scholarly journals Epigenetic Modulation of TLR4 Expression by Sulforaphane Increases Anti-Inflammatory Capacity in Porcine Monocyte-Derived Dendritic Cells

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 490
Author(s):  
Xueqi Qu ◽  
Christiane Neuhoff ◽  
Mehmet Ulas Cinar ◽  
Maren Pröll ◽  
Ernst Tholen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dendritic Cells ◽  
Epigenetic Modifications ◽  
Dna Demethylation ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Hdac Activity ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
Epigenetic Modulation

Inflammation is regulated by epigenetic modifications, including DNA methylation and histone acetylation. Sulforaphane (SFN), a histone deacetylase (HDAC) inhibitor, is also a potent immunomodulatory agent, but its anti-inflammatory functions through epigenetic modifications remain unclear. Therefore, this study aimed to investigate the epigenetic effects of SFN in maintaining the immunomodulatory homeostasis of innate immunity during acute inflammation. For this purpose, SFN-induced epigenetic changes and expression levels of immune-related genes in response to lipopolysaccharide (LPS) stimulation of monocyte-derived dendritic cells (moDCs) were analyzed. These results demonstrated that SFN inhibited HDAC activity and caused histone H3 and H4 acetylation. SFN treatment also induced DNA demethylation in the promoter region of the MHC-SLA1 gene, resulting in the upregulation of Toll-like receptor 4 (TLR4), MHC-SLA1, and inflammatory cytokines’ expression at 6 h of LPS stimulation. Moreover, the protein levels of cytokines in the cell culture supernatants were significantly inhibited by SFN pre-treatment followed by LPS stimulation in a time-dependent manner, suggesting that inhibition of HDAC activity and DNA methylation by SFN may restrict the excessive inflammatory cytokine availability in the extracellular environment. We postulate that SFN may exert a protective and anti-inflammatory function by epigenetically influencing signaling pathways in experimental conditions employing porcine moDCs.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2455
Author(s):  
Chun-Shan Liu ◽  
Reka Toth ◽  
Ali Bakr ◽  
Ashish Goyal ◽  
Md Saiful Islam ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Drug Effects ◽  
Diacylglycerol Kinase ◽  
Dna Demethylation ◽  
Dermal Fibroblasts ◽  
Common Component ◽  
Radiation Induced ◽  
Marker Expression ◽  
Epigenetic Modulation ◽  
Genomic Editing

Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis.

scholarly journals Anti-Inflammatory Activities of Compounds Isolated from the Rhizome of Anemarrhena asphodeloides

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2631 ◽  
Author(s):  
Zeyuan Wang ◽  
Jianfeng Cai ◽  
Qing Fu ◽  
Lingping Cheng ◽  
Lehao Wu ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Microglial Cells ◽  
No Production ◽  
Dependent Manner ◽  
Platycodin D ◽  
Protein Levels ◽  
Chemical Structures ◽  
Ic50 Values ◽  
Anti Inflammatory ◽  
Anemarrhena Asphodeloides

Fifteen unreported compounds in Anemarrhena asphodeloides, iriflophene (3), hostaplantagineoside C (7), tuberoside G (8), spicatoside B (9), platycodin D (14), platycoside A (15), platycodin D2 (16), polygalacin D2 (17), platycodin D3 (18), isovitexin (20), vitexin (21), 3,4-dihydroxyallylbenzene-3-O-α-l-rhamnopyranosyl(1→6)-β-d-glucopyranoside (22), iryptophan (24), adenosine (25), α-d-Glucose monoallyl ether (26), together with eleven known compounds (1, 2, 4–6, 10–13, 19 and 23), were isolated from the rhizomes of Anemarrhena asphodeloides. The chemical structures of these compounds were characterized using HRMS and NMR. The anti-inflammatory activities of the compounds were evaluated by investigating their ability to inhibit LPS-induced NO production in N9 microglial cells. Timosaponin BIII (TBIII) and trans-hinokiresinol (t-HL) exhibited significant inhibitory effects on the NO production in a dose-dependent manner with IC50 values of 11.91 and 39.08 μM, respectively. Immunoblotting demonstrated that TBIII and t-HL suppressed NO production by inhibiting the expressions of iNOS in LPS-stimulated N9 microglial cells. Further results revealed that pretreatment of N9 microglial cells with TBIII and t-HL attenuated the LPS-induced expression tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at mRNAs and protein levels. Moreover, the activation of nuclear factor-κB (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were inhibited by TBIII and t-HL, respectively. Our findings indicate that the therapeutic implication of TBIII and t-HL for neurogenerative disease associated with neuroinflammation.

scholarly journals Gene activation precedes DNA demethylation in response to infection in human dendritic cells

2019 ◽  
Vol 116 (14) ◽  
pp. 6938-6943 ◽  
Author(s):  
Alain Pacis ◽  
Florence Mailhot-Léonard ◽  
Ludovic Tailleux ◽  
Haley E. Randolph ◽  
Vania Yotova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dendritic Cells ◽  
Transcriptional Activation ◽  
Time Course ◽  
Gene Activation ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Distal Enhancer ◽  
Human Dendritic Cells

DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells withMycobacterium tuberculosis. We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.

scholarly journals Chrysin Modulates Aberrant Epigenetic Variations and Hampers Migratory Behavior of Human Cervical (HeLa) Cells

2022 ◽  
Vol 12 ◽  
Author(s):  
Ritu Raina ◽  
Abdulmajeed G. Almutary ◽  
Sali Abubaker Bagabir ◽  
Nazia Afroze ◽  
Sharmila Fagoonee ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Suppressor ◽  
Histone Modification ◽  
Hela Cells ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Global Dna Methylation ◽  
Dependent Manner ◽  
Suppressor Genes ◽  
Protein Levels

Purpose: Plant-derived phytochemicals have shown epigenetic modulatory effect in different types of cancer by reversing the pattern of DNA methylation and chromatin modulation, thereby restoring the function of silenced tumor-suppressor genes. In the present study, attempts have been made to explore chrysin-mediated epigenetic alterations in HeLa cells.Methods: Colony formation and migration assays followed by methylation-specific PCR for examining the methylation status of CpG promoters of various tumor-suppressor genes (TSGs) and the expression of these TSGs at the transcript and protein levels were performed. Furthermore, global DNA methylation; biochemical activities of DNA methyltransferases (DNMTs), histone methyl transferases (HMTs), histone deacetylases (HDACs), and histone acetyl transferases (HATs) along with the expression analysis of chromatin-modifying enzymes; and H3 and H4 histone modification marks analyses were performed after chrysin treatment.Results: The experimental analyses revealed that chrysin treatment encourages cytostatic behavior as well as inhibits the migration capacity of HeLa cells in a time- and dose-dependent manner. Chrysin reduces the methylation of various tumor-suppressor genes, leading to their reactivation at mRNA and protein levels. The expression levels of various chromatin-modifying enzymes viz DNMTs, HMTs, HDACs, and HATS were found to be decreased, and H3 and H4 histone modification marks were modulated too. Also, reduced global DNA methylation was observed following the treatment of chrysin.Conclusion: This study concludes that chrysin can be used as a potential epigenetic modifier for cancer treatment and warrants for further experimental validation.

scholarly journals Insulin-Attenuated Inflammatory Response of Dendritic Cells in Diabetes by Regulating RAGE-PKCβ1-IRS1-NF-κB Signal Pathway: A Study on the Anti-Inflammatory Mechanism of Insulin in Diabetes

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Liding Zhao ◽  
Ya Li ◽  
Qingbo Lv ◽  
Min Wang ◽  
Yi Luan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Response ◽  
Neutralizing Antibody ◽  
Serine Phosphorylation ◽  
Dependent Manner ◽  
Diabetic Mice ◽  
Mice Model ◽  
Cytokines And Chemokines ◽  
Anti Inflammatory ◽  
Immune Maturation

Background. Diabetes is associated with chronic inflammation, and dendritic cells (DCs) have proinflammatory effect in diabetes. The anti-inflammatory effect of insulin on diabetes is not entirely clear. The study aims to examine insulin-induced effects on the inflammatory response in DCs. Methods. Twenty-one C57BL/6 mice were divided into 3 groups. Streptozotocin was injected into the diabetic mice model. The bone marrow-derived DCs (BMDCs) were obtained from C57BL/6 mice. CD83, CD86, and type II major histocompatibility complex (MHC-II) of BMDCs were measured by flow cytometry. The fluctuations in the RNA levels of cytokines and chemokines were analyzed by quantitative RT-PCR. The concentrations of IFN-γ and TNF-α were calculated using ELISA kits, and the proteins were detected using western blot. Results. In CD11c+ DCs derived from the spleens with hyperglycemia, the expression of CD83 and CD86 in diabetic mice was significantly upregulated, coupled with a higher secretion level of cytokines and chemokines, and increased phosphorylation of NF-κB and IκB. Insulin therapy was found to have a reversal effect on the inflammatory response and immune maturation in DCs. In AGEs-BSA-stimulated BMDCs, insulin repressed the immune maturation and downregulated the expression of RAGE, phospho-PKCβ1, and serine phospho-IRS1 in an adose-dependent manner. Such effects can be abolished by PMA, but not IR-neutralizing antibody. AGEs-BSA-induced BMDCs immune maturation was inhibited by the neutralizing antibody of RAGE, the PKCβ1 inhibitor, or the IRS1 siRNA. Conclusions. Insulin has the capability of attenuating the inflammatory response of DCs in diabetes, partly through the downregulation of RAGE expression followed by the inhibition of PKCβ1 phosphorylation and IRS1 serine phosphorylation, resulting in the inactivation of IR binding-independent NF-κB. This might partly explain the antiatherogenic effect of insulin on diabetes.

DNA methylation: from model plants to vegetable crops

2021 ◽  
Author(s):  
Wen-Feng Nie
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Developmental Process ◽  
Epigenetic Modifications ◽  
Dna Demethylation ◽  
Leafy Vegetables ◽  
Vegetable Crops ◽  
Human Beings ◽  
Horticultural Crops ◽  
Active Dna Demethylation

As a subgroup of horticultural crops, vegetable food is a kind of indispensable energy source for human beings, providing necessary nutritional components including vitamins, carbohydrates, dietary fiber, and active substances such as carotenoids and flavonoids. The developmental process of vegetable crops is not only regulated by environmental stimulations, but also manipulated by both genetic and epigenetic modifications. Epigenetic modifications are composed by several regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs. Among these modifications, DNA methylation functions in multiple biological pathways ranging from fundamental development to environmental stimulations by mediating transcriptomic alterations, resulting in the activation or silencing of target genes. In recent years, intensive studies have revealed that DNA methylation is essential to fruit development and ripening, indicating that the epigenome of fruit crops could be dynamically modified according to the specific requirements in the commercial production. Firstly, this review will present the mechanisms of DNA methylation, and update the understanding on active DNA demethylation in Arabidopsis thaliana. Secondly, this review will summarize the recent progress on the function of DNA methylation in regulating fruit ripening. Moreover, the possible functions of DNA methylation on controlling the expansion of edible organs, senescence of leafy vegetables, and anthocyanin pigmentation in several important vegetable crops will be discussed. Finally, this review will highlight the intractable issues that need to be resolved in the application of epigenome in vegetable crops, and provide perspectives for the potential challenges in the further studies.

scholarly journals Anti-Inflammatory Compounds from Vietnamese Piper bavinum

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Viet Dung Hoang ◽  
Phi Hung Nguyen ◽  
Minh Thu Doan ◽  
Manh Hung Tran ◽  
Nhu Tuan Huynh ◽  
...  
Keyword(s):  
Raw 264.7 Cells ◽  
No Production ◽  
Dependent Manner ◽  
Protein Levels ◽  
Chemical Structures ◽  
Anti Inflammatory ◽  
First Time ◽  
Dose Dependent ◽  
Potent Inhibitory Activity

This study reports the anti-inflammatory activity-guided fractionation of the aerial part of Piper bavinum C. CD. (Piperaceae) that led to the isolation of eight secondary metabolites (1–8). The chemical structures of 1–8 were established mainly by NMR and mass spectra. Compound 5 was isolated from P. bavinum for the first time. All the isolated compounds were evaluated against LPS-induced NO production in macrophage RAW 264.7 cells in vitro. Among them, compound 4 showed the most potent inhibitory activity against the LPS-induced NO production with an IC50 value of 5.2 μM followed by compound 5 that inhibited NO production with an IC50 value of 13.5 μM. In the protein levels, compound 4 suppressed LPS-induced COX-2 and iNOS expressions in a dose-dependent manner. The results suggested that P. bavinum and its constituents might exert anti-inflammatory effects.

scholarly journals DNA Methylation Repels Binding of HIF Transcription Factors to Maintain Tumour Immunotolerance

2020 ◽  
Author(s):  
Flora D’anna ◽  
Laurien Van Dyck ◽  
Jieyi Xiong ◽  
Hui Zhao ◽  
Rebecca V. Berrens ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factors ◽  
Immune Checkpoint ◽  
Binding Sites ◽  
Dna Demethylation ◽  
Transcript Expression ◽  
Dependent Manner ◽  
Cell Type ◽  
Dna Hypomethylation ◽  
Cell Type Specific

AbstractBackgroundHypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia.ResultsHere, we report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modelling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid-down by the differential expression and binding of other transcription factors under normoxia control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated. Genetic and pharmacological DNA demethylation, but also cancer-associated DNA hypomethylation, expose these binding sites, inducing HIF-dependent expression of cryptic transcripts. In line with such cryptic transcripts being more prone to cause double-stranded RNA and viral mimicry, we observe low DNA methylation and high cryptic transcript expression in tumours with high immune checkpoint expression, but not in tumours with low immune checkpoint expression, where they would compromise tumour immunotolerance. In a low-immunogenic tumour model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumour growth.ConclusionsOur data elucidate the mechanism underlying cell-type specific responses to hypoxia, and suggest DNA methylation and hypoxia to underlie tumour immunotolerance.

scholarly journals Multi-Omics Data Integration Reveals Link Between Epigenetic Modifications and Gene Expression in Sugar Beet (Beta Vulgaris Subsp. Vulgaris) in Response to Cold

2021 ◽  
Author(s):  
Sindy Gutschker ◽  
José Maria Corral ◽  
Alfred Schmiedl ◽  
Frank Ludewig ◽  
Wolfgang Koch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Sugar Beet ◽  
Beta Vulgaris ◽  
Environmental Conditions ◽  
Epigenetic Modifications ◽  
Dna Demethylation ◽  
Omics Data ◽  
Dna Hypomethylation ◽  
Transcriptional Responses

Abstract BackgroundDNA methylation is thought to influence the expression of genes, especially in response to changing environmental conditions and developmental changes. Sugar beet (Beta vulgaris ssp. vulgaris), and other biennial or perennial plants are inevitably exposed to fluctuating temperatures throughout their lifecycle and might even require such stimulus to acquire floral competence. Therefore, plants such as beets, need to fine-tune their epigenetic makeup to ensure phenotypic plasticity towards changing environmental conditions while at the same time steering essential developmental processes. Different crop species may show opposing reactions towards the same abiotic stress, or, vice versa, identical species may respond differently depending on the specific kind of stress. ResultsIn this study, we investigated common effects of cold treatment on genome-wide DNA methylation and gene expression of two Beta vulgaris accessions via multi-omics data analysis. Cold exposure resulted in a pronounced reduction of DNA methylation levels, which particularly affected methylation in CHH context (and to a lesser extent CHG) and was accompanied by transcriptional downregulation of the chromomethyltransferase CMT2 and strong upregulation of several genes mediating active DNA demethylation. Conclusion Integration of methylomic and transcriptomic data revealed that, rather than methylation having directly influenced expression, epigenetic modifications correlated with changes in expression of known players involved in DNA (de)methylation. In particular, cold triggered upregulation of genes putatively contributing to DNA demethylation via the ROS1 pathway. Our observations suggest that these transcriptional responses precede the cold-induced global DNA-hypomethylation in non-CpG, preparing beets for additional transcriptional alterations necessary for adapting to upcoming environmental changes.

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