Genome-Wide Differential Methylation Profiles from Two Terpene-Rich Medicinal Plant Extracts Administered in Osteoarthritis Rats.
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ABSTRACT:
SUBMITTER: Shin Y
PROVIDER: S-EPMC8227118 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Our study aimed to identify differentially methylated regions (i.e., genomic region where multiple adjacent CpG sites show differential methylation) and their enriched genomic pathways associated with knee osteoarthritis pain (KOA). We recruited cognitively healthy middle to older aged (age 45-85) adults with (n = 182) and without (n = 31) self-reported KOA pain. We also extracted DNA from peripheral blood that was analyzed using MethylationEPIC arrays. The R package minfi (Aryee et al., 2014) was used to perform methylation data preprocessing and quality control. To investigate biological pathways impacted by differential methylation, we performed pathway enrichment analysis using Ingenuity Pathway Analysis (IPA) to identify canonical pathways and upstream regulators. Annotated genes within ± 5 kb of the putative differentially methylated regions (DMRs, p < 0.05) were subjected to the IPA analysis. There was no significant difference in age, sex, study site between no pain and pain group (p > 0.05). Non-Hispanic black individuals were overrepresented in the pain group (p = 0.003). At raw p < 0.05 cutoff, we identified a total of 19,710 CpG probes, including 13,951 hypermethylated CpG probes, for which DNA methylation level was higher in the groups with highest pain grades. We also identified 5,759 hypomethylated CpG probes for which DNA methylation level was lower in the pain groups with higher pain grades. IPA revealed that pain-related DMRs were enriched across multiple pathways and upstream regulators. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e., antigen presentation, PD-1, PD-L1 cancer immunotherapy, B cell development, IL-4 signaling, Th1 and Th2 activation pathway, and phagosome maturation). Moreover, in terms of upstream regulators, NDUFAF3 was the most significant (p = 8.6E-04) upstream regulator. Our findings support previous preliminary work suggesting the importance of epigenetic regulation of the immune system in knee pain and the need for future work to understand the epigenetic contributions to chronic pain.
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Project description:BackgroundPharyngitis is an inflammatory condition of the pharynx and associated structures commonly caused by the Group A streptococci (GAS). There is a growing interest in discovering plant-based anti-inflammatory compounds as potential alternatives to conventional drugs. This study evaluated anti-inflammatory activity of phytochemical-rich extracts prepared from 12 herbal plants using human tonsil epithelial cells (HTonEpiC) in vitro.MethodsThe HTonEpiC were induced by a mixture of lipoteichoic acid (LTA) and peptidoglycan (PGN) (10 µg/mL; bacterial antigens) for 4 h and then exposed to ethanol extracts (EE) or aqueous extracts (AE) for 20 h. The secretion of four pro-inflammatory cytokines was measured using enzyme-linked immunosorbent assays (ELISA). Total phenolic and total flavonoid contents of the extracts were determined using spectrophotometric methods.ResultsThe herbal plant extracts (≤5 µg/mL) were not cytotoxic to HTonEpiC. The extracts exhibited a broad range of reduction (1.2%-92.6%) of secretion of interleukin-8 (IL-8), human beta defensin-2 (hBD-2), epithelial-derived neutrophil activating protein-78 (ENA-78), and granulocyte chemotactic protein-2 (GCP-2). Both EE and AE of clove, ginger, and echinacea flower and EE from danshen root significantly inhibited the pro-inflammatory cytokine production as induced by LTA and PGN in HTonEpiCs at the concentrations of 1 and 5 µg/mL.DiscussionOur observations indicate that danshen root, clove, ginger, and echinacea flower extracts exhibit an anti-inflammatory effect in HTonEpiCs. The most efficacious extracts from danshen root, clove, ginger and echinacea flowers have potential to be used as natural sources for developing phytotherapeutic products in the management of painful inflammation due to streptococcal pharyngitis.
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Project description:Leucocalocybe mongolica is a known medicinal mushroom in China. It possesses many biological activities. This study investigated the effect of L. mongolica petroleum ether and water extracts (200, 500, and 1,000 mg/kg BW) on mammary gland differentiation during lactation. However, prolactin, growth hormone, progesterone, and estrogen levels were determined in serum by ELISA assay. Immunofluorescence, western blot, and real-time PCR were utilized to evaluate the expression levels of β-casein, α-Lactalbumin, prolactin receptor, progesterone receptor, and STAT-5a. The immunohistochemistry staining was used to detect the presence of steroid receptors. The results showed that petroleum ether and water extracts increased milk yield and milk content of calcium, total fat, total carbohydrate, and total protein. Prolactin and growth hormone levels were significantly upregulated in all treated groups compared with the control group. In contrast, progesterone and estrogen were downregulated. The high doses of petroleum ether and water extracts increased the expression levels of β-Cas, α-Lactalb, PRLR, PR, and STAT-5a. The observation of histological sections showed that the extracts induced higher mammary gland differentiation than the control group. This study is the first to use mushrooms as nutritional supplements to improve milk production and mammary gland differentiation during lactation.
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Project description:Water extracts of both Morus alba L. root bark (MBW) and Cornus officinalis Siebold and Zucc fruit (CFW) have traditionally been used to promote men's health in the elderly in Asia. We determined that the 12-week consumption of MBW and CFW could alleviate testosterone-deficiency syndrome and osteoarthritis (OA) symptoms in testosterone-deficient rats, and the action mechanisms were explored. Rats with bilateral orchiectomy (ORX) were fed a 45% fat diet containing either 0.5% MBW (ORX-MBW), 0.5% CFW(ORX-CFW), or 0.5% dextrin (ORX-CON). Sham-operated rats also received 0.5% dextrin (Non-ORX-CON). After 8 weeks of treatment, all rats had an injection of monoiodoacetate (MIA) into the left knee, and they continued the same diet for the additional 4 weeks. ORX-CFW and ORX-MBW partially prevented the reduction of serum testosterone concentrations and decreased insulin resistance, compared to the ORX-CON. ORX-CFW and ORX-MBW protected against the reduction of bone mineral density (BMD) and lean body mass (LBM) compared to the ORX-CON. The limping and edema scores were lower in the order of the ORX-CON, ORX-CRF = ORX-MBW, and Non-ORX-CON (p < 0.05). The scores for pain behaviors, measured by weight-distribution on the OA leg and maximum running velocity on a treadmill, significantly decreased in the same order as limping scores. ORX-MBW protected against the increased expression of matrix metalloproteinase (MMP)-3 and MMP-13 and reduced the production of inflammatory markers such as TNF-α and IL-1β, by MIA in the articular cartilage, compared to the ORX-CON (p < 0.05). The cartilage damage near the tidemark of the knee and proteoglycan loss was significantly less in ORX-MBW than ORX-CON. In conclusion, MBW, possibly CFW, could be effective alternative therapeutic agents for preventing osteoarthritis in testosterone-deficient elderly men.
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Project description:As the geriatric population and life expectancy increase, the interest in preventing geriatric diseases, such as sarcopenia, is increasing. However, the causes of sarcopenia are unclear, and current diagnostic methods for sarcopenia are unreliable. We hypothesized that the changes in the expression of certain miRNAs may be associated with the pathophysiology of sarcopenia. Herein, we analyzed the miRNA expression profiles in the blood of young (3-months-old) healthy rats, old sarcopenic (17-months-old) rats, and age-matched (17-months-old) control rats. The changes in miRNA expression levels were analyzed using Bowtie 2 software. A total of 523 miRNAs were detected in the rat serum. Using scatter plots and clustering heatmap data, we found 130 miRNAs that were differentially expressed in sarcopenic rats (>2-fold change) compared to the expression in young healthy and age-matched control rats. With a threshold of >5-fold change, we identified 14 upregulated miRNAs, including rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-133c, rno-miR-208a-3p, and rno-miR434-5p among others in the serum of sarcopenic rats. A protein network map based on these 14 miRNAs identified the genes involved in skeletal muscle differentiation, among which Notch1, Egr2, and Myocd represented major nodes. The data obtained in this study are potentially useful for the early diagnosis of sarcopenia and for the identification of novel therapeutic targets for the treatment and/or prevention of sarcopenia.
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Project description:To attain effective and safe pharmacotherapy, formulations in (pre)term neonates should enable extensive dose flexibility. During product development and subsequent authorization and clinical use of such formulations, there is also a need for informed decisions on excipient exposure: in addition to the need to improve the knowledge on active compounds, there is a similar need to improve the knowledge on excipients in neonates. Excipients are added to formulations as co-solvent, surfactant, preservative, colorant and/or sweetener as vehicle(s) to result in a suitable (e.g. taste, shelf life, stability) product. Progress has been made in the awareness, knowledge and access to this knowledge on the clinical pharmacology of excipients in neonates. This is thanks to different initiatives focussing on epidemiological data, excipient pharmacokinetics, or building datasets to create this knowledge. We highlight the Safe Excipient Exposure in Neonates and Small Children (SEEN) and propylene glycol project to illustrate the feasibility to build knowledge, and discuss the methods applied and problems observed during these studies. The information generated in these and other studies (European Study on Neonatal Exposure to Excipients, ESNEE) should be integrated in repositories like the Safety and Toxicity of Excipients for Paediatrics (STEP) to facilitate access to all stakeholders. This merged knowledge should have impact and assist in improving the quality of risk assessment and decision making during drug development, applying a risk-benefit framework (explicit justification of excipients, plan product development early and engage all stakeholders, data sharing and modeling, challenges related to new excipients, context sensitive risk-benefit analysis).
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Project description:Histone H3 tail modifications are among the earliest chromatin changes in the X-chromosome inactivation process. In this study we investigated the relative profiles of two important repressive marks on the X chromosome: methylation of H3 lysine 9 (K9) and 27 (K27). We found that both H3K9 dimethylation and K27 trimethylation characterize the inactive X in somatic cells and that their relative kinetics of enrichment on the X chromosome as it undergoes inactivation are similar. However, dynamic changes of H3K9 and H3K27 methylation on the inactivating X chromosome compared to the rest of the genome are distinct, suggesting that these two modifications play complementary and perhaps nonredundant roles in the establishment and/or maintenance of X inactivation. Furthermore, we show that a hotspot of H3K9 dimethylation 5' to Xist also displays high levels of H3 tri-meK27. However, analysis of this region in G9a mutant embryonic stem cells shows that these two methyl marks are dependent on different histone methyltransferases.
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Project description:MotivationBoth β-value and M-value have been used as metrics to measure methylation levels. The M-value is more statistically valid for the differential analysis of methylation levels. However, the β-value is much more biologically interpretable and needs to be reported when M-value method is used for conducting differential methylation analysis. There is an urgent need to know how to interpret the degree of differential methylation from the M-value. In M-value linear regression model, differential methylation M-value ΔM can be easily obtained from the coefficient estimate, but it is not straightforward to get the differential methylation β-value, Δβ since it cannot be obtained from the coefficient alone.ResultsTo fill the gap, we have built a bridge to connect the statistically sound M-value linear regression model and the biologically interpretable Δβ. In this article, three methods were proposed to calculate differential methylation values, Δβ from M-value linear regression model and compared with the Δβ directly obtained from β-value linear regression model. We showed that under the condition that M-value linear regression model is correct, the method M-model-coef is the best among the four methods. M-model-M-mean method works very well too. If the coefficients α0, α2,…αp are not given (as 'MethLAB' package), the M-model-M-mean method should be used. The Δβ directly obtained from β-value linear regression model can give very biased results, especially when M-values are not in (-2, 2) or β-values are not in (0.2, 0.8).Availability and implementationThe dataset for example is available at the National Center for Biotechnology Information Gene Expression Omnibus repository, GSE104778.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC6449748 | biostudies-literature
Project description:As a salt-adaptive plant, the date palm (Phoenix dactylifera L.) requires a suitable mechanism to adapt to the stress of saline soils. There is growing evidence that DNA methylation plays an important role in regulating gene expression in response to abiotic stresses, including salinity. Thus, the present study sought to examine the differential methylation status that occurs in the date palm genome when plants are exposed to salinity, and to identify salinity responsive genes that are regulated by DNA methylation. To achieve these, whole-genome bisulfite sequencing (WGBS) was employed and mRNA was sequenced from salinity-treated and untreated roots. The WGBS analysis included 324,987,795 and 317,056,091 total reads of the control and the salinity-treated samples, respectively. The analysis covered about 81% of the total genomic DNA with about 40% of mapping efficiency of the sequenced reads and an average read depth of 17-fold coverage per DNA strand, and with a bisulfite conversion rate of around 99%. The level of methylation within the differentially methylated regions (DMRs) was significantly (p < 0.05, FDR ? 0.05) increased in response to salinity specifically at the mCHG and mCHH sequence contexts. Consistently, the mass spectrometry and the enzyme-linked immunosorbent assay (ELISA) showed that there was a significant (p < 0.05) increase in the global DNA methylation in response to salinity. mRNA sequencing revealed the presence of 6,405 differentially regulated genes with a significant value (p < 0.001, FDR ? 0.05) in response to salinity. Integration of high-resolution methylome and transcriptome analyses revealed a negative correlation between mCG methylation located within the promoters and the gene expression, while a positive correlation was noticed between mCHG/mCHH methylation rations and gene expression specifically when plants grew under control conditions. Therefore, the methylome and transcriptome relationships vary based on the methylated sequence context, the methylated region within the gene, the protein-coding ability of the gene, and the salinity treatment. These results provide insights into interplay among DNA methylation and gene expression, and highlight the effect of salinity on the nature of this relationship, which may involve other genetic and epigenetic players under salt stress conditions. The results obtained from this project provide the first draft map of the differential methylome and transcriptome of date palm when exposed to an abiotic stress.
| S-EPMC5774813 | biostudies-literature
Project description:BackgroundEpigenetic gene silencing is one of the major causes of carcinogenesis. Its widespread occurrence in cancer genome could inactivate many cellular pathways including DNA repair, cell cycle control, apoptosis, cell adherence, and detoxification. The abnormal promoter methylation might be a potential molecular marker for cancer management.MethodsFor rapid identification of potential targets for aberrant methylation in gynecological cancers, methylation status of the CpG islands of 34 genes was determined using pooled DNA approach and methylation-specific PCR. Pooled DNA mixture from each cancer type (50 cervical cancers, 50 endometrial cancers and 50 ovarian cancers) was made to form three test samples. The corresponding normal DNA from the patients of each cancer type was also pooled to form the other three control samples. Methylated alleles detected in tumors, but not in normal controls, were indicative of aberrant methylation in tumors. Having identified potential markers, frequencies of methylation were further analyzed in individual samples. Markers identified are used to correlate with clinico-pathological data of tumors using chi2 or Fisher's exact test.ResultsAPC and p16 were hypermethylated across the three cancers. MINT31 and PTEN were hypermethylated in cervical and ovarian cancers. Specific methylation was found in cervical cancer (including CDH1, DAPK, MGMT and MINT2), endometrial cancer (CASP8, CDH13, hMLH1 and p73), and ovarian cancer (BRCA1, p14, p15, RIZ1 and TMS1). The frequencies of occurrence of hypermethylation in 4 candidate genes in individual samples of each cancer type (DAPK, MGMT, p16 and PTEN in 127 cervical cancers; APC, CDH13, hMLH1 and p16 in 60 endometrial cancers; and BRCA1, p14, p16 and PTEN in 49 ovarian cancers) were examined for further confirmation. Incidence varied among different genes and in different cancer types ranging from the lowest 8.2% (PTEN in ovarian cancer) to the highest 56.7% (DAPK in cervical cancer). Aberrant methylation for some genes (BRCA1, DAPK, hMLH1, MGMT, p14, p16, and PTEN) was also associated with clinico-pathological data.ConclusionThus, differential methylation profiles occur in the three types of gynecologic cancer. Detection of methylation for critical loci is potentially useful as epigenetic markers in tumor classification. More studies using a much larger sample size are needed to define the potential role of DNA methylation as marker for cancer management.
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