Person:
López Torres, Bernardo

First Name

Bernardo

Last Name

López Torres

URI

https://hdl.handle.net/20.500.14352/80418

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Veterinaria

Department

Farmacología y Toxicología

Identifiers

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Now showing 1 - 10 of 12

Pyrethroid insecticide lambda-cyhalothrin induces hepatic cytochrome P450 enzymes, oxidative stress and apoptosis in rats
(Science of the Total Environment, 2018) Martínez Caballero, María Aranzazu; Ares Lombán, Irma; Rodríguez, Jose Luis; Martínez Caballero, Marta; Roura-Martínez, David; Castellano Santos, Víctor Jesús; López Torres, Bernardo; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón
This study aimed to examine in rats the effects of the Type II pyrethroid lambda-cyhalothrin on hepatic microsomal cytochrome P450 (CYP) isoform activities, oxidative stress markers, gene expression of proinflammatory, oxidative stress and apoptosis mediators, and CYP isoform gene expression and metabolism phase I enzyme PCR array analysis. Lambda-cyhalothrin, at oral doses of 1, 2, 4 and 8 mg/kg bw for 6 days, increased, in a dose-dependent manner, hepatic activities of ethoxyresorufin O-deethylase (CYP1A1), methoxyresorufin O-demethylase (CYP1A2), pentoxyresorufin O-depentylase (CYP2B1/2), testosterone 7α- (CYP2A1), 16β-(CYP2B1), and 6β-hydroxylase (CYP3A1/2), and lauric acid 11- and 12-hydroxylase (CYP4A1/2). Similarly, lambda-cyhalothrin (4 and 8 mg/kg bw, for 6 days), in a dose-dependent manner, increased significantly hepatic CYP1A1, 1A2, 2A1, 2B1, 2B2, 2E1, 3A1, 3A2 and 4A1 mRNA levels and IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions. PCR array analysis showed from 84 genes examined (P b 0.05; fold change N 1.5), changes in mRNA levels in 18 genes: 13 up-regulated and 5 down-regulated. A greater fold change reversion than 3-fold was observed on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes. Ingenuity Pathway Analysis (IPA) groups the expressed genes into biological mechanisms that aremainly related to drug metabolism. In the top canonical pathways, Oxidative ethanol degradation III together with Fatty Acid α-oxidation may be significant pathways for lambda-cyhalothrin. Our results may provide further understanding of molecular aspects involved in lambda-cyhalothrin-induced liver injury.
Brown marine algae Gongolaria baccata extract protects Caco-2 cells from oxidative stress induced by tert-butyl hydroperoxide
(Food and Chemical Toxicology, 2021) Martínez Caballero, María Aranzazu; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Maximiliano Guerra, Jorge Enrique; Rodriguez, J.L; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Peteiro, C.; Rubiño, S; Hortos, M
Gongolaria baccata (S.G. Gmelin) is marine brown seaweed mainly found on the coasts of the Baltic Sea south to the Mediterranean Sea, Canary Islands, Mauritania and Western Sahara. Herein, we report the cell viability and protective effects attributed to molecular mechanisms underlying antioxidant response to survive oxidative stress injuries. Caco-2 cells were submitted to oxidative stress by treatment with tert-butylhydroperoxide (tert-BOOH). The extract prevented cell damage and enhanced activity of antioxidant defenses (NQO1 and GST activities and GSH levels) reduced by treatment with tert-BOOH. The increases of MDA levels, the amount of intracellular ROS and caspase 3/7 activity induced by tert-BOOH were prevented when cells were treated with the G. baccata extract. Moreover, G. baccata extract caused up-regulation of GSTM2, Nrf2, and AKT1 gene expressions, as well as G. baccata extract reduced significantly Bax, BNIP3, APAF1, ERK1, JNK1, MAPK1, P38, P53, NFκB1, TNFα, IL-6, IL-1β and HO-1 gene expressions related to apoptosis, proinflammation and oxidative stress induced by tert-BOOH. These results suggest that G.baccata extract protected the cells against oxidative damage and inflammation; protective effects that could be linked to their bioactive constituents. Hence, this brown seaweed G. baccata extract could be used for the development of functional foods and/or nutraceuticals.
Toxicologic evidence of developmental neurotoxicity of type II pyrethroids cyfluthrin and alpha-cypermethrin in SH-SY5Y cells
(Food and Chemical Toxicology, 2020) Martínez Caballero, María Aranzazu; López Torres, Bernardo; Rodriguez, J.L.; Martínez Caballero, Marta; Maximiliano Guerra, Jorge Enrique; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Ares Lombán, Irma
We attempted to identify cellular mechanisms as an approach to screen chemicals for the potential to cause developmental neurotoxicity. We examine, in SH-SY5Y cells, whether apoptosis and oxidative stress via reactive oxygen species (ROS) generation, caspase 3/7 activation, gene expression (Bax, Bcl-2, Casp-3, BNIP3, p53 and Nrf2) alterations and necrosis by release of cytosolic adenylate kinase (AK), underlie direct effects of the pyrethroids cyfluthrin and alpha-cypermethrin. We also determined transcriptional alterations of genes (TUBB3, NEFL, NEFH, GAP43, CAMK2A, CAMK2B, WNT3A, WNT5A, WNT7A, SYN1 and PIK3C3) linked to neuronal development and maturation. Our results indicate that cyfluthrin and alpha-cypermethrin have the ability to elicit concentration-dependent increases in AK release, cellular ROS production, caspase 3/7 activity and gene expression of apoptosis and oxidative stress mediators. Both pyrethroids caused changes in mRNA expression of key target genes linked to neuronal development. These changes might reflect in a subsequent neuronal dysfunction. Our study shows that SH-SY5Y cell line is a valuable in vitro model for predicting development neurotoxicity. Our research provides evidence that cyfluthrin and alpha-cypermethrin have the potential to act as developmental neurotoxic compounds. Additional information is needed to improve the utility of this in vitro model and/or better understand its predictive capability.
Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways
(Environment International, 2020) Martínez Caballero, María Aranzazu; Rodríguez, José Luis; López Torres, Bernardo; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Maximiliano Guerra, Jorge Enrique; Anadón Navarro, Arturo Ramón; Ares Lombán, Irma
Glyphosate-containing herbicides are the most used agrochemicals in the world. Their indiscriminate application raises some concerns regarding the possible health and environmental hazards. In this study, we investigated in human neuroblastoma cell line SH-SY5Y if oxidative stress, altered neurodevelopment and cell death pathways are involved in response to glyphosate and its metabolite aminomethylphosphonic acid (AMPA) exposures. MTT and LDH assays were carried out to assess the glyphosate and AMPA cytotoxicity. Lipid peroxides measured as malondialdehyde (MDA), nitric oxide (NO) and reactive oxygen species (ROS) production, and caspase-Glo 3/7 activity were evaluated. The neuroprotective role of melatonin (MEL), Trolox, N-acetylcysteine (NAC) and Sylibin against glyphosate- and AMPA-induced oxidative stress was examined. Glyphosate and AMPA effects on neuronal development related gene transcriptions, and gene expression profiling of cell death pathways by Real-Time PCR array were also investigated. Glyphosate (5 mM) and AMPA (10 mM) induced a significant increase in MDA levels, NO and ROS production and caspase 3/7 activity. Glyphosate exposure induced up-regulation of Wnt3a, Wnt5a, Wnt7a, CAMK2A, CAMK2B and down-regulation of GAP43 and TUBB3 mRNA expression involved in normal neural cell development. In relation to gene expression profiling of cell death pathways, of the 84 genes examined in cells a greater than 2-fold change was observed for APAF1, BAX, BCL2, CASP3, CASP7, CASP9, SYCP2, TNF, TP53, CTSB, NFκB1, PIK3C3, SNCA, SQSTMT, HSPBAP1 and KCNIPI mRNA expression for glyphosate and AMPA exposures. These gene expression data can help to define neurotoxic mechanisms of glyphosate and AMPA. Our results demonstrated that glyphosate and AMPA induced cytotoxic effects on neuronal development, oxidative stress and cell death via apoptotic, autophagy and necrotic pathways and confirmed that glyphosate environmental exposure becomes a concern. This study demonstrates that SH-SY5Y cell line could be considered an in vitro system for pesticide screening.
Oxidative stress, the blood–brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants
(Acta Pharmaceutica Sinica B, 2023) Feng, Jin; Zheng, Youle; Guo, Mingyue; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Martínez Larrañaga, María Rosa; Wang, Xu; Anadón Navarro, Arturo Ramón; Martínez Caballero, María Aranzazu
In recent years, growing awareness of the role of oxidative stress in brain health has prompted antioxidants, especially dietary antioxidants, to receive growing attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied dietary antioxidants include active substances such as vitamins, carotenoids, flavonoids and polyphenols. Dietary antioxidants are found in usually consumed foods such as fresh fruits, vegetables, nuts and oils and are gaining popularity due to recently growing awareness of their potential for preventive and protective agents against NDs, as well as their abundant natural sources, generally non-toxic nature, and ease of long-term consumption. This review article examines the role of oxidative stress in the development of NDs, explores the ‘two-sidedness’ of the blood–brain barrier (BBB) as a protective barrier to the nervous system and an impeding barrier to the use of antioxidants as drug medicinal products and/or dietary antioxidants supplements for prevention and therapy and reviews the BBB permeability of common dietary antioxidant suplements and their potential efficacy in the prevention and treatment of NDs. Finally, current challenges and future directions for the prevention and treatment of NDs using dietary antioxidants are discussed, and useful information on the prevention and treatment of NDs is provided.
Antimicrobial sensitisers: Gatekeepers to avoid the development of multidrug-resistant bacteria
(Journal of Controlled Release, 2024) Wang, Hanfei; Yang, Yingying; Wang, Simeng; Badawy, Sara; Wang, Xu; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Martínez Caballero, María Aranzazu; De Smedt, Stefaan
The resistance of multidrug-resistant bacteria to existing antibiotics forces the continued development of new antibiotics and antibacterial agents, but the high costs and long timeframe involved in the development of new agents renders the hope that existing antibiotics may again play a part. The “antibiotic adjuvant” is an indirect antibacterial strategy, but its vague concept has, in the past, limited the development speed of related drugs. In this review article, we put forward an accurate concept of a “non-self-antimicrobial sensitisers (NSAS)”, to distinguish it from an “antibiotic adjuvant”, and then discuss several scientific methods to restore bacterial sensitivity to antibiotics, and the sources and action mechanism of existing NSAS, in order to guide the development and further research of NSAS.
Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells
(Metabolites, 2023) Zhao, Yongxia; Ye, Xiaochun; Xiong, Zhifeng; Ihsan, Awais; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Wang, Xu; Martínez Caballero, María Aranzazu
Cancer is a huge challenge for people worldwide. High reactive oxygen species (ROS) levels are a recognized hallmark of cancer and an important aspect of cancer treatment research. Abnormally elevated ROS levels are often attributable to alterations in cellular metabolic activities and increased oxidative stress, which affects both the development and maintenance of cancer. Moderately high levels of ROS are beneficial to maintain tumor cell genesis and development, while toxic levels of ROS have been shown to be an important force in destroying cancer cells. ROS has become an important anticancer target based on the proapoptotic effect of toxic levels of ROS. Therefore, this review summarizes the role of increased ROS in DNA damage and the apoptosis of cancer cells caused by changes in cancer cell metabolism, as well as various anticancer therapies targeting ROS generation, in order to provide references for cancer therapies based on ROS generation.
Protective effects of culture extracts (CB08035-SCA and CB08035-SYP) from Marinobacter hydrocarbonoclasticus (strain CB08035) against oxidant-induced stress in human colon carcinoma Caco-2 cells
(Food and Chemical Toxicology, 2020) Martínez Caballero, María Aranzazu; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Rodríguez, José Luis; Maximiliano Guerra, Jorge Enrique; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Rosa, José Manuel de la; Cueto, Mercedes
The present study investigated the effect of culture extracts (CB08035-SCA and CB08035-SYP) from Marinobacter hydrocarbonoclasticus (strain CB08035) on cell viability and the potential protective effects attributed to molecular mechanisms underlying antioxidant response to survive oxidative stress injuries. Caco-2 cells were submitted to oxidative stress by treatment with tert-butyl hydroperoxide (t-BOOH). Both extracts prevented cell damage and enhanced activity of antioxidant defenses (NQO1 and GST activities and GSH levels) reduced by treatment with t-BOOH. Increased ROS and caspase 3/7 activity induced by t-BOOH were dose-dependently prevented when cells were treated with the extracts. CB08035-SCA caused up-regulation of Nrf2, AKT1 and Bcl-2 gene expressions. Moreover, CB08035-SCA and CB08035-SYP treatments reduced significantly Bax, BNIP3, APAF1, ERK1, JNK1, MAPK1, NFκB1, TNFα, IL-6, IL-1β and HO-1 gene expressions of apoptosis, proinflammation and oxidative stress induced by t-BOOH. CB08035-SCA and CB08035-SYP CPE extracts confer a significant protection against oxidative insults to cells. Our results show that culture extracts CB08035-SCA and CB08035-SYP from M. hydrocarbonoclasticus (strain CB08035) appeared to have antioxidant potential, based on their ability to protect antioxidant enzymes and mRNA gene expressions linked to apoptosis/oxidative pathways. These results suggest that culture extracts CB08035-SCA and CB08035-SYP can be a potential ingredient in the pharmaceutical and cosmeceutical industries.
Dopaminergic and serotoninergic systems as preferential targets of the pyrethroid tefluthrin exposure in the rat brain
(Environmental Research, 2024) Maximiliano Guerra, Jorge Enrique; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Martínez Caballero, María Aranzazu
The monoaminergic systems dopamine (DA) and serotonin (5-HT) play important roles in neuromodulation, such as motor control, cognitive, affective, and neuroendocrine functions. In the present research study, we addressed the hypothesis that exposure to Type I pyrethroid tefluthrin may specifically target the dopaminergic and serotoninergic systems. Tefluthrin could modify brain monoamine neurotransmitters, DA and 5-HT levels as well as dopaminergic and serotoninergic signaling pathways. Adult male Wistar rats were treated with tefluthrin [2.2, 4.4 and 5.5 mg/kg bw, equivalent to 1/10, 1/5 and 1/4 of the acute oral rat lethal dose 50 (LD50) value] by oral gavage, six days. After last dose of tefluthrin, DA and 5-HT and metabolites levels were determined in brain regions (striatum, hippocampus, prefrontal cortex and hypothalamus). Tefluthrin induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in prefrontal cortex tissue. Here, we studied that in vivo exposure to tefluthrin may alter DA and 5-HT neurotransmission in prefrontal cortex. Transcripts related to (i) dopaminergic [dopamine transporter 1 (Dat1), tyrosine hydroxylase (TH), dopamine receptors (Drd1, Drd2)], (ii) serotoninergic [serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2), serotonin receptors (5-HT1A, 5-HT2A)] and (iii) DA and 5-HT degradation [monoamine oxidases (MAOA, MAOB)] signaling pathways were investigated. Results showed that tefluthrin induced down-regulation of transcripts responsible for the synthesis and action of DA (TH, Drd1, Drd2) and 5-HT (SERT, TPH2). In contrast, tefluthrin treatment induced up-regulation of genes involved in DA transporter (Dat1), 5-HT receptors (5-HT1A, 5-HT2A) and monoamine oxidases (MAOA, MAOB). Given the integral roles of mitochondrial dysfunction and dopaminergic and serotoninergic alterations as hallmarks of neurodegenerative diseases, our data suggest that tefluthrin may be a candidate for pesticides contributing to neurodegenerative disorders pathogenesis by causing damage to the DA and 5-HT systems.
Oxidative stress and related gene expression effects of cyfluthrin in human neuroblastoma SH-SY5Y cells: Protective effect of melatonin
(Environmental Research, 2019) Martínez Caballero, María Aranzazu; Rodríguez, J.L.; López Torres, Bernardo; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Ares Lombán, Irma
This study was designed to assess oxidative stress induction in human neuroblastoma SH-SY5Y cells in response to cyfluthrin exposure. Cell viability MTT assay was carried out to assess cyfluthrin cytotoxicity; IC30 and IC50 values for cyfluthrin were calculated to be 4.81 ± 0.92 μM and 19.39 ± 3.44 μM, respectively. Cyfluthrin induced a significant increase in ROS generation, lipid peroxides measured as malondialdehyde (MDA) and nitric oxide (NO) production and a significant decrease in NQO1 activity. The antioxidant activity of melatonin (MEL), Trolox, N-acetylcysteine (NAC) and Sylibin against cyfluthrin-induced oxidative stress was examined. Cyfluthrin increased significantly gene expressions of apoptosis, proinflammation and oxidative stress (Bax, Bcl-2, Casp-3, BNIP3, AKT1, p53, APAF1, NFκB1, TNFα and Nrf2) mediators. In the most genes, the mRNA levels induced by cyfluthrin were partially reduced by MEL (1 μM). Cyfluthrin effects on gene expression profiling of oxidative stress pathway by Real-Time PCR array analysis showed that of the 84 genes examined, (fold change > 1.5) changes in mRNA levels were detected in 31 genes: 13 upregulated and 18 down-regulated. A fold change>3.0 fold was observed on upregulated CYBB, DUOX1, DUOX2, AOX1, BNIP3, HSPA1A, NOS2, and NQO1 genes. The greater fold change reversion (2.5 fold) by MEL (1 μM) was observed on cyfluthrin-upregulated CYBB, AOX1, BNIP3 and NOS2 genes. These results demonstrated that oxidative stress is a key element in cyfluthrin induced neurotoxicity as well as MEL may play a role in reducing cyfluthrin-induced oxidative stress.