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Роль антиоксидантов в множестве миеломы: диагностика, прогнозирование и терапевтическое применение: обзор сюжета.

Множественная миэлома (ММ) — злокачественная клетка B-клеток с моноклональными плазменными клетками, производящими нефункциональные иммуноглобулины. Она по-прежнему неизлечима из-за de novo или приобретенного сопротивления злокачественных клеток стандартным химиотерапиям. Таким образом, понимание механизма терапевтического сопротивления имеет важнейшее значение для разработки более эффективных мер вмешательства и определения новых целей лечения. MM - это разнородная болезнь, характеризующаяся сложными генетическими изменениями, которые имеют решающее значение для прогнозирования стратификации.

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… In addition, vitamin C (ascorbate) regulates the demethylation of DNA and histones. … DNA demethylation favors the expression of tumor suppressor genes and improve chemo-sensitivity. 95 Ten-eleven translocation (TET) dioxygenases initiate DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). …

ATGL sensitizes hepatocellular carcinoma cells to genotoxic drugs by modulating p53 acetylation/phosphorylation status.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases. Few therapeutic options are available for HCC patients due to intrinsic drug resistance or the low efficacy of conventional chemotherapeutic drugs, including genotoxic agents. We previously demonstrated that adipose triglyceride lipase (ATGL) is downregulated in HCC and shows anti-neoplastic activity by affecting sensitivity to different therapeutic approaches. On the basis of this evidence, we assessed the contribution of ATGL activity to the modulation of the DNA damage response induced by genotoxic drugs. W

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… Schäfer A Gadd45 proteins: key players of repair-mediated DNA demethylation Adv Exp Med Biol 2013 793 35 50 10.1007/978-1-4614-8289-5_3 24104472 Schäfer A. Gadd45 proteins: key players of repair-mediated DNA demethylation. Adv Exp Med Biol. 2013;793:35–50. 24104472 10.1007/978-1-4614-8289-5_3 14. …

С-терминальный связывающий белок 2 - новый дезинфицирующий опухоль, направленный на MYC-IRF4 ось в множестве миеломы.

Клетки с множественной миеломой (MM) подвержены зависимости от MYC, а их непосредственные цели по трансактивации IRF4 направлены на распространение и выживание. MYC и IRF4 по-прежнему считаются "ненаркоманными", поскольку большинство мелких ингибиторов молекулярного происхождения страдают от низкой производительности, неоптимальных фармакокинетических свойств и нежелательных нецелевых эффектов. Косвенное подавление MYC/IRF4 проявляется в качестве терапевтической уязвимости MM. Здесь мы обнаружили неоцененную опухоль, впечатляющую роль связующего белка С-терминала 2 (CTBP2) в MM путем сильного

Maintenance Therapy in AML.

Recent advances in therapeutics coupled with steady improvements in supportive care for patients with acute myeloid leukemia (AML) have led to improved outcomes. Despite these advances, even in patients that achieve a complete remission with initial therapy high rates of relapse remain a clinical dilemma. For decades, investigators have attempted strategies of maintenance therapy to prolong both remission duration and overall survival in patients with AML. These approaches have included cytotoxic chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecule therapy. Overall,

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… There is rationale for the combination of HMAs and immune checkpoint blockade, with demethylation of PD1 promoter associated with worse response in MDS and AML and increased expression of immune checkpoint molecules in patients with MDS treated with HMA ( 75 , 76 ). … A comparison of limited consolidation chemotherapy therapy or not, and demethylation maintenance or not in older patients with AML and high risk MDS: Long term results of the UK NCRI AML16 trial. Haematologica (2015) 100(S1):513. 47. …

Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4.

Pluripotent and tissue-specific stem cells, such as blood-forming stem cells, are maintained through a balance of quiescence, self-renewal, and differentiation. Self-renewal is a specialized cell division that generates daughter cells with the same features as the parental stem cell. Although many factors are involved in the regulation of self-renewal, perhaps the most well-known factors are members of the Krüppel-like factor (KLF) family, especially KLF4, because of the landmark discovery that this protein is required to reprogram somatic cells into induced pluripotent stem cells. Because KLF

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… It was recently reported that TET2 binds to KLF4 through protein‐to‐protein interaction to drive locus‐specific demethylation during reprogramming of B cells into iPSCs 64 . … Transcription factors drive Tet2‐mediated enhancer demethylation to reprogram cell fate . Cell Stem Cell 2018 ; 23 : 727e9 – 741e9 . 30220521 10.1016/j.stem.2018.08.016 65 Allsopp RC , Morin GB , DePinho R et al. …

Митохондриальная передача метаболических перепрограмм и лекарственная устойчивость в метастазе костей: механизмы и терапевтические стратегии.

Кость это one из наиболее распространенных участков удаленного метастаза в твердых опухолях, в частности рак груди, рак простаты и рак легких. Метатические повреждения костей часто свидетельствуют о стойком сопротивлении многосистемной терапии, включая химиотерапию, целевую терапию, эндокринную терапию и ингибиторы иммунных контрольно-пропускных пунктов (ИПК). Накопляющиеся данные свидетельствуют о том, что метаболическая перепрограммирование в пределах костной микроокружающей среды способствует этому сопротивлению, однако механизмы в верхнем течении по-прежнему недостаточно понятны. В качеств

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… Accompanying accumulation of acetyl-CoA and α-KG drives histone acetylation and DNA demethylation through metabolism–epigenetics crosstalk, establishing a “metabolic memory” mechanism that sustains long-term therapy resistance. … Expansion of the acetyl-coenzyme A (acetyl-CoA) pool promotes increased histone H3 lysine 27 acetylation (H3K27ac) marks, activating metabolic gene cluster expression ( 147 ). α-KG mediates DNA demethylation through ten-eleven translocation (TET) enzymes, relieving the silencing of metabolism-related …

IDH Mutations in Glioma: Molecular, Cellular, Diagnostic, and Clinical Implications.

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via i

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… JmjC-KDMs JmjC-KDMs are enzymes that regulate gene expression through demethylation and chromatin scaffolding functions [ 30 ]. … Active DNA Demethylation at Enhancers during the Vertebrate Phylotypic Period Nat. Genet. 2016 48 417 426 10.1038/ng.3522 26928226 PMC5912259 50. Sanstead P.J. Ashwood B. Dai Q. He C. Tokmakoff A. …

Overview on Molecular Biomarkers for Laryngeal Cancer: Looking for New Answers to an Old Problem.

Laryngeal squamous cell cancer (LSCC) accounts for almost 25-30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving the onset and progression of this neoplasm is emerging. However, major efforts are still required for the identification of molecular markers useful for both early diagnosis and prognostic definition of LSCC that is still characterized by significant morbidity and mortality. Non-coding RNAs appear the most promising

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… The observation was validated by DNA demethylation experiments, where decitabine treatment of two LSCC cell lines restored low levels of genes’ transcription. … Global S100A4 promoter demethylation induces an increase of tumor invasiveness, as demonstrated in both LSCC tissue samples and HEp-2 cell line treated with DNA methyltransferase inhibitor. …

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma.

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumo

Epimutational profile of hematologic malignancies as attractive target for new epigenetic therapies.

In recent years, recurrent somatic mutations in epigenetic regulators have been identified in patients with hematological malignancies. Furthermore, chromosomal translocations in which the fusion protein partners are themselves epigenetic regulators or where epigenetic regulators are recruited/targeted by oncogenic fusion proteins have also been described. Evidence has accumulated showing that "epigenetic drugs" are likely to provide clinical benefits in several hematological malignancies, granting their approval for the treatment of myelodysplastic syndromes and cutaneous T-cell lymphomas. A

Perturbing Enhancer Activity in Cancer Therapy.

Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation.

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… Histone demethylation mediated by the nuclear amine oxidase homolog LSD1 Cell 2004 119 941 953 10.1016/j.cell.2004.12.012 15620353 103. Rothbart S.B. Strahl B.D. Interpreting the language of histone and DNA modifications Biochim. Biophys. … Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4 Nature 2010 464 792 796 10.1038/nature08839 20228790 108. Hu Q. Kwon Y.S. Nunez E. Cardamone M.D. Hutt K.R. Ohgi K.A. Garcia-Bassets I. Rose D.W. Glass C.K. Rosenfeld M.G. …

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome-Relevance as Complementary Prognostic Biomarkers.

Oxidative stress and abnormal DNA methylation have been implicated in cancer, including myelodysplastic syndromes (MDSs). This fact leads us to investigate whether oxidative stress is correlated with localized and global DNA methylations in the peripheral blood of MDS patients. Sixty-six MDS patients and 26 healthy individuals were analyzed. Several oxidative stress and macromolecule damage parameters were analyzed. Localized (gene promotor) and global DNA methylations (5-mC and 5-hmC levels; LINE-1 methylation) were assessed. MDS patients had lower levels of reduced glutathione and total anti

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… TET2 belongs to a family of methylcytosine dioxygenases, a group of enzymes that oxidize the methyl group of 5-mC to 5-hmC and other methylcytosines, facilitating demethylation [ 63 ]. This fact could contribute, at least in part, to the decreased ratio of 5-hmC/5-mC observed here. … Since repeated DNA sequences, such as LINE-1, are enriched in CpG sites, it has been considered that global hypomethylation largely arises from the demethylation of these sequences [ 64 ]. …

High-Dose Vitamin C in Advanced-Stage Cancer Patients.

High-dose intravenously administered vitamin C (IVC) is widely used in cancer patients by complementary and alternative medicine practitioners. The most frequent indications for IVC therapy result from the belief in its effectiveness as a potent anti-cancer agent which additionally enhances chemosensitivity of cancer cells and reduces chemotherapy-related toxicities and fatigue intensity. In this narrative review, we decided to deal with this issue, trying to answer the question whether there is any scientific evidence supporting the rationale for application of high-dose IVC therapy in advanc

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… Ascorbate regulates the transcription of hypoxia inducible factor-1α (HIF-1α) [ 25 ] and acts as a co-factor for enzymes named ten-eleven translocation (TET) family dioxygenases, essential in the demethylation of 5-methylcytosine in DNA [ 49 ]. … The Jumonji C (JmjC)-domain-containing histone demethylases also require ascorbate as a co-factor for histone demethylation [ 50 ]. …

Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.

Ammonium metabolism represents a critically understudied yet pivotal driver of prostate tumorigenesis and tumor microenvironment (TME) remodeling. The interplay between tumor metabolic reprogramming and the tumor microenvironment has emerged as a critical frontier in oncology research. While previous studies on prostate cancer metabolism have predominantly focused on lipid metabolism and the Warburg effect, the role of ammonium metabolism, particularly the urea cycle in tumor immune regulation remains insufficiently explored. This metabolic reprogramming constitutes a central node connecting c

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… Decreased β-lactam degradation releases α-KG-dependent demethylation at the Foxp3 locus, which promotes the generation of suppressive Tregs and inhibits TH1 differentiation ( 138 ). … GLUL, overexpressed in pancreatic and liver cancers due to c-Myc driven promoter demethylation, supports tumor growth ( 105 ). …

High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.

Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and b

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… Particularly, active DNA demethylation is carried out by the TET enzymes, which are frequently mutated in haematological malignancies. … In the treatment of cancer, high-dose VitC has been shown to induce DNA demethylation by restoring and regulating TET aberrant levels [ 3 ]. …

Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3-3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the saliv

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… Apparently, the SGEC from SS patients were associated with a 7-fold decrease in DNMT1 and a 2-fold increase in demethylating partner Gadd45-alpha expression. This demethylation process was also associated in part with the infiltration of SG by B cells and the pathology severity [ 45 ]. … Different studies have also reported a link between demethylating drugs and SS. In fact, mice receiving an oral administration of hydralazine or isoniazid (demethylating agents) for several weeks develop a pathology similar to SS in terms of immunological features and autoantibodies production. …

Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies.

Medulloblastomas are the most common malignant pediatric brain tumors, representing approximately 20% of the central nervous system cancers in children. These tumors are highly heterogeneous and classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic and epigenetic profiles that influence tumor behavior, therapeutic response, and patient outcomes. Advances in molecular diagnostics have improved the subclassification of medulloblastomas, yet treatment outcomes for high-risk subtypes, particularly Group 3, remain poor, with current modalities often asso

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… and differentiation Improves event-free survival when combined with chemotherapy Phase II trials Metformin Targets mitochondrial complex I, induces energy stress, activates AMPK Preclinical evidence supporting use for KDM6A-linked metabolic dysregulation Preclinical studies Hydralazine Induces DNA demethylation … Hydralazine, an antihypertensive agent, induces DNA demethylation, reactivates PRDM6 , and reduces chemotherapy resistance in preclinical studies [ 87 ] . …

Immune checkpoints represent a promising breakthrough in targeted therapy and prognosis of myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a hematological malignancy of undetermined etiology, possibly linked to chromosomal structural alterations, genetic mutations, presentation and carcinogenicity of variant antigens on cell surface, and the generation of pro-inflammatory microenvironment in the bone marrow. Current drugs are unable to cure this disease, and therefore, decreasing the survival and proliferation of malignant cells to delay disease progression and extend the survival time of patients becomes the primary approach to management. In recent years, the immune system has received increasi

Control of viral infections by epigenetic-targeted therapy.

Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase ("shock and k

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… This is explained by the ability of MAOis to inhibit the LSD-1 mediated demethylation of lysine residues via a flavin-adenine-dinucleotide-dependent reaction [ 172 , 173 ], resulting in the accumulation of repressive H3K9 chromatin marks at the IE promoters. … Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors. JCO. 2004;22:1373–1381. doi: 10.1200/JCO.2004.04.185. 205. Ritchie D, Piekarz RL, Blombery P, Karai LJ, Pittaluga S, Jaffe ES, et al. …

Research advances of lactylation modification in breast cancer.

Breast cancer (BC), a leading cause of cancer mortality in women, involves complex molecular mechanisms including post-translational modifications (PTMs). While common PTMs are well-studied, lactylation-a novel PTM linking metabolism to epigenetics-has emerged as a critical regulator in BC pathogenesis. The high concentration of lactate caused by the Warburg effect makes lactylation in tumor tissue possible. Machine learning enhances the discovery and analysis of lactylation sites by processing large datasets, revealing patterns that influence tumor behavior and patient outcomes. This review o

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… Additionally, histone lactylation enhances ALKBH3 expression, leading to SP100A m1A demethylation and reduced RNA and protein levels. This results in PML body loss, further driving ocular melanoma progression [ 49 ]. … Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A. Nucleic Acids Res. 2024;52:2273–89. 50. Li L, et al. …