Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway

Journal of Cancer Research and Clinical Oncology, Journal Year: 2024, Volume and Issue: 150(5)

Published: May 4, 2024

Abstract Purpose Acute myeloid leukemia (AML) is a refractory hematologic malignancy that poses serious threat to human health. Exploring alternative therapeutic strategies capable of inducing modes cell death, such as ferroptosis, holds great promise viable and effective intervention. Methods We analyzed online database data collected clinical samples verify the expression function BMAL1 in AML. conducted experiments on AML proliferation, cycle, chemotherapy resistance by overexpressing/knocking down using assays MDA detection BODIPY 581/591 C11 staining. validated transcriptional regulation HMGB1 through ChIP assay, luciferase RNA level detection, western blotting. Finally, we confirmed results our at animal level. Results up-regulation an observed phenomenon patients. Furthermore, there existed strong correlation between elevated levels inferior prognosis individuals with found knocking inhibited growth blocking cycle. Conversely, overexpressing promoted proliferation. Moreover, research revealed ferroptosis cells BMAL1-HMGB1-GPX4 pathway. can enhance efficacy certain first-line cancer drugs, including venetoclax, dasatinib, sorafenib. Conclusion Our suggest plays crucial regulatory role drug resistance, ferroptosis. could be potential important target for

Language: Английский

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Transcription of Clock Genes in Medulloblastoma

Cancers, Journal Year: 2025, Volume and Issue: 17(4), P. 575 - 575

Published: Feb. 8, 2025

We investigated the transcription of circadian clock genes in publicly available datasets gene expression medulloblastoma (MB) tissues using R2 Genomics Analysis and Visualization Platform. Differential core among four consensus subgroups MB (defined 2012 as Group 3, 4, SHH group, WNT group) included (CLOCK, NPAS2, PER1, PER2, CRY1, CRY2, BMAL1, BMAL2, NR1D1, TIMELESS) which encode proteins that regulate (CIPC, FBXL21, USP2). The over-expression several genes, including CIPC, was found individuals with isochromosome 17q chromosomal aberration 3 4. most significant biological pathways associated were ribosome subunits, phototransduction, GABAergic synapse, signaling pathway, Fanconi anemia pathway. Survival analysis examined Kaplan-Meier method Cox proportional hazards regression model through Two significantly related to survival CRY1 USP2. data suggest proteins, USP2, be potential therapeutic targets MB.

Language: Английский

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A prognostic model of lung adenocarcinoma constructed based on circadian rhythm genes and its potential clinical significance

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 18, 2025

Lung adenocarcinoma (LUAD) is a common pathological category of lung cancer. Circadian rhythm (CR) disruption has been demonstrated to impact on tumorigenesis in mouse models. The aim this study was mine genes relevant CR LUAD and construct corresponding risk model. CRRGs from GSEA-MsigDB were filtered by overlapping DEGs NC specimens, two clusters with survival clinical discrepancies, CRRGs. Cox regression analysis (univariate multivariate) used establish CR-relevant model, which validated both the training validation sets. Differences immune infiltration, immunotherapy, drug sensitivity between subgroups explored. Prognostic gene expression tested cancer paracancer tissue samples using RT-qPCR. A grand total prognostic (CDK1 HLA-DMA) related screened. AUC values model predicting 1/3/5-years patients greater than 0.6, indicating that efficiency decent. Then, results CIBERSORT noticeable differences tumor microenvironment high- low-risk subgroups. In addition, score could be performed estimate effectiveness immunotherapy patients. three drugs (homoharringtonine, lapatinib, palbociclib) evaluated Ultimately, experimental confirmed trends CDK1 HLA-DMA our collected line TCGA-LUAD dataset. conclusion, based constructed bioinformatics analysis, might supply new insight into improved prognosis LUAD.

Language: Английский

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The mutual impacts of stem cells and sleep: opportunities for improved stem cell therapy

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 29, 2025

Abstract Sleep is an indispensable physiological function regulated by circadian rhythms, which influence the biological pathways and overall health of body. crucial for maintenance restoration bodily systems, disturbances can lead to various sleep disorders, impair both mental physical health. Treatment options these disorders encompass lifestyle modifications, psychotherapy, medications, therapies such as light therapy surgery. Not only deprivation has a significant impact on essential organs, but it also influences types stem cells in In this review, we explore connection between cells, highlighting how rhythms regulate cell activities that are vital tissue regeneration homeostasis. Disruptions hinder self-renewal, homing, proliferation, function, differentiation, thereby affecting We discuss transplantation their products may help improve quality affects behavior, implications therapies. Notably, while certain transplantations disrupt sleep, enhancing efficacy Finally, be utilized model offering valuable insights into underlying mechanisms.

Language: Английский

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Core Molecular Clock Factors Regulate Osteosarcoma Stem Cell Survival and Behavior via CSC/EMT Pathways and Lipid Droplet Biogenesis

Cells, Journal Year: 2025, Volume and Issue: 14(7), P. 517 - 517

Published: March 31, 2025

The circadian clock, an intrinsic 24 h cellular timekeeping system, regulates fundamental biological processes, including tumor physiology and metabolism. Cancer stem cells (CSCs), a subpopulation of cancer with self-renewal tumorigenic capacities, are implicated in initiation, recurrence, metastasis. Despite growing evidence for the clock’s involvement regulating CSC functions, its precise regulatory mechanisms remain largely unknown. Here, using human osteosarcoma (OS) model (143B), we have shown that core molecular clock factors critical OS cell survival behavior via direct modulation lipid metabolic pathways. In single-cell-derived spheroid formation assays, 143B exhibited robust spheroid-forming capacity under 3D culture conditions. Furthermore, siRNA-mediated depletion components (i.e., BMAL1, CLOCK, CRY1/2, PER1/2)—essential positive negative elements feedback loop—significantly reduced CSCs isolated from vivo xenografts. contrast, knockdown secondary clock-stabilizing factor genes NR1D1 NR1D2 had little effect. We also found or CRY1/2 markedly impaired migration invasion capacities CSCs. At level, silencing distinctly altered expression associated properties epithelial–mesenchymal transition (EMT) addition, disruption significantly droplet by downregulating involved lipogenesis (e.g., DGAT1, FASN, ACSL4, PKM2, CHKA, SREBP1), which closely linked to CSC/EMT processes. transcriptomic analysis patient samples revealed compared other genes, CRY1 was highly expressed tumors relative controls, strong correlations prognosis, survival, LD biogenesis gene expression. These findings highlight role metabolism, underscoring therapeutic potential targeting machinery enhance treatment outcomes.

Language: Английский

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Tissue mechanics in tumor heterogeneity and aggression

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor is population cancer-associated fibroblasts myeloid cells stiffen extracellular matrix. The heterogeneously stiffened matrix in turn activates cellular mechanotransduction creates hypoxic metabolically hostile microenvironment. elevated mechanosignaling also drive aggression by fostering cell growth, survival, invasion, compromising antitumor immunity, expanding cancer stem frequency, increasing mutational burden, which promote intratumor heterogeneity. Delineating molecular mechanisms whereby mechanics regulate these phenotypes should help to clarify basis for heterogeneity identify novel therapeutic targets could improve patient outcome. Here, we discuss role driving through its impact on

Language: Английский

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Innovative therapeutic strategies for cardiovascular disease.

PubMed, Journal Year: 2023, Volume and Issue: 22, P. 690 - 715

Published: Jan. 1, 2023

As a significant non-communicable disease, cardiovascular disease is the leading cause of death for both men and women, comprises almost twenty percent deaths in most racial ethnic groups, can affect greater than twenty-five million individuals worldwide over age twenty, impacts global economies with far-reaching financial challenges. Multiple factors onset that include high serum cholesterol levels, elevated blood pressure, tobacco consumption secondhand smoke exposure, poor nutrition, physical inactivity, obesity, concurrent diabetes mellitus. Yet, addressing any these cannot completely eliminate or progression disorders. Novel strategies are necessary to target underlying mechanisms. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), histone deacetylase, limit injury, assist stem cell development, oversee metabolic homeostasis through nicotinamide adenine dinucleotide (NAD+) pathways, foster trophic factor protection, control senescence modulation telomere function. Intimately tied SIRT1 pathways mammalian forkhead transcription (FoxOs) which modulate cardiac reduce oxidative stress, repair microcirculation disturbances, atherogenesis autophagy, apoptosis, ferroptosis. AMP activated protein kinase (AMPK) also critical among oversight cellular metabolism, insulin sensitivity, mitochondrial function, inflammation, susceptibility viral infections such as severe acute respiratory syndrome coronavirus impact disease. relationship intricate complex requires detailed insight successfully translate into clinical care

Language: Английский

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Circadian clock disruption and growth of kidney cysts in autosomal dominant polycystic kidney disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the

Language: Английский

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Abnormal Histopathological Expression of Klotho, Ferroptosis, and Circadian Clock Regulators in Pancreatic Ductal Adenocarcinoma: Prognostic Implications and Correlation Analyses

Biomolecules, Journal Year: 2024, Volume and Issue: 14(8), P. 947 - 947

Published: Aug. 5, 2024

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, significant translational potential improving patient outcomes. In this study, we evaluated the prognostic significance ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), KLOTHO in retrospective cohort 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) multiple statistical analyses (Kaplan-Meier curves, correlograms, multinomial linear regression models) were performed. Our findings reveal that are directly associated PDAC mortality, while inversely associated. Notably, TFRC emerged as strongest risk marker mortality (HR = 35.905), whereas CLOCK was identified most protective 0.01832). Correlation indicate positively correlated each other, regulators, which also correlate expression. contrast, exhibit inverse correlations markers. Among variables examined, only presence chronic pathologies showed association expression patterns several proteins studied. These underscore complexity pathogenesis highlight need further research into specific molecular mechanisms driving disease progression.

Language: Английский

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Self-sustainable Catalytic Nucleic Acid Circuit Powered Hybrid CRISPR-Cas Systems for Point-of-Care Diagnosis of Circadian Clock Gene from Cell Lysates

Journal of Analysis and Testing, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Language: Английский

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