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1.
Environ Monit Assess ; 193(6): 317, 2021 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-33942176

RESUMEN

Monocrotophos (MCP) is a highly toxic and broad-spectrum pesticide extensively used for agricultural and household purposes. The present study was aimed to evaluate the genotoxicity and alterations in the biochemical and physiological conditions induced by monocrotophos in a non-target organism, an estuarine bivalve, Donax incarnatus. The bivalves were exposed to three sub-lethal concentrations (6.8, 13.7, and 27.45 ppm) of MCP for a period of 72 h. DNA damage was assessed using the comet assay. Oxidative stress was analyzed using catalase, glutathione peroxidase, and superoxide dismutase. Neurotoxicity was evaluated using the acetylcholinesterase assay (AChE) and the physiological condition was assessed using the condition index (CI). A significant concentration-dependent increase of DNA damage was observed as well as a decline in the activities of the antioxidant enzymes. However, a decrease in DNA damage was observed with advancing time. A significant decrease of AChE activity and CI was observed in the bivalves exposed to MCP. Positive correlations were also observed between DNA damage and the antioxidant enzymes whereas negative correlations were observed between AChE and the antioxidant enzymes indicating MCP toxicity mediated by oxidative stress.


Asunto(s)
Bivalvos , Monocrotofos , Plaguicidas , Animales , Daño del ADN , Monitoreo del Ambiente , Monocrotofos/toxicidad , Plaguicidas/toxicidad
2.
An Acad Bras Cienc ; 93(2): e20190652, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33950142

RESUMEN

The Itaqui Port Complex (northeastern Brazil) is one of the largest Brazilian port facilities, whose effluents and waste are dumped directly into the estuarine waters. Although environmental monitoring has been a concern around this site, there has been no toxicogenetics study on organisms living in this environment. Thus, we assessed the toxicogenetics potential of the estuarine waters surrounding Itaqui, using the native catfish Sciades herzbergii as a biomonitor. We found a significantly higher frequency of genetic damage and mutations in the animals collected near to Itaqui in both seasons compared to the reference site (distant from Itaqui with no port activities). We also quantified chemical elements in the surface water and sediments near the port and found that clorine, phosphorus, zinc, and boron were above the limits set by the Brazilian legislation. We suggest that such contaminants are involved in the origin of DNA damage. Moreover, we recommend including toxicogenetics assays in the environmental monitoring of pollutants, as well as in the definition of their allowable limits, as they could be used as law enforcement tools and help to predict large-scale contamination events associated with port activities.


Asunto(s)
Bagres , Contaminantes Químicos del Agua , Animales , Brasil , Bagres/genética , Daño del ADN , Monitoreo del Ambiente , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad
3.
Mol Biol (Mosk) ; 55(2): 181-193, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33871434

RESUMEN

The base and nucleotide excision DNA repair (BER and NER) systems are aimed at removing specific types of damaged DNA, i.e., oxidized, alkylated, or deaminated bases in the case of BER and bulky damage caused by UV radiation or chemical carcinogens in the case of NER. In some cases, however, the repair process follows a more complex scenario, which implies that the repair pathways exchange proteins and interact with each other to form a common interactome. This review describes the BER and NER mechanisms and discusses the current data on the involvement of the NER proteins in the repair of DNA lesions caused by oxidative stress and the BER proteins in the removal of bulky DNA adducts. We also discuss the role of poly(ADP-ribose) polymerase 1 in the regulation of the BER and NER processes and their coordination in the repair of complex (cluster) lesions.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN/genética , ADN/metabolismo , Reparación del ADN/genética , Nucleótidos , Estrés Oxidativo/genética
4.
Mol Biol (Mosk) ; 55(2): 194-209, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33871435

RESUMEN

In mammalian cells, base excision repair (BER) is the main pathway responsible for the correction of a variety of chemically modified DNA bases. DNA packaging in chromatin affects the accessibility of damaged sites to the enzymes involved in repair processes. This review presents data concerning the enzymes involved in BER. Within the nucleosome core particle (NCP), the accessibility of damaged DNA to enzymes is hindered by the presence of a histone octamer. This means that the removal of DNA lesions largely depends on their rotational and translational positioning in the NCP, as well as on the specific features of each enzyme.


Asunto(s)
Reparación del ADN , Nucleosomas , Animales , Cromatina , ADN/genética , Daño del ADN/genética , Reparación del ADN/genética , Nucleosomas/genética
5.
Mol Biol (Mosk) ; 55(2): 210-222, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33871436

RESUMEN

Nucleoli, the largest subnuclear compartments, are formed around arrays of ribosomal gene repeats transcribed by RNA polymerase I. The primary function of nucleoli is ribosome biogenesis. Specific DNA damage response mechanisms exist to maintain the genomic stability of ribosomal repeats. Here, we provide a snapshot of our current understanding of processes involved in nucleolar DNA damage response. We discuss structure and function of ribosomal repeats, techniques developed for studying DNA damage response in nucleoli, as well as molecular mechanisms of DNA damage-induced repression of nucleolar transcription and nucleoli reorganization.


Asunto(s)
Nucléolo Celular , Inestabilidad Genómica , Nucléolo Celular/genética , Daño del ADN , ADN Ribosómico , Humanos , ARN Ribosómico , Ribosomas
6.
Mol Biol (Mosk) ; 55(2): 223-242, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33871437

RESUMEN

The GO system is part of the DNA base excision repair pathway and is required for the error-free repair of 8-oxoguanine (oxoG), one of the most common oxidative DNA lesions. Due to the ability of oxoG to form oxoG:A mispairs, this base is highly mutagenic. Its repair requires the action of two enzymes: 8-oxoguanine DNA glycosylase (Fpg or MutM in bacteria and OGG1 in eukaryotes), which removes oxoG from oxoG:C pairs, and adenine DNA glycosylase (MutY in bacteria and MUTYH in eukaryotes), which removes A from oxoG:A mispairs to prevent mutations. The third enzyme of the system (MutT in bacteria and MTH1 or NUDT1 in eukaryotes) hydrolyzes 8-oxo-2'-deoxyguanosine triphosphate, thus preventing its incorporation into DNA. Recent data point to the proteins of the GO system as promising targets for the therapy of cancer, autoimmune diseases, and bacterial infections. This review highlights the structure and specificity of the GO system in bacteria and eukaryotes and its unique role in mutation avoidance.


Asunto(s)
Reparación del ADN , Estrés Oxidativo , Daño del ADN , Reparación del ADN/genética , Mutagénesis , Mutación , Estrés Oxidativo/genética
7.
Mol Biol (Mosk) ; 55(2): 277-288, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33871441

RESUMEN

The human N-glycosylases SMUG1 and MBD4 catalyze the removal of uracil residues from DNA resulting from cytosine deamination or replication errors. For polymorphic variants of SMUG1 (G90C, P240H, N244S, N248Y) and the MBD4^(cat) catalytic domain (S470L, G507S, R512W, H557D), the structures of enzyme-substrate complexes were obtained by molecular dynamic simulation. It was experimentally found that the SNP variants of SMUG1, N244S and N248Y, had increased catalytic activity compared to the wild-type enzyme, probably due to the acceleration of the dissociation of the enzyme-product complex and an increase in the enzyme turnover rate. All other SNP variants of SMUG1 (G90C, P240H) and MBD4^(cat), in which amino acid substitutions disrupted the substrate binding region and/or active site, had significantly lower catalytic activity than the wild-type enzymes.


Asunto(s)
Reparación del ADN , Uracil-ADN Glicosidasa , ADN , Daño del ADN , Endodesoxirribonucleasas , Humanos , Uracilo , Uracil-ADN Glicosidasa/genética , Uracil-ADN Glicosidasa/metabolismo
8.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809300

RESUMEN

Alzheimer's disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.


Asunto(s)
Enfermedad de Alzheimer/terapia , Ejercicio Físico/fisiología , Estrés Oxidativo/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/rehabilitación , Daño del ADN/genética , Reparación del ADN/genética , Imagen de Difusión Tensora/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Transducción de Señal/genética
9.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810274

RESUMEN

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and PK083 a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Carbazoles/farmacología , Mutágenos/farmacología , Antineoplásicos/química , Neoplasias de la Mama/genética , Carbazoles/química , Daño del ADN , Metilación de ADN , Epigénesis Genética/efectos de los fármacos , Femenino , Histonas/metabolismo , Humanos , Células MCF-7 , Mutágenos/química , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo
10.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799521

RESUMEN

Climate change, environmental pollution and pathogen resistance to available chemical agents are part of the problems that the food industry has to face in order to ensure healthy food for people and livestock. One of the promising solutions to these problems is the use of cold atmospheric pressure plasma (CAPP). Plasma is suitable for efficient surface decontamination of seeds and food products, germination enhancement and obtaining higher yields in agricultural production. However, the plasma effects vary due to plasma source, treatment conditions and seed type. In our study, we tried to find the proper conditions for treatment of barley grains by diffuse coplanar surface barrier discharge, in which positive effects of CAPP, such as enhanced germination or decontamination effects, would be maximized and harmful effects, such as oxidation and genotoxic potential, minimized. Besides germination parameters, we evaluated DNA damage and activities of various germination and antioxidant enzymes in barley seedlings. Plasma exposure resulted in changes in germination parameters and enzyme activities. Longer exposures had also genotoxic effects. As such, our findings indicate that appropriate plasma exposure conditions need to be carefully optimized in order to preserve germination, oxidation balance and genome stability, should CAPP be used in agricultural practice.


Asunto(s)
Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Germinación/efectos de los fármacos , Hordeum/efectos de los fármacos , Gases em Plasma/farmacología , Plantones/efectos de los fármacos , Semillas/efectos de los fármacos , Daño del ADN , ADN de Plantas/genética , ADN de Plantas/metabolismo , Hordeum/enzimología , Hordeum/genética , Hordeum/crecimiento & desarrollo , Oxidación-Reducción , Estrés Oxidativo , Peroxidasa/genética , Peroxidasa/metabolismo , Raíces de Plantas , Brotes de la Planta , Plantones/enzimología , Plantones/genética , Plantones/crecimiento & desarrollo , Semillas/enzimología , Semillas/genética , Semillas/crecimiento & desarrollo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo
11.
Artículo en Inglés | MEDLINE | ID: mdl-33806616

RESUMEN

This study aimed to assess the association of exposure to particle-bound (PM2.5) polycyclic aromatic hydrocarbons (PAHs) with potential genotoxicity and cancer risk among children living near the petrochemical industry and comparative populations in Malaysia. PM2.5 samples were collected using a low-volume sampler for 24 h at three primary schools located within 5 km of the industrial area and three comparative schools more than 20 km away from any industrial activity. A gas chromatography-mass spectrometer was used to determine the analysis of 16 United States Environmental Protection Agency (USEPA) priority PAHs. A total of 205 children were randomly selected to assess the DNA damage in buccal cells, employing the comet assay. Total PAHs measured in exposed and comparative schools varied, respectively, from 61.60 to 64.64 ng m-3 and from 5.93 to 35.06 ng m-3. The PAH emission in exposed schools was contributed mainly by traffic and industrial emissions, dependent on the source apportionment. The 95th percentiles of the incremental lifetime cancer risk estimated using Monte Carlo simulation revealed that the inhalation risk for the exposed children and comparative populations was 2.22 × 10-6 and 2.95 × 10-7, respectively. The degree of DNA injury was substantially more severe among the exposed children relative to the comparative community. This study reveals that higher exposure to PAHs increases the risk of genotoxic effects and cancer among children.


Asunto(s)
Contaminantes Atmosféricos , Neoplasias , Hidrocarburos Policíclicos Aromáticos , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Niño , Daño del ADN , Monitoreo del Ambiente , Humanos , Malasia , Mucosa Bucal , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Material Particulado/análisis , Material Particulado/toxicidad , Hidrocarburos Policíclicos Aromáticos/análisis , Hidrocarburos Policíclicos Aromáticos/toxicidad , Medición de Riesgo , Instituciones Académicas , Estaciones del Año
12.
Wiad Lek ; 74(3 cz 2): 613-618, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33843622

RESUMEN

OBJECTIVE: The aim: of this work was to experimentally study the modifying role of toxic substances (phenol) in the manifestation of genotoxic and immunological changes in the body when exposed to a carcinogen (benzo[a]pyrene). PATIENTS AND METHODS: Materials and methods: Investigations were carried out in the chronic experiment on white random-bred male mice. Genotoxic (micronucleus test), immunologic and pathomorphological methods were used. RESULTS: Results: As a result of the experiment on white outbred mice during the isolated peroral administration of benzo[a]pyrene (a single dose of 0.1 mg) and in combination with phenol (single doses of 0.1 mg; 0.002 mg) a carcinogenic effect (forestomach papillomas) has been established as well as general patterns of the manifestation of genotoxic and immunological changes regarding carcinogenesis and their dependence on the dose and duration of the administration of the substances in the early stages of the experiment. The established patterns involved parallelism of development and unidirectionality of the genotoxic effect (increasing of micronucleus incidence) and suppression of the T-cell immunity by the end of the month as well as reliable negative correlation between them. CONCLUSION: Conclusions: It has been established that phenol has a modifying effect on carcinogenesis, which was shown as an increase in the micronuclei frequency, intensification of immunosuppression in the early stages and an increase in the multiplicity factor of the development of forestomach tumors.


Asunto(s)
Benzo(a)pireno , Carcinógenos , Animales , Benzo(a)pireno/toxicidad , Carcinogénesis , Carcinógenos/toxicidad , Terapia Combinada , Daño del ADN , Masculino , Ratones
13.
Pestic Biochem Physiol ; 174: 104797, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33838701

RESUMEN

Tebuconazole (TEB) is a common triazole fungicide that has been widely used for the control of plant pathogenic fungi, suggesting that mammal exposure occurs regularly. Several studies demonstrated that TEB exposure has been linked to a variety of toxic effects, including neurotoxicity, immunotoxicity, reprotoxicity and carcinogenicity. However, there is a few available data regarding the molecular mechanism involved in TEB-induced toxicity. The current study was undertaken to investigate the toxic effects of TEB in HCT116 cells. Our results showed that TEB caused cytotoxicity by inhibiting cell viability as assessed by the MTT assay. Furthermore, we have demonstrated that TEB induced a significant increase in the reactive oxygen species (ROS) production leading to the induction of lipid peroxidation and DNA fragmentation and increased superoxide dismutase (SOD) and catalase (CAT) activities. Moreover, TEB exposure induced mitochondrial membrane potential loss and caspase-9/-3 activation. Treatment with general caspases inhibitor (Z-VAD-fmk) significantly prevented the TEB-induced cell death, indicating that TEB induced caspases-dependent cell death. These findings suggest the involvement of oxidative stress and apoptosis in TEB-induced toxicity in HCT116.


Asunto(s)
Daño del ADN , Triazoles , Animales , Apoptosis , Células HCT116 , Humanos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Triazoles/toxicidad
14.
Environ Monit Assess ; 193(5): 243, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33821353

RESUMEN

The aim of this study was to assess the genotoxic effects of sediment elutriates of an aquatic ecosystem. Sediment samples were taken from Limache stream, located in central Chile. The tests were carried out on sediment elutriates. Genotoxicity was determined by bioassay with Allium cepa. The percentage of germination, root growth, mitotic index, and frequency of chromosome aberrations were determined. The results show a significant increase in chromosome aberrations and decrease of the mitotic index in Allium cepa in all the sediment elutriates compared to the control. No significant differences were observed in the percentages of germination or root growth among the sediment elutriates. A negative correlation was found between the mitotic index and chromosomal aberrations. In conclusion, genotoxic variables are more sensitive than growth variables. The sediments contain chemical agents in bioavailable concentrations that produce genotoxic effects. Allium cepa test proved to be a sensitive indicator of genotoxic contaminants in sediment elutriates of the Limache stream in central Chile.


Asunto(s)
Allium , Cebollas , Chile , Aberraciones Cromosómicas , Daño del ADN , Ecosistema , Monitoreo del Ambiente , Humanos , Índice Mitótico , Raíces de Plantas , Ríos
15.
Nat Commun ; 12(1): 2327, 2021 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-33875663

RESUMEN

Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/genética , Especies Reactivas de Oxígeno/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Animales , Línea Celular Tumoral , Daño del ADN , Femenino , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos C57BL , Ratones Desnudos , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
16.
BMC Cancer ; 21(1): 432, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879103

RESUMEN

BACKGROUND: Muscle invasive urothelial bladder carcinoma (MIBC) present RB1 and TP53 somatic alterations in a variable percentage of tumors throughout all molecular subtypes. MIBCs with neuroendocrine features have a high response rate to immunity checkpoint inhibitors (ICIs). Whether the presence of somatic co-alterations in these 2 genes in MIBCs is relevant to their responsiveness to ICIs is not known. METHODS: The potential correlation of different genomic biomarkers of response to ICIs like tumor mutational burden (TMB), single nucleotide variants (SNV) predicted neoantigens, DNA damage response (DDR) genes, DNA somatic signatures and TILs infiltrate was explored in patients with somatic co-alterations in RB1 and TP53 (RB1&TP53) as compared with patients with no alterations in any (double wild type, DWT) or with alterations in just one of the 2 genes. The Cancer Genome Atlas (TCGA) pancancer BLCA dataset of cystectomy specimens (n = 407) with mutation, copy number alterations and transcriptomic (RNA sequencing) data as well as the IMVigor 210 study (n = 348) of metastatic urothelial bladder cancers treated with atezolizumab (PD-L1 inhibitor) with clinical response data containing transcriptomic (RNA sequencing), along with a subset (n = 274) with mutation and copy number data were used for this purpose. A novel tumor microenvironment metascore (TMM) was developed based in a LASSO regularized Cox model with predictive and prognostic ability. RESULTS: Samples with co-altered RB1&TP53: a) were enriched in immunity effectors (CD8 cytotoxic lymphocytes, NK cells) and display higher scores of a T cell inflamed signature; b) have a higher TMB, higher number of SNV predicted neoantigens and higher TILs fractions; c) have a higher number of DDR mutated and deep deleted DDR genes; d) have DNA somatic signatures 2 and 13 related to APOBEC mutagenesis. Using the IMVigor 210 dataset, RB1&TP53 samples had the highest response rate to atezolizumab and a strong correlation with TMB and TMM. The consensus molecular subtype classification in the IMVigor 210 dataset showed a significant correlation with both the response to treatment (p = 0.001, Chisquare) and the presence of RB1 and TP53 genomic alterations (p < 0.001, Chisquare). CONCLUSIONS: RB1&TP53 co-alterations are strongly associated with genomic biomarkers of response to ICIs in MIBCs.


Asunto(s)
Biomarcadores de Tumor , Mutación , Proteínas de Unión a Retinoblastoma/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/etiología , Adulto , Anciano , Daño del ADN , Femenino , Genómica/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas de Unión a Retinoblastoma/metabolismo , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/mortalidad
17.
Int J Nanomedicine ; 16: 2849-2877, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33883895

RESUMEN

Background: Exosomes are endosome-derived nano-sized vesicles that have emerged as important mediators of intercellular communication and play significant roles in various diseases. However, their applications are rigorously restricted by the limited secretion competence of cells. Therefore, strategies to enhance the production and functions of exosomes are warranted. Studies have shown that nanomaterials can significantly enhance the effects of cells and exosomes in intercellular communication; however, how palladium nanoparticles (PdNPs) enhance exosome release in human leukemia monocytic cells (THP-1) remains unclear. Therefore, this study aimed to address the effect of PdNPs on exosome biogenesis and release in THP-1 cells. Methods: Exosomes were isolated by ultracentrifugation and ExoQuickTM and characterized by dynamic light scattering, nanoparticle tracking analysis system, scanning electron microscopy, transmission electron microscopy, EXOCETTM assay, and fluorescence polarization. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Results: PdNP treatment enhanced the biogenesis and release of exosomes by inducing oxidative stress, endoplasmic reticulum stress, apoptosis, and immunomodulation. The exosomes were spherical in shape and had an average diameter of 50-80 nm. Exosome production was confirmed via total protein concentration, exosome counts, acetylcholinesterase activity, and neutral sphingomyelinase activity. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in PdNP-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from PdNP-treated THP-1 cells than in those isolated from control cells. THP-1 cells pre-treated with N-acetylcysteine or GW4869 showed significant decreases in PdNP-induced exosome biogenesis and release. Conclusion: To our knowledge, this is the first study showing that PdNPs stimulate exosome biogenesis and release and simultaneously increase the levels of cytokines and chemokines by modulating various physiological processes. Our findings suggest a reasonable approach to improve the production of exosomes for various therapeutic applications.


Asunto(s)
Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico , Exosomas/metabolismo , Inmunomodulación/efectos de los fármacos , Leucemia/patología , Nanopartículas del Metal/toxicidad , Estrés Oxidativo , Paladio/toxicidad , Acetilcolinesterasa/metabolismo , Acetilcisteína/farmacología , Compuestos de Anilina/farmacología , Antioxidantes/metabolismo , Compuestos de Bencilideno/farmacología , Biomarcadores de Tumor/metabolismo , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Daño del ADN , Estrés del Retículo Endoplásmico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia/sangre , Nanopartículas del Metal/ultraestructura , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Esfingomielina Fosfodiesterasa/metabolismo , Células THP-1
18.
Nat Commun ; 12(1): 2428, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33893291

RESUMEN

Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV. SETDB1 coordinates histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN/genética , Heterocromatina/genética , Animales , Línea Celular Tumoral , Ensamble y Desensamble de Cromatina/genética , ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Heterocromatina/efectos de la radiación , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Humanos , Células MCF-7 , Metilación , Ratones , Células 3T3 NIH , Rayos Ultravioleta
19.
Molecules ; 26(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799355

RESUMEN

Biocompatible tryptophan-derived copper (1) and zinc (2) complexes with norharmane (ß-carboline) were designed, synthesized, characterized, and evaluated for the potential anticancer activity in vitro and in vivo. The in vitro cytotoxicity of both complexes 1 and 2 were assessed against two cancerous cells: (human breast cancer) MCF7 and (liver hepatocellular cancer) HepG2 cells with a non-tumorigenic: (human embryonic kidney) HEK293 cells. The results exhibited a potentially decent selectivity of 1 against MCF7 cells with an IC50 value of 7.8 ± 0.4 µM compared to 2 (less active, IC50 ~ 20 µM). Furthermore, we analyzed the level of glutathione, lipid peroxidation, and visualized ROS generation to get an insight into the mechanistic pathway and witnessed oxidative stress. These in vitro results were ascertained by in vivo experiments, which also supported the free radical-mediated oxidative stress. The comet assay confirmed the oxidative stress that leads to DNA damage. The histopathology of the liver also ascertained the low toxicity of 1.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Carbolinas/farmacología , Cobre/farmacología , Triptófano/farmacología , Animales , Neoplasias de la Mama/metabolismo , Línea Celular , Línea Celular Tumoral , Ensayo Cometa/métodos , Daño del ADN/efectos de los fármacos , Femenino , Glutatión/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Células MCF-7 , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Zinc/farmacología
20.
Molecules ; 26(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803643

RESUMEN

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention.


Asunto(s)
Ciclodextrinas/farmacología , Neoplasias Cutáneas/prevención & control , Protectores Solares/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/química , Antioxidantes/farmacología , Ciclodextrinas/administración & dosificación , Ciclodextrinas/química , Daño del ADN , Preparaciones de Acción Retardada , Composición de Medicamentos , Estabilidad de Medicamentos , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Humanos , Estructura Molecular , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Solubilidad , Protectores Solares/administración & dosificación , Protectores Solares/química , Rayos Ultravioleta/efectos adversos
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