Search Results (27)

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation. Full article

Chromium (Cr) is a toxic heavy metal that affects the food chain and poses a severe threat to food safety. Nonetheless, the N6-methyladenosine (m6A) transcriptomic regulation mechanisms of Cr tolerance genes in rice are not well understood. This study found that rice roots exhibit competitive and synergistic interactions with trace elements under Cr stress. Through a comprehensive transcriptome analysis of m6A methylation profiles under Cr stress, differentially methylated genes (DMGs) closely related to the plasma membrane, oxidoreductase activity, and protein phosphorylation were identified. A significant number of differentially expressed genes (DEGs) associated with heavy metal transporter domains, metalloproteases, metal ion transporters, and other cation transporters were strongly induced by Cr. Additionally, OsHMT9.1 exhibited extensive hypomethylation and up-regulation in Cr-exposed roots and was confirmed to be a regulatory factor for Cr tolerance. Enhanced plant resistance to Cr in oshmt9.1 was accompanied by increased levels of P, K, S, and Ca and decreased levels of Mn and Cu. These results suggest that knocking out OsHMT9.1 can promote Cr detoxification in rice by modulating the balance between Cr and other trace elements. These findings provide new insights into the molecular regulation and stress response of rice under Cr stress through transcriptome m6A methylation patterns. Full article

Histone methyltransferases (HMTs) and histone demethylases (HDMs) are critical enzymes that regulate chromatin dynamics and gene expression through the addition and removal of methyl groups on histone proteins. HMTs, such as PRC2 and SETD2, are involved in the trimethylation of histone H3 at lysine 27 and lysine 36, influencing gene silencing and activation. Dysregulation of these enzymes often leads to abnormal gene expression and contributes to tumorigenesis. In contrast, HDMs including KDM7A and KDM2A reverse these methylation marks, and their dysfunction can drive disease progression. In cancer, the aberrant activity of specific HMTs and HDMs can lead to the silencing of tumor suppressor genes or the activation of oncogenes, facilitating tumor progression and resistance to therapy. Conversely, in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), disruptions in histone methylation dynamics are associated with neuronal loss, altered gene expression, and disease progression. We aimed to comprehend the odd activity of HMTs and HDMs and how they contribute to disease pathogenesis, highlighting their potential as therapeutic targets. By advancing our understanding of these epigenetic regulators, this review provides new insights into their roles in cancer and neurodegenerative diseases, offering a foundation for future research. Full article

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (C_max/DW)), elimination (terminal half-life (T_1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and C_max/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and C_max/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T_1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, C_max, and CL/F of 5-HMT, which should be confirmed in other studies. Full article

Histone acetylation and methylation, governed by various histone modification (HM) gene families, are vital for plant biological processes. However, there are limited studies that have explored HMs in ornamental horticultural trees, including sweet osmanthus (Osmanthus fragrans). We performed genome-wide search and identified 208 OfHMs, encompassing 81 histone methyltransferases (OfHMTs), 51 histone demethylases (OfHDMs), 49 histone acetyltransferases (OfHATs) and 27 histone deacetylases (HDACs). Our comprehensive analysis covered chromosome locations, gene structures, conserved domains, cis-acting elements, phylogenetic comparisons, protein interaction networks and functional enrichment pathways for these gene families. Additionally, tandem and fragment replications were unveiled as contributors to the expansion of OfHMs, with some genes exhibiting positive selection. Furthermore, we examined OfHM expression profiles across various tissues and flowering stages, and under 5′-azacytidine (Aza) and ethylene treatments. Most OfHMs displayed heightened expression in leaves, and were downregulated during the flower opening and senescence stages, including OfPRMTs, OfHDTs, OfHDAs, OfSRTs, OfJMJs and OfHAGs; 75.86% and 80.77% of the differentially expressed OfHMs were upregulated after Aza and ethylene treatments, including OfHAGs, OfHDAs and OfSDGs. This study offers a comprehensive analysis of the OfHM gene family, which indicated their potential involvement in ethylene and Aza responses, and in the flowering process. These findings provide valuable insights into the role of OfHMs in flowering and stress responses. Full article

Histone post-translational modifications (PTMs) represent a key mechanism in the thermal adaptation of the honeybee Apis mellifera. In this study, a chromatin immunoprecipitation assay and qPCR were employed to explore the changes in the methylation states of H3K4m2, H3K4m3, H3K27m2 and H3K27m3 associated with l2efl (ID: 72474, 724405, 724488), histone methyltransferases (HMTs) ((trx) and PR-set7) and Polycomb (Pc) and (Su(z)12) genes in A. m. jemenitica (tolerant subspecies) and A. m. carnica (susceptible subspecies) in response to heat treatment (42 °C for 1 h). The results revealed significant enrichment fold changes in the methylation/demethylation of most H3K4 and H3K27 marks at all targeted genes. These changes increased the profusion of l2efl (ID: 72474, 724405, 724488), histone methyltransferases (HMTs) (trx) and Polycomb (Pc) and Su(z)12 and decreased the profusion of HMT (PR-set7) in both honeybee subspecies. The changes in the methylation enrichment folds of histone methyltransferases (HMTs) ((trx), PR-set) and Polycomb (Pc), Su(z)12 genes demonstrate the well-harmonized coordination of epigenetic gene regulation in response to heat treatment. Compared to the control, the changes in the methylation enrichment folds of H3K4m3 at Polycomb Su(z)12 were about 30× and 100× higher in treated A. m. jemenitica and A.m. carnica, respectively. Similarly, changes in the methylation/demethylation enrichment folds of HMT (trx) and Polycomb (Pc) and Su(z)12 were 2–3× higher in A. m. carnica than in A. m. jemenitica after treatment (42 °C). It is evident that post-translational chromatin modification in both honeybee subspecies can diminish heat stress impact by (I) increasing the transcriptional provision of l2efl associated with survival and (II) increasing the silencing of genes associated with general cellular activities. Full article

The p21-activated kinases (PAKs) are important signaling proteins. They contribute to a surprisingly wide range of cellular processes and play critical roles in a number of human diseases including cancer, neurological disorders and cardiac diseases. To get a better understanding of PAK functions, mechanisms and integration of various cellular activities, we screened for proteins that bind to the budding yeast PAK Ste20 as an example, using the split-ubiquitin technique. We identified 56 proteins, most of them not described previously as Ste20 interactors. The proteins fall into a small number of functional categories such as vesicle transport and translation. We analyzed the roles of Ste20 in glucose metabolism and gene expression further. Ste20 has a well-established role in the adaptation to changing environmental conditions through the stimulation of mitogen-activated protein kinase (MAPK) pathways which eventually leads to transcription factor activation. This includes filamentous growth, an adaptation to nutrient depletion. Here we show that Ste20 also induces filamentous growth through interaction with nuclear proteins such as Sac3, Ctk1 and Hmt1, key regulators of gene expression. Combining our observations and the data published by others, we suggest that Ste20 has several new and unexpected functions. Full article

Changes in epigenetic programming have been proposed as being key events in the initiation and progression of childhood cancers. HMT euchromatic histone lysine methyltransferase 2 (G9a, EHMT2), which is encoded by the G9a (Ehmt2) gene, as well as its related protein GLP, which is encoded by the GLP/Ehmt1 gene, participate in epigenetic regulation by contributing to a transcriptionally repressed chromatin state. G9a/GLP activation has been reported in several cancer types. Herein, we evaluated the role of G9a in two solid pediatric tumors: neuroblastoma (NB) and Ewing sarcoma (ES). Our results show that G9a/Ehmt2 and GLP/Ehmt1 expression is higher in tumors with poorer prognosis, including St4 International Neuroblastoma Staging System (INSS) stage, MYCN amplified NB, and metastatic ES. Importantly, higher G9a and GLP levels were associated with shorter patient overall survival (OS) in both NB and ES. Moreover, pharmacological inhibition of G9a/GLP reduced cell viability in NB and ES cells. These findings suggest that G9a and GLP are associated with more aggressive NB and ES tumors and should be further investigated as being epigenetic targets in pediatric solid cancers. Full article

The rising prevalence of lifestyle diseases, such as type 2 diabetes, cardiovascular diseases, and metabolic syndrome, has increased the need for effective dietary interventions. This study aimed to evaluate the effects of heat-moisture-treated high-amylose rice (HA-HMT) on body weight, lipid metabolism, and gut microbiome composition in a rat model of obesity. Starch digestibility—specifically, resistant starch—has been shown to provide various health benefits, including improved metabolic health and gut microbiome composition. We employed a sequential approach: firstly, utilizing diet-induced obesity rat models fed with HMT-processed and HMT-non-processed low- or high-amylose rice to investigate the potential of amylose content or HMT to alter phenotypic characteristics and lipid metabolism; and secondly, using the optimal rice flour identified in the previous step to explore the underlying mechanisms. Our findings indicate that heat-moisture treatment, rather than the level of the amylose content of the rice, contributes to the observed anti-obesity and cholesterol-lowering effects. We identified candidate genes contributing to the cholesterol-regulating potential and demonstrated that HMT rice flour could influence the gut microbiome, particularly the Ruminococcus taxa. This study provides valuable insights into the health benefits of HA-HMT rice and supports its potential as a functional food ingredient in the management of obesity and cholesterol-related disorders. Full article

Epigenetics has long been recognized as a significant field in biology and is defined as the investigation of any alteration in gene expression patterns that is not attributed to changes in the DNA sequences. Epigenetic marks, including histone modifications, non-coding RNAs, and DNA methylation, play crucial roles in gene regulation. Numerous studies in humans have been carried out on single-nucleotide resolution of DNA methylation, the CpG island, new histone modifications, and genome-wide nucleosome positioning. These studies indicate that epigenetic mutations and aberrant placement of these epigenetic marks play a critical role in causing the disease. Consequently, significant development has occurred in biomedical research in identifying epigenetic mechanisms, their interactions, and changes in health and disease conditions. The purpose of this review article is to provide comprehensive information about the different types of diseases caused by alterations in epigenetic factors such as DNA methylation and histone acetylation or methylation. Recent studies reported that epigenetics could influence the evolution of human cancer via aberrant methylation of gene promoter regions, which is associated with reduced gene function. Furthermore, DNA methyltransferases (DNMTs) in the DNA methylation process as well as histone acetyltransferases (HATs)/histone deacetylases (HDACs) and histone methyltransferases (HMTs)/demethylases (HDMs) in histone modifications play important roles both in the catalysis and inhibition of target gene transcription and in many other DNA processes such as repair, replication, and recombination. Dysfunction in these enzymes leads to epigenetic disorders and, as a result, various diseases such as cancers and brain diseases. Consequently, the knowledge of how to modify aberrant DNA methylation as well as aberrant histone acetylation or methylation via inhibitors by using epigenetic drugs can be a suitable therapeutic approach for a number of diseases. Using the synergistic effects of DNA methylation and histone modification inhibitors, it is hoped that many epigenetic defects will be treated in the future. Numerous studies have demonstrated a link between epigenetic marks and their effects on brain and cancer diseases. Designing appropriate drugs could provide novel strategies for the management of these diseases in the near future. Full article

Broccoli sprouts have high isothiocyanate and selenium accumulation capacity. This study used a combination of methods, including physiological and biochemical, gene transcription and proteomic, to investigate the isothiocyanate and endogenous selenium accumulation mechanisms in broccoli sprouts under exogenous sodium selenite treatment during germination. Compared with the control, the sprouts length of broccoli sprouts under exogenous selenium treatment was significantly lower, and the contents of total phenol and malondialdehyde in 6-day-old broccoli sprouts were substantially higher. The contents of isothiocyanate and sulforaphane in 4-day-old were increased by up-regulating the relative expression of genes of UGT74B1, OX-1, and ST5b. The relative expression of BoSultr1;1, BoSMT, BoHMT1, and BoCOQ5-2 genes regulating selenium metabolism was significantly up-regulated. In addition, 354 proteins in 4-day-old broccoli sprouts showed different relative abundance compared to the control under selenium treatment. These proteins were classified into 14 functional categories. It was discovered that metabolic pathways and biosynthetic pathways of secondary metabolites were significantly enriched. The above results showed that exogenous selenium was beneficial in inducing the accumulation of isothiocyanate and selenium during the growth of broccoli sprouts. Full article

The ability of animal orthologs of human mitochondrial transcription factor A (hTFAM) to support the replication of human mitochondrial DNA (hmtDNA) does not follow a simple pattern of phylogenetic closeness or sequence similarity. In particular, TFAM from chickens (Gallus gallus, chTFAM), unlike TFAM from the “living fossil” fish coelacanth (Latimeria chalumnae), cannot support hmtDNA replication. Here, we implemented the recently developed GeneSwap approach for reverse genetic analysis of chTFAM to obtain insights into this apparent contradiction. By implementing limited “humanization” of chTFAM focused either on amino acid residues that make DNA contacts, or the ones with significant variances in side chains, we isolated two variants, Ch13 and Ch22. The former has a low mtDNA copy number (mtCN) but robust respiration. The converse is true of Ch22. Ch13 and Ch22 complement each other’s deficiencies. Opposite directionalities of changes in mtCN and respiration were also observed in cells expressing frog TFAM. This led us to conclude that TFAM’s contributions to mtDNA replication and respiratory chain biogenesis are genetically separable. We also present evidence that TFAM residues that make DNA contacts play the leading role in mtDNA replication. Finally, we present evidence for a novel mode of regulation of the respiratory chain biogenesis by regulating the supply of rRNA subunits. Full article

This study was performed to design a hydrogel membrane that exhibits antibacterial properties and guides different tissues. Gelatin and hyaluronic acid were used as the main structures, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was used as a cross-linker, and temoporfin was used as an antibacterial agent. The results revealed that the hydrogel membrane impregnated with temoporfin (HM-T) had a fixation index of >89%. Temoporfin was used in conjunction with a diode laser and did not significantly affect EDC-induced cross-linking. The inhibitory activity of temoporfin showed that HM-T15 and HM-T30 (light exposure for 15 and 30 min, respectively) had remarkable antibacterial properties. The cell survival rate of HM-T15 was 73% of that of the control group, indicating that temoporfin exposure for 15 min did not exert cytotoxic effects on L-929 cells. HM and HM-T15 hydrogel membranes showed good cell adhesion and proliferation after 14 days of dark incubation. However, the hydrogel membrane containing temoporfin significantly reduced pro-inflammatory gene expression. In summary, the HM-T15 group showed potential as a biodegradable material for biocompatible tissue-guarded regeneration membranes with antibacterial properties. This study demonstrated the potential of temoporfin for innovative biomaterials and delivery systems applied to new regenerative periodontal therapies. Full article

Taraxacum kok-saghyz (Tks), also known as the Russian dandelion, is a recognized alternative source of natural rubber quite comparable, for quality and use, to the one obtained from the so-called rubber tree, Hevea brasiliensis. In addition to that, Tks roots produce several other compounds, including inulin, whose use in pharmaceutical and dietary products is quite extensive. Histone-modifying genes (HMGs) catalyze a series of post-translational modifications that affect chromatin organization and conformation, which, in turn, regulate many downstream processes, including gene expression. In this study, we present the first analysis of HMGs in Tks. Altogether, we identified 154 putative Tks homologs: 60 HMTs, 34 HDMs, 42 HATs, and 18 HDACs. Interestingly, whilst most of the classes showed similar numbers in other plant species, including M. truncatula and A. thaliana, HATs and HMT-PRMTs were indeed more abundant in Tks. Composition and structure analysis of Tks HMG proteins showed, for some classes, the presence of novel domains, suggesting a divergence from the canonical HMG model. The analysis of publicly available transcriptome datasets, combined with spatial expression of different developmental tissues, allowed us to identify several HMGs with a putative role in metabolite biosynthesis. Overall, our work describes HMG genomic organization and sets the premises for the functional characterization of epigenetic modifications in rubber-producing plants. Full article

The rate-determining role of tyrosinase makes it a critical component in the mechanism that is responsible for melanogenesis. Thirteen (Z)-5-(substituted benzylidene)-3-phenyl-2-thioxothiazolidin-4-one ((Z)-BPTT) analogs were designed based on the structural features of two potent tyrosinase inhibitors, viz. (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT) and (Z)-2-(2,4-dihydroxybenzylidene)benzo[4,5]imidazo[2,1-b]thiazol-3(2H)-one (compound I). The trisubstituted double bond geometry of the (Z)-BPTT analogs that were generated by Knoevenagel condensation was determined using vicinal ¹H and ¹³C coupling constants in ¹³C NMR spectra. Four analogs, numbers 1–3 and 6, inhibited mushroom tyrosinase 9 to 29 times more potently than kojic acid did. Kinetic study results indicated that these four analogs inhibited mushroom tyrosinase competitively and this was supported by docking simulation. Also, docking results using human tyrosinase suggested that analogs 2 and 3 might be potent human tyrosinase inhibitors. In vitro studies using B16F10 cells (a melanoma cell line) showed that analogs 1, 2, 3, and 6 inhibited cellular tyrosinase and melanin production more than kojic acid did, without perceptible cytotoxicity. In particular, analog 2, which possesses a catechol group, exerted an extremely potent anti-melanogenic effect. In addition, analog 2 showed strong scavenging activity against DPPH and ABTS radicals. Furthermore, analog 2 not only reduced ROS levels, which induce melanogenesis, but it also suppressed tyrosinase and MITF (microphthalamia-associated transcription factor) protein levels and the expressions of melanogenesis-related genes. These results suggest that analog 2 is an efficient tyrosinase inhibitor that alleviates melanogenesis by dual mechanisms of (i) the inhibition of melanogenesis-related proteins and genes and (ii) the direct inhibition of tyrosinase activity. Full article