this regard, compounds with antioxidant activity offer a viable option to alleviate ozone-induced damage. Using enzymatic technology, we have developed a process that enables the production of an extract with biostimulant properties from okara, an industrial soybean byproduct. The biostimulant, named as OEE (Okara Enzymatic Extract), is water-soluble and is enriched in bioactive compounds present in okara, such as isoflavones. Additionally, it contains a significant fraction of protein hydrolysates contributing to its functional effect. Given its antioxidant capacity, we aimed to investigate whether OEE could alleviate ozone-induced damage in plants. For that, pepper plants (Capsicum annuum) exposed to ozone were treated with a foliar application of OEE. Results: OEE mitigated ozone-induced damage, as evidenced by the net photosynthetic rate, electron transport rate, effective quantum yield of PSII, and delayed fluorescence. This protection was confirmed by the level of expression of genes associated with photosystem II. The beneficial effect was primarily due to its antioxidant activity, as evidenced by the lipid peroxidation rate measured through malondialdehyde content. Additionally, OEE triggered a mild oxidative response, indicated by increased activities of antioxidant enzymes in leaves (catalase, superoxide dismutase, and guaiacol peroxidase) and the oxidative stress index, providing further protection against ozone-induced stress. Conclusions: The present results support that OEE protects plants from ozone exposure. Taking into consideration that the promotion of plant resistance against abiotic damage is an important goal of biostimulants, we assume that its use as a new biostimulant could be considered.
In Vivo PET Detection of Lung Micrometastasis in Mice by Targeting Endothelial VCAM-1 Using a Dual-Contrast PET/MRI Probe
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-06-28) Melemenidis, Stavros; Knight, James C.; Kersemans, Veerle; Perez-Balderas, Francisco; Zarghami, Niloufar; Sarmiento Soto, Manuel; Sibson, Nicola R.; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Cancer Research UK (CRUK); Comprehensive Cancer Imaging Centre (CCIC)
Current clinical diagnostic imaging methods for lung metastases are sensitive only to large tumours (1–2 mm cross-sectional diameter), and early detection can dramatically improve treatment. We have previously demonstrated that an antibody-targeted MRI contrast agent based on microparticles of iron oxide (MPIO; 1 μm diameter) enables the imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Using a mouse model of lung metastasis, upregulation of endothelial VCAM-1 expression was demonstrated in micrometastasis-associated vessels but not in normal lung tissue, and binding of VCAM-MPIO to these vessels was evident histologically. Owing to the lack of proton MRI signals in the lungs, we modified the VCAM-MPIO to include zirconium-89 (89Zr, t1/2 = 78.4 h) in order to allow the in vivo detection of lung metastases by positron emission tomography (PET). Using this new agent (89Zr-DFO-VCAM-MPIO), it was possible to detect the presence of micrometastases within the lung in vivo from ca. 140 μm in diameter. Histological analysis combined with autoradiography confirmed the specific binding of the agent to the VCAM-1 expressing vasculature at the sites of pulmonary micrometastases. By retaining the original VCAM-MPIO as the basis for this new molecular contrast agent, we have created a dual-modality (PET/MRI) agent for the concurrent detection of lung and brain micrometastases.
Direct Interaction between Marine Cyanobacteria Mediated by Nanotubes
(American Association for the Advancement of Science, 2024) Angulo Cánovas, Elisa; Bartual, Ana; López Igual, Rocío; Luque, Ignacio; Radzinski, Nikolai P.; Shilova, Irina; Anjur Dietrich, Maya; García Jurado, Gema; Úbeda, Bárbara; González Reyes, José Antonio; Muñoz Marín, María del Carmen; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Gobierno de España; Ministerio de Ciencia e Innovación (MICIN). España; Simons Foundation Life Sciences; SCOPE Award; Simons Postdoctoral Fellowship in Marine Microbial Ecology; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Frontier Projects
Microbial associations and interactions drive and regulate nutrient fluxes in the ocean. However, physical contact between cells of marine cyanobacteria has not been studied thus far. Here, we show a mechanism of direct interaction between the marine cyanobacteria Prochlorococcus and Synechococcus, the intercellular membrane nanotubes. We present evidence of inter-and intra-genus exchange of cytoplasmic material between neighboring and distant cells of cyanobacteria mediated by nanotubes. We visualized and measured these structures in xenic and axenic cultures and in natural samples. We show that nanotubes are produced between living cells, suggesting that this is a relevant system of exchange material in vivo. The discovery of nanotubes acting as exchange bridges in the most abundant photosynthetic organisms in the ocean may have important implications for their interactions with other organisms and their population dynamics.
Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response
(Springer Nature, 2024-08-27) García Revilla, Juan; Ruiz Laza, Rocío; Espinosa Oliva, Ana María; Santiago Pavón, Martiniano; García Domínguez, Irene; Camprubí Ferrer, Lluís; Bachiller Sánchez Arévalo, Sara; Deierborg, Tomas; Joseph, Bertrand; Martínez de Pablos, Rocío; Rodríguez Gómez, José Antonio; Venero Recio, José Luis; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
Parkinson’s Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc). Apoptosis is thought to play a critical role in the progression of PD, and thus understanding the effects of antiapoptotic strategies is crucial for developing potential therapies. In this study, we developed a unique genetic model to selectively delete Casp3, the gene encoding the apoptotic protein caspase-3, in dopaminergic neurons (TH-C3KO) and investigated its effects in response to a subacute regime of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, which is known to trigger apoptotic loss of SNpc dopaminergic neurons. We found that Casp3 deletion did not protect the dopaminergic system in the long term. Instead, we observed a switch in the cell death pathway from apoptosis in wild-type mice to necrosis in TH-C3KO mice. Notably, we did not find any evidence of necroptosis in our model or in in vitro experiments using primary dopaminergic cultures exposed to 1-methyl-4-phenylpyridinium in the presence of pan-caspase/caspase-8 inhibitors. Furthermore, we detected an exacerbated microglial response in the ventral mesencephalon of TH-C3KO mice in response to MPTP, which mimicked the microglia neurodegenerative phenotype (MGnD). Under these conditions, it was evident the presence of numerous microglial phagocytic cups wrapping around apparently viable dopaminergic cell bodies that were inherently associated with galectin-3 expression. We provide evidence that microglia exhibit phagocytic activity towards both dead and stressed viable dopaminergic neurons through a galectin-3-dependent mechanism. Overall, our findings suggest that inhibiting apoptosis is not a beneficial strategy for treating PD. Instead, targeting galectin-3 and modulating microglial response may be more promising approaches for slowing PD progression.
Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality
(Nature, 2024-07-24) Mora Romero, Bella; Capelo Carrasco, Nicolás; Pérez Moreno, Juan José; Álvarez Vergara, María Isabel; Trujillo Estrada, Laura Isabel; Romero Molina, Carmen; Martínez Márquez, Emilio; Morano Catalan, Noelia; Vizuete Chacón, María Luisa; López Barneo, José; Nieto González, José Luis; García-Junco Clemente, Pablo; Vitorica Ferrández, Francisco Javier; Gutiérrez, Antonia; Macías, David; Rosales Nieves, Alicia E.; Pascual Bravo, Alberto; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.

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