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Cardiovascular diseases (CVD), including coronary heart disease and stroke, comprise the number one cause of mortality worldwide. A major contributor to CVD is atherosclerosis, which is a low-grade inflammatory disease of vasculature that involves a pathological build-up of plaque within the arterial walls. Studies have shown that regulation of gene expression via transcription factors and epigenetic mechanisms play a fundamental role in transcriptomic changes linked to the development of atherosclerosis. Chromatin remodeling is a reversible phenomenon and studies have supported the clinical application of chromatin-modifying agents for the prevention and treatment of CVD. In addition, pre-clinical studies have identified multiple transcription factors as potential therapeutic targets in combating atherosclerotic CVD. Although interaction between transcription factors and epigenetic mechanisms facilitate gene regulation, a limited number of studies appreciate this crosstalk in the context of CVD. Here, we reviewed this gene regulatory mechanism underappreciated in atherosclerosis, which will highlight the mechanisms underlying novel therapeutics targeting epigenetic modifiers and transcription factors in atherosclerosis.

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Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade of pathogenic events, including transcriptional dysregulation. Genotype-phenotype correlations in MJD are incomplete, suggesting an influence of additional factors, such as epigenetic modifications, underlying the MJD pathogenesis. DNA methylation is known to impact the pathophysiology of neurodegenerative disorders through gene expression regulation and increased methylation has been reported for other SCAs. In this work we aimed to analyse global methylation in MJD carriers. Global 5-mC levels were quantified in blood samples of 33 MJD mutation carriers (patients and preclinical subjects) and 33 healthy controls, matched by age, sex, and smoking status. For a subset of 16 MJD subjects, a pilot follow-up analysis with two time points was also conducted. No differences were found in median global 5-mC levels between MJD mutation carriers and controls and no correlations between methylation levels and clinical or genetic variables were detected. Also, no alterations in global 5-mC levels were observed over time. Our findings do not support an increase in global blood methylation levels associated with MJD.

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The use of doubled haploid (DH) technology enables the development of new varieties of plants in less time than traditional breeding methods. In microspore embryogenesis (ME), stress treatment triggers microspores towards an embryogenic pathway, resulting in the production of DH plants. Epigenetic modifiers have been successfully used to increase ME efficiency in a number of crops. In wheat, only the histone deacetylase inhibitor trichostatin A (TSA) has been shown to be effective. In this study, inhibitors of epigenetic modifiers acting on histone methylation (chaetocin and CARM1 inhibitor) and histone phosphorylation (aurora kinase inhibitor II (AUKI-II) and hesperadin) were screened to determine their potential in ME induction in high- and mid-low-responding cultivars. The use of chaetocin and AUKI-II resulted in a higher percentage of embryogenic structures than controls in both cultivars, but only AUKI-II was superior to TSA. In order to evaluate the potential of AUKI-II in terms of increasing the number of green DH plants, short and long application strategies were tested during the mannitol stress treatment. The application of 0.8 µM AUKI-II during a long stress treatment resulted in a higher percentage of chromosome doubling compared to control DMSO in both cultivars. This concentration produced 33% more green DH plants than the control in the mid-low-responding cultivar, but did not affect the final ME efficiency in a high-responding cultivar. This study has identified new epigenetic modifiers whose use could be promising for increasing the efficiency of other systems that require cellular reprogramming.

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Scientists are making efforts to search for new metabolites as they are essential lead molecules for the drug discovery, much required due to the evolution of multi drug resistance and new diseases. Moreover, higher production of known drugs is required because of the ever growing population. Microorganisms offer a vast collection of chemically distinct compounds that exhibit various biological functions. They play a crucial role in safeguarding crops, agriculture, and combating several infectious ailments and cancer. Research on fungi have grabbed a lot of attention after the discovery of penicillin, most of the compounds produced by fungi under normal cultivation conditions are discovered and now rarely new compounds are discovered. Treatment of fungi with the epigenetic modifiers has been becoming very popular since the last few years to boost the discovery of new molecules and enhance the production of already known molecules. Epigenetic literally means above genetics that actually does not alter the genome but alter its expression by altering the state of chromatin from heterochromatin to euchromatin. Chromatin in heterochromatin state usually doesn't express because it is closely packed by histones in this state. Epigenetic modifiers loosen the packing of chromatin by inhibiting DNA methylation and histone deacetylation and thus permit the expression of genes that usually remain dormant. This study delves into the possibility of utilizing epigenetic modifying agents to generate pharmacologically significant secondary metabolites from fungi.

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Brain tumors are the most common solid tumor in children and the leading cause of cancer-related deaths. Over the last few years, improvements have been made in the diagnosis and treatment of children with Central Nervous System tumors. Unfortunately, for many patients with high-grade tumors, the overall prognosis remains poor. Lower survival rates are partly attributed to the lack of efficacious therapies. The advent and success of immune checkpoint inhibitors (ICIs) in adults have sparked interest in investigating the utility of these therapies alone or in combination with other drug treatments in pediatric patients. However, to achieve improved clinical outcomes, the establishment and selection of relevant and robust preclinical pediatric high-grade brain tumor models is imperative. Here, we review the information that influenced our model selection as we embarked on an international collaborative study to test ICIs in combination with epigenetic modifying agents to enhance adaptive immunity to treat pediatric brain tumors. We also share challenges that we faced and potential solutions.

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Omega-3 (n - 3) and omega-6 (n - 6) polyunsaturated fatty acids (PUFAs) are vital for human health, but an imbalance between these types is associated with chronic diseases, including cancer. Alpha-linolenic acid (ALA), a n - 3 PUFA, shows promise as an anticancer agent in both laboratory and animal studies. However, the precise molecular mechanisms underlying ALA's actions against cancer-related epigenetic modifiers (CaEpM) remain unclear. To understand this, we employed network pharmacology (NP) and molecular docking techniques. Our study identified 51 potential ALA targets and GO and KEGG pathway analysis revealed possible molecular targets and signaling pathways of ALA against CaEpM. From PPI analysis, EZH2, KAT2B, SIRT1, KAT2A, KDM6B, EHMT2, WDR5, SETD7, SIRT2, and HDAC3 emerged as the top 10 potential targets. Additionally, GeneMANIA functional association (GMFA) network analysis of these top 10 targets was performed to enhance NP insights and explore ALA's multi-target approach. After an exhaustive analysis of the core FGN subnetwork, it became evident that 9 out of the 15 targets-namely EZH2, SUZ12, EED, PARP1, HDAC3, DNMT1, NCOR2, KAT2B, and TRRAP-manifested evidently strong and abundant interconnections among each other. Molecular docking of both top 10 targets and core FGN targets confirmed strong binding affinity between ALA and SIRT2, WDR5, KDM6B, EHMT2, HDAC3, EZH2, PARP1, and KAT2B, underscoring their roles in ALA's anti-CaEpM mechanism. Our findings suggest that ALA may target key signaling pathways related to transcriptional regulation, microRNA involvement, stem cell pluripotency and cellular senescence in cancer epigenetics. These findings illuminate ALA's potential as a multi-target agent against CaEpM.Communicated by Ramaswamy H. Sarma.

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Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications. Here, we discuss the potential roles of a leaky gut in the development of depressive disorders via changes in gut microbiota-derived metabolites with epigenetic effects. Next, we will deliberate how altering the gut microbiome composition contributes to the development of depressive disorders via epigenetic alterations. In particular, we focus on how microbiota-derived metabolites such as butyrate as an epigenetic modifier, probiotics, maternal diet, polyphenols, drugs (e.g., antipsychotics, antidepressants, and antibiotics), and fecal microbiota transplantation could positively alleviate depressive-like behaviors by modulating the epigenetic landscape. Finally, we will discuss challenges associated with recent therapeutic approaches for depressive disorders via microbiome-related epigenetic shifts, as well as opportunities to tackle such problems.

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Peripheral T-cell lymphomas (PTCLs) are a group of diseases with a low incidence, high degree of heterogeneity, and a dismal prognosis in most cases. Because of the low incidence of these diseases, there have been few therapeutic novelties developed over time. Nevertheless, this fact is changing presently as epigenetic modifiers have been shown to be recurrently mutated in some types of PTCLs, especially in the cases of PTCLs not otherwise specified (PTCL-NOS), T follicular helper (TFH), and angioimmunoblastic T-cell lymphoma (AITL). These have brought about more insight into PTCL biology, especially in the case of PTCLs arising from TFH lymphocytes. From a biological perspective, it has been observed that ten-eleven translocators (TET2) mutated T lymphocytes tend to polarize to TFH, while Tregs lose their inhibitory properties. IDH2 R172 was shown to have inhibitory effects on TET2, mimicking the effects of TET2 mutations, as well as having effects on histone methylation. DNA methyltransferase 3A (DNMT3A) loss-of-function, although it was shown to have opposite effects to TET2 from an inflammatory perspective, was also shown to increase the number of T lymphocyte progenitors. Aside from bringing about more knowledge of PTCL biology, these mutations were shown to increase the sensitivity of PTCLs to certain epigenetic therapies, like hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACis). Thus, to answer the question from the title of this review: We found the Achilles heel, but only for one of the Achilles.

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The continuous burden of human immunodeficiency virus-1 in Sub-Saharan Africa, coupled with the inability of antiretroviral agents to eradicate HIV-1 from viral reservoirs, the potential risks of drug resistance development, and the development of adverse effects, emphasizes the need to develop a new class of HIV-1 inhibitors. Here, we cultivated four endophytic fungal isolates from a medicinal plant, Albizia adianthifolia with the addition of small epigenetic modifiers, sodium butyrate, and valproic acid, to induce the expression of biosynthetic gene clusters encoding active secondary metabolites with probable anti-HIV activities. We identified a non-toxic crude extract of the endophytic fungus Penicillium chrysogenum treated with sodium butyrate to possess significantly greater anti-HIV activity than the untreated extracts. Penicillium chrysogenum P03MB2 showed anti-HIV activity with an IC50 of 0.6024 µg/mL compared to untreated fungal crude extract (IC50 5.053 µg/mL) when treated with sodium butyrate. The profile of secondary metabolite compounds from the bioactive, partially purified extracts were identified by gas chromatography-mass spectrometry (GC-MS), and more bioactive compounds were detected in treated P. chrysogenum P03MB2 fractions than in untreated fractions. Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro (13.64%), cyclotrisiloxane, hexamethyl (8.18%), cyclotetrasiloxane, octamethyl (7.23%), cyclopentasiloxane, decamethyl (6.36%), quinoline, 1,2-dihydro-2,24-trimethyl (5.45%), propanenitrile (4.55%), deca-6,9-diene (4.55%), dibutyl phthalate (4.55%), and silane[1,1-dimethyl-2-propenyl)oxy]dimethyl (2.73%) were the most abundant compounds. These results indicate that treatment of endophytic fungi with small epigenetic modifiers enhances the secretion of secondary metabolites with stronger anti-HIV-1 properties, acknowledging the feasibility of epigenetic modification as an innovative approach for the discovery of cryptic fungal metabolites which can be developed into therapeutic compounds.

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Peripheral T-cell lymphomas (PTCLs) are a diverse and uncommon type of lymphoid malignancies with a dismal prognosis. Recent advances in genomic studies have shown recurring mutations that are changing our knowledge of the disease's molecular genetics and pathogenesis. As such, new targeted therapies and treatments to improve disease outcomes are currently being explored. In this review, we discussed the current understanding of the nodal PTCL biology with potential therapeutic implications and gave our insights on the promising novel therapies that are currently under study such as immunotherapy, chimeric antigen receptor T-cell therapy, and oncolytic virotherapy.

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In this study, we aimed to understand the interplay of the epigenetic modifier genes DNMT1 and TET1 along with HPV infection in the cervical epithelium and how it changes during tumorigenesis. For this purpose, initially the bioinformatical analysis (methylation and expression profile) of DNMT1 and TET1 was analyzed in the TCGA dataset. Next genetic (deletion) and epigenetic profiling (promoter methylation) of DNMT1 and TET1 were done in our sample pool and also validated in CACX cell lines as well. The results were further correlated with different clinicopathological parameters. Our data revealed that HPV infection in basal/parabasal layers of cervical epithelium actually disrupts the epigenetic homeostasis of DNMT1 and TET1 proteins which ultimately leads to the high expression of DNMT1 along with further reduction in TET1 protein during the development of carcinoma. Further, in-depth look into the results revealed that comparatively low methylation frequency of DNMT1 coupled with high promoter methylation and deletion frequency [22-46%] of TET1 were the plausible reasons of their antagonistic expression profile during the progression of the disease. Interestingly, the prevalence of DNMT1 [9.1%] and TET1 promoter methylation [22.7%] found in both the plasma DNA of the respective CACX patients implicated its diagnostic importance in this study. Lastly, molecular alteration of TET1 alone or in combination with DNMT1 showed the worst overall survival among the patients. Hence, it may be concluded that an inverse molecular profile of DNMT1 and TET1 genes seen in the proliferative basal-parabasal layers of the cervical epithelium was aggravated during the development of CACX along with genetic and epigenetic changes due to HPV infection.

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INTRODUCTION: Despite recent developments in the landscape of urothelial carcinoma (UC) treatment, platinum combination chemotherapy still remains a milestone. Recently immunotherapeutic agents have gained ever-growing attractivity, particularly in the metastatic setting. Novel chemotherapeutic strategies and agents, such as antibody-drug conjugates (ADCs), and powerful combination regimens have been developed to overcome the resistance of most UC to current therapies. AREAS COVERED: Herein, we review the current standard-of-care chemotherapy, the development of ADCs, the rationale for combining therapy regimens with chemotherapy in current trials, and future directions in UC management. EXPERT OPINION: Immunotherapy has prompted a revolution in the treatment paradigm of UC. However, only a few patients experience a long-term response when treated with single-agent immunotherapies. Combination treatments are necessary to bypass resistance mechanisms and broaden the clinical utility of current options. Current evidence supports the intensification of standard-of-care chemotherapy with maintenance immunotherapy. However, the optimal sequence, combination, and duration must be determined to achieve individual longevity with acceptable health-related quality of life. In that regard, ADCs appear as a promising alternative for single and combination strategies in UC, as they specifically target the tumor cells, thereby, theoretically improving treatment efficacy and avoiding extensive off-target toxicities.

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Human umbilical cord (hUC) derived mesenchymal stem cells (MSCs) can be progressively differentiated into multiple lineages including hepatic lineages, and thus provide an excellent in vitro model system for the study of hepatic differentiation. At present, hepatic differentiation protocols are based on the use of soluble chemicals in the culture medium and provide immature hepatic like cells. Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) are two important epigenetic modifiers that regulate stem cell differentiation. Therefore, this study aimed to investigate the role of HDACi, valproic acid (VPA) and DNMTi,5-azacytidine (5-aza) along with a hepatic inducer in the hepatic differentiation of hUC-MSCs. hUC-MSCs were characterized via immunocytochemistry and flow cytometry. The final concentrations of VPA and 5-aza were optimized via MTT cytotoxicity assay. All treated groups were assessed for the presence of hepatic genes and proteins through qPCR and immunocytochemistry, respectively. The results showed that the pretreatment of epigenetic modifiers not only increased the hepatic genes but also increased the expression of the hepatic proteins. VPA induces hepatic differentiation in hUC-MSCs with significant gene expression of hepatic markers i.e., FOXA2 and CK8. Moreover, VPA pretreatment enhanced the expression of hepatic proteins AFP and TAT. The pretreatment of 5-aza shows significant gene expression of hepatic marker LDL-R. However, 5-aza treatment failed to induce hepatic protein expression. The results of the current study highlighted the effectiveness of epigenetic modifiers in the hepatic differentiation of hUC-MSCs. These differentiated cells can be employed in cell-based therapeutics for hepatic diseases in future.

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Epigenetic mechanisms of gene regulation are important for the proper differentiation of cells used for therapeutic and regenerative purposes. The primary goal of the present study was to investigate the impacts of 5-aza-2' deoxycytidine (5-AZA-dc)- and/or trichostatin A (TSA)-mediated approaches applied to epigenomically modulate the ex vivo expanded equine chondrocytes maintained in monolayer culture on the status of chondrogenic cytodifferentiation at the transcriptome level. The results of next-generation sequencing of 3' mRNA-seq libraries on stimulated and unstimulated chondrocytes of the third passage showed no significant influence of 5-AZA-dc treatment. Chondrocytes stimulated with TSA or with a combination of 5-AZA-dc+TSA revealed significant expressional decline, mainly for genes encoding histone and DNA methyltransferases, but also for other genes, many of which are enriched in canonical pathways that are important for chondrocyte biology. The TSA- or 5-AZA-dc+TSA-induced upregulation of expanded chondrocytes included genes that are involved in histone hyperacetylation and also genes relevant to rheumatoid arthritis and inflammation. Chondrocyte stimulation experiments including a TSA modifier also led to the unexpected expression incrementation of genes encoding HDAC3, SIRT2, and SIRT5 histone deacetylases and the MBD1 CpG-binding domain protein, pointing to another function of the TSA agent besides its epigenetic-like properties. Based on the transcriptomic data, TSA stimulation seems to be undesirable for chondrogenic differentiation of passaged cartilaginous cells in a monolayer culture. Nonetheless, obtained transcriptomic results of TSA-dependent epigenomic modification of the ex vivo expanded equine chondrocytes provide a new source of data important for the potential application of epigenetically altered cells for transplantation purposes in tissue engineering of the equine skeletal system.

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Acute kidney injury (AKI) is commonly associated with severe human diseases, and often worsens the outcome in hospitalized patients. The mammalian kidney has the ability to recover spontaneously from AKI; however, little progress has been made in the development of supportive treatments. Increasing evidence suggest that histone deacetylases (HDAC) and NF-κB promote the pathogenesis of AKI, and inhibition of Hdac activity has a protective effect in murine models of AKI. However, the role of HDAC at the early stages of recovery is unknown. We used the zebrafish pronephros model to study the role of epigenetic modifiers in the immediate repair response after injury to the tubular epithelium. Using specific inhibitors, we found that the histone deacetylase Hdac2, Hdac6, and Hdac8 activities are required for the repair via collective cell migration. We found that hdac6, hdac8, and nfkbiaa expression levels were upregulated in the repairing epithelial cells shortly after injury. Depletion of hdac6, hdac8, or nfkbiaa with morpholino oligonucleotides impaired the repair process, whereas the combined depletion of all three genes synergistically suppressed the recovery process. Furthermore, time-lapse video microscopy revealed that the lamellipodia and filopodia formation in the flanking cells was strongly reduced in hdac6-depleted embryos. Our findings suggest that Hdac activity and NF-κB are synergistically required for the immediate repair response in the zebrafish pronephros model of AKI, and the timing of HDAC inhibition might be important in developing supportive protocols in the human disease.

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BACKGROUND: Gamma delta (γδ) T lymphocytes are promising candidate for adoptive T cell therapy, however, their treatment efficacy is not satisfactory. Vδ2 T cells are unique to primates and few suitable models are available to assay their anti-tumour function. METHODS: We tested human γδ T cell activation, tumour infiltration, and tumour-killing in four three-dimensional (3D) models, including unicellular, bicellular and multicellular melanoma spheroids, and patient-derived melanoma organoids. We studied the effects of checkpoint inhibitors on γδ T cells and performed a small molecule screen using these platforms. RESULTS: γδ T cells rapidly responded to melanoma cells and infiltrated melanoma spheroids better than αß T cells in PBMCs. Cancer-associated fibroblasts (CAFs) in bicellular spheroids, stroma cells in multicellular melanoma spheroids and inhibitory immune cells in organoids significantly inhibited immune cell infiltrates including γδ T cells and lessened their cytotoxicity to tumour cells. Tumour-infiltrating γδ T cells showed exhausted immunophenotypes with high checkpoints expression (CTLA-4, PD-1 and PD-L1). Immune checkpoint inhibitors increased γδ T cell infiltration of 3D models and killing of melanoma cells in all four 3D models. Our small molecule screen assay and subsequent mechanistic studies demonstrated that epigenetic modifiers enhanced the chemotaxis and cytotoxicity of γδ T cells through upregulating MICA/B, inhibiting HDAC6/7 pathway and downregulating the levels of PD-L1 and PD-L2 in CAFs and tumour cells. These compounds increased CXCR4 and CD107a expression, IFN-γ production and decreased PD-1 expression of γδ T cells. CONCLUSIONS: Tumour-infiltrating γδ T cells show exhausted immunophenotypes and limited anti-tumour capacity in melanoma 3D models. Checkpoint inhibitors and epigenetic modifiers enhance anti-tumour functions of γδ T cells. These four 3D models provided valuable preclinical platforms to test γδ T cell functions for immunotherapy.

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Endophytic fungi are capable of producing a great diversity of bioactive metabolites. However, the presence of silent and lowly expressed genes represents a main challenge for the discovery of novel secondary metabolites with different potential uses. Epigenetic modifiers have shown to perturb the production of fungal metabolites through the induction of silent biosynthetic pathways leading to an enhanced chemical diversity. Moreover, the addition of bioprecursors to the culture medium has been described as a useful strategy to induce specific biosynthetic pathways. The aim of this study was to assess the effects of different chemical modulators on the metabolic profiles of an endophytic fungal strain of Cophinforma mamane (Botryosphaeriaceae), known to produce 3 thiodiketopiperazine (TDKP) alkaloids (botryosulfuranols A-C), previously isolated and characterized by our team. Four epigenetic modifiers, 5-azacytidine (AZA), sodium butyrate (SB), nicotinamide (NIC), homoserine lactone (HSL) as well as 2 amino acids, l-phenylalanine and l-tryptophan, as bioprecursors of TDKPs, were used. The metabolic profiles were analysed by UHPLC-HRMS/MS under an untargeted metabolomics approach. Our results show that the addition of the two amino acids in C. mamane culture and the treatment with AZA significantly reduced the production of the TDKPs botryosulfuranols A, B and C. Interestingly, the treatment with HSL significantly induced the production of different classes of diketopiperazines (DKPs). The treatment with AZA resulted as the most effective epigenetic modifier for the alteration of the secondary metabolite profile of C. mamane by promoting the expression of cryptic genes.

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During embryogenesis and further development, mammalian epigenome undergoes global remodeling, which leads to the emergence of multiple fate-restricted cell lines as well as to their further differentiation into different specialized cell types. There are multiple lines of evidence suggesting that all these processes are mainly controlled by epigenetic mechanisms such as DNA methylation, histone covalent modifications, and the regulation of ATP-dependent remolding of chromatin structure. Based on the histone code hypothesis, distinct chromatin covalent modifications can lead to functionally distinct chromatin structures and thus distinctive gene expression that determine the fate of the cells. A large amount of recently accumulated data showed that small molecule biologically active compounds that involved in the regulation of chromatin structure and function in discriminative signaling environments can promote changes in cells fate. These data suggest that agents that involved in the regulation of chromatin modifying enzymes combined with factors that modulate specific cell signaling pathways could be effective tools for cell reprogramming. The goal of this review is to gather the most relevant and most recent literature that supports this proposition.

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Microbial enzymes have gained interest for their widespread use in various industries and medicine due to their stability, ease of production, and optimization. Endophytic fungi in plant tissues produce a wide range of secondary metabolites and enzymes, which exhibit a variety of biological activities. The present review illustrates promising applications of enzymes produced by endophytic fungi and discusses the characteristic features of the enzymes, application of the endophytic fungal enzymes in therapeutics, agriculture, food, and biofuel industries. Endophytic fungi producing ligninolytic enzymes have possible biotechnological applications in lignocellulosic biorefineries. The global market of industrially important enzymes, challenges, and future prospects are illustrated. However, the commercialization of endophytic fungal enzymes for industrial purposes is yet to be explored. The present review suggests that endophytic fungi can produce various enzymes and may become a novel source for upscaling the production of enzymes of industrial use.