Comparative transcriptome analysis reveals hormone, transcriptional and epigenetic regulation involved in prickle formation in Zanthoxylum armatum.

Zanthoxylum armatum is an evergreen plant with high economical and medicinal values. The presence of prickles on stems and leaves is undesirable for them make picking difficult. To date, little is known of prickle formation in Z. armatum. Herein, the morphological and molecular features of prickle initiation in prickless (WC) and three types of prickly Z. armatum were characterized. Compared to WC, the levels of cytokinin and auxin were increased, while GA and JA declined in prickly Z. armatum. Transcriptome analysis identified 6258 differentially expressed genes (DEGs) between prickless and prickly Z. armatum. Among them, several DEGs related to hormone metabolism and signaling, including LOG7, CKX3, AHK1, three DELLAs, six JAZs and TIR1, were candidate genes involved in prickle formation. Transcription factors associated with prickle formation were screened, including MYB6-1/MYB6-2, WER, GL3-2, SPL4/5, SOC1, and SCL32. Of them, MYB6-1 and WER might negatively regulate prickles initiation via interacting with GL3-2. Additionally, the histone acetylation and DNA methylation levels, the transcripts of histone acetyltransferase/deacetylase and DNA methyltransferases showed significant differences between prickless and prickly plants, indicating their involvements in prickle initiation. These findings illustrate the regulation of prickle formation might be mediated by phytohormones (especially cytokinin), transcription factors and epigenetic modifications in Z. armatum.

In utero and postnatal exposure to Foeniculum vulgare and Linum usitatissimum seed extracts: modifications of key enzymes involved in epigenetic regulation and estrogen receptors expression in the offspring's ovaries of NMRI mice.

BACKGROUND: Early-life exposure to exogenous estrogens such as phytoestrogens (plant-derived estrogens) could affect later health through epigenetic modifications. Foeniculum vulgare (fennel) and Linum usitatissimum (flax) are two common medicinal plants with high phytoestrogen content. Considering the developmental epigenetic programming effect of phytoestrogens, the main goal of the present study was to evaluate the perinatal exposure with life-long exposure to hydroalcoholic extracts of both plants on offspring's ovarian epigenetic changes and estrogen receptors (ESRs) expression level as signaling cascades triggers of phytoestrogens. METHODS: Pregnant mice were randomly divided into control (CTL) that received no treatment and extract-treated groups that received 500 mg/kg/day of fennel (FV) and flaxseed (FX) alone or in combination (FV + FX) during gestation and lactation. At weaning, female offspring exposed to extracts prenatally remained on the maternal-doses diets until puberty. Then, the ovaries were collected for morphometric studies and quantitative real-time PCR analysis. RESULTS: A reduction in mRNA transcripts of the epigenetic modifying enzymes DNMTs and HDACs as well as estrogen receptors was observed in the FV and FX groups compared to the CTL group. Interestingly, an increase in ESRα/ESRß ratio along with HDAC2 overexpression was observed in the FV + FX group. CONCLUSION: Our findings clearly show a positive relationship between pre and postnatal exposure to fennel and flaxseed extracts, ovarian epigenetic changes, and estrogen receptors expression, which may affect the estrogen signaling pathway. However, due to the high phytoestrogen contents of these extracts, the use of these plants in humans requires more detailed investigations.

Prenatal EGCG consumption causes obesity and perturbs glucose homeostasis in adult mice.

Epigallocatechin gallate (EGCG) has a wide consumption for its health advantages. The current study investigates the effects of prenatal EGCG administration on glucose metabolism and obesity in adulthood. Pregnant C57BL/6J mice were supplemented with EGCG in drinking water (3 µg/mL) for 16 d. Abdominal obesity was observed in both male and female adult mice, which was associated with the upregulation of adipose-specific genes, including C/ebpα and Srebf1 (Srebf1 only in males), and the downregulation of genes related to lipolysis, such as Acox1, Atgl and Pdk4 (only in males) in visceral adipose tissue. Elevated fasting glucose levels and hyperinsulinemia were observed in adult males, while females exhibit lower glucose level in glucose tolerance test, which might be due to reduced glucagon levels. Though hepatic expression of the insulin receptor signaling pathway was upregulated in males and was not altered in females, prenatal treatment with EGCG downregulated the expression of this signaling pathway in the skeletal muscle of adult mice, which was further demonstrated in primary human skeletal muscle cells treated with EGCG. The methylation levels in promotor of genes related to the insulin receptor signaling were matched with their transcription in mice, while the expression of acetylated histones was downregulated in human skeletal muscle cells. These results suggest that EGCG consumption during pregnancy should be a risk factor for the disruption of glucose homeostasis in adulthood.

Research advances on the role of epigenetic modifications in the long-term progression of alcoholic liver disease / 药学学报

There are more than 60 million alcoholic liver disease (ALD) patients in China, which has become a public health problem that cannot be ignored. Moreover, the social problem of "alcohol culture" is still hardly to solve, so that safe and effective prevention and treatment for ALD are in urgent need clinically. Previous studies on ALD have focused on the direct damaging effects of alcohol and its toxic metabolites, while recent studies have shown that the pathogenesis of ALD also include alcohol metabolic reprogramming and endogenous metabolites disorder. Although the endogenous metabolites have no direct toxicity, its long-term effect should not be ignored. These endogenous metabolites could change epigenetic modifications, cause widespread and persistent abnormal gene expression and signal pathway activation abnormally to promote metabolic reprogramming and stamp it as "metabolic memory", which manifest pathological changes and promote ALD, especially liver fibrosis/cirrhosis and liver cancer. Based on this, the article reviews the important epigenetic modifications caused by related metabolites in ALD and their associated effects. The role of traditional Chinese medicine (TCM) and its active ingredients in regulating epigenetics was also analyzed. The results suggest that regulation of epigenetics and alteration of "metabolic memory" may be a novel mechanism of TCM in the prevention and treatment of ALD.

Melatonin protects oocytes from cadmium exposure-induced meiosis defects by changing epigenetic modification and enhancing mitochondrial morphology in the mouse.

Cadmium (Cd) is one major environmental pollutant that can cause detrimental impacts on human as well as animal reproductive systems as a result of oxidative stress. It is widely acknowledged that melatonin secreted principally by the pineal gland is not only a natural potent antioxidant but also a free radical scavenger, whereas concerning how to alleviate the toxic effects of Cd on oocyte maturation remains elusive. In this investigation, it was the first time to explore the protective effects and potential mechanism of melatonin on meiotic maturation of mouse oocytes exposed to Cd in vitro medium. We found that Cd exerts adverse effects on meiotic maturation progression by disrupting the normal function of mitochondrion combined with the aberrant mitochondrial distribution and decreased membrane potential and altering epigenetic modification, including H3K9me2 and H3K4me2. Additionally, it was observed that Cd exposure disrupted the morphology of spindle organization and caused chromosome misalignment, which might be through changing the level of acetylated tubulin, whereas melatonin administration alleviated the toxic impacts of Cd on oocytes. Furthermore, the mitochondrial morphology-related genes mRNA expression and protein expression of autophagy-related genes was also investigated. The results suggested that melatonin supplementation significantly altered the mRNA expression of mitochondrial dynamics-related genes, rather than the expression of mitophagy-related proteins. Taken together, our results validated that melatonin administration has a certain protective impact against oocytes meiosis maturation defects induced by cadmium through changing epigenetic modification and enhancing mitochondrial morphology rather than mitophagy.

Global analysis of cytosine and adenine DNA modifications across the tree of life.

Interpreting the function and metabolism of enzymatic DNA modifications requires both position-specific and global quantities. Sequencing-based techniques that deliver the former have become broadly accessible, but analytical methods for the global quantification of DNA modifications have thus far been applied mostly to individual problems. We established a mass spectrometric method for the sensitive and accurate quantification of multiple enzymatic DNA modifications. Then, we isolated DNA from 124 archean, bacterial, fungal, plant, and mammalian species, and several tissues and created a resource of global DNA modification quantities. Our dataset provides insights into the general nature of enzymatic DNA modifications, reveals unique biological cases, and provides complementary quantitative information to normalize and assess the accuracy of sequencing-based detection of DNA modifications. We report that only three of the studied DNA modifications, methylcytosine (5mdC), methyladenine (N6mdA) and hydroxymethylcytosine (5hmdC), were detected above a picomolar detection limit across species, and dominated in higher eukaryotes (5mdC), in bacteria (N6mdA), or the vertebrate central nervous systems (5hmdC). All three modifications were detected simultaneously in only one of the tested species, Raphanus sativus. In contrast, these modifications were either absent or detected only at trace quantities, across all yeasts and insect genomes studied. Further, we reveal interesting biological cases. For instance, in Allium cepa, Helianthus annuus, or Andropogon gerardi, more than 35% of cytosines were methylated. Additionally, next to the mammlian CNS, 5hmdC was also detected in plants like Lepidium sativum and was found on 8% of cytosines in the Garra barreimiae brain samples. Thus, identifying unexpected levels of DNA modifications in several wild species, our resource underscores the need to address biological diversity for studying DNA modifications.

KDM4C Contributes to Trophoblast-like Stem Cell Conversion from Porcine-Induced Pluripotent Stem Cells (piPSCs) via Regulating CDX2.

Studies on ESRRB-regulating porcine-induced pluripotent stem cells (piPSCs) converted to trophoblast-like stem cells (TLSCs) contribute to the understanding of early embryo development. However, the epigenetic modification regulation network during the conversion is poorly understood. Here, the global change in histone H3 Lysine 4, 9, 27, 36 methylation and Lysine 27 acetylation was investigated in piPSCs and TLSCs. We found a high modification profile of H3K36me2 in TLSCs compared to that of piPSCs, whereas the profiles of other modifications remained constant. KDM4C, a H3K36me3/2 demethylase, whose gene body region was combined with ESRRB, was upregulated in TLSCs. Moreover, KDM4 inhibitor supplementation rescued the AP-negative phenotype observed in TLSCs, confirming that KDM4C could regulate the pluripotency of TLSCs. Subsequently, KDM4C replenishment results show the significantly repressed proliferation and AP-positive staining of TLSCs. The expressions of CDX2 and KRT8 were also upregulated after KDM4C overexpression. In summary, these results show that KDM4C replaced the function of ESRRB. These findings reveal the unique and crucial role of KDM4C-mediated epigenetic chromatin modifications in determination of piPSCs' fate and expand the understanding of the connection between piPSCs and TSCs.

Enhancement of cordycepin production from Cordyceps militaris culture by epigenetic modification.

Cordycepin (3'-deoxyadenosine) is a nucleoside analogue and biosynthesised by Cordyceps militaris, an entomopathogenic fungus. In this study, an epigenetic modifier was applied to static liquid cultures to enhance cordycepin production. C. militaris was cultured in a static liquid culture, and valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, was supplemented in order to modifying the epigenetic status. Gene regulatory network was explored to understand the molecular mechanisms underlying cordycepin production. 50 micromolar of VPA enhanced cordycepin production by 41.187% via the upregulation of 5'-nucleotidase, adenylate kinase, phosphorybosyltransferase, Cns1, Cns2, Cnsa3, and Cns4 of C. militaris for at least 2 days after VPA treatment. The maximum production of cordycepin was 2,835.32 ± 34.35 mg/L in 400 mL-working volume. A scaled-up culture was established with a working volume of 10 L, which led to the slight decrease of cordycepin production. This might due to multifactorial effects, for instance limited aeration and an uneven dispersion of nutrients in the culture system. This scaled-up culture was still needed further optimization. The modification of epigenetic status by VPA significantly enhanced cordycepin production by altering key gene regulatory network of C. militaris. The strategy established in this study might be applicable to other microorganism culture in order to improving the production of bioactive compounds. This work aimed to enhance the production of cordycepin by modifying the epigenetic status of C. militaris, in which subsequently altered gene regulatory network of cordycepin biosynthesis pathway. The weekly supplementation of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, significantly improve cordycepin production over 40%, compared to the untreated control, and the gene regulatory network of C. militaris was also adapted.

Genetic and molecular mechanisms underlying root architecture and function under heat stress-A hidden story.

Heat stress events are resulting in a significant negative impact on global food production. The dynamics of cellular, molecular and physiological homoeostasis in aboveground parts under heat stress are extensively deciphered. However, root responses to higher soil/air temperature or stress signalling from shoot to root are limited. Therefore, this review presents a holistic view of root physio-morphological and molecular responses to adapt under hotter environments. Heat stress reprogrammes root cellular machinery, including crosstalk between genes, phytohormones, reactive oxygen species (ROS) and antioxidants. Spatio-temporal regulation and long-distance transport of phytohormones, such as auxin, cytokinin and abscisic acid (ABA) determine the root growth and development under heat stress. ABA cardinally integrates a signalling pathway involving heat shock factors, heat shock proteins and ROS to govern heat stress responses. Additionally, epigenetic modifications by transposable elements, DNA methylation and acetylation also regulate root growth under heat stress. Exogenous application of chemical compounds or biological agents such as ascorbic acid, metal ion chelators, fungi and bacteria can alleviate heat stress-induced reduction in root biomass. Future research should focus on the systemic effect of heat stress from shoot to root with more detailed investigations to decipher the molecular cues underlying the roots architecture and function.

Curcumol inhibits malignant biological behaviors and TMZ-resistance in glioma cells by inhibiting long noncoding RNA FOXD2-As1-promoted EZH2 activation.

Currently, conventional treatment is not sufficient to improve the survival of glioma patients. Hence, adopting novel personalized treatment programs is imperative. Curcumol, a Chinese herbal medicine extract from the roots of Rhizoma Curcumae, has attracted significant interest due to its beneficial pharmacological activities. The current study revealed that curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance in glioma cells in vitro and in vivo. Next, the potential molecular mechanisms of curcumol in inhibiting glioma were investigated. We found that the long non-coding RNA (lncRNA) FOXD2-As1 might contribute to the effects of curcumol on glioma cells. Enforced expression of FOXD2-As1 attenuated the curcumol-induced reduction in glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-As1 reversed the inhibitory effect of curcumol on the binding ability of EZH2 and H3K27me3 modification in the promoter regions of anti-oncogenes. Our results showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-As1-mediated EZH2 activation. Our study offers the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

Changes Induced by Mind-Body Intervention Including Epigenetic Marks and Its Effects on Diabetes.

Studies have evidenced that epigenetic marks associated with type 2 diabetes (T2D) can be inherited from parents or acquired through fetal and early-life events, as well as through lifelong environments or lifestyles, which can increase the risk of diabetes in adulthood. However, epigenetic modifications are reversible, and can be altered through proper intervention, thus mitigating the risk factors of T2D. Mind-body intervention (MBI) refers to interventions like meditation, yoga, and qigong, which deal with both physical and mental well-being. MBI not only induces psychological changes, such as alleviation of depression, anxiety, and stress, but also physiological changes like parasympathetic activation, lower cortisol secretion, reduced inflammation, and aging rate delay, which are all risk factors for T2D. Notably, MBI has been reported to reduce blood glucose in patients with T2D. Herein, based on recent findings, we review the effects of MBI on diabetes and the mechanisms involved, including epigenetic modifications.

A Computational Approach to Investigate the HDAC6 and HDAC10 Binding Propensity of Psidium guajava-derived Compounds as Potential Anticancer Agents.

BACKGROUND: Different parts of Psidium guajava are consumed as food and used for medicinal purposes around the world. Although studies have reported their antiproliferative effects via different biochemical mechanisms, their modulatory effects on epigenetic modification of DNA molecules via histone deacetylases (HDACs) are largely unknown. OBJECTIVE: This study was carried out to investigate the histone deacetylase 6 (HDAC6) and histone deacetylase 10 (HDAC10) binding propensity of guava-derived compounds, using in silico methods, in other to identify compounds with HDAC inhibitory potentials. METHODS: Fifty-nine guava-derived compounds and apicidin, a standard HDAC inhibitor, were docked with HDAC6 and HDAC10 using AutodockVina after modeling (SWISS-MODEL server) and validating (ERRAT and VERIFY-3D) the structure of HDAC10. Molecular interactions between the ligands and the HDACs were viewed with Discovery Studio Visualizer. Prediction of binding sites, surface structural pockets, active sites, area, shape and volume of every pocket and internal cavities of proteins was done using Computed Atlas of Surface Topography of proteins (CASTp) server, while absorption, distribution, metabolism, and excretion (ADME) study of notable compounds was done using Swiss online ADME web tool. RESULTS: 2α-hydroxyursolic acid, asiatic acid, betulinic acid, crategolic acid, guajadial A and B, guavacoumaric acid, guavanoic acid, ilelatifol D, isoneriucoumaric acid, jacoumaric acid, oleanolic acid, psiguadial A, B, and C demonstrated maximum interaction with the selected HDACs. ADME studies revealed that although isoneriucoumaric and jacoumaric acid ranked very high as HDAC inhibitors, they both violated the Lipinski's rule of 5. CONCLUSION: This study identified 13 drugable guava-derived compounds that can be enlisted for further studies as potential HDAC6 and HDAC10 inhibitors.

Yin Yang-1 suppresses CD40 ligand-CD40 signaling-mediated anti-inflammatory cytokine interleukin-10 expression in pulmonary adventitial fibroblasts by promoting histone H3 tri-methylation at lysine 27 modification on interleukin-10 promoter.

During the pathogenesis of early pulmonary arterial hypertension (PAH), pulmonary arterial adventitial fibroblast act as an initiator and mediator of inflammatory processes that predispose vessel walls to excessive vasoconstriction and pathogenic vascular remodeling. Emerging studies report that Yin Yang-1 (YY-1) plays important roles in inflammatory response and vascular injury. Our recent study finds that activation of CD40 ligand (CD40L)-CD40 signaling promotes pro-inflammatory phenotype of pulmonary adventitial fibroblasts. However, whether YY-1 is involved in CD40L-CD40 signaling-triggered inflammatory response in pulmonary adventitial fibroblasts and its underlying mechanism is still unclear. Here, we show that soluble CD40L (sCD40L) stimulation promotes YY-1 protein expression and suppresses anti-inflammatory cytokine, interleukin 10 (IL-10) expression in pulmonary adventitial fibroblasts, while YY-1 knockdown prevents sCD40L-mediated reduction of IL-10 expression via enhancing IL-10 gene transactivation. Further, we find that sCD40L stimulation significantly increases histone H3 tri-methylation at lysine 27 (H3K27me3) modification on IL-10 promoter in pulmonary adventitial fibroblasts, and YY-1 knockdown prevents the effect of sCD40L on IL-10 promoter by reducing the interaction with enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, binding to IL-10 promoter. Moreover, we find that sCD40L stimulation promotes YY-1 protein, but not messenger RNA (mRNA) expression, via decreasing N6-methyladenosine methylation on YY-1 mRNA to suppress YTHDF2-medicated mRNA decay. Overall, this in-depth study shows that the activation of CD40L-CD40 signaling upregulates YY-1 protein expression in pulmonary adventitial fibroblasts, which results in increasing YY-1 and EZH2 binding to the IL-10 promoter region to enhance H3K27me3 modification, eventually leading to suppression of IL-10 transactivation. This study first uncovers the roles of YY-1 on CD40L-CD40 signaling-triggered inflammatory response in pulmonary adventitial fibroblasts.

MiR399d and epigenetic modification comodulate anthocyanin accumulation in Malus leaves suffering from phosphorus deficiency.

Inorganic phosphorus (Pi) deficiency induces anthocyanin accumulation in the leaves of some plant species; however, the molecular mechanisms underlying this phenomenon have not been well characterized. Here, we showed that microRNA399d (miR399d), high-affinity Pi transporter McPHT1;4, and McMYB10 are strongly induced in Malus leaves suffering from Pi deficiency. By culturing explants of transiently transformed plants in MS medium under conditions of Pi sufficiency and Pi deficiency, miR399d and McPHT1;4 were shown to play essential roles in the response to Pi deficiency and to play positive roles in the regulation of anthocyanin biosynthesis. Silencing of McHDA6 expression and treatment with the inhibitor trichostatin A suggested that the low expression of McHDA6 simultaneously reduced the transcription of McMET1 and decreased the methylation level of the McMYB10 promoter; however, the expression of McMYB10 and anthocyanin content were increased. Bimolecular fluorescence complementation and yeast two-hybrid assays revealed that McHDA6 binds directly to McMET1 through its BAH2 and DNMT1-RFD domains. Based on the results of our study, we propose a mechanism for the molecular regulation of anthocyanin biosynthesis, namely, the miR399d and epigenetic modification comodulation model, to explain the phenomenon in which leaves turn red under conditions of Pi deficiency.

Inhibition of Histone Methyltransferase G9a Attenuates Noise-Induced Cochlear Synaptopathy and Hearing Loss.

Posttranslational modification of histones alters their interaction with DNA and nuclear proteins, influencing gene expression and cell fate. In this study, we investigated the effect of G9a (KMT1C, EHMT2), a major histone lysine methyltransferase encoded by the human EHMT2 gene and responsible for histone H3 lysine 9 dimethylation (H3K9me2) on noise-induced permanent hearing loss (NIHL) in adult CBA/J mice. The conditions of noise exposure used in this study led to losses of cochlear synapses and outer hair cells (OHCs) and permanent auditory threshold shifts. Inhibition of G9a with its specific inhibitor BIX 01294 or with siRNA significantly attenuated these pathological features. Treatment with BIX 01294 also prevented the noise-induced decrease of KCNQ4 immunolabeling in OHCs. Additionally, G9a was increased in cochlear cells, including both outer and inner sensory hair cells, some spiral ganglion neurons (SGNs), and marginal cells, 1 h after the completion of the noise exposure. Also subsequent to noise exposure, immunoreactivity for H3K9me2 appeared in some nuclei of OHCs following a high-to-low frequency gradient with more labeled OHCs in the 45-kHz than the 32-kHz region, as well as in the marginal cells and in some SGNs of the basal turn. These findings suggest that epigenetic modifications of H3K9me2 are involved in NIHL and that pharmacological targeting of G9a may offer a strategy for protection against cochlear synaptopathy and NIHL.

Effect of Recipes for Tonifying Kidney and Replenishing Qi on Learning and Memory-related Genes in Aged Rats / 中国实验方剂学杂志

Objective:To observe the effects of recipes for tonifying kidney and replenishing Qi, Zuoguiwan (ZG) and Yiqi Congming Tang(YQ) on memory capacity, expressions of learning and memory-related genes expression, and explore the changes in relevant epigenetic modification enzymes. Method:SD male rats with natural aging (24 months old) were used as animal models and randomly divided into aged control group, aged ZG group(12.12 g·kg-1), aged YQ group(10.18 g·kg-1), aged compound group(11.15 g·kg-1) and aged antagonist RU38486 group(5×10-3g·kg-1). Another 5 months old male SD rats were included as the young control group. Morris water maze method was used to observe the spatial learning and memory ability of the rats. The co-localizations of histone deacetylase 2 (HDAC2) and methyl CpG binding protein 2 (MeCP2) in hippocampus of rats in each group were observed by laser confocal microscope. The changes in expressions of glucocorticoid receptor (GR), synapsin1(Syn-1), HDAC2, and histone acetyltransferase 1(HAT1) proteins in hippocampus of each group were detected by Western blot, and mRNA expression of HDAC2 was detected by Real-time fluorescence quantitative polymerase Chain reaction (Real-time PCR). At the same time, the effects of ZG, YQ and compound decoction in alleviating the above-mentioned abnormal changes were observed. Result:Compared with the young control group(control group), the latency of the aged control group was significantly prolonged (PPPPPPPConclusion:ZG group, YQ group, and compound group can improve the spatial learning and memory abilities of aged rats by increasing the expression of learning-memory-associated protein GR and epigenetic modification enzyme HAT1, and reducing the expression of HDAC2 and the co-localization of HDAC2 protein and MeCP2 in the nucleus.

YY1 binds to the E3' enhancer and inhibits the expression of the immunoglobulin κ gene via epigenetic modifications.

The rearrangement and expression of immunoglobulin genes are regulated by enhancers and their binding transcriptional factors that activate or suppress the activities of the enhancers. The immunoglobulin κ (Igκ) gene locus has three important enhancers: the intrinsic enhancer (Ei), 3' enhancer (E3'), and distal enhancer (Ed). Ei and E3' are both required for Igκ gene rearrangement during early stages of B-cell development, whereas optimal expression of the rearranged Igκ gene relies on both E3' and Ed. The transcription factor YY1 affects the expression of many genes involved in B-cell development, probably by mediating interactions between their enhancers and promoters. Herein, we found that YY1 binds to the E3' enhancer and suppresses Igκ expression in B lymphoma cells by epigenetically modifying the enhancer. Knocking down YY1 enhanced Igκ expression, which was associated with increased levels of E2A (encoded by the TCF3 gene) and its binding to the E3' enhancer. Moreover, in germinal centre B cells and plasma cells, YY1 expression was reversely associated with Igκ levels, implying that YY1 might facilitate antibody affinity maturation in germinal centre B cells through the transient attenuation of Igκ expression.

Endophytic Fungi: A Source of Potential Antifungal Compounds.

The emerging and reemerging forms of fungal infections encountered in the course of allogeneic bone marrow transplantations, cancer therapy, and organ transplants have necessitated the discovery of antifungal compounds with enhanced efficacy and better compatibility. A very limited number of antifungal compounds are in practice against the various forms of topical and systemic fungal infections. The trends of new antifungals being introduced into the market have remained insignificant while resistance towards the introduced drug has apparently increased, specifically in patients undergoing long-term treatment. Considering the immense potential of natural microbial products for the isolation and screening of novel antibiotics for different pharmaceutical applications as an alternative source has remained largely unexplored. Endophytes are one such microbial community that resides inside all plants without showing any symptoms with the promise of producing diverse bioactive molecules and novel metabolites which have application in medicine, agriculture, and industrial set ups. This review substantially covers the antifungal compounds, including volatile organic compounds, isolated from fungal endophytes of medicinal plants during 2013⁻2018. Some of the methods for the activation of silent biosynthetic genes are also covered. As such, the compounds described here possess diverse configurations which can be a step towards the development of new antifungal agents directly or precursor molecules after the required modification.

Mechanisms of action involved in ozone-therapy in skin diseases.

Ozone-therapy initially applied in medicine by an empirical approach, has now reached a new stage where most of the biological mechanisms of ozone action have been clarified, that refers to antimicrobial effects, immunoregulation, antioxidant defenses and epigenetic modification. Current ozone medical preparation in dermatology mainly classified as ozone hydrotherapy, ozonated oil externally used and ozone autohemotherapy (OAHT). Admittedly, ozone is widely used in various fields against gram-negative and gram-positive bacteria, viruses, and fungi. More recently, great progress has been obtained in wound healing which is a multiphase process that consists of three overlapping but distinct stages: inflammation, tissue proliferation and remodeling. While the exact mechanisms of ozone-therapy still remain unclear. Therefore, more evidence is required before ozone can be presented as a promising method for the management and prevention of various skin diseases. In this review, we review the application status of ozone in dermatology and summarize possible mechanisms of ozone-therapy on skin diseases, aims to shed a light on providing a series of theoretical basis for its applications.

Biotin-mediated epigenetic modifications: Potential defense against the carcinogenicity of benzo[a]pyrene.

Environmental pollution and an unhealthy lifestyle result in direct exposure to dangerous chemicals that can modify endogenous pathways and induce malignant transformation of human cells. Although the molecular mechanisms of tumorigenesis are still not well understood, epigenetic alteration may be associated with exogenous chemical-induced carcinogenicity. Given the association between nutrition and cancer, nutrient supplementation may reduce aberrant epigenetic modifications induced by chemicals, thus decreasing carcinogenesis. This paper provides an overview of the epigenetic events caused by benzo[a]pyrene, a procarcinogenic and environmental pollutant, and biotin, an essential water-soluble vitamin, and investigates potential connections between them. This paper also discusses the potential inhibitory effect of biotin-related epigenetic modifications on the carcinogenicity of benzo[a]pyrene. The effect of nutritional supplementation on tumorigenesis involving epigenetic modifications is also discussed.