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Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools.

Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the op

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… pathways leading to cell cycle arrest ( Figure 1 ), e.g., increased phosphorylation of histone H2AX (γ-H2AX) and accumulation of cyclin-dependent kinase (CDK) inhibitors (CKIs) such as tumor protein p53 (TP53 or p53), p21 Cip1 (p21), and p16 Ink4a (p16), and by the increase of senescence-associated heterochromatin … Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113 (6), 703–716. 10.1016/S0092-8674(03)00401-X Nasiri H., Valedkarimi Z., Aghebati-Maleki L., Majidi J. (2018). …

Novel roles of PIWI proteins and PIWI-interacting RNAs in human health and diseases.

Non-coding RNA has aroused great research interest recently, they play a wide range of biological functions, such as regulating cell cycle, cell proliferation, and intracellular substance metabolism. Piwi-interacting RNAs (piRNAs) are emerging small non-coding RNAs that are 24-31 nucleotides in length. Previous studies on piRNAs were mainly limited to evaluating the binding to the PIWI protein family to play the biological role. However, recent studies have shed more lights on piRNA functions; aberrant piRNAs play unique roles in many human diseases, including diverse lethal cancers. Therefore

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… Rhino, a heterochromatin protein 1 (HP1) family protein, first binds to this mark and simultaneously recruits Deadlock and Cutoff proteins to form a Rhino-Deadlock -Cutoff (RDC) complex [ 40 , 41 ]. RDC activates the transcription of piRNA clusters through irregular mechanisms. … Abbreviations Piwi-interacting RNAs RNA-induced silencing complex RNA polymerase II Histone H3 Lys9 Heterochromatin protein 1 Rhino-Deadlock-Cutoff TATA box-binding protein-associated Factor 2 Flamenco Aubergine Argonaute 3 Zucchini Armitage Transposable element Cytosine phospho-guanine …

The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy.

Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies. Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas. In

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… regulation of GLI1 promoter sequences through methylation of DNA and the histone code. ( B ) Epigenome analysis based on post-translational modifications in histone lysine residues, which modulate the interaction of transcription factors upon promoter regions, in euchromatin (H3K27ac and H3K4me3) or heterochromatin … Cell Biochem 2004 93 57 67 https://doi.org/10.1002/jcb.20179 15352162 10.1002/jcb.20179 104 Izzo A Schneider R Chatting histone modifications in mammals Brief Funct Genomics 2010 9 429 43 https://doi.org/10.1093/bfgp/elq024 21266346 10.1093/bfgp/elq024 PMC3080777 105 Hahn M Dambacher S Schotta G Heterochromatin …

Demethylating Agents in the Treatment of Cancer.

Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We als

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… Transcriptionally inactive heterochromatin, tightly compacted, typically harbors hypermethylated DNA while active euchromatin is conversely unmethylated [ 7 ]. … Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 2003;13:1192–1200. doi: 10.1016/s0960-9822(03)00432-9. 38. …

Abstracts of the 12th European Cytogenomics Conference 2019 : Salzburg, Austria. 6-9 July 2019

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… Various repeat types have been isolated including heterochromatin- and nucleolar-associated tandem repeats and centromeric repeats. Applying bioinformatic analysis of total RNAseq as well as long-read sequencing data we showed that many repeat types are transcribed into lncRNAs. …

Polyphenols bind G4-Quadruplex structures and act as epigenetic modifiers with anti-cancer effects.

G4-quadruplexes (G4s) are non-canonical structures of nucleic acids that develop in guanine rich regions of DNA and RNA. Due to their presence in oncogenic promoters and telomeres, G4s represent attractive targets in anticancer drug designs. G4s have also been the subject of recent research regarding their role as epigenetic modulators, supporting their participation in epigenetic processes that control gene expression. The development of small compounds that preferentially target G4s have led to a better understanding of how G4s control these mechanisms. Natural products have greatly contribu

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… Resveratrol enhances the stability of TERRA G4 and markers of telomeric heterochromatin, promoting apoptosis in myeloma cells (Cusanelli and Chartrand, 2015[ 35 ]). … Notably, studies have demonstrated that resveratrol can increase TERRA transcript expression and telomeric heterochromatin markers (H3K27me3 and H4K20me3), decreasing the proliferation of multiple myeloma cells. …

Drug delivery for age-related bone diseases: From therapeutic targets to common and emerging therapeutic strategies.

With the accumulation of knowledge on aging, people have gradually realized that among the many factors that cause individual aging, the accumulation of aging cells is an essential cause of organ degeneration and, ultimately, age-related diseases. Most cells present in the bone microenvironment gradually age over time, leading to an imbalance of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis. This imbalance contributes to age-related bone loss and the development of age-related bone diseases, such as osteoporosis. Bone aging can prolong the lifespan and delay the developmen

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… morphology, increased senescence-associated β-galactosidase (SA-β-gal) activity, accumulation of SASP, activation of DNA damage response (DDR), increased expression of cyclin-dependent kinase (CDK) inhibitors p16 (CDKN2A) and p21 (CDKN1A), telomere dysfunction, and formation of senescence-associated heterochromatin … Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a) Cell Cycle. 2011;10(3):457–468. doi: 10.4161/cc.10.3.14707. Koushki K., et al. …

Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor.

Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR's clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient's quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into

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… BAHD1 is an important regulator of gene silencing during the formation of heterochromatin and plays an important role in inhibiting proliferation and survival genes or as a regulator of inflammation through the TNF signaling pathway ( Zhu et al., 2015 ). … Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome . Front. Genet. 6 , 339 . 10.3389/fgene.2015.00339 26648976 PMC4664705 Liu X. J. Zhang Y. Liu T. Xu Z. Z. Park C. K. Berta T. ( 2014 ). …

Histone Deacetylases (HDACs) Guided Novel Therapies for T-cell lymphomas.

T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination

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… HDACs play a key role in the homeostasis maintenances of histone acetylation euchromatin and heterochromatin in living system 9 , 10 . … Histone deacetylase inhibition redistributes topoisomerase IIbeta from heterochromatin to euchromatin. Nucleus. 2011;2:61–71. doi: 10.4161/nucl.2.1.14194. 10. Zhang Q, Dai Y, Cai Z, Mou L. HDAC Inhibitors: Novel Immunosuppressants for Allo- and Xeno- Transplantation. …

JMJD3 suppresses tumor progression in oral tongue squamous cell carcinoma patients receiving surgical resection.

BackgroundJumonji domain-containing-3 (JMJD3) is reported to be a histone H3 lysine 27 (H3K27) demethylase and a tumor suppressor gene. The present study designed to investigate the crucial role of JMJD3 in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection.MethodsWe enrolled a total of 156 OTSCC patients receiving surgical resection, including 73 patients (47%) with high expression of JMJD3 and 83 patients (53%) harboring low expression of JMJD3. Two OTSCC cell lines, SAS and Cal 27, were used to explore the modulation of cancer. GSK-J4, a potent inhibitor of

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… The function of Rb is mediated by p16, and methylation of Rb facilitates the interaction with protein kinase CDK4; JMJD3/Rb interaction together links to heterochromatin, contributing to cancer senescence. …

Lost in transcription: molecular mechanisms that control HIV latency.

Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover,

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… As heterochromatin is more compact and structured than euchromatin, it is repressive for transcription. The compaction of chromatin and its accessibility for transcription factors depend on post-translational modifications of histones and epigenetic marks. … SUV39H1 and G9a are involved in heterochromatin formation at the HIV promoter and as a consequence, increase HIV gene silencing [ 80 , 81 ]. G9a inhibits basal and induced HIV gene expression by TNFα or Tat [ 82 ]. …

Человеческие эндогенные ретровирусы как новые терапевтические цели в нейродегенеративных расстройствах.

Человеческие эндогенные ретровирусы составляют приблизительно 8% генома человека и служат фрагментами древних антиретровирусных инфекций. Хотя они, как правило, удерживаются в замалчиваемом состоянии с помощью надежных эпигенетических механизмов, конкретные группы HERV, в частности HERV-W и HERV-K, могут депрессировать в конкретных патологических условиях, что способствует инициированию и продвижению нейро-воспалительных и нейродегенеративных процессов. Доклинические исследования и клинические испытания, такие, как исследования моноклонных антител, показывают, что прямая ориентация на эти элем

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… Our cells treat HERV loci much like other transposable elements, densely packaging them into heterochromatin. DNA methylation of CpG sites in HERV promoters and histone tail modifications create a repressive chromatin environment and represent the two major epigenetic control mechanisms [ 4 , 84 ]. …

Использование естественных экзоцитозных везикул для борьбы с возрастными заболеваниями: от возрастных драйверов до терапевтических возможностей.

Старение — это сложный биологический процесс, приводящий к увеличению нагрузки возрастных заболеваний (ARD). Клеточная старость, включающая необратимое остановку клеточного цикла и выделение фенотипа секреторной активности при старении (SASP), играет центральную роль в старении и развитии ARD. Естественные экзоцитические везикулы (NEVs) — это везикулы, полученные из клеток, органов и тканей без искусственных вмешательств. В последние годы NEVs привлекли внимание как медиаторы межклеточной коммуникации, и показали многофункциональный потенциал в регулировании клеточной старости и ARD. С одной с

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… . 54 , 56 , 57 In terms of metabolism, NAD⁺ concentrations decrease; glutamine metabolism is reduced. 58 Other relatively typical features include DNA damage, accumulation of dysfunctional mitochondria and oxidative damage, SASP, SA-β-galactosidase (SA-β-gal) accumulation, and senescence-associated heterochromatin … The cell shows DNA damage, increased reactive oxygen species, lipofuscin, beta-galactosidase and senescence-associated heterochromatin foci. The text ′Senescent cells′ is visible. The second part, labeled B, illustrates the effects of senescent cells. …

Non-Coding RNAs: The "Dark Side Matter" of the CLL Universe.

For many years in the field of onco-hematology much attention has been given to mutations in protein-coding genes or to genetic alterations, including large chromosomal losses or rearrangements. Despite this, biological and clinical needs in this sector remain unmet. Therefore, it is not surprising that recent studies have shifted from coded to non-coded matter. The discovery of non-coding RNAs (ncRNAs) has influenced several aspects related to the treatment of cancer. In particular, in chronic lymphocytic leukemia (CLL) the knowledge of ncRNAs and their contextualization have led to the ident

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… Moreover, lincRNA-p21 is associated with the H3K9 methyltransferase SETDB1 and the DNA methyltransferase DNMT1, sustaining H3K9me3 and CpG methylation at pluripotency gene promoters and linking TP53 to heterochromatin regulation [ 52 ]. …

Synthetic lethality and DNA damage response targeting in cancer stem cells: a comprehensive review.

This comprehensive review explores the critical intersection of Synthetic Lethality (SL) and DNA Damage Response (DDR) targeting within Cancer Stem Cells (CSCs), a subpopulation central to tumor initiation, metastasis, and therapeutic resistance. CSCs exhibit unique biological properties, including enhanced DNA repair mechanisms and metabolic plasticity, rendering them intrinsically resistant to conventional therapies. The fundamental mechanisms of DDR pathways and their dysregulation in cancer are delineated, highlighting how these vulnerabilities can be exploited through SL. The review synth

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, th

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… Histone acetylation also performs a fundamental position in higher-order chromatin structure [ 22 ], nucleosome assembly [ 23 ] and preventing the spread of heterochromatin [ 24 ]. … Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones. Nucleic Acids Res. 2021;49(21):12136–12151. doi: 10.1093/nar/gkab1044. 25. Singh M, et al. …

Small RNA Sequencing Identifies PIWI-Interacting RNAs Deregulated in Glioblastoma-piR-9491 and piR-12488 Reduce Tumor Cell Colonies In Vitro.

Glioblastoma (GBM) is the most frequently occurring primary malignant brain tumor of astrocytic origin. To change poor prognosis, it is necessary to deeply understand the molecular mechanisms of gliomagenesis and identify new potential biomarkers and therapeutic targets. PIWI-interacting RNAs (piRNAs) help in maintaining genome stability, and their deregulation has already been observed in many tumors. Recent studies suggest that these molecules could also play an important role in the glioma biology. To determine GBM-associated piRNAs, we performed small RNA sequencing analysis in the discove

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… PiRNAs present one of the subclasses of short non-coding RNAs, 24–32 nucleotides in length, which act as regulators of active transposons by induction of heterochromatinization in transposon loci or by direct cleavage of complementary transposon transcripts in piRISC complexes by the associated PIWI …

Prognostic value of circulating markers of neutrophil activation, neutrophil extracellular traps, coagulation and fibrinolysis in patients with terminal cancer.

Predicting survival accurately in patients with advanced cancer is important in guiding interventions and planning future care. Objective tools are therefore needed. Blood biomarkers are appealing due to their rapid measurement and objective nature. Thrombosis is a common complication in cancer. Recent data indicate that tumor-induced neutrophil extracellular traps (NETs) are pro-thrombotic. We therefore performed a comprehensive investigation of circulating markers of neutrophil activation, NET formation, coagulation and fibrinolysis in 106 patients with terminal cancer. We found that neutrop

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… PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Frontiers Immunol. 2012;3:307. doi: 10.3389/fimmu.2012.00307. 43. Wang Y, et al. …

Update on the role of autologous hematopoietic stem cell transplantation in multiple myeloma.

Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease er

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… Evidence for a novel mechanism for gene amplification in multiple myeloma: 1q12 pericentromeric heterochromatin mediates breakage-fusion-bridge cycles of a 1q12 approximately 23 amplicon. Br J Haematol. 2009;147:484–494. doi: 10.1111/j.1365-2141.2009.07869.x. 58. …

Kidney-Tonifying, Phlegm-Resolving, and Blood Stasis-Removing Therapy for Multiple Myeloma: Protocol for a Randomized Controlled Trial on Epigenetic and Immune Modulation.

BACKGROUND: Multiple myeloma (MM) is characterized by kidney deficiency, phlegm, and blood stasis as core findings, specifically in Traditional Chinese Medicine (TCM), and the kidney-tonifying, phlegm-resolving, and blood stasis-removing (KPR) method is a fundamental therapeutic approach for MM in TCM. Western medicine primarily focuses on targeted immunotherapy or chemotherapy for MM treatment, whereas TCM characterizes MM through distinct pathological patterns that directly correspond to immune microenvironment dysregulation. Emerging evidence implicates the PHD finger protein 19 (PHF19)/enh

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… Stasis-eliminating herbs, such as Hedyotis diffusa and ground beetle Eupolyphaga sinensis , may inhibit EZH2 interaction, preventing heterochromatin propagation. …