RESUMEN
Cadmium, a common metal pollutant, has been demonstrated to induce type 2 diabetes by disrupting pancreatic ß cells function. In this study, transcriptome microarray was utilized to identify differential gene expression in oxidative damage to pancreatic ß cells following cadmium exposure. The results indicated that a series of mRNAs, LncRNAs, and miRNAs were altered. Of the differentially expressed miRNAs, miR-29a-3p exhibited the most pronounced alteration, with an 11.62-fold increase relative to the control group. Following this, the target gene of miR-29a-3p was identified as Col3a1 through three databases (miRDB, miRTarbase and Tarbase), which demonstrated a decrease across the transcriptome microarray. The upstream target gene of miR-29a-3p was identified as NONMMUT036805, with decreased expression observed in the microarray. Finally, the expression trend of NONMMUT036805/miR-29a-3p/Col3a1 was reversed following NAC pretreatment. This was accompanied by a reduction in oxidative damage indicators, MDA/ROS/GSH-Px appeared to be negatively affected to varying degrees. In conclusion, this study has demonstrated that multiple RNAs are altered during cadmium exposure-induced oxidative damage in pancreatic ß cells. The NONMMUT036805/miR-29a-3p/Col3a1 axis has been shown to be involved in this process, which provides a foundation for the identification of potential targets for cadmium toxicity intervention.
Asunto(s)
Cadmio , Células Secretoras de Insulina , MicroARNs , Estrés Oxidativo , ARN Endógeno Competitivo , Animales , Ratones , Cadmio/toxicidad , Línea Celular , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , ARN Endógeno Competitivo/genética , ARN Endógeno Competitivo/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , TranscriptomaRESUMEN
Cadmium can lead to the death of pancreatic ß cells, thus affecting the synthesis and secretion of insulin. However, the specific mechanisms underlying the cadmium-induced pancreatic ß cell death have not been fully understood. In this study, roles of m6A modification in regulating protein processing in endoplasmic reticulum (PPER) pathway in cadmium-induced pancreatic ß cell death were explored. Our results demonstrated that cell viability and RNA m6A modification level were decreased, while apoptosis rates increased after CdSO4 treatment in pancreatic ß cells (NIT-1). In addition, expressions of Bcl-2, Xbp1, Col3a1, Bax, Chop, Dnajb1, and Hsp90aa1 were all significantly changed in CdSO4 treatment cells. The m6A agonist entacapone (Ent) can prominently reverse the cytotoxicity effects of CdSO4 and alleviate the changes of protein expression induced by CdSO4 treatment. By contrast, m6A inhibitor 3-Deazaadenosine (DAA) can synergistically enhance the cytotoxicity of CdSO4 and aggravate the disorder of protein levels caused by CdSO4 treatment. Interestingly, the results of the immunoprecipitation experiment indicate that Ythdc2, one of m6A binding proteins, may regulate the PPER pathway molecules in an m6A-dependent manner. In summary, our findings provide new directions for the prevention and treatment of the impairment of pancreatic ß cell function induced by cadmium.
Asunto(s)
Cadmio , Células Secretoras de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Animales , Cadmio/toxicidad , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Estrés del Retículo Endoplásmico/efectos de los fármacosRESUMEN
N6-methyladenine (m6A) and 5-methylcytosine (m5C) are two common forms of RNA methylation that play an important role in the epigenetics of type 2 diabetes mellitus (T2DM). One type of cell death, ferroptosis, has been implicated in islet ß-cell damage in T2DM. Notably, RNA methylation, an upstream regulatory mechanism of mRNAs, can regulate the expression of ferroptosis signaling molecules, thereby affecting cell proliferation and death. Here, we found that the ferroptosis signaling pathway was activated in pancreas of T2DM rats, followed by significant changes in m6A/m5C modification regulatory molecules. These detection data together with the prediction results that m6A and m5C exist in the mRNAs of ferroptosis molecules, we speculate that m6A and m5C are probably involved in pancreatic cell damage by modifying of ferroptosis signaling molecules. In short, our findings provide a new research idea for future studies on the molecular mechanisms of pancreatic cell damage and point to a new direction for exploring the mechanisms of ferroptosis from the perspective of RNA methylation modification.
Asunto(s)
5-Metilcitosina , Diabetes Mellitus Tipo 2 , Ferroptosis , Páncreas , Animales , Ratas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Páncreas/metabolismo , Páncreas/patología , Masculino , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Transducción de Señal , Ratas Sprague-Dawley , Metilación , ARN Mensajero/metabolismo , ARN Mensajero/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologíaRESUMEN
Both dysregulation of N6-methyladenosine (m6A) regulatory proteins and Nrf2 signaling molecules are involved in the process of injury to multiple tissues. However, changes of m6A regulatory proteins and Nrf2 signaling molecules in liver tissue of T2DM remain unclear. In present study, changes of m6A regulatory proteins (Mettl3, Mettl16, Fto, Alkbh5 and Ythdc2) and Nrf2 signaling molecules (Nrf2, Sod1, Ho-1, Gclc) were detected in the liver tissues of T2DM rats, which constructed by high fat-diet feeding and intraperitoneal injection of streptozotocin. Our results indicated that the morphology of liver tissues from T2DM rats showed obvious abnormalities, as well as levels of liver function indicators and expressions of Nrf2 signaling molecules Nrf2, Sod1, Ho-1 were significantly increased in T2DM rats when compared with those in corresponding control rats. More importantly, m6A regulatory proteins such as Mettl3, Mettl16, Fto, Alkbh5 and Ythdc2 were dramatically higher than those in control rat. In a word, m6A regulatory proteins and Nrf2 signaling molecules may significantly change in liver tissue of T2DM rats. And This provides clues and ideas for the study of liver injury in T2DM from the perspective of RNA epigenetics in the future.
RESUMEN
Long non-coding RNAs (LncRNAs) play important regulatory roles in oxidative damage. Resveratrol, curcumin, and cyanidin are phytogenic antioxidants widely existing in nature and they have been proved to antagonize certain heavy metal-induced oxidative damage in cells. However, can they antagonize oxidative damage induced by cadmium in islet ß cells? Are their mechanisms of antagonizing oxidative damage related to LncRNAs? In this study, we first detected the cell viability of each group by CCK8 assay. Next, reactive oxygen species (ROS) were detected by the fluorescent probe. The contents of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) were detected according to the instructions of corresponding kits. At last, the levels of LncRNAs were detected by fluorescence quantitative real-time polymerase chain reaction (qPCR). The results showed that resveratrol, curcumin and cyanidin were able to reverse the reduction of cell viability induced by cadmium (CdSO4). Further determination revealed that SOD activities of the resveratrol+CdSO4, curcumin+CdSO4, and cyanidin+CdSO4 treatment groups increased significantly, and ROS levels and MDA contents dramatically decreased when compared with single CdSO4-treated group. More importantly, the levels of three CdSO4-elevated LncRNAs (NONMMUT029382, ENSMUST00000162103, ENSMUST00000117235) were all decreased and levels of three CdSO4-inhibited LncRNAs (NONMMUT036805, NONMMUT014565, NONMMUT065427) were increased after the pretreatment of resveratrol, curcumin and cyanidin. In summary, resveratrol, curcumin and cyanidin may effectly reverse the cadmium-induced oxidative damage and suggest that phytogenic antioxidants may prevent cells from cadmium-induced oxidative damage through changing the levels of LncRNAs.
Asunto(s)
Antocianinas , Antioxidantes , Cadmio , Supervivencia Celular , Curcumina , Células Secretoras de Insulina , Malondialdehído , Estrés Oxidativo , ARN Largo no Codificante , Especies Reactivas de Oxígeno , Resveratrol , Superóxido Dismutasa , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Resveratrol/farmacología , Supervivencia Celular/efectos de los fármacos , Cadmio/toxicidad , Superóxido Dismutasa/metabolismo , Malondialdehído/metabolismo , Curcumina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citología , Antocianinas/farmacología , Animales , Línea CelularRESUMEN
Lead is a common environmental heavy metal contaminant. Humans are highly susceptible to lead accumulation in the body, which causes nervous system damage and leads to a variety of nervous system diseases, such as Alzheimer's disease, Parkinson's disease, and autism spectrum disorder. Recent research has focused on the mechanisms of lead-induced neurotoxicity at multiple levels, including DNA methylation, histone modifications, and non-coding RNAs, which are involved in various lead-induced nervous system diseases. We reviewed the latest articles and summarised the emerging roles of DNA methylation, histone modification, and non-coding RNAs in lead-induced neurotoxicity. Our summary provides a theoretical basis and directions for future research on the prevention, diagnosis, and treatment of lead-induced neurological diseases.
Asunto(s)
Trastorno del Espectro Autista , Enfermedades del Sistema Nervioso , Humanos , Plomo/toxicidad , Epigénesis Genética , Metilación de ADNRESUMEN
N6-methyladenosine (m6A), one of the most common RNA methylation modifications, has emerged in recent years as a new layer of the regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification, m6A not only occurs on mRNAs but also on Long non-coding RNAs (LncRNAs). As we all known, despite LncRNAs cannot encode proteins, they affect the expression of proteins by interacting with mRNAs or miRNAs, thus playing important roles in the occurrence and development of a variety of tumors. Up to now, it has been widely accepted that m6A modification on LncRNAs affects the fate of the corresponding LncRNAs. Interestingly, levels and functions of m6A modifications are also mediated by LncRNAs through affecting the m6A methyltransferases (METTL3, METTL14, WTAP, METTL16, etc.), demethylases (FTO, ALKBH5) and methyl-binding proteins (YTHDFs, YTHDCs, IGF2BPs, HNRNPs, etc.), which are collectively referred to as "m6A regulators". In this review, we summarized the mutual regulation mechanisms between N6-methyladenosine modification and LncRNAs in cancer progression, metastasis, invasion and drug resistance. In detail, we focus on the specific mechanisms of m6A modification, which is mediated by methyltransferases and demethylases, involves in the regulation of LncRNA levels and functions in the first part. And section two intensively displays the mediation roles of LncRNAs in m6A modification via changing the regulatory proteins. At last part, we described the interaction effects between LncRNAs and methyl-binding proteins of m6A modification during various tumor occurrence and development.
RESUMEN
N6-metyladenosine (m6A), one of the most common RNA methylation modifications in mammals, has attracted extensive attentions owing to its regulatory roles in a variety of physiological and pathological processes. As a reversible epigenetic modification on RNAs, m6A is dynamically mediated by the functional interplay among the regulatory proteins of methyltransferases, demethylases and methyl-binding proteins. In recent years, it has become increasingly clear that m6A modification is associated with the production and function of microRNAs (miRNAs). In this review, we summarize the specific kinds of m6A modification methyltransferases, demethylases and methyl-binding proteins. In particular, we focus on describing the roles of m6A modification and its regulatory proteins in the production and function of miRNAs in a variety of pathological and physiological processes. More importantly, we further discuss the mediating mechanisms of miRNAs in m6A modification and its regulatory proteins during the occurrence and development of various diseases.
Asunto(s)
MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Adenosina/metabolismo , Metilación , Metiltransferasas/metabolismo , Epigénesis Genética , Proteínas Portadoras/metabolismo , Factores de Transcripción/metabolismo , Mamíferos/metabolismoRESUMEN
It is controversial that high-fluoride and high-iodine combined exposure affects the prevalence of dental fluorosis and goiter. The aim of this study was to explore the potential association between high-fluoride and high-iodine combined exposure with dental fluorosis and goiter. We retrieved relevant articles from PubMed, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database and China Science and Technology Journal Database (VIP). The query format was 1 # "Fluorosis" OR "Fluoride," 2 # "Iodine" OR "Iodide," and 3 # 1 AND 2. A total of 20 papers were included in this study after independent review by two investigators. Our analysis showed that high-fluoride and high-iodine biphasic exposure was significantly associated with the prevalence of goiter (OR = 4.69, 95% CI 2.82-7.80, P < 0.001). The prevalence of dental fluorosis was also significantly raised (OR = 11.71, 95% CI 7.57-18.14, P < 0.001). Sensitivity analysis suggested that combined statistics of multiple studies were reliable. For goiter, subgroup analysis revealed study province, sample size and published year as sources of heterogeneity (P < 0.001). For dental fluorosis, only sample size was the impact factor of heterogeneity. As well, funnel plot, Begg's test and Egger's test suggested there was no publication bias (P > 0.05). Overall, our study demonstrates that high-fluoride and high-iodine combined exposure is a risk factor for occurrence of dental fluorosis and goiter. The chronic of high-fluoride and high-iodine combined exposure is a significant higher risk of disease than normal.
Asunto(s)
Fluorosis Dental , Bocio , Yodo , Humanos , Fluoruros/toxicidad , Fluoruros/análisis , Fluorosis Dental/epidemiología , Fluorosis Dental/etiología , Factores de Riesgo , PrevalenciaRESUMEN
As a common environmental heavy metal pollutant, cadmium has been well evidenced to cause kidney damage; yet, the underlying mechanisms are still not fully clarified. In this study, cell viability of human renal tubular epithelial cell (HK-2) was determined by CCK-8 assay after treatment with CdSO4. Then, apoptotic morphology of cells was observed by Hoechst staining and level of reactive oxygen species (ROS) was detected by fluorescent probes. Subsequently, mRNA levels of Nrf2, HO-1, m6A methyltransferases (METTL3, METTL14, METTL16, WATP), m6A demethylases (FTO, ALKBH5), m6A methyl-binding proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2) were detected by real-time polymerase chain reaction (RT-PCR), closely followed by correlation analysis between Nrf2 mRNA levels and m6A methyltransferases and demethylases. Lastly, protein expressions of Nrf2, METTL3, and FTO were tested by western blotting assay. The detection results demonstrated that the treatment of CdSO4 decreased viability while increased apoptosis rate. The Nrf2 mRNA level in CdSO4-treated cells was significantly increased when compared with that in the control cells, and the HO-1 mRNA level elevated with the increasing of CdSO4 concentrations. In addition, mRNA levels of METTL3, METTL14, METTL16, WTAP, FTO, and methyl-binding proteins in CdSO4-treated cells were all higher than those in corresponding control cells. Further determination showed that protein expressions of Nrf2, METTL3, and FTO were also upregulation under the treatment of CdSO4. Lastly, correlation analysis indicated that mRNA level of Nrf2 was positively correlated with mRNA levels of m6A methyltransferases and demethylases. In a word, our results demonstrated that the molecular changes of Nrf2 signaling pathway are correlated with the levels of m6A regulatory proteins, suggesting that there may be a regulatory relationship between Nrf2 signaling pathway and m6A regulatory proteins in the process of cadmium-induced renal cell cytotoxicity.
Asunto(s)
Cadmio , Factor 2 Relacionado con NF-E2 , Humanos , Cadmio/toxicidad , Cadmio/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Estrés Oxidativo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Riñón/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismoRESUMEN
N6-methyladenosine (m6A) modification and m6A-modified Long non-coding RNAs (LncRNAs) play crucial roles in various pathological processes, yet their changes and relationship in cadmium-induced oxidative damage are largely unknown. Here, five m6A-modified LncRNAs (LncRNA-TUG1, LncRNA-PVT1, LncRNA-MALAT1, LncRNA-XIST, LncRNA-NEAT1), which have been evidenced to involve in oxidative damage, were selected and their binding proteins were submitted to bioinformatics analysis. Our analysis results showed that these five m6A-modified LncRNAs bound to different regulatory proteins of m6A modification, implicating that m6A modification on LncRNAs may synergistically control by multiple regulatory proteins. Furthermore, the detection data revealed that levels of m6A modification, methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) were all significantly decreased in CdSO4-induced oxidative damage, which was demonstrated by increasing ROS accumulation and MDA contents as well as decreasing SOD activities. More importantly, LncRNA-MALAT1 and LncRNA-PVT1 indicated downward trend and showed positive relationship with m6A modification. Collectively, our results showed that m6A modification and m6A-modified LncRNAs may involve in oxidative damage induced by cadmium.
Asunto(s)
Adenosina/análogos & derivados , Compuestos de Cadmio/toxicidad , Células Secretoras de Insulina/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , ARN Largo no Codificante/metabolismo , Sulfatos/toxicidad , Adenosina/química , Adenosina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Biología Computacional , Células Secretoras de Insulina/metabolismo , Ratones , Especies Reactivas de OxígenoRESUMEN
Metal cadmium (Cd) and its compounds are ubiquitous industrial and environmental pollutants and they have been believed to exert severe damage to multiple organs and tissues. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are the two most common noncoding RNAs and have pivotal roles in various cellular and physiological processes. Since the importance of miRNAs and lncRNAs in Cd toxicity has been widely recognized, we focus our interests on the current researches of miRNAs and lncRNAs as well as their regulation roles in Cd toxicity. In this paper, the keywords "cadmium" in combination with "miRNA" or "LncRNA" or "noncoding RNA" was used to retrieve relevant articles in PubMed, EMbase, CNKI, Wan Fang, and CBM databases. The literatures which contained the above keywords and carried out in animals (in vivo and in vitro) have been collected, collated, analyzed, and summarized. Our summary results showed that hundreds of miRNAs and lncRNAs are involved in the Cd toxicity, which have been demonstrated as multiple organ injury, reproductive toxicity, malignant transformation, and abnormal repair of DNA damage. In this paper, we also discussed the blank in present research field of Cd toxicity as well as suggested some ideas for future study in Cd toxicity.