ECM Stiffness-Induced Redox Signaling Enhances Stearoyl Gemcitabine Efficacy in Pancreatic Cancer

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 870 - 870

Published: March 3, 2025

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its dense fibrotic stroma that promotes drug resistance and tumor progression. While patient-derived organoids (PDOs) have emerged as promising tools for modeling PDAC evaluating therapeutic responses, current PDO models grown in soft matrices fail replicate tumor's stiff extracellular matrix (ECM), limiting their predictive value advanced disease. We developed a biomimetic model using gelatin-based varying stiffness, achieved through modulated transglutaminase crosslinking rates, better simulate desmoplastic microenvironment. Using this platform, we investigated organoid morphology, proliferation, chemoresistance gemcitabine (Gem) lipophilic derivative, 4-N-stearoyl (Gem-S). Mechanistic studies focused on interplay between ECM hypoxia-inducible factor (HIF) expression, nuclear erythroid 2-related 2 (Nrf2) pathway resistance. stiffer demonstrated enhanced stemness features, including rounded morphology elevated cancer stem cell (CSC) marker expression. Matrix stiffness-induced correlated with upregulation ABC transporters oxidative stress adaptive responses. activated Nrf2 promoting mitigation, Gem-S suppressed levels induced stress, leading increased reactive oxygen species (ROS) death. Both compounds reduced HIF showing greater efficacy. Our study reveals stiffness critical mediator promotion modulation pathways. demonstrates promise overcoming by disrupting Nrf2-mediated responses inducing stress. These findings underscore importance biomechanically accurate suggest dual targeting mechanical pathways may improve treatment outcomes.

Language: Английский

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Bisboronic Ester-Enabled Redox-Targeted Cancer Therapy: A Cascade ROS Consumption Approach for Efficient Elimination of Cancer Cells

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Elevated levels of reactive oxygen species (ROS) in cancer cells, arising from their altered metabolism, represent a distinctive therapeutic target. Here, we introduce the first example bisboronic esters as potent agents for rapidly disrupting redox homeostasis, selectively inducing oxidative stress to eliminate cells. Structure-activity relationship studies revealed that both electronic and steric factors significantly influence cytotoxicity, with most effective compounds achieving IC50 values low 0.63 μM. Confocal imaging confirmed rapid intracellular depletion ROS, leading severe metabolic imbalance efficient cell death. This study highlights potential boronate-based therapeutics redox-targeted therapy, which may provide promising foundation development innovative anticancer strategies.

Language: Английский

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Effects of reduced extracellular sodium on proliferation and invasive activity of renal cell carcinoma cell lines

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 8, 2025

Hyponatremia is the most common electrolyte disorder in cancer patients and associated with a worse outcome. This finding has also been reported metastatic renal cell carcinoma (mRCC). We have previously demonstrated that low extracellular sodium concentrations ([Na+]) increase proliferation invasion several human lines. The aim of present study was to evaluate vitro effects mild [Na+] alterations on two mRCC lines, ACHN Caki-1. After growth reduced [Na+], we observed even reductions significantly enhanced different key features, including proliferation, migration. Furthermore, reduction reactive oxygen species (ROS) levels significant antioxidant Nrf2/HMOX-1 pathway. Since an excess ROS causes death, this clarifies role maintaining balance between oxidant tumor environment, promoting survival. Although further clinical studies are needed, aiming for instance determine whether serum correction improves outcome mRCC, our findings suggest attention should be deserved setting.

Language: Английский

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The cistrome response to hypoxia in human umbilical vein endothelial cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

ABSTRACT Transcriptional signaling during hypoxic stress is primarily governed by hypoxia-inducible transcription factors (HIFs), which bind to hypoxia response elements (HREs) in gene regulatory regions. However, only a small proportion (∼1%) of known HREs are occupied HIFs hypoxia, suggesting the involvement additional pathways. To address this gap, we utilized MOA-seq, an MNase-based assay that enables genome-wide, high-resolution (<30 bp) identification factor (TF) occupancy footprints within open chromatin. We applied cistrome profiling approach nuclei from cultured endothelial cells exposed normoxia or for 1, 3, 24 hours, revealing thousands hypoxia-modulated genomic sites with dynamic TF footprints. The affected genes were enriched canonical hypoxia-induced pathways, such as angiogenesis. Motif analysis identified over 100 candidate TFs potentially mediating complex multifaceted response. followed up these observations quantitative footprint clustering gain mechanistic insight into how concurrent networks might choreograph responses. found 10 distinct MOA-defined kinetic clusters, half contained HIF1A motifs. HIF1A-proximal binding revealed co-activators, whereas motifs non-HIF1A clusters implicated HIF1A-independent These findings highlight utility unraveling hypoxia. KEY POINTS MOA-seq mapped at 21,765 normoxia, including 7,444 beyond ENCODE cCREs. Hypoxia and 24h changes genes. Clustering distinguished HIF1A-associated cofactors TFs.

Language: Английский

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The Impact of the Delivery Method on Oxidative Stress in Neonates: A Cross-Sectional Study

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(7), P. 2269 - 2269

Published: March 26, 2025

Background/Objectives: Oxidative stress is a factor that may adversely affect the development of foetus, course labour, and newborn health. This study aimed to determine association between labour method, oxidative parameters, neonatal condition. Methods: The material was umbilical cord blood from newborns delivered vaginally (n = 60) or by caesarean section 108). total antioxidant status (TAS), superoxide dismutase activity (SOD), glutathione peroxidase (GPx), reductase (GR) were determined using colorimetric methods. concentration chemical elements (Zn, Cu, Mn) estimated, atomic absorption spectrometry (ASA). Results: SOD significantly lower in with an Apgar score below 10 at 5th minute life compared highest points (p 0.041). In neonates (CS), but not born (VB) neonates, scores less than maximum number 0.02). Conclusions: reduced could be related increased during labour. Bupivacaine-induced seems cause downregulation caesarean-delivered newborns. observed CS decreased requires confirmation based on larger cohort neonates.

Language: Английский

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Loss of vitamin D receptor induces premature ovarian insufficiency through compromising the 7-dehydrocholesterol-dependent anti-aging effects

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: April 10, 2025

Vitamin D has the potential to therapeutically affect endocrine parameters of premature ovarian insufficiency (POI) patients. Previous research indicated that serum vitamin levels tend decline with age and in individuals POI. However, precise impact deficiency on female fertility, especially their function, remains unclear. receptor (VDR) mice provide a model investigate possible effect reproduction. In this study, we observed abnormal follicular development Vdr mice. This anomaly is associated reduced expression anti-Mullerian hormone (AMH) disrupted aromatase disrupts secretion. Moreover, our findings indicate disturbs redox balance, resulting oxidative stress ovary, which further suppresses granulosa cell function accelerates aging. Mechanistically, loss inhibits de novo cholesterol synthesis by transcriptional repression Hmgcr , antioxidant anti-aging effects intermediate product 7-dehydrocholesterol (7-DHC) are also decreased. Treatment 7-DHC effectively reduces ROS alleviates aging KGN cells deficient . conclusion, results show impairs follicle maturation secretion accelerating aging, as result 7-DHC.

Language: Английский

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Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: June 12, 2024

Language: Английский

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Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8972 - 8972

Published: Aug. 17, 2024

Epithelial-mesenchymal transition (EMT) is a process in which an epithelial cell undergoes multiple modifications, acquiring both morphological and functional characteristics of mesenchymal cell. This dynamic initiated by various inducing signals that activate numerous signaling pathways, leading to the stimulation transcription factors. EMT plays significant role cancer progression, such as metastasis tumor heterogeneity, well drug resistance. In this article, we studied molecular mechanisms, epigenetic regulation, cellular plasticity EMT, microenvironmental factors influencing process. We included vivo vitro models investigation clinical implications use curing oncological patients targeting its therapies. Additionally, review concludes with future directions challenges wide field EMT.

Language: Английский

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Bisdemethoxycurcumin mitigates traumatic brain injury in rats by modulating autophagy and oxidative stress via heat shock protein 90 alpha family class A member 1-mediated nuclear translocation of transcription factor EB

Brain Research Bulletin, Journal Year: 2025, Volume and Issue: unknown, P. 111221 - 111221

Published: Jan. 1, 2025

Language: Английский

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Oxidative Stress Enhances Rubella Virus Infection in Immortalized Human First-Trimester Trophoblasts

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1041 - 1041

Published: Jan. 25, 2025

Rubella infection (RuV) during early pregnancy is a known cause of congenital rubella syndrome (CRS). However, the mechanisms by which virus crosses placenta and infects fetus are not fully understood. It has been that various kinds cell stresses can occur formation. Previously, we demonstrated low-glucose-induced endoplasmic reticulum stress could drastically enhance RuV in immortalized human first-trimester trophoblast cells. In this study, investigated roles oxidative these Oxidative was induced Swan.71 cells culturing them medium containing hydrogen peroxide (H2O2) concentrations durations (50 µM or 100 for 24 h, 150 1 h). with clinical strain performed h post-treatment, capsid proteins were visualized at 48 post-infection (hpi) using flow cytometry (FCM) fluorescence microscopy (IF), respectively. The findings significantly enhanced infection, as evidenced FCM analysis, showing twofold increase rate, confirmed IF assay. Additionally, increased intracellular viral replication observed 3 dpi. These suggest may promote maternal-to-fetal transmission rubella, contributing to development CRS.

Language: Английский

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