RESUMEN
Post-traumatic stress disorder (PTSD) presents distinct sex-specific differences in both symptom expression and treatment outcomes, with the underlying biological mechanisms still remain unclear. Epigenetic modifications, particularly histone acetylation, have been increasingly recognized as critical factors in the pathophysiology of PTSD. Valproic acid (VPA), a potent histone deacetylase (HDAC) inhibitor, has shown promise in modulating epigenetic responses and improving therapeutic outcomes is PTSD, though its effect may differ between sexes. This study aimed to explore the sex-specific epigenetic changes in response to trauma and the impact of VPA treatment in a rat model of PTSD induced by predator scent stress. Sprague-Dawley rats of both sexes were randomly assigned to stressed and non-stressed groups and treated with either VPA (100 mg/kg) or vehicle. Anxiety levels were assessed using the elevated plus maze, followed by analysis of histone H3 and H4 acetylation, HDAC activity, and c-fos expression in the hippocampus. Our findings revealed that traumatic stress led to increased freezing time and anxiety levels, with more pronounced effects observed in females. Additionally, we have identified sex-specific differences in hippocampal epigenetic modifications; stressed females exhibited higher H3 acetylation, and VPA-treated stressed males showed increased H4 acetylation. These results highlight the importance of considering sex differences in the epigenetic mechanism underlying PTSD and suggest that personalized therapeutic approaches may be necessary to address these complexities.
Asunto(s)
Epigénesis Genética , Inhibidores de Histona Desacetilasas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático , Ácido Valproico , Animales , Ácido Valproico/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/metabolismo , Masculino , Femenino , Epigénesis Genética/efectos de los fármacos , Ratas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Modelos Animales de Enfermedad , Histonas/metabolismo , Caracteres Sexuales , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Acetilación/efectos de los fármacos , Ansiedad/tratamiento farmacológicoRESUMEN
Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.
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Quitosano , Dextranos , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Melanoma , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Quitosano/química , Quitosano/análogos & derivados , Dextranos/química , Animales , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/inmunología , Ratones , Humanos , Epigénesis Genética/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Hidrogeles/química , Línea Celular Tumoral , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Many neurodegenerative and psychiatric malignancies like Parkinson' disease (PD) originate from an imbalance of 17ß-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.
Asunto(s)
Calpaína , Quitosano , Mitocondrias , Nanopartículas , Enfermedad de Parkinson , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Calpaína/metabolismo , Calpaína/genética , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Nanopartículas/química , Quitosano/química , Humanos , Ratones , Epigénesis Genética/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Supervivencia Celular/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression. METHODS: In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants. MAIN BODY: Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes. CONCLUSION: Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.
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Antidepresivos , Metilación de ADN , Epigénesis Genética , Epigénesis Genética/efectos de los fármacos , Humanos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Metilación de ADN/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Animales , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Histonas/metabolismo , Estrés Psicológico/genéticaRESUMEN
The use of antitumor drugs represents a reliable strategy for cancer therapy. Unfortunately, drug resistance has become increasingly common and contributes to tumor metastasis and local recurrence. The tumor immune microenvironment (TME) consists of immune cells, cytokines and immunomodulators, and collectively they influence the response to treatment. Epigenetic changes including DNA methylation and histone modification, as well as increased drug exportation have been reported to contribute to the development of drug resistance in cancers. In the past few years, the majority of studies on tumors have only focused on the development and progression of a tumor from a mechanistic standpoint; few studies have examined whether the changes in the TME can also affect tumor growth and drug resistance. Recently, emerging evidence have raised more concerns regarding the role of TME in the development of drug resistance. In the present review, it was discussed how the suppressive TME adapts to drug resistance characterized by the cooperation of immune cells, cytokines, immunomodulators, stromal cells and extracellular matrix. Furthermore, it was reviewed how these immunological or metabolic changes alter immunosurveillance and thus facilitate tumor drug resistance. In addition, potential targets present in the TME for developing novel therapeutic strategies to improve individualized therapy for cancer treatment were revealed.
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Resistencia a Antineoplásicos , Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Epigénesis Genética/efectos de los fármacos , Animales , Citocinas/metabolismoRESUMEN
This study explores the impact of royal jelly (RJ) on small intestinal epigenomic changes. RJ, produced by honeybees, is known for its effects on metabolic diseases. The hypothesis is that RJ induces epigenomic modifications in small intestinal epithelial cells, affecting gene expression and contributing to metabolic health. Male db/m and db/db mice were used to examine RJ's effects through mRNA sequencing and CUT&Tag methods. This study focused on histone modifications and gene expression changes, with statistical significance set at p < 0.05. RJ administration improved insulin sensitivity and lipid metabolism without affecting body weight. GO and KEGG pathway analyses showed significant enrichment in metabolic processes, cellular components, and molecular functions. RJ altered histone modifications, increasing H3K27me3 and decreasing H3K23Ac in genes associated with the G2M checkpoint. These genes, including Smc2, Mcm3, Ccnd1, Rasal2, Mcm6, and Mad2l1, are linked to cancer progression and metabolic regulation. RJ induces beneficial epigenomic changes in small intestinal epithelial cells, improving metabolic health and reducing cancer-associated gene expression. These findings highlight RJ's potential as a therapeutic agent for metabolic disorders. Further research is needed to fully understand the mechanisms behind these effects and their implications for human health.
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Epigenómica , Ácidos Grasos , Intestino Delgado , Animales , Ácidos Grasos/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patología , Ratones , Masculino , Epigenómica/métodos , Histonas/metabolismo , Epigénesis Genética/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field. The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs. Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.
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Analgésicos Opioides , Cannabinoides , Receptores de Cannabinoides , Humanos , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/farmacología , Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Receptores de Cannabinoides/metabolismo , Animales , Dolor/tratamiento farmacológico , Dolor/metabolismo , Cannabidiol/uso terapéutico , Cannabidiol/farmacología , Receptores Opioides/metabolismo , Epigénesis Genética/efectos de los fármacos , Manejo del Dolor/métodos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Endocannabinoides/metabolismoRESUMEN
As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.
Asunto(s)
Arginina , Metilación de ADN , Reposicionamiento de Medicamentos , Glioblastoma , Metformina , Temozolomida , Metformina/farmacología , Metformina/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Arginina/metabolismo , Reposicionamiento de Medicamentos/métodos , Metilación de ADN/efectos de los fármacos , Línea Celular Tumoral , Temozolomida/uso terapéutico , Temozolomida/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , 5-Metilcitosina/metabolismo , 5-Metilcitosina/análogos & derivadosRESUMEN
Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development.
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Ameloblastos , Fluoruros , Histonas , Animales , Ratones , Acetilación/efectos de los fármacos , Histonas/metabolismo , Ameloblastos/metabolismo , Ameloblastos/efectos de los fármacos , Fluoruros/farmacología , Fluoruros/toxicidad , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , Epigénesis Genética/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacologíaRESUMEN
Hexafluoropropylene oxide trimer acid (HFPO-TA), an alternative to perfluorooctanoic acid, has been shown to have estrogenic effects. However, its potential to disrupt fish sex differentiation during gonadal development remains unknown. Therefore, this study exposed zebrafish to HFPO-TA from approximately 2 hours post fertilization (hpf) to 60 days post fertilization (dpf) to investigate its effects on sex differentiation. Results indicated that HFPO-TA disrupted steroid hormone homeostasis, delayed gonadal development in both sexes, and resulted in a female-skewed sex ratio in zebrafish. HFPO-TA exposure up-regulated gene expressions of cyp19a1a, esr1, vtg1 and foxl2, while down-regulated those of amh, sox9a and dmrt1. These suggested that HFPO-TA dysregulated the expressions of key genes related to sex differentiation of zebrafish, promoted the production and activation of estrogen, and further induced the feminization. Interestingly, we observed promoter hypomethylation of cyp19a1a and promoter hypermethylation of amh in male zebrafish, which were negatively associated with their gene expressions. These suggested that HFPO-TA dysregulated these key genes through DNA methylation in their promoters. Therefore, the HFPO-TA disrupted the sex differentiation of zebrafish through an epigenetic mechanism involving DNA methylation, ultimately skewing the sex ratio towards females. Overall, this study demonstrated adverse effects of HFPO-TA on fish sex differentiation and provided novel insights into the underlying epigenetic mechanism.
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Metilación de ADN , Epigénesis Genética , Diferenciación Sexual , Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/genética , Diferenciación Sexual/efectos de los fármacos , Femenino , Masculino , Metilación de ADN/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Razón de Masculinidad , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Fluorocarburos/toxicidadRESUMEN
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.
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Acrilamidas , Adenocarcinoma del Pulmón , Compuestos de Anilina , Daño del ADN , Resistencia a Antineoplásicos , Epigénesis Genética , Receptores ErbB , Neoplasias Pulmonares , Humanos , Acrilamidas/farmacología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Daño del ADN/efectos de los fármacos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Epigénesis Genética/efectos de los fármacos , Animales , Línea Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/genética , Ratones , Proteínas del Grupo Polycomb/metabolismo , Proteínas del Grupo Polycomb/genética , Ratones Desnudos , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/genética , Inhibidores de Proteínas Quinasas/farmacología , Proliferación Celular/efectos de los fármacos , Ubiquitinación/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Indoles , PirimidinasRESUMEN
BACKGROUND: This study investigated the association of prenatal and early childhood exposure to air pollution with epigenetic age acceleration (EAA) at six years of age using the Environment and Development of Children Cohort (EDC Cohort) MATERIALS & METHODS: Air pollution, including particulate matter [< 2.5⯵m (PM2.5) and < 10⯵m (PM10) in an aerodynamic diameter], nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO), and sulfur dioxide (SO2) were estimated based on the residential address for two periods: 1) during the whole pregnancy, and 2) for one year before the follow-up in children at six years of age. The methylation levels in whole blood at six years of age were measured, and the methylation clocks, including Horvath's clock, Horvath's skin and blood clock, PedBE, and Wu's clock, were estimated. Multivariate linear regression models were constructed to analyze the association between EAA and air pollutants. RESULTS: A total of 76 children in EDC cohort were enrolled in this study. During the whole pregnancy, interquartile range (IQR) increases in exposure to PM2.5 (4.56⯵g/m3) and CO (0.156â¯ppm) were associated with 0.406 years and 0.799 years of EAA (Horvath's clock), respectively. An IQR increase in PM2.5 (4.76⯵g/m3) for one year before the child was six years of age was associated with 0.509 years of EAA (Horvath's clock) and 0.289 years of EAA (Wu's clock). PM10 (4.30⯵g/m3) and O3 (0.003â¯ppm) exposure in the period were also associated with EAA in Horvath's clock (0.280 years) and EAA in Horvath's skin and blood clock (0.163 years), respectively. CONCLUSION: We found that prenatal and childhood exposure to ambient air pollutants is associated with EAA among children. The results suggest that air pollution could induce excess biological aging even in prenatal and early life.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Epigénesis Genética , Material Particulado , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Embarazo , Contaminantes Atmosféricos/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Material Particulado/toxicidad , Niño , Masculino , Epigénesis Genética/efectos de los fármacos , Contaminación del Aire/efectos adversos , Estudios de Cohortes , Envejecimiento , Monóxido de Carbono/toxicidad , Exposición a Riesgos Ambientales/efectos adversos , Ozono/toxicidad , Dióxido de Nitrógeno/toxicidad , Metilación de ADN/efectos de los fármacos , Exposición Materna/efectos adversos , ChinaRESUMEN
BACKGROUND: Recent research suggests that epigenetic modifications may mediate the behavioral effects of cannabis, influencing exocannabinnoids' long term effects in cognitive function and its role in the emergence of psychotic symptoms. BASIC PROCEDURES: In this systematic scoping review, we assessed the current evidence of epigenetic effects associated with the use of cannabis or exocannabinoid administration and their relationship with behavioral and emotional symptoms. We searched PubMed, Cochrane CENTRAL, and Web of Science, up to January 2022, using the terms "cannabis" and "epigenetics." The search yielded 178 articles, of which 43 underwent full article revision; 37 articles were included in the review. MAIN FINDINGS: The gathered evidence included observational cross-sectional studies conducted on human subjects and experimental designs using animal models that conveyed disparity in administration dosage, methods of cannabis use assessment and targeted epigenetic mechanisms. Nine studies performed epigenome-wide analysis with identification of differentially methylated sites; most of these studies found a global hypomethylation, and enrichment in genes related to cellular survival and neurodevelopment. Other studies assessed methylation at specific genes and found that cannabis exposure was associated with reduced methylation at Cg05575921, DNMT1, DRD2, COMT, DLGAP2, Arg1, STAT3, MGMT, and PENK, while hypermethylation was found at DNMT3a/b, NCAM1, and AKT1. CONCLUSIONS: The review found evidence of an exocannabinoid-induced epigenetic changes that modulate depressive-anxious, psychotic, and addictive behavioural phenotypes. Further studies will require dosage exposure/administration uniformization and a customized pool of genes to assess their suitability as biomarkers for psychiatric diseases.
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Epigénesis Genética , Humanos , Epigénesis Genética/efectos de los fármacos , Animales , Uso de la Marihuana/genética , Cannabis , Cannabinoides/farmacología , Emociones/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Síntomas Afectivos/genéticaRESUMEN
Colon cancer (CC) is a significant cause of death worldwide, particularly in Saudi Arabia. To increase the accuracy of diagnosis and treatment, it is important to discover new specific biomarkers for CC. The main objectives of this research are to identify potential specific biomarkers for the early diagnosis of CC by analyzing the expressions of eight cancer testis (CT) genes, as well as to analyze how epigenetic mechanisms control the expression of these genes in CC cell lines. Tissue samples were collected from 15 male patients with CC tissues and matched NC tissues for gene expression analysis. The expression levels of specific CT genes, including ADAD1, DMRTC2, PRSS54, SYCE1, SYCP1, TEX101, TEX48, and TMPRSS12, were assessed using quantitative techniques. To validate the gene expression patterns, we used publicly available CC statistics. To investigate the effect of inhibition of DNA methylation and histone deacetylation on CT gene expression, in vitro experiments were performed using HCT116 and Caco-2 cell lines. There was no detected expression of the genes neither in the patient samples nor in NC tissues, except for TEX48, which exhibited upregulation in CC samples compared to NC tissues in online datasets. Notably, CT genes showed expression in testis samples. In vitro, experiments demonstrated significant enhancement in mRNA expression levels of ADAD1, DMRTC2, PRSS54, SYCE1, SYCP1, TEX101, TEX48, and TMPRSS12 following treatment with 5-aza-2'-deoxycytidine and trichostatin A in HCT116 and Caco-2 cell lines. Epigenetic treatments modify the expression of CT genes, indicating that these genes can potentially be used as biomarkers for CC. The importance of conducting further research to understand and target epigenetic mechanisms to improve CC treatment cannot be overemphasized.
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Neoplasias del Colon , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias del Colon/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Masculino , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células CACO-2 , Metilación de ADN/efectos de los fármacos , Células HCT116 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Azacitidina/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Persona de Mediana Edad , Ácidos Hidroxámicos/farmacología , Decitabina/farmacologíaRESUMEN
Multiple myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 form a subcomplex of many chromatin remodeling complexes implicated in cancer progression. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt's lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility. CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB-6644 in MM cells, but experimental validation refuted this hypothesis.
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ATPasas Asociadas con Actividades Celulares Diversas , ADN Helicasas , Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , ADN Helicasas/genética , ADN Helicasas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/antagonistas & inhibidores , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proliferación Celular/efectos de los fármacos , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Drug residues that contaminate food and water represent a serious concern for human health. The major concerns regard the possible irrational use of these contaminants, since this might increase the amplitude of exposure. Multiple sources contribute to the overall exposure to contaminants, including agriculture, domestic use, personal, public and veterinary healthcare, increasing the possible origin of contamination. In this review, we focus on crop pesticides and veterinary drug residues because of their extensive use in modern agriculture and farming, which ensures food production and security for the ever-growing population around the world. We discuss crop pesticides and veterinary drug residues with respect to their worldwide distribution and impacts, with special attention on their harmful effects on human reproduction and embryo development, as well as their link to epigenetic alterations, leading to intergenerational and transgenerational diseases. Among the contaminants, the most commonly implicated in causing such disorders are organophosphates, glyphosate and antibiotics, with tetracyclines being the most frequently reported. This review highlights the importance of finding new management strategies for pesticides and veterinary drugs. Moreover, due to the still limited knowledge on inter- and transgenerational effects of these contaminants, we underlie the need to strengthen research in this field, so as to better clarify the specific effects of each contaminant and their long-term impact.
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Desarrollo Embrionario , Fertilidad , Plaguicidas , Drogas Veterinarias , Humanos , Desarrollo Embrionario/efectos de los fármacos , Fertilidad/efectos de los fármacos , Exposición Dietética/efectos adversos , Animales , Residuos de Medicamentos/análisis , Epigénesis Genética/efectos de los fármacos , Residuos de Plaguicidas/análisisRESUMEN
Monobutyl phthalate (MBP) is the primary active metabolite of dibutyl phthalate (DBP), the key plasticizer component. A substantial body of evidence from studies conducted on both animals and humans indicates that MBP exposure could result in harmful impacts on toxicity pathways. In addition, it can seriously affect human and animal reproductive health. In our present study, we showed that exposure to MBP causes abnormal epigenetic modifications in porcine oocytes and failure of early embryonic development. However, glycine (Gly) can protect oocytes and early embryos from damage caused by MBP. Our study indicated a significant decrease in the percentage of porcine oocytes that reached the metaphase II (MII) phase when exposed to MBP. SET-domain-containing 2(SETD2)-mediated H3K36me3 histone methylation was detected, and the results showed that MBP significantly decreased the protein expression of H3K36me3 and SETD2. Moreover, the expression of the DNA break markers γH2AX and the mRNA expression of Asf1a, and Asf1b increased in the MBP group. The detection of DNA methylation marker proteins showed that MBP significantly increased the fluorescence intensity of 5-methylcytosine (5mC). The results from our RT-qPCR analysis demonstrated a significant decrease in the mRNA expression of the DNA methylation-related genes Dnmt1 and Dnmt3a, as well as the embryonic developmental potential-related genes Oct4 and Nanog, in porcine oocytes following exposure to MBP. Additionally, the mRNA expression of p53 significantly increased. Subsequently, the effects of MBP on early embryonic development were examined via parthenogenesis activation (PA) and in vitro fertilization (IVF). Exposure to MBP significantly impacted the development of embryos in both PA and IVF processes. The TUNEL staining data showed that MBP significantly increased embryonic apoptosis. However, Gly can ameliorate MBP-induced defects in oocyte epigenetic modifications and early embryonic development.
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Metilación de ADN , Desarrollo Embrionario , Epigénesis Genética , Glicina , Oocitos , Ácidos Ftálicos , Animales , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Desarrollo Embrionario/efectos de los fármacos , Porcinos , Epigénesis Genética/efectos de los fármacos , Glicina/análogos & derivados , Glicina/toxicidad , Ácidos Ftálicos/toxicidad , Metilación de ADN/efectos de los fármacos , Femenino , Plastificantes/toxicidad , Histonas/metabolismoRESUMEN
Inhaled particulate matter (PM) is a key factor in millions of yearly air pollution-related deaths worldwide. The oxidative potential of PM indicates its ability to promote an oxidative environment. Excessive reactive oxygen species (ROS) can cause cell damage via oxidative stress, leading to inflammation, endoplasmic reticulum stress, airway remodeling, and various cell death modes (apoptosis, ferroptosis, pyroptosis). ROS can also interact with macromolecules, inducing DNA damage and epigenetic modifications, disrupting homeostasis. These effects have been studied extensively in vitro and confirmed in vivo. This review explores the oxidative potential of airborne particles and PM-induced ROS-mediated cellular damage observed in vitro, highlighting the link between oxidative stress, inflammation, and cell death modes described in the latest literature. The review also analyzes the effects of ROS on DNA damage, repair, carcinogenicity, and epigenetics. Additionally, the latest developments on the potential of antioxidants to prevent ROS's harmful effects are described, providing future perspectives on the topic.
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Antioxidantes , Daño del ADN , Estrés Oxidativo , Material Particulado , Especies Reactivas de Oxígeno , Estrés Oxidativo/efectos de los fármacos , Material Particulado/toxicidad , Humanos , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Daño del ADN/efectos de los fármacos , Contaminantes Atmosféricos/toxicidad , Epigénesis Genética/efectos de los fármacosRESUMEN
This study examines the effects of Roundup Transorb® (RDT) exposure on reproductive functions and ovarian miRNA expression in Austrolebias charrua. Exposure to RDT (at 0.065 or 5â¯mg. L-1 for 96â¯h) significantly disrupts fertility, evidenced by changes in fertilization rates and egg diameter. Profiling of ovarian miRNAs identified a total 205 miRNAs in A. charrua. Among these, three miRNAs were upregulated (miR-10b-5p, miR-132-3p, miR-100-5p), while ten miRNAs were downregulated (miR-499-5p, miR-375, miR-205-5p, miR-206-3p, miR-203a-3p, miR-133b-3p, miR-203b-5p, miR-184, miR-133a-3p, miR-2188-5p) compared to non-exposed fish. This study reveals that differentially expressed miRNAs are linked to molecular pathways such as steroid hormone biosynthesis, lipid and carbohydrate metabolism, bioenergetics, and antioxidant defense. It also analyzes molecular interactions between miRNAs and target genes during RDT exposure in annual killifish, providing insights into biomarkers in ecotoxicology. Moreover, it provides scope for developing environmental health assessment models based on epigenomic endpoints, supporting the protection of biodiversity and ecosystem services through the quantification of stress responses in living organisms exposed to pesticides.
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Epigénesis Genética , MicroARNs , Reproducción , Contaminantes Químicos del Agua , Animales , MicroARNs/genética , Femenino , Contaminantes Químicos del Agua/toxicidad , Epigénesis Genética/efectos de los fármacos , Reproducción/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/metabolismo , Insecticidas/toxicidad , Peces/genética , Peces KilliRESUMEN
The unsustainable use of manmade chemicals poses significant threats to biodiversity and human health. Emerging evidence highlights the potential of certain chemicals to cause transgenerational impacts on metabolic health. Here, we investigate male transmitted epigenetic transgenerational effects of the anti-androgenic herbicide linuron in the pancreas of Xenopus tropicalis frogs, and their association with metabolic phenotypes. Reduced representation bisulfite sequencing (RRBS) was used to assess genome-wide DNA methylation patterns in the pancreas of adult male F2 generation ancestrally exposed to environmentally relevant linuron levels (44 ± 4.7 µg/L). We identified 1117 differentially methylated regions (DMRs) distributed across the X. tropicalis genome, revealing potential regulatory mechanisms underlying metabolic disturbances. DMRs were identified in genes crucial for pancreatic function, including calcium signalling (clstn2, cacna1d and cadps2), genes associated with type 2 diabetes (tcf7l2 and adcy5) and a biomarker for pancreatic ductal adenocarcinoma (plec). Correlation analysis revealed associations between DNA methylation levels in these genes and metabolic phenotypes, indicating epigenetic regulation of glucose metabolism. Moreover, differential methylation in genes related to histone modifications suggests alterations in the epigenetic machinery. These findings underscore the long-term consequences of environmental contamination on pancreatic function and raise concerns about the health risks associated with transgenerational effects of pesticides.