RNA A-to-I editing, environmental exposure, and human diseases.

Epigenetic modifications have gained attention since they can be potentially changed with environmental stimuli and can be associated with adverse health outcomes. Epitranscriptome field has begun to attract attention with several aspects since RNA modifications have been linked with critical biological processes and implicated in diseases. Several RNA modifications have been identified as reversible indicating the dynamic features of modification which can be altered by environmental cues. Currently, we know more than 150 RNA modifications in different organisms and on different bases which are modified by various chemical groups. RNA editing, which is one of the RNA modifications, occurs after transcription, which results in RNA sequence different from its corresponding DNA sequence. Emerging evidence reveals the functions of RNA editing as well as the association between RNA editing and diseases. However, the RNA editing field is beginning to grow up and needs more empirical evidence in regard to disease and toxicology. Thus, this review aims to provide the current evidence-based studies on RNA editing modifying genes for genotoxicity and cancer. The review presented the association between environmental xenobiotics exposure and RNA editing modifying genes and focused on the association between the expression of RNA editing modifying genes and cancer. Furthermore, we discussed the future directions of scientific studies in the area of RNA modifications, especially in the RNA editing field, and provided a knowledge-based framework for further studies.

Up-to-date on the evidence linking miRNA-related epitranscriptomic modifications and disease settings. Can these modifications affect cross-kingdom regulation?

The field of epitranscriptomics is rapidly developing. Several modifications (e.g. methylations) have been identified for different RNA types. Current evidence shows that chemical RNA modifications can influence the whole molecule's secondary structure, translatability, functionality, stability, and degradation, and some are dynamically and reversibly modulated. miRNAs, in particular, are not only post-transcriptional modulators of gene expression but are themselves submitted to regulatory mechanisms. Understanding how these modifications are regulated and the resulting pathological consequences when dysregulation occurs is essential for the development of new therapeutic targets. In humans and other mammals, dietary components have been shown to affect miRNA expression and may also induce chemical modifications in miRNAs. The identification of chemical modifications in miRNAs (endogenous and exogenous) that can impact host gene expression opens up an alternative way to select new specific therapeutic targets.Hence, the aim of this review is to briefly address how RNA epitranscriptomic modifications can affect miRNA biogenesis and to summarize the existing evidence showing the connection between the (de)regulation of these processes and disease settings. In addition, we hypothesize on the potential effect certain chemical modifications could have on the potential cross-kingdom journey of dietary plant miRNAs.

Exposure to glyphosate and tetrachlorvinphos induces cytotoxicity and global DNA methylation in human cells.

Two organophosphate pesticides-glyphosate and tetrachlorvinphos-have been announced as carcinogens to humans by various authorities, including the European Chemical Agency and the Environmental Protection Agency. We aimed to investigate molecular mechanisms associated with carcinogenicity and to examine changes in global m5C DNA methylation and cytotoxic potential in A549 lung epithelial cells in response to glyphosate and tetrachlorvinphos, and differential gene expression of m5C DNA methyltransferase genes in Sprague Dawley rats to Roundup (commercial formulation of glyphosate). Global m5C level significantly increased after 1500 µM glyphosate exposure for 24 h. We determined that exposure to tetrachlorvinphos did not significantly increase the m5C level in A549 cells for 24 h. Additionally, we did not observe significant DNA methylation alteration for both pesticides after 12 h exposure. In the animal study, we observed that DNA methyltransferase genes (DNMT3b and DNMT3a) showed significantly higher expression in Roundup-exposed rats than the control group in the liver and kidney. We also observed that a significant cytotoxic effect was determined after the treatment of the cells with higher concentrations of glyphosate and tetrachlorvinphos. Our results revealed that DNA methylation could be modified by exposure to glyphosate and that exposure to Roundup was associated with the differential expression level of m5C DNA methylation methyltransferase. Finally, exposure to both pesticides increased cytotoxicity.

Environmental exposures and RNA N6-Methyladenosine modified long Non-Coding RNAs.

Recent advances in the field of RNA modifications and long non-coding RNAs (lncRNAs) have provided substantial evidence on important biological functions. LncRNAs are defined as longer than 200 nucleotides which are not translated into proteins. The term "epitranscriptome" refers to all modifications in RNA types. Adenine-6 methylation (m6A) is the most common, dynamic and prominent modifications in coding and non-coding RNAs and has critical and previously unappreciated functional roles. Accumulation evidence indicated the association between RNA m6A modification and cancer and nonmalignant diseases. Recent studies reported that several lncRNAs including MALAT1, MEG3, XIST, GAS5, and KCNK15-AS1 are subject to m6A modification. It can be suggested that lncRNAs modified by m6A modification have substantive roles in diseases. Currently limited data are available regarding how environmental exposure affects m6A-modified lncRNAs. Furthermore, we do not know the interaction of environmental exposure and m6A-modified lncRNAs in development of adverse human health outcomes. Thus, in this systematic review, we aimed to present the data of the studies that reported a significant association between environmental exposure and expression/DNA methylation of m6A-modified long non-coding RNAs.

Environmental epitranscriptomics.

Chemical modifications of RNA molecules have gained increasing attention since evidence emerged for their substantive roles in a range of biological processes, such as the stability and translation of mRNA transcripts. More than 150 modifications have been identified in different organisms to date, collectively known as the 'epitranscriptome', with 6-methyladenosine (m6A), 5-methylcytidine (m5C), pseudouridine and N1-methyladenosine (m1A) the most extensively investigated. Although we are just beginning to elucidate the roles of these modifications in cellular functions, there is already evidence for their dysregulation in diseases such as cancer and neurodevelopmental disorders. There is currently more limited knowledge regarding how environmental exposures affect the epitranscriptome and how this may mediate disease risk, but evidence is beginning to emerge. Here, we review the current evidence for the impact of environmental exposures such as benzo[a]pyrene, bisphenol A, pesticides, metals and nanoparticles upon RNA modifications and the expression of their 'writers' (methyl transferases), 'erasers' (demethylases) and 'readers'. We discuss future directions of the field and identify areas of particular promise and consider the technical challenges that are faced.

Total circulating cell-free miRNA in plasma as a predictive biomarker of the thyroid diseases.

BACKGROUND: Thyroid cancer is a common endocrine cancer. Great progress has been made in resolving its molecular mechanisms in recent years. The molecular changes observed in thyroid cancer can be used as biomarkers for diagnostic, prognostic and therapeutic purposes. MicroRNAs (miRNAs) are important components in biological and metabolic pathways, such as developmental stages, signal transduction, cell maintenance, and differentiation. Hence, their malfunctioning can expose humans to malignancies. miRNA expressions have been shown to be dysregulated in different tumor types, like thyroid cancer, and may cause tumor initiation and progression. In previous studies, only cancer has been studied, and miRNA has been detected from the tissues in all the studies performed. In this study, we have focused on thyroid diseases such as bening nodules and Hashimoto's disease, which might be the cause of thyroid cancer, and have carried out miRNA tests in the blood samples taken from the arms thyroid patients. MATERIAL AND METHOD: The present study was conducted on the blood samples of 100 thyroid patients. Of the 100 patients in our study, 33 consisted of patients with thyroiditis, while 37 patients were diagnosed with benign thyroid nodules and 30 patients had thyroid cancer. For the control group, 18 patients were included. The plasma samples were analyzed, and the total miRNA levels were determined. RESULTS: We found that the ccf-miRNA amount of benign patients is significantly lower than that of the controls. Similarly, the miRNA amount in the controls is significantly higher than that of the thyroiditis (P = 0.06) and the malign groups miRNA (P = 0.084). Although the present study has a low number of patients, the plasma samples could be used as a source of circulating miRNAs. In addition, the total miRNA of thyroid diseases could be used as a biomarker for different types of thyroid diseases. We could suggest, for future study, that specific miRNAs in bodily fluid might show specific properties to be used as biomarkers of thyroid diseases.

Comet assay for assessment of DNA damage in greenhouse workers exposed to pesticides.

Purpose: The main goal of the present study was to determine DNA damage in pesticide-exposed greenhouse workers and pesticides non-exposed controls. Materials and methods: The DNA damage was measured by alkaline comet assay method (pH > 13) in 41 greenhouse workers and 45 non-exposed individuals as the control. Pesticide exposure was assessed by duration of working in the greenhouse and pesticide application in the greenhouse time. DNA damage was estimated by arbitrary unit and damage frequency. Results: Arbitrary unit and damage frequency were consistently significantly higher in greenhouse workers than those of the controls (p = 0.001). In terms of gender in greenhouse, DNA damage of female workers was significantly higher than those in male workers (p < 0.05). We found significant correlation between DNA damage and working hours spent. Multiple linear regression analysis showed that working hours in the greenhouse as an indication of pesticide exposure were significantly associated with the DNA damage, which can be attributed to the genotoxic potential of the pesticide mixture. Conclusions: The comet assay is sensitive to detect the damage exposed to chronic effect of pesticides in greenhouse workers. Significant DNA damage was obtained for the exposed group, which was associated with the pesticide exposure.

Exposure to environmental toxicants reduces global N6-methyladenosine RNA methylation and alters expression of RNA methylation modulator genes.

The epitranscriptome comprises more than 100 forms of RNA modifications. Of these, N6-methyladenosine (m6A) is the most abundantform of RNA methylation, with roles in modulating mRNA transcript processing and regulation. The aims of the study weretoexamine changes inm6A RNA methylation in A549 lung epithelial cells in response to environmental toxicants, anddifferential gene expression of m6A modulator genes ('readers', 'writers' and 'erasers') in human subjects exposed toparticulate matter (PM) and in lung cancer tissueusing publicly-available microarray datasets. Global m6A methylation levelsweremeasured in total RNA after exposuretotwo carcinogens (PM and sodium arsenite) for 24- and 48-h, and totwo endocrine disruptors (bisphenol A and vinclozolin)for 24-h.Global m6A methylation level significantly decreased with exposure to >62 µg/mlPM, >1 µM sodium arsenite, >1  µM bisphenol A (BPA), and0.1  µM vinclozolin. In an analysis of a published dataset derived from a population study, we observed that m6A writers (METTL3 and WTAP), erasers (FTO and ALKBH5) and readers (HNRPC) showed significantly higher expression among participants in the high-PM2.5exposure group compared to those in the low-exposure control group (all p < 0.05). Further, the m6A writer METTL3shows reduced expression in lung tumors in comparison to normal lung epithelia (p < 0.0001). Our findings reveal that m6A RNA methylation can be modified by exposure to environmental toxicants, and exposure to particulate matter is associated with differential expression level of m6A RNA methylation modification machinery.

In vitro genotoxic and cytotoxic effects of doxepin and escitalopram on human peripheral lymphocytes.

Antidepressants are drugs used for the treatment of many psychiatric conditions including depression. There are findings suggesting that these drugs might have genotoxic, carcinogenic, and/or mutagenic effects. Therefore, the present in vitro study is intended to investigate potential genotoxic and cytotoxic effects of the antidepressants escitalopram (selective serotonin reuptake inhibitor) and doxepin (Tricyclic antidepressant) on human peripheral lymphocytes cytokinesis-block micronucleus (CBMN), sister chromatid exchange (SCE), and single cell gel electrophoresis (alkaline comet assay) were used for the purpose of the study. In the study, four different concentrations of both drugs (1, 2.5, 5, and 10 µg/mL) were administered to human peripheral lymphocytes for 24 h. The tested concentrations of both drugs were found to exhibit no cytotoxic and mitotic inhibitory effects. SCE increase caused by 5 and 10 µg/mL of escitalopram was found statistically significant, while no statistically significant increase was observed in DNA damage and micronucleus (MN) formation. Moreover, the increase caused by doxepin in MN formation was not found statistically significant. Besides, 10 µg/mL of doxepin was demonstrated to significantly increase arbitrary unit and SCE formation. These findings suggest that the investigated concentrations of escitalopram and doxepin were non-cytotoxic but potentially genotoxic at higher concentrations.

Traffic-Related Air Pollution, Blood Pressure, and Adaptive Response of Mitochondrial Abundance.

BACKGROUND: Exposure to black carbon (BC), a tracer of vehicular-traffic pollution, is associated with increased blood pressure (BP). Identifying biological factors that attenuate BC effects on BP can inform prevention. We evaluated the role of mitochondrial abundance, an adaptive mechanism compensating for cellular-redox imbalance, in the BC-BP relationship. METHODS AND RESULTS: At ≥ 1 visits among 675 older men from the Normative Aging Study (observations=1252), we assessed daily BP and ambient BC levels from a stationary monitor. To determine blood mitochondrial abundance, we used whole blood to analyze mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA) using quantitative polymerase chain reaction. Every standard deviation increase in the 28-day BC moving average was associated with 1.97 mm Hg (95% confidence interval [CI], 1.23-2.72; P<0.0001) and 3.46 mm Hg (95% CI, 2.06-4.87; P<0.0001) higher diastolic and systolic BP, respectively. Positive BC-BP associations existed throughout all time windows. BC moving averages (5-day to 28-day) were associated with increased mtDNA/nDNA; every standard deviation increase in 28-day BC moving average was associated with 0.12 standard deviation (95% CI, 0.03-0.20; P=0.007) higher mtDNA/nDNA. High mtDNA/nDNA significantly attenuated the BC-systolic BP association throughout all time windows. The estimated effect of 28-day BC moving average on systolic BP was 1.95-fold larger for individuals at the lowest mtDNA/nDNA quartile midpoint (4.68 mm Hg; 95% CI, 3.03-6.33; P<0.0001), in comparison with the top quartile midpoint (2.40 mm Hg; 95% CI, 0.81-3.99; P=0.003). CONCLUSIONS: In older adults, short-term to moderate-term ambient BC levels were associated with increased BP and blood mitochondrial abundance. Our findings indicate that increased blood mitochondrial abundance is a compensatory response and attenuates the cardiac effects of BC.

Associations of Annual Ambient Fine Particulate Matter Mass and Components with Mitochondrial DNA Abundance.

BACKGROUND: Fine particulate matter (PM2.5) represents a mixture of components with potentially different toxicities. However, little is known about the relative effects of PM2.5 mass and PM2.5 components on mitochondrial DNA (mtDNA) abundance, which may lie on the pathway of PM2.5-associated disease. METHODS: We studied 646 elderly male participants in the Normative Aging Study from Greater Boston to investigate associations of long-term exposure to PM2.5 mass and PM2.5 components with mtDNA abundance. We estimated concentrations of pollutants for the 365-day preceding examination at each participant's address using spatial- and temporal-resolved chemical transport models. We measured blood mtDNA abundance using RT-PCR. We applied a shrinkage and selection method (adaptive LASSO) to identify components most predictive of mtDNA abundance, and fit multipollutant linear mixed-effects models with subject-specific intercept to estimate the relative effects of individual PM component. RESULTS: MtDNA abundance was negatively associated with PM2.5 mass in the previous year and-after adjusting for PM2.5 mass-several PM2.5 components, including organic carbon, sulfate (marginally), and nitrate. In multipollutant models including as independent variables PM2.5 mass and PM2.5 components selected by LASSO, nitrate was associated with mtDNA abundance. An SD increase in annual PM2.5-associated nitrate was associated with a 0.12 SD (95% confidence intervals [CI] = -0.18, -0.07) decrease in mtDNA abundance. Analyses restricted to PM2.5 annual concentration below the current 1-year U.S. Environmental Protection Agency standard produced similar results. CONCLUSIONS: Long-term exposures to PM2.5-associated nitrate were related to decreased mtDNA abundance independent of PM2.5 mass. Mass alone may not fully capture the potential of PM2.5 to oxidize the mitochondrial genome.See video abstract at, http://links.lww.com/EDE/B274.

Impacts of the Mitochondrial Genome on the Relationship of Long-Term Ambient Fine Particle Exposure with Blood DNA Methylation Age.

The mitochondrial genome has long been implicated in age-related disease, but no studies have examined its role in the relationship of long-term fine particle (PM2.5) exposure and DNA methylation age (DNAm-age)-a novel measure of biological age. In this analysis based on 940 observations between 2000 and 2011 from 552 Normative Aging Study participants, we determined the roles of mitochondrial DNA haplogroup variation and mitochondrial genome abundance in the relationship of PM2.5 with DNAm-age. We used the GEOS-chem transport model to estimate address-specific, one-year PM2.5 levels for each participant. DNAm-age and mitochondrial DNA markers were measured from participant blood samples. Nine haplogroups (H, I, J, K, T, U, V, W, and X) were present in the population. In fully adjusted linear mixed-effects models, the association of PM2.5 with DNAm-age (in years) was significantly diminished in carriers of haplogroup V (Pinteraction = 0.01; ß = 0.18, 95%CI: -0.41, 0.78) compared to noncarriers (ß = 1.25, 95%CI: 0.58, 1.93). Mediation analysis estimated that decreases in mitochondrial DNA copy number, a measure of mitochondrial genome abundance, mediated 12% of the association of PM2.5 with DNAm-age. Our data suggests that the mitochondrial genome plays a role in DNAm-age relationships particularly in the context of long-term PM2.5 exposure.

Effects of environmental noise exposure on DNA methylation in the brain and metabolic health.

Environmental noise exposure is associated with adverse effects on human health including hearing loss, heart disease, and changes in stress-related hormone levels. Alteration in DNA methylation in response to environmental exposures is a well-known phenomenon and it is implicated in many human diseases. Understanding how environmental noise exposures affect DNA methylation patterns may help to elucidate the link between noise and adverse effects on health. In this pilot study we examined the effects of environmental noise exposure on DNA methylation of genes related to brain function and investigated whether these changes are related with metabolic health. We exposed four groups of male Wistar rats to moderate intensity noise (70-75dB with 20-4000Hz) at night for three days as short-term exposure, and for three weeks as long-term exposure. Noise exposure was limited to 45dB during the daytime. Control groups were exposed to only 45dB, day and night. We measured DNA methylation in the Bdnf, Comt, Crhr1, Mc2r, and Snca genes in tissue from four brain regions of the rats (hippocampus, frontal lobe, medulla oblongata, and inferior colliculus). Further, we measured blood pressure and body weight after long-term noise exposure. We found that environmental noise exposure is associated with gene-specific DNA methylation changes in specific regions of the brain. Changes in DNA methylation are significantly associated with changes in body weight (between Bdnf DNA methylation and Δ body weight: r=0.59, p=0.018; and between LINE-1 ORF DNA methylation and Δ body weight: =-0.80, p=0.0004). We also observed that noise exposure decreased blood pressure (p=0.038 for SBP, p=0.017 for DBP and p 0. 017 for MAP) and decreased body weight (ß=-26g, p=0.008). In conclusion, environmental noise exposures can induce changes in DNA methylation in the brain, which may be associated with adverse effects upon metabolic health through modulation of response to stress-related hormones.

Micronuclei, nucleoplasmic bridges, and nuclear buds induced in human lymphocytes by the fungicide signum and its active ingredients (boscalid and pyraclostrobin).

The aim of this study was to investigate the genotoxic and cytotoxic potential of the Signum fungicide and its active ingredients (boscalid and pyraclostrobin) on human peripheral blood lymphocytes using the cytokinesis-block micronucleus (CBMN) assay. Micronuclei (MNi), nucleoplasmic bridges (NPBs), nuclear bud (NBUDs) formations, and the cytokinesis-block proliferation index (CBPI) were evaluated in treated lymphocytes in Go (cells were treated and then kept in culture without stimulation for 24 h) and proliferation phases (cells were treated after 44 h culture in medium containing phytohemagglutinin). MN formation in lymphocytes treated in G0 statistically increased at doses of 2, 6, and 25 µg/mL signum; 0.5 and 2 µg/mL boscalid; and 0.5, 1.5, and 2 µg/mL pyraclostrobin; while NPB formation increased at a dose of 0.25 µg/mL pyraclostrobin. All concentrations of each fungicide did not statistically increase NBUD formation, while the cytotoxicity increased the dependent on concentration in lymphocytes treated in G0 . Doses of 0.5, 1, 1.5, and 3 µg/mL signum; 0.5, 1, and 1.5 µg/mL boscalid; and 0.75 µg/mL pyraclostrobin statistically increased the MN formation in proliferating lymphocytes. NPB formation increased in proliferating lymphocytes at doses of 1, 1.5, 2, and 3 µg/mL signum and at a dose of 0.75 µg/mL pyraclostrobin. In addition, a dose of 0.75 µg/mL pyraclostrobin increased NBUD frequencies. Cytotoxicity increased with increasing concentrations of each fungicide. It is concluded that signum, boscalid, and pyraclostrobin may be genotoxic and cytotoxic in vitro human peripheral blood lymphocytes in consideration of each of the two protocols. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 723-732, 2014.

Occupational exposure to radiation among health workers: Genome integrity and predictors of exposure.

The current study aimed to investigate genomic instabilities in healthcare workers who may experience varying levels of radiation exposure through various radiological procedures. It also sought to determine if factors related to the work environment and dosimeter reading could effectively explain the observed genomic instabilities. Utilizing the cytokinesis-block micronucleus assay (CBMN) on peripheral blood lymphocytes, we assessed a spectrum of genomic aberrations, including nucleoplasmic bridge (NPB), nuclear budding (NBUD), micronucleus (MN) formation, and total DNA damage (TDD). The study uncovered a statistically significant increase in the occurrence of distinct DNA anomalies among radiology workers (with a significance level of P < 0.0001 for all measurements). Notably, parameters such as total working hours, average work duration, and time spent in projection radiography exhibited significant correlations with MN and TDD levels in these workers. The dosimeter readings demonstrated a positive correlation with the frequency of NPB and NBUD, indicating a substantial association between radiation exposure and these two genomic anomalies. Our multivariable models identified the time spent in projection radiography as a promising parameter for explaining the overall genomic instability observed in these professionals. Thus, while dosimeters alone may not fully explain elevated total DNA damage, intrinsic work environment factors hold potential in indicating exposure levels for these individuals, providing a complementary approach to monitoring.

Protocol for chromatin immunoprecipitation of histone modifications in frozen adipose tissue.

Chromatin immunoprecipitation (ChIP) combined with sequencing has revolutionized our understanding of gene regulation; however, its application to frozen adipose tissue presents unique challenges due to the high levels of lipid content. Here, we present a protocol for ChIP of histone modifications in human frozen adipose tissue. We describe steps for tissue preparation, chromatin isolation, sonication, pre-clearing of chromatin, and immunoprecipitation. We then detail procedures for elution, crosslink reversal, chromatin purification, quality control, and library synthesis.

Evaluation of background DNA damage in a Turkish population measured by means of the cytokinesis-block micronucleus cytome assay.

This study aimed to determine the background incidence of micronuclei (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) in the peripheral blood lymphocytes of a population in the province of Çanakkale, Turkey. Seventy-one individuals living under similar socio-economic conditions, not exposed to an X-ray examination during the last six months, receiving no medical treatment and not involved in agricultural activities were evaluated. In addition to genetic end-points, the cytokinesis-block proliferation index (CBPI) was determined. MN and NBUD frequencies gradually increased with age. MN frequencies of the older group were ∼7 fold higher than those of the younger group. Multiple linear regression analysis showed that apart from age, no significant effects of various confounding factors on MN and NBUD were observed. NPB frequencies were affected by gender. In the present study, no statistically significant effect was found of smoking on the genetic end-points evaluated, which agrees with results from other studies.

The emergent role of mitochondrial RNA modifications in metabolic alterations.

Mitochondrial epitranscriptomics refers to the modifications occurring in all the different RNA types of mitochondria. Although the number of mitochondrial RNA modifications is less than those in cytoplasm, substantial evidence indicates that they play a critical role in accurate protein synthesis. Recent evidence supported those modifications in mitochondrial RNAs also have crucial implications in mitochondrial-related diseases. In the light of current knowledge about the involvement, the association between mitochondrial RNA modifications and diseases arises from studies focusing on mutations in both mitochondrial and nuclear DNA genes encoding enzymes involved in such modifications. Here, we review the current evidence available for mitochondrial RNA modifications and their role in metabolic disorders, and we also explore the possibility of using them as promising targets for prevention and early detection. Finally, we discuss future directions of mitochondrial epitranscriptomics in these metabolic alterations, and how these RNA modifications may offer a new diagnostic and theragnostic avenue for preventive purposes. This article is categorized under: RNA Processing > RNA Editing and Modification.

Evaluation of metal concentrations in mussel M. galloprovincialis in the Dardanelles Strait, Turkey in regard of safe human consumption.

Concentrations of the elements were evaluated for the first time in Mytilus galloprovincialis in the Dardanelles (Canakkale Strait-Turkey). The concentration of elements were measured in samples collected in 2007, 2008 and 2009, while the concentrations of Fe and Ni were evaluated in samples taken in 2009. The maximum concentrations of Cd, Cr, Cu, Pb, Zn, Fe, and Ni were found to be 1.59, 6.04, 12.01, 6.03, 319.6, 402.79, and 3.52 mg/kg, respectively. In terms of the nutritional aspect, taking into account the values recommended by world health authorities, the concentration of elements can generally be considered not to be at levels posing a health risk.

RNA modifications as emerging therapeutic targets.

The field of epitranscriptome, posttranscriptional modifications to RNAs, is still growing up and has presented substantial evidences for the role of RNA modifications in diseases. In terms of new drug development, RNA modifications have a great promise for therapy. For example, more than 170 type of modifications exist in various types of RNAs. Regulatory genes and their roles in critical biological process have been identified and they are associated with several diseases. Current data, for example, identification of inhibitors targeting RNA modifications regulatory genes, strongly support the idea that RNA modifications have potential as emerging therapeutic targets. Therefore, in this review, RNA modifications and regulatory genes were comprehensively documented in terms of drug development by summarizing the findings from previous studies. It was discussed how RNA modifications or regulatory genes can be targeted by altering molecular mechanisms. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > RNA Editing and Modification.