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Epigenetic Mechanisms Involved in the Cardiovascular Toxicity of Anticancer Drugs.

The cardiovascular toxicity of anticancer drugs promotes the development of cardiovascular diseases. Therefore, cardiovascular toxicity is an important safety issue that must be considered when developing medications and therapeutic applications to treat cancer. Among anticancer drugs, members of the anthracycline family, such as doxorubicin, daunorubicin and mitoxantrone, are known to cause cardiotoxicity and even heart failure. Using human-induced pluripotent stem cell-derived cardiomyocytes in combination with "Omic" technologies, we identified several cardiotoxicity mechanisms and signal t

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… polymerase II (RNAPII) can initiate the gene expression process in euchromatin. … (Me, methyl; HDAC, histone deacetylases; RNAPII, RNA polymerase II; PRC 2, polycomb repressive complex 2; HMTs, histone methyltransferases; HTAs). …

Ebastine exerts antitumor activity and induces autophagy by activating AMPK/ULK1 signaling in an IPMK-dependent manner in osteosarcoma.

Numerous studies have confirmed that in addition to interfering with the tumor inflammatory environment, anti-inflammatory agents can directly increase apoptosis and sensitivity to conventional therapies and decrease invasion and metastasis, making them useful candidates for cancer therapy. Here, we first used high-throughput screening and had screened one compound candidate, ebastine (a H1-histamine receptor antagonist), for osteosarcoma therapy. Cell viability assays, colony formation assays, wound healing assays, and Transwell assays demonstrated that ebastine elicited antitumor effects in

Regulation of microRNAs by natural agents: new strategies in cancer therapies.

MicroRNAs (miRNAs) are short noncoding RNA which regulate gene expression by messenger RNA (mRNA) degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many

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… They are first transcribed by RNA polymerase II as long primary miRNA molecules (pri-miRNAs) before being processed into short hairpin RNAs of ~70 nucleotides known as pre-miRNA by Drosha (RNase III enzyme) and DGCR8 (DiGeorge syndrome critical region 8) [ 19 ]. … polymerase II The EMBO Journal 2004 23 20 4051 4060 2-s2.0-8144225486 15372072 10.1038/sj.emboj.7600385 PMC524334 19 Denli AM Tops BBJ Plasterk RHA Ketting RF Hannon GJ Processing of primary microRNAs by the Microprocessor complex Nature 2004 432 7014 231 235 2-s2.0-9144224451 15531879 10.1038/nature03049 …

Long non-coding RNA LINC00968 attenuates drug resistance of breast cancer cells through inhibiting the Wnt2/β-catenin signaling pathway by regulating WNT2.

BackgroundBreast cancer is one the most common cancers, making it the second leading cause of cancer-related death among women. Long non-coding RNAs (lncRNAs), with tightly regulated expression patterns, also serve as tumor suppressor during tumorigenesis. The present study aimed to elucidate the role of LINC00968 in breast cancer via WNT2-mediated Wnt2/β-catenin signaling pathway.MethodsBreast cancer chip GSE26910 was utilized to identify differential expression in LINC00968 and WNT2. The possible relationship among LINC00968, transcriptional repressor HEY and WNT2 was analyzed and then verif

Current status and perspectives of genetic testing in gastrointestinal cancer (Review).

Genetic testing has become widespread in daily medical care for gastrointestinal (GI) cancers. However, unlike breast cancer and non-small cell lung cancer, in which personalized medicine targeting various driver genes is standardized, the incidence of targeted gene abnormalities in GI cancers is low. Nevertheless, such abnormalities may be linked to therapeutic agents and the further development of therapeutic agents for personalized medicine for GI cancers is desired. A liquid biopsy is of great benefit in offering clinical decision support, in applications such as GI cancer screening, surgi

Chemotherapeutic agents for the treatment of hepatocellular carcinoma: efficacy and mode of action.

Hepatocellular carcinoma (HCC) is a dreaded malignancy that every year causes half a million deaths worldwide. Being an aggressive cancer, its incidence exceeds 700,000 new cases per year worldwide with a median survival of 6-8 months. Despite advances in prognosis and early detection, effective HCC chemoprevention or treatment strategies are still lacking, therefore its dismal survival rate remains largely unchanged. This review will characterize currently available chemotherapeutic drugs used in the treatment of HCC. The respective mode(s) of action, side effects and recommendations will be

MicroRNA in Acromegaly: Involvement in the Pathogenesis and in the Response to First-Generation Somatostatin Receptor Ligands.

Acromegaly is a chronic and systemic disease due to excessive growth hormone and insulin-like growth factor type I caused, in the vast majority of cases, by a GH-secreting pituitary adenoma. About 40% of these tumors have somatic mutations in the stimulatory G protein alpha-subunit 1 gene. The pathogenesis of the remaining tumors, however, is still not fully comprehended. Surgery is the first-line therapy for these tumors, and first-generation somatostatin receptor ligands (fg-SRL) are the most prescribed medications in patients who are not cured by surgery. MicroRNAs are small, non-coding RNA

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… In the classical pathway, miRNAs are mainly transcribed by RNA polymerase II in a hairpin structure known as pri-miRNA [ 27 ]. Furthermore, few miRNAs are transcribed by RNA polymerase III [ 26 ]. … Figure 1 Classical pathway: miRNA synthesis. (1) miRNA is mostly transcribed by RNA polymerase II through genomic regions. (2) pri-miRNA, a hairpin sequence, is then processed by DROSHA and DGCR8 proteins, which results in pre-miRNA. (3) pre-miRNA is transported to the cytoplasm through Exportin 5. ( …

Chemotherapy Side-Effects: Not All DNA Damage Is Equal.

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark

Feline Coronavirus Infection

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Epigenetic mechanisms in cardiovascular complications of diabetes: towards future therapies.

The pathophysiological mechanisms of cardiovascular disease and microvascular complications in diabetes have been extensively studied, but effective methods of prevention and treatment are still lacking. In recent years, DNA methylation, histone modifications, and non-coding RNAs have arisen as possible mechanisms involved in the development, maintenance, and progression of micro- and macro-vascular complications of diabetes. Epigenetic changes have the characteristic of being heritable or deletable. For this reason, they are now being studied as a therapeutic target for the treatment of diabe

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… Among these proteins, bromodomain and extraterminal (BET) proteins bind acetylated histone marks and coordinate the recruitment of RNA Polymerase II. Their role will discuss later in this review. … All the components possess 2 bromodomains BD1 and BD2 and an extraterminal (ET) domain (Fig. 2 A) that can bind the histone acetylation, facilitating transcription factors, RNA polymerase II (RNAPol-II) and coactivators recruitment to target gene promoters and enhancers (Guo et al. 2023 ; Ali et al. …

RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges.

G protein-coupled receptors (GPCRs) are the major targets of existing drugs for a plethora of human diseases and dominate the pharmaceutical market. However, over 50% of the GPCRs remain undruggable. To pursue a breakthrough and overcome this situation, there is significant clinical research for developing RNA-based drugs specifically targeting GPCRs, but none has been approved so far. RNA therapeutics represent a unique and promising approach to selectively targeting previously undruggable targets, including undruggable GPCRs. However, the development of RNA therapeutics faces significant cha

The Biogenesis and Functions of piRNAs in Human Diseases.

Piwi-interacting RNAs (piRNAs) are a novel type of small noncoding RNAs, which are 26-30 nt in length and bind to Piwi proteins. These short RNAs were originally discovered in germline cells and are considered as key regulators for germline maintenance. A growing body of evidence has now extended our views into piRNA biological significance showing that they can also regulate gene expression in somatic cells through transposon silencing, epigenetic programming, DNA rearrangements, mRNA turnover, and translational control. Mounting studies have revealed that the dysregulation of piRNAs may caus

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… Additionally, piRNA precursors are 5′ methyl-guanosine capped and 3′ terminated. 23 , 24 On the contrary, dual-strand clusters lack clear signatures of RNA polymerase II (RNA Pol II) promoters, such as H3K4me3 and peaks of RNA Pol II, and non-polyadenylated piRNA precursors are produced ( Figure 1 ). … Cutoff suppresses RNA polymerase II termination to ensure expression of piRNA precursors. Mol. Cell. 2016;63:97–109. doi: 10.1016/j.molcel.2016.05.010. 26. Le Thomas A., Rogers A.K., Webster A., Marinov G.K., Liao S.E., Perkins E.M., Hur J.K., Aravin A.A., Tóth K.F. …

APOBEC3B reporter myeloma cell lines identify DNA damage response pathways leading to APOBEC3B expression.

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) DNA cytosine deaminase 3B (A3B) is a DNA editing enzyme which induces genomic DNA mutations in multiple myeloma and in various other cancers. APOBEC family proteins are highly homologous so it is especially difficult to investigate the biology of specifically A3B in cancer cells. To easily and comprehensively investigate A3B function in myeloma cells, we used CRISPR/Cas9 to generate A3B reporter cells that contain 3×FLAG tag and IRES-EGFP sequences integrated at the end of the A3B gene. These reporter cells stably express

Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.

Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, an

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… HOXB8 and FOSL1 form IDR-mediated nuclear condensates at super-enhancers, increase chromatin accessibility, recruit RNA polymerase II, and activate metastasis- and drug resistance-associated genes. … Conversely, condensates at super-enhancer regions increase chromatin accessibility and recruit RNA polymerase II, activating metastasis- and drug resistance–associated genes. c Oncogenic condensates in Ewing sarcoma. …

Структурные механизмы связывания и активации контактного фторфора RhoBAST.

Флуоресцентный аптамер RhoBAST, который связывает и активирует фторфоре-квахер, содержащий тетраметилродамин-динитроанилин с высокой аффективностью, супер-высокой яркостью, удивительной фотостабильностью и быстрообменными кинетиками, демонстрирует отличные результаты в суперразрешении изображений РНК. Здесь мы определим кокристальную структуру RhoBAST в комплексе с тетраметилродамином-динитроанилином, чтобы прояснить молекулярную основу активации лиганда и флуоресцентной активности. Строение имеет асимметричную архитектуру типа "А" для RhoBAST с полуоткрытым связующим карманом, скрывающим ксан

Genome Instability in Multiple Myeloma: Facts and Factors.

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete

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… SNPs at 5q15 are linked with ELL2 encoding for the elongation factor of RNA polymerase II, which regulates immunoglobulin mRNA processing in plasma cells [ 376 , 377 , 378 ]. … ELL2 travels with the RNA polymerase II across the IGH μ- and γ-gene segments and mediates the association of polyadenylation-cleavage factor CstF-64 with the RNA polymerase II and switching to a secretory-specific poly(A) site [ 378 ]. …

Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.

Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation

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… For example, in ESCC, succinylation negatively regulates H3K9me2 levels, thereby promoting ESCC metastasis; during replication stress response, H2AK119 decrotonylation promotes H2AK119 ubiquitination, leading to RNA polymerase II release near reversed replication forks and subsequent transcriptional … The accumulation of ubiquitinated H2AK119 at stalled replication forks facilitates RNA polymerase II release and nearby transcriptional repression, ultimately mitigating TRCs, TRC‐related R‐loop formation, and DNA double‐strand breaks [ 85 ]. …

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

Role of B-Cell in the Pathogenesis of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease, characterized by fibrosis, vasculopathy, and autoimmunity. Recent advances have highlighted the significant implications of B-cells in SSc. B-cells are present in affected organs, their subpopulations are disrupted, and they display an activated phenotype, and the regulatory capacities of B-cells are impaired, as illustrated by the decrease in the IL-10+ producing B-cell subpopulation or the inhibitory membrane co-receptor density. Recent multi-omics evidence highlights the role of B-cells mainly in the early stage of SSc and p

Gene Expression Profiles Identify Biomarkers of Resistance to Decitabine in Myelodysplastic Syndromes.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by inefficient hematopoiesis and the potential development of acute leukemia. Among the most notable advances in the treatment of MDS is the hypomethylating agent, decitabine (5-aza-2'deoxycytidine). Although decitabine is well known as an effective method for treating MDS patients, only a subset of patients respond and a tolerance often develops, leading to treatment failure. Moreover, decitabine treatment is costly and causes unnecessary toxicity. Therefore, clarifying the mechanism of decitabine resista

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… Category | Term | Description | Count | p -Value BP | GO:0045893 | Regulation of transcription, DNA-templated | 15 | 5.89 × 10 −7 GO:0045944 | Regulation of transcription from RNA polymerase II promoter | 18 | 1.01 × 10 −5 GO:0008285 | Negative regulation of cell proliferation | 9 | 3.59 × 10 −5 GO:0043066 … polymerase II distal enhancer sequence-specific binding | 3 | 0.0029 GO:0003682 | Chromatin binding | 6 | 0.0081 GO:0003677 | DNA binding | 12 | 0.0155 GO:0046982 | Protein heterodimerization activity | 6 | 0.0162 GO:0019903 | Protein phosphatase binding | 3 | 0.0173 GO:0004672 | Protein kinase activity …