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1.
Toxicol Appl Pharmacol ; 472: 116573, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37269932

RESUMEN

Arsenic is associated with the development of breast cancer. However, the molecular mechanisms of arsenic induction of breast cancer are not fully defined. Interaction with zinc finger (ZnF) motifs in proteins is one of the proposed mechanisms of arsenic toxicity. GATA3 is a transcription factor that regulates the transcription of genes associated with cell proliferation, cell differentiation and the epithelial-mesenchymal transition (EMT) in mammary luminal cells. Given that GATA3 possesses two ZnF motifs essential for the function of this protein and that arsenic could alter the function of GATA3 through interaction with these structural motifs, we evaluated the effect of sodium arsenite (NaAsO2) on GATA3 function and its relevance in the development of arsenic-induced breast cancer. Breast cell lines derived from normal mammary epithelium (MCF-10A), hormone receptor-positive and hormone receptor negative breast cancer cells (T-47D and MDA-MB-453, respectively) were used. We observed a reduction on GATA3 protein levels at non-cytotoxic concentrations of NaAsO2 in MCF-10A and T-47D, but not in MDA-MB-453 cells. This reduction was associated with an increase in cell proliferation and cell migration in MCF-10A, but not in T-47D or MDA-MB-453 cells. The evaluation of cell proliferation and EMT markers indicate that the reduction on GATA3 protein levels by arsenic, disrupts the function of this transcription factor. Our data indicate that GATA3 is a tumor suppressor in the normal mammary epithelium and that arsenic could act as an initiator of breast cancer by disrupting the function of GATA3.


Asunto(s)
Arsénico , Neoplasias de la Mama , Factor de Transcripción GATA3 , Femenino , Humanos , Arsénico/toxicidad , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Células Epiteliales/metabolismo , Factor de Transcripción GATA3/antagonistas & inhibidores , Factor de Transcripción GATA3/metabolismo , Factores de Transcripción
2.
J Neurooncol ; 161(1): 165-174, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36525166

RESUMEN

PURPOSE: Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients. METHODS: We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumor samples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort). RESULTS: In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival. CONCLUSIONS: The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Femenino , Humanos , Masculino , Astrocitoma/patología , Biomarcadores , Neoplasias Encefálicas/patología , ADN/uso terapéutico , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Mutación , Pronóstico , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética
3.
Int J Mol Sci ; 24(11)2023 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-37298413

RESUMEN

Bisphenol A (BPA) is a ubiquitous synthetic compound used as a monomer in the production of polycarbonate plastics and epoxy resins. Even at low doses, BPA has been associated with the molecular progression of diseases such as obesity, metabolic syndrome, and hormone-regulated cancers due to its activity as an endocrine-disrupting chemical (EDC). Consequently, the use of BPA has been regulated worldwide by different health agencies. BPA structural analogs such as bisphenol S and bisphenol F (BPS and BPF) have emerged as industrial alternatives, but their biological activity in the molecular progression of cancer remains unclear. Prostate cancer (PCa) is a hormone-dependent cancer, and the role of BPA structural analogs in PCa progression is still undescribed. In this work, we use an in vitro model to characterize the transcriptomic effect of low-concentration exposure to bisphenol A, S, or F in the two main stages of the disease: androgen dependency (LNCaP) and resistance (PC-3). Our findings demonstrated that the low concentration exposure to each bisphenol induced a differential effect over PCa cell lines, which marks the relevance of studying the effect of EDC compounds through all the stages of the disease.


Asunto(s)
Neoplasias de la Próstata , Transcriptoma , Masculino , Humanos , Compuestos de Bencidrilo/toxicidad , Compuestos de Bencidrilo/análisis , Línea Celular , Neoplasias de la Próstata/genética , Hormonas
4.
Toxicol Appl Pharmacol ; 431: 115738, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34619159

RESUMEN

Millions of people worldwide are exposed to arsenic, a metalloid listed as one of the top chemical pollutants of concern to human health. Epidemiological and experimental studies link arsenic exposure to the development of cancer and other diseases. Several mechanisms have been proposed to explain the effects induced by arsenic. Notably, arsenic and its metabolites interact with proteins by direct binding to individual cysteine residues, cysteine clusters, zinc finger motifs, and RING finger domains. Consequently, arsenic interactions with proteins disrupt the functions of proteins and may lead to the development and progression of diseases. In this review, we focus on current evidence in the literature that implicates the interaction of arsenic with proteins as a mechanism of arsenic toxicity. Data show that arsenic-protein interactions affect multiple cellular processes and alter epigenetic regulation, cause endocrine disruption, inhibit DNA damage repair mechanisms, and deregulate gene expression, among other adverse effects.


Asunto(s)
Intoxicación por Arsénico/etiología , Arsenicales/efectos adversos , Disruptores Endocrinos/efectos adversos , Contaminantes Ambientales/efectos adversos , Proteínas/metabolismo , Animales , Intoxicación por Arsénico/genética , Intoxicación por Arsénico/metabolismo , Arsenicales/metabolismo , Cisteína , Reparación del ADN/efectos de los fármacos , Disruptores Endocrinos/metabolismo , Contaminantes Ambientales/metabolismo , Epigénesis Genética/efectos de los fármacos , Humanos , Unión Proteica , Proteínas/genética , Dominios RING Finger , Medición de Riesgo , Dedos de Zinc
5.
Cell Mol Neurobiol ; 41(6): 1285-1297, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32535722

RESUMEN

Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account for 25% of the risk of developing gliomas. In this study, we assessed the risk of astrocytoma associated with variants in AGT, known by its role in angiogenesis, TP53, a well-known tumor suppressor and the DNA repair gene MGMT in a Mexican population. A case-control study was performed in 49 adult Mexican patients with grade II-IV astrocytoma. Sequencing of exons and untranslated regions of AGT, MGMT, and TP53 from was carried in an Ion Torrent platform. Individuals with Mexican Ancestry from the 1000 Genomes Project were used as controls. Variants found in our cohort were then assessed in a The Cancer Genome Atlas astrocytoma pan-ethnic validation cohort. Variants rs1926723 located in AGT (OR 2.74, 1.40-5.36 95% CI), rs7896488 in MGMT (OR 3.43, 1.17-10.10 95% CI), and rs4968187 in TP53 (OR 2.48, 1.26-4.88 95% CI) were significantly associated with the risk of astrocytoma after multiple-testing correction. This is the first study where the AGT rs1926723 variant, TP53 rs4968187, and MGMT rs7896488 were found to be associated with the risk of developing an astrocytoma.


Asunto(s)
Angiotensinógeno/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Variación Genética/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Adulto , Astrocitoma/epidemiología , Astrocitoma/patología , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/patología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad
6.
J Dual Diagn ; 16(2): 177-190, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31774731

RESUMEN

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.


Asunto(s)
Perfilación de la Expresión Génica , Trastornos del Humor , Corteza Prefrontal/metabolismo , Trastornos Relacionados con Sustancias , Suicidio Completo , Adolescente , Adulto , Alcoholismo/epidemiología , Alcoholismo/genética , Alcoholismo/metabolismo , Autopsia , Causas de Muerte , Comorbilidad , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Diagnóstico Dual (Psiquiatría) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/epidemiología , Trastornos del Humor/genética , Trastornos del Humor/metabolismo , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/metabolismo , Suicidio Completo/estadística & datos numéricos , Adulto Joven
7.
Toxicol Appl Pharmacol ; 380: 114700, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31398423

RESUMEN

Exposure to arsenic is associated with increased risk of developing insulin resistance and type 2 diabetes. The proteases calpain-1 (CAPN1), calpain-2 (CAPN2) and calpain-10 (CAPN10) and their endogenous inhibitor calpastatin (CAST) regulate glucose uptake in skeletal muscle and adipocytes. We investigated whether arsenic disrupts GLUT1 trafficking and function through calpain inhibition, using lymphocytes as a cell model. Lymphocytes from healthy subjects were treated with 0.1 or 1 µM of sodium arsenite for 72 h and challenged with 3.9 or 11.1 mM of glucose. Our results showed that arsenite inhibited GLUT1 trafficking, glucose uptake, and calpain activity in the presence of 11.1 mM of glucose. These correlated with a decrease in the autolytical fragment of 50 kDa of CAPN1 and increased levels of CAST, but there were no changes in CAPN2 and CAPN10. We used a cell-free system to evaluate the effect of arsenite over CAPN1, finding that arsenite induced CAPN1 autolysis. To confirm that calpains are involved in GLUT1 trafficking and glucose uptake in lymphocytes, we generated stable CAPN1 or CAPN10 knockdowns in Jurkat cells using short hairpin RNA (shRNA). CAPN1 knockdown induced glucose uptake, while CAPN10 knockdown diminished glucose uptake, which correlated with a significant reduction of calpain activity after the pulse with 11.1 mM of glucose. These data showed that CAPN10 was responsible for the induction of calpain activity after the challenge with 11.1 mM of glucose and that CAPN1 and CAPN10 regulate glucose uptake in lymphocytes. Altogether, our results suggest that arsenite impairs GLUT1 trafficking and function through calpain dysregulation.


Asunto(s)
Arsénico/toxicidad , Arsenitos/toxicidad , Calpaína/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Linfocitos/efectos de los fármacos , Compuestos de Sodio/toxicidad , Adulto , Línea Celular , Glucosa/metabolismo , Humanos , Linfocitos/metabolismo , Masculino , Transporte de Proteínas , Adulto Joven
8.
Chem Res Toxicol ; 32(7): 1441-1448, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31243981

RESUMEN

The influence of pesticide exposure in alteration of DNA methylation patterns of specific genes is still limited, specifically in natural antisense transcripts (NAT), such as the WRAP53α gene. The aim of this study was to determine the methylation of the WRAP53α gene in mestizo and indigenous populations as well as its relationship with internal (age, sex, and body mass index) and external factors (pesticide exposure and micronutrient intake). A cross-sectional study was conducted including 91 mestizo individuals without occupational exposure to pesticides, 164 mestizo urban sprayers and 189 indigenous persons without occupational exposure to pesticides. Acute pesticide exposure was evaluated by measurement of urinary dialkylphosphate (DAP) concentration by gas chromatograph coupled to a mass spectrometer. Anthropometric characteristics, unhealthy habits, and chronic pesticide exposure were assessed using a structured questionnaire. The frequency of macro- and micronutrient intake was determined using SNUT software. DNA methylation of the WRAP53α gene was determined by pyrosequencing of bisulfite-modified DNA. The mestizo sprayers group had the higher values of %5mC. In addition, this group had the most DAP urinary concentration with respect to the indigenous and reference groups. Bivariate analysis showed an association between %5mC of the WRAP53α gene with micronutrient intake and pesticide exposure in mestizo sprayers, whereas changes in %5mC of the WRAP53α gene was associated with body mass index in the indigenous group. These data suggest that the %5mC of the WRAP53α gene can be influenced by pesticide exposure and ethnicity in the study population, and changes in the WRAP53α gene might cause an important cell process disturbance.


Asunto(s)
Metilación de ADN/efectos de los fármacos , ADN/metabolismo , Chaperonas Moleculares/genética , Organofosfatos/toxicidad , Plaguicidas/toxicidad , Telomerasa/genética , Adulto , Estudios Transversales , ADN/sangre , Femenino , Fumigación/efectos adversos , Humanos , Masculino , México , Exposición Profesional/análisis , Organofosfatos/orina
9.
Immunopharmacol Immunotoxicol ; 41(1): 140-149, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30714433

RESUMEN

Context: Influenza is a severe, life-threatening viral disease that can be prevented by vaccination. However, the anti-influenza human vaccine failed to show the required efficacy both in infants under 5 years old and in the elder population, who are among those with the highest risk of developing severe complications after influenza infection. Therefore, it is of high importance to improve the vaccine efficacy and ensure its safety in these susceptible populations. GK-1, a novel 18-aa peptide adjuvant, has been proved to increase the immunogenicity of the human influenza vaccine in both young and aged mice. Objective: A preclinical study of the toxicity profile of GK-1 following the World Health Organization guidelines to support its use was herein conducted. Material and methods: GK-1 was synthetically produced following Good Manufacturing Practices. The toxicological evaluation of GK-1 peptide was performed in rats after repeated dose-ranging trials by the subcutaneous route. The mutagenic potential of GK-1 was assessed by the micronucleus, chromosomal aberration, and Ames tests, in accordance with OECD Guidelines. Results: GK-1 did not show toxic effects at doses up to 12.5mg/kg, corresponding to 25 times the dose intended for human use. No indications of mutagenic potential were observed. GK-1 after dermal administration was well tolerated locally. Conclusion: The efficacy of GK-1 to improve influenza vaccine protection, along with the absence of toxicity and mutagenicity, as reported herein, support the evaluation of this peptide in a clinical trial as a novel adjuvant for human use.


Asunto(s)
Adyuvantes Inmunológicos/toxicidad , Aberraciones Cromosómicas/efectos de los fármacos , Daño del ADN , Vacunas contra la Influenza/inmunología , Péptidos Cíclicos/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Gripe Humana/prevención & control , Inyecciones Subcutáneas , Masculino , Pruebas de Mutagenicidad , Péptidos Cíclicos/inmunología , Ratas Wistar , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Pruebas de Toxicidad Crónica
10.
Hereditas ; 153: 13, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-28096775

RESUMEN

BACKGROUND: Neonatal lesion in the ventral hippocampus (NLVH) is a validated animal model to study schizophrenia from a neurodevelopmental perspective. This animal model is also used to investigate how neonatal lesions may alter the genetic expression of dopaminergic receptors. The present study compares mRNA expression levels of dopamine receptors (drd2 and drd3) in lymphocytes and brain of NLVH animals at two different age stages: young and adult. METHODS: The NLVH procedure was performed on 20 male Wistar rats at postnatal days 5-7. The mRNA expression levels of drd2 and drd3 genes in lymphocytes, nucleus accumbens, hippocampus and prefrontal cortex were measured and analyzed at postnatal days 45 and 90. The results were compared and contrasted with respective sham groups. RESULTS: In lymphocytes, only in NLVH-adult group we observed drd2 mRNA expression, while drd2 mRNA expression was not observed in the NLVH-juvenile rats; on the other hand, the drd3 mRNA expression did not show significant statistical differences. In hippocampus no differences were observed between drd2 mRNA or drd3 mRNA expression when comparing juvenile/adult shams with NLVH groups. In the prefrontal area, a decrease in drd2 mRNA expression levels were observed in the NLVH-adult group (F(1,3) = 52.83, p = 0,005) in comparison to the sham-adult group. Finally, in the nucleus accumbens, a strong decrease of drd3 mRNA expression was observed in the NLVH-adult group in comparison to the sham-adult group (F(1,3) = 123,2, p < 0.001). CONCLUSIONS: Our results show that differences in drd2 and drd3 mRNA levels in NLVH-adults are patent when compared to the sham-adult group or with the NLVH-juvenile group. These findings suggest that the expression levels may be regulated during adulthood, leading to behavioral and neurochemical changes related to schizophrenia. Therefore, more studies are necessary to determine the role of dopamine receptors as possible molecular markers for neurodevelopmental changes associated with schizophrenia.


Asunto(s)
Hipocampo/metabolismo , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/genética , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Hipocampo/patología , Linfocitos/metabolismo , Masculino , Núcleo Accumbens/patología , Corteza Prefrontal/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética
11.
Carcinogenesis ; 36 Suppl 1: S61-88, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26106144

RESUMEN

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.


Asunto(s)
Carcinogénesis/inducido químicamente , Carcinógenos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Inestabilidad Genómica/efectos de los fármacos , Sustancias Peligrosas/efectos adversos , Neoplasias/inducido químicamente , Neoplasias/etiología , Animales , Humanos
12.
Theor Biol Med Model ; 12: 19, 2015 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-26385365

RESUMEN

BACKGROUND: The FA/BRCA pathway repairs DNA interstrand crosslinks. Mutations in this pathway cause Fanconi anemia (FA), a chromosome instability syndrome with bone marrow failure and cancer predisposition. Upon DNA damage, normal and FA cells inhibit the cell cycle progression, until the G2/M checkpoint is turned off by the checkpoint recovery, which becomes activated when the DNA damage has been repaired. Interestingly, highly damaged FA cells seem to override the G2/M checkpoint. In this study we explored with a Boolean network model and key experiments whether checkpoint recovery activation occurs in FA cells with extensive unrepaired DNA damage. METHODS: We performed synchronous/asynchronous simulations of the FA/BRCA pathway Boolean network model. FA-A and normal lymphoblastoid cell lines were used to study checkpoint and checkpoint recovery activation after DNA damage induction. The experimental approach included flow cytometry cell cycle analysis, cell division tracking, chromosome aberration analysis and gene expression analysis through qRT-PCR and western blot. RESULTS: Computational simulations suggested that in FA mutants checkpoint recovery activity inhibits the checkpoint components despite unrepaired DNA damage, a behavior that we did not observed in wild-type simulations. This result implies that FA cells would eventually reenter the cell cycle after a DNA damage induced G2/M checkpoint arrest, but before the damage has been fixed. We observed that FA-A cells activate the G2/M checkpoint and arrest in G2 phase, but eventually reach mitosis and divide with unrepaired DNA damage, thus resolving the initial checkpoint arrest. Based on our model result we look for ectopic activity of checkpoint recovery components. We found that checkpoint recovery components, such as PLK1, are expressed to a similar extent as normal undamaged cells do, even though FA-A cells harbor highly damaged DNA. CONCLUSIONS: Our results show that FA cells, despite extensive DNA damage, do not loss the capacity to express the transcriptional and protein components of checkpoint recovery that might eventually allow their division with unrepaired DNA damage. This might allow cell survival but increases the genomic instability inherent to FA individuals and promotes cancer.


Asunto(s)
Ciclo Celular , Daño del ADN , Reparación del ADN , Anemia de Fanconi/patología , Western Blotting , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular , Reparación del ADN/efectos de los fármacos , Densitometría , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Mitomicina/farmacología , Mutación/genética
13.
J Toxicol Environ Health A ; 78(1): 7-14, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25424543

RESUMEN

Two pyrethroids, permethrin and allethrin, are often combined for large-scale use in public health programs to control vector-borne diseases. In this study, the genotoxic potential of a commercial formulation of permethrin and allethrin was examined using cultured human peripheral blood lymphocytes (PBL). Genotoxicity was evaluated using the cytokinesis-block micronucleus cytome (CBMN cyt) assay by measuring the frequency of micronuclei (MN), nuclear division index (NDI), formation of nucleoplasmic bridges (NPB) and nuclear buds (NBUD), as well as apoptotic and necrotic cells. Human PBL were treated with different concentrations of a permethrin/allethrin mixture (1/0.01, 5/0.07, and 10/0.14 µg/ml) for 24 or 36 h. The highest concentration (10/0.14 µg/ml) of permethrin/allethrin mixture significantly increased MN frequency and percent apoptotic cells after incubations for 24 or 36 h. The NDI was markedly decreased in response to treatment with 5/0.07 or 10/0.14 µg/ml permethrin/allethrin for both 24 and 36 h. Exposure to the permethrin/allethrin mixture did not significantly alter formation of NBUD, NPB, or percent necrotic cells. The MN frequency was significantly correlated with the number of apoptotic and necrotic cells but inversely correlated with NDI. Data demonstrated that a mixture of permethrin and allethrin induced concentration- and time-dependent cytotoxic and genotoxic damage to human PBL in vitro.


Asunto(s)
Aletrinas/toxicidad , Daño del ADN/efectos de los fármacos , Linfocitos/efectos de los fármacos , Permetrina/toxicidad , Apoptosis/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinesis/efectos de los fármacos , Humanos , Pruebas de Micronúcleos , Mutágenos/toxicidad , Necrosis/inducido químicamente , Necrosis/patología
14.
Tumour Biol ; 35(5): 3981-95, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24470139

RESUMEN

Cancer remains a public health problem with a high unmet medical demand. However, in recent decades, the knowledge of several functional molecular and biological traits that distinguish tumor cells from normal cells, known as the hallmarks of cancer as described by Hannahan and Weinberg, has led to new and modern therapeutic approaches against this disease. Most cancer drugs are deliberately developed for specific molecular targets that involve these hallmarks. In this review, we address the currently available cancer drugs and development of new drugs from the perspective of their interaction with these hallmarks as well as the pathways and mechanisms involved.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Terapia Molecular Dirigida , Neoplasias/patología , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inestabilidad Genómica , Humanos , Mutación , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/genética , Neovascularización Patológica/etiología
15.
Front Endocrinol (Lausanne) ; 14: 1165415, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37229459

RESUMEN

Introduction: Insulin resistance in muscle can originate from a sedentary lifestyle, hypercaloric diets, or exposure to endocrine-disrupting pollutants such as arsenic. In skeletal muscle, insulin stimulates glucose uptake by translocating GLUT4 to the sarcolemma. This study aimed to evaluate the alterations induced by sucrose and arsenic exposure in vivo on the pathways involved in insulinstimulated GLUT4 translocation in the quadriceps and gastrocnemius muscles. Methods: Male Wistar rats were treated with 20% sucrose (S), 50 ppm sodium arsenite (A), or both (A+S) in drinking water for 8 weeks. We conducted an intraperitoneal insulin tolerance (ITT) test on the seventh week of treatment. The quadriceps and gastrocnemius muscles were obtained after overnight fasting or 30 min after intraperitoneal insulin injection. We assessed changes in GLUT4 translocation to the sarcolemma by cell fractionation and abundance of the proteins involved in GLUT4 translocation by Western blot. Results: Male rats consuming S and A+S gained more weight than control and Atreated animals. Rats consuming S, A, and A+S developed insulin resistance assessed through ITT. Neither treatments nor insulin stimulation in the quadriceps produced changes in GLUT4 levels in the sarcolemma and Akt phosphorylation. Conversely, A and A+S decreased protein expression of Tether containing UBX domain for GLUT4 (TUG), and A alone increased calpain-10 expression. All treatments reduced this muscle's protein levels of VAMP2. Conversely, S and A treatment increased basal GLUT4 levels in the sarcolemma of the gastrocnemius, while all treatments inhibited insulin-induced GLUT4 translocation. These effects correlated with lower basal levels of TUG and impaired insulin-stimulated TUG proteolysis. Moreover, animals treated with S had reduced calpain-10 protein levels in this muscle, while A and A+S inhibited insulin-induced Akt phosphorylation. Conclusion: Arsenic and sucrose induce systemic insulin resistance due to defects in GLUT4 translocation induced by insulin. These defects depend on which muscle is being analyzed, in the quadriceps there were defects in GLUT4 retention and docking while in the gastrocnemius the Akt pathway was impacted by arsenic and the proteolytic pathway was impaired by arsenic and sucrose.


Asunto(s)
Arsénico , Resistencia a la Insulina , Ratas , Masculino , Animales , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Calpaína , Músculo Cuádriceps , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sacarosa/metabolismo , Sacarosa/farmacología , Ratas Wistar , Músculo Esquelético/metabolismo , Transducción de Señal
16.
Viral Immunol ; 36(8): 550-561, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37603294

RESUMEN

Current evidence shows higher production of cytokines and antibodies against severe acute respiratory coronavirus 2 (SARS-CoV-2) in severe and critical cases of Coronavirus Disease 2019 (COVID-19) in comparison with patients with moderate or mild disease. A recent hypothesis proposes an important role of genotoxicity and cytotoxicity in the induction of the cytokine storm observed in some patients at later stages of the disease. Interestingly, in this study, we report significantly higher levels of interleukin (IL)-1ß, IL-6, MCP-1, and IL-4 cytokines in mild COVID-19 patients versus severe cases, as well as a high frequency of karyorrhexis (median [Me] = 364 vs. 20 cells) and karyolysis (Me = 266 vs. 52 cells) in the mucosal epithelial cells of both groups of patients compared with uninfected individuals. Although we observed higher levels of anti-SARS-CoV-2 IgM and IgG antibodies in COVID-19 patients, IgM antibodies were significantly higher only in mild cases, for the N and the S viral antigens. High levels of IgG antibodies were observed in both mild and severe cases. Our results showed elevated concentrations of proinflammatory and anti-inflammatory cytokines in mild cases, which may reflect an active innate immune response and could be related to the higher IgM and IgG antibody levels found in those patients. In addition, we found that SARS-CoV-2 infection induces cytotoxic damage in the oral mucosa, highlighting the importance of studying the genotoxic and cytotoxic events induced by infection and its role in the pathophysiology of COVID-19.


Asunto(s)
COVID-19 , Humanos , Citocinas , SARS-CoV-2 , Anticuerpos Antivirales , Inmunoglobulina G , Inmunoglobulina M
17.
Mutat Res Rev Mutat Res ; 789: 108411, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35690420

RESUMEN

The coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is challenging global health and economic systems. In some individuals, COVID-19 can cause a wide array of symptoms, affecting several organs, such as the lungs, heart, bowels, kidneys and brain, causing multiorgan failure, sepsis and death. These effects are related in part to direct viral infection of these organs, immunological deregulation, a hypercoagulatory state and the potential for development of cytokine storm syndrome. Since the appearance of COVID-19 is recent, the long-term effects on the health of recovered patients remain unknown. In this review, we focused on current evidence of the mechanisms of DNA damage mediated by coronaviruses. Data supports that these viruses can induce DNA damage, genomic instability, and cell cycle deregulation during their replication in mammalian cells. Since the induction of DNA damage and aberrant DNA repair mechanisms are related to the development of chronic diseases such as cancer, diabetes, neurodegenerative disorders, and atherosclerosis, it will be important to address similar effects and outcomes in recovered COVID-19 patients.


Asunto(s)
COVID-19 , Animales , Daño del ADN/genética , Humanos , Pulmón , Mamíferos , SARS-CoV-2
18.
Front Endocrinol (Lausanne) ; 13: 878280, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35651975

RESUMEN

Exposure to arsenic in drinking water is a worldwide health problem. This pollutant is associated with increased risk of developing chronic diseases, including metabolic diseases. Metabolic syndrome (MS) is a complex pathology that results from the interaction between environmental and genetic factors. This condition increases the risk of developing type 2 diabetes, cardiovascular diseases, and cancer. The MS includes at least three of the following signs, central obesity, impaired fasting glucose, insulin resistance, dyslipidemias, and hypertension. Here, we summarize the existing evidence of the multiple mechanisms triggered by arsenic to developing the cardinal signs of MS, showing that this pollutant could contribute to the multifactorial origin of this pathology.


Asunto(s)
Arsénico , Diabetes Mellitus Tipo 2 , Contaminantes Ambientales , Síndrome Metabólico , Arsénico/toxicidad , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/complicaciones , Factores de Riesgo
19.
Mutagenesis ; 26(1): 19-26, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21164178

RESUMEN

Micronucleus (MN) is a biomarker widely used in biomonitoring studies carried out to determine the genetic risk associated to pesticide exposure. Many in vitro and in vivo studies, as well as epidemiological approaches, have demonstrated the ability of certain chemical pesticides to produce genetic effects including cancer and other chronic pathologies in humans; thus, biomonitoring studies have been carried out to characterise the genetic risk associated to pesticide exposure. It must be noted that 'pesticide exposure' is a broad term covering complex mixtures of chemicals and many variables that can reduce or potentiate their risk. In addition, there are large differences in pesticides used in the different parts of the world. Although pesticides constitute a wide group of environmental pollutants, the main focus on their risk has been addressed to people using pesticides in their working places, at the chemical industry or in the crop fields. Here, we present a brief review of biomonitoring studies carried out in people occupationally exposed to pesticides and that use MN in lymphocytes or buccal cells as a target to determine the induction of genotoxic damage. Thus, people working in the chemical industry producing pesticides, people spraying pesticides and people dedicated to floriculture or agricultural works in general are the subject of specific sections. MN is a valuable genotoxic end point when clear exposure conditions exist like in pesticide production workers; nevertheless, better study designs are needed to overcome the uncertainty in exposure, genetic susceptibility and statistical power in the studies of sprayers and floriculture or agricultural workers.


Asunto(s)
Exposición a Riesgos Ambientales , Micronúcleos con Defecto Cromosómico/inducido químicamente , Pruebas de Micronúcleos , Exposición Profesional , Plaguicidas/toxicidad , Daño del ADN , Monitoreo del Ambiente , Femenino , Humanos , Masculino
20.
Artículo en Inglés | MEDLINE | ID: mdl-33865538

RESUMEN

Using a rabbit model, we investigated whether maternal intake of a high-fat and high-carbohydrate diet (HFCD) before and during pregnancy induces an increase in micronuclei frequency and oxidative stress in offspring during adulthood. Female rabbits received a standard diet (SD) or HFCD for two months before mating and during gestation. The offspring from both groups were nursed by foster mothers fed SD until postnatal day 35. After weaning, all the animals received SD until postnatal day 440. At postnatal day 370, the frequency of micronuclei in peripheral blood reticulocytes (MN-RETs) increased in the male offspring from HFCD-fed mothers compared with the male offspring from SD-fed mothers. Additionally, fasting serum glucose increased in the offspring from HFCD-fed mothers compared with the offspring from SD-fed mothers. At postnatal day 440, the offspring rabbits were challenged with HFCD or continued with SD for 30 days. There was an increase in MN-RET frequency in the male rabbits from HFCD-fed mothers, independent of the type of challenging diet consumed during adulthood. The challenge induced changes in serum cholesterol, LDL and HDL that were influenced by the maternal diet and offspring sex. We measured malondialdehyde in the liver of rabbits as an oxidative stress marker after diet challenge. Oxidative stress in the liver only increased in the female offspring from HFCD-fed mothers who were also challenged with this same diet. The data indicate that maternal overnutrition before and during pregnancy is able to promote different effects depending on the sex of the animals, with chromosomal instability in male offspring and oxidative stress and hypercholesterolemia in female offspring. Our data might be important in the understanding of chronic diseases that develop in adulthood due to in utero exposure to maternal diet.


Asunto(s)
Daño del ADN , Hipernutrición/genética , Efectos Tardíos de la Exposición Prenatal/genética , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Hipernutrición/complicaciones , Hipernutrición/patología , Estrés Oxidativo/fisiología , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/patología , Efectos Tardíos de la Exposición Prenatal/patología , Conejos , Caracteres Sexuales
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