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Research progress on ferroptosis in Myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of malignancies characterized by clonal proliferation of hematopoietic stem cells, ineffective hematopoiesis, peripheral cytopenias, and a high risk of transformation to acute myeloid leukemia. Current therapeutic strategies for MDS have limited efficacy. Thus, identifying new therapeutic targets and prognostic biomarkers is a critical future research direction. Ferroptosis, a new type of iron-dependent programmed cell death, has become a recent hotspot in the field of oncology research. Recent results have demonstrated that iron metabolism, lipid me

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment.

Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechan

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… demethylation and regulate epigenetic gene expression. … Vitamin c induces tet-dependent DNA demethylation and a blastocyst-like state in ES cells . Nature ( 2013 ) 500 : 222–6 . doi: 10.1038/nature12362 PMC3893718 23812591 51 Hamaguchi R Ito T Narui R Morikawa H Uemoto S Wada H . …

Gene editing and CRISPR in the clinic: current and future perspectives.

Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases whic

Epigenome-Driven Strategies for Personalized Cancer Immunotherapy.

Fighting cancer remains one of the greatest challenges for science in the 21st century. Advances in immunotherapy against different types of cancer have greatly contributed to the treatment, remission, and cure of patients. In this context, knowledge of epigenetic phenomena, their relationship with tumor cells and how the immune system can be epigenetically modulated represent some of the greatest advances in the development of anticancer therapies. Epigenetics is a rapidly growing field that studies how environmental factors can affect gene expression without altering DNA sequence. Epigenomic

High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies.

Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly heterogeneous group of tumors characterized by an incidence of 650,000 new cases and 350,000 deaths per year worldwide and a male to female ratio of 3:1. The main risk factors are alcohol and tobacco consumption and Human Papillomavirus (HPV) infections. HNSCC cases are divided into two subgroups, the HPV-negative (HPV-) and the HPV-positive (HPV+) which have different clinicopathological and molecular profiles. However, patients are still treated with the same therapeutic regimens. It is thus of utmost importance to characterize the mo

Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential.

Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increa

Epigenetics-targeted drugs: current paradigms and future challenges.

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifyin

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… demethylation and binds to DNA via the CXXC zinc finger domain 913 TET2 Active DNA demethylation and binds to DNA via the interaction with DNA binding proteins 914 TET3 Active DNA demethylation and binds to DNA via the CXXC zinc finger domain 915 Reader MeCP1 Preferentially binds to methylated DNA and … demethylation and binds to DNA via the CXXC zinc finger domain | 913 TET2 | Active DNA demethylation and binds to DNA via the interaction with DNA binding proteins | 914 TET3 | Active DNA demethylation and binds to DNA via the CXXC zinc finger domain | 915 Reader | MeCP1 | Preferentially binds to methylated …

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.

The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by reg

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… In the disease mechanism, DNMT3A expression decreases the inhibition of methylation of the promoter of angiotensin receptor 1a while increasing DNA demethylation and promoting the expression of angiotensin receptor 1a [ 12 ]. …

Decoding the epitranscriptome: a new frontier for cancer therapy and drug resistance.

As the role of RNA modification in gene expression regulation and human diseases, the "epitranscriptome" has been shown to be an important player in regulating many physiological and pathological processes. Meanwhile, the phenomenon of cancer drug resistance is becoming more and more frequent, especially in the case of cancer chemotherapy resistance. In recent years, research on relationship between post-transcriptional modification and cancer including drug resistance has become a hot topic, especially the methylation of the sixth nitrogen site of RNA adenosine-m6A (N6-methyladenosine). m6A m

Drugs and Epigenetic Molecular Functions. A Pharmacological Data Scientometric Analysis.

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in c

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… demethylation | Alkb homolog 2, alpha-ketoglutarate dependent dioxygenase | ALKBH2 | 121642 DNA demethylation | Alkb homolog 3, alpha-ketoglutarate dependent dioxygenase | ALKBH3 | 221120 DNA demethylation | FTO alpha-ketoglutarate dependent dioxygenase | FTO | 79068 DNA demethylation | Apolipoprotein … Gemcitabine Functions Epigenetically by Inhibiting Repair Mediated DNA Demethylation. PLoS ONE. 2010;5:e14060. doi: 10.1371/journal.pone.0014060. 69. Arce C., Segura-Pacheco B., Perez-Cardenas E., Taja-Chayeb L., Candelaria M., Duennas-Gonzalez A. …

Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells.

BACKGROUND AND PURPOSE: Certain nuclear receptors (NRs) such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and farnesoid X receptor (FXR) mediate induction of some cytochrome P450 enzymes and ABC transporters but conflicting reports exist. The purpose of this study was to assess the reasons for these discrepancies and use a standardized approach to compare activators of NRs. EXPERIMENTAL APPROACH: Dexamethasone, pregnenolone 16alpha-carbonitrile, rifampicin, phenobarbital and chenodeoxycholic acid were incubated with HepG2, Caco-2 and cryopreserved human hepatocytes

RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect.

Retinoid X receptor (RXR) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG

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… RXR Agonists Facilitated DNA Demethylation in the CpG Islands within the CRBN Promoter DNA methylation is one of the epigenetic events that plays important roles in transcriptional repression, genomic imprinting, and genomic stability [ 41 , 42 ]. … AGN194204 and LG101506 are less effective in inducing DNA demethylation of the CpG islands ( Figure 4 A and Figure S6 ). …

Epigenetic regulation in gynecological cancers: a paradigm shift in immunotherapy strategies.

Recent advances in immunotherapy have transformed the therapeutic landscape of gynecological cancers; however, durable responses remain limited by tumor heterogeneity and immune evasion mechanisms. Emerging evidence highlights epigenetic modifications comprising of DNA methylation, histone modifications, and RNA methylation as pivotal regulators of the tumor immune microenvironment and immunotherapy efficacy. This review comprehensively explores how these epigenetic alterations modulate immune cell infiltration, antigen presentation, immune checkpoint expression, and tumor immunogenicity acros

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… Conversely, DNA demethylation is mediated by the Ten-eleven translocation (TET) enzyme family, TET1, TET2, and TET3, which serve as erasers, by oxidizing 5mC into 5-hydroxymethylcytosine (5hmC) and further derivatives [ 60 ]. … Interestingly, only a fraction of patients exhibited this effect, suggesting that DNA demethylation may require additional chromatin remodeling events, such as enhancer–promoter interactions, to maintain oncogene expression. …

The prince and the pauper. A tale of anticancer targeted agents.

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consiste

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… Hydralazine as anticancer agent The first observations on DNA demethylation as a hydralazine off-target effect were performed in 1988 in the course of experiments to prove that this drug could induce self-reactivity in cloned T-cell lines and DNA hypomethylation [ 167 ], followed by reports on its ability …

Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies.

Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lympho

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… Passive DNA demethylation happened in dividing cells, where newly incorporated cytosine remains unmethylated by DNMT1 inhibition or dysfunction. … Active DNA demethylation can happen in both dividing and nondividing cells, which requires enzymes to remove 5mC to develop a permissive state for subsequent gene expression. 214 – 217 Enzymes in active DNA demethylation involve the ten-eleven translocation (TET) methylcytosine dioxygenases, activation-induced …

Epigenetic Regulation of Autophagy in Bone Metabolism.

The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's i

Epigenetic Modifiers: Exploring the Roles of Histone Methyltransferases and Demethylases in Cancer and Neurodegeneration.

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 c

Epigenetic therapy in myeloproliferative neoplasms: evidence and perspectives.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, originate from a stem cell-derived clonal myeloproliferation that manifests itself with variable haematopoietic cell lineage involvement; they are characterized by a high degree of similarities and the chance to transform each to the other and to evolve into acute leukaemia. Their molecular pathogenesis has been associated with recurrent acquired mutations in janus kinase 2 (JAK2) and myeloproliferative leukemia virus oncogene

Interleukin-32: a Pandora's box in human immunodeficiency virus infection.

Human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), has been estimated to infect around 40.8 million people globally. This virus can persist and thrive in the presence of antiretroviral therapy, which is a major obstacle to HIV eradication. Therefore, understanding host immunological factors that underlie HIV persistence and pathogenesis can lead to the development of immunotherapeutic interventions. Interleukin-32 (IL-32) is an orphan cytokine with multiple isoforms and a complex signal transduction pathway that transmits through non-specific receptors.

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… In CD4+ T cells and natural killer (NK) cells, DNA demethylation (deMe) within the enhancer region is essential for IL-32 transcription activation. … The proinflammatory cytokine tnfα Induces dna demethylation-dependent and -independent activation of interleukin-32 expression . …

Targeted and epigenetic therapies for acute myeloid leukemia treatment.

This article provides a comprehensive overview of targeted and epigenetic therapies for acute myeloid leukemia (AML), highlighting their role in advancing treatment strategies. Recognizing that AML arises from complex genetic and epigenetic alterations, a deeper understanding of its pathogenesis has paved the way for precision medicine. The article reviews key targeted therapies, including IDH inhibitors (e.g., ivosidenib, enasidenib) for IDH mutations, FLT3 inhibitors (e.g., midostaurin, gilteritinib) for FLT3 alterations, BCL2 inhibitors (e.g., venetoclax) impacting apoptosis, and emerging M

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… IDH inhibitors, such as ivosidenib and enasidenib, target mutant IDH1 or IDH2 enzymes, reducing oncometabolite 2-hydroxyglutarate levels to restore normal DNA demethylation. …