Cellular landscape of adrenocortical carcinoma at single-nuclei resolution

Molecular and Cellular Endocrinology, Journal Year: 2024, Volume and Issue: 590, P. 112272 - 112272

Published: May 15, 2024

Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with molecular pathology that remains incompletely understood. To gain novel insights into cellular landscape ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC samples and analysed these alongside snRNA-seq normal glands (NAGs). We find microenvironment to be relatively devoid immune cells compared NAG tissues, consistent known high purity values for as an immunologically "cold" tumour. Our analysis identifies three separate groups are characterised by different relative compositions adrenocortical cell types. These include populations specifically enriched in most clinically aggressive hormonally active tumours, displaying hallmarks reorganised mechanobiology dysregulated steroidogenesis, respectively. also identified validated population mitotically strongly overexpress genes POLQ, DIAPH3 EZH2 support expansion LGR4+ progenitor-like or cell-of-origin candidate carcinogenesis. Trajectory inference suggests fate adopted malignant upon differentiation associated copy number allelic balance state imprinted DLK1/MEG3 genomic locus, which verified assessing bulk DNA methylation status. In conclusion, our results therefore provide new clinical heterogeneity revealing how genetic perturbations healthy renewal zonation basis disease pathogenesis.

Language: Английский

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A bioprinted sea-and-island multicellular model for dissecting human pancreatic tumor-stroma reciprocity and adaptive metabolism

Biomaterials, Journal Year: 2024, Volume and Issue: 310, P. 122631 - 122631

Published: May 24, 2024

Language: Английский

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m1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

Clinical & Experimental Metastasis, Journal Year: 2025, Volume and Issue: 42(2)

Published: Jan. 22, 2025

In recent years, the emphasis has shifted to understanding role of N1-methyladenosine (m1A) in tumor progression as little is known about its regulatory effect on mRNA and metastasis colorectal cancer (CRC). We performed methylated RNA immunoprecipitation sequencing tissues tumor-adjacent normal from three patients with CRC determine m1A profile CRC. The expression diaphanous-related formin 3 (DIAPH3) correlation clinicopathological characteristics were evaluated using immunohistochemistry online datasets. DIAPH3 migration invasion cells was wound healing assay, Transwell assay xenograft metastatic model. downstream targets screened mass spectrometry. By co-transfecting siRNA a keratin 19 (KRT19) ectopic plasmid into cells, DIAPH3-KRT19 signaling axis confirmed. level modifications increased simultaneously tissues. addition, high significantly associated an advanced stage. After knockdown DIAPH3, capabilities suffered notable decline, which could be rescued by overexpressing KRT19. proteasome inhibitor MG132 block degradation KRT19 induced silencing. Our study reveals that modified methylation. Silencing suppresses potentially through proteasome-dependent

Language: Английский

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Chemoproteomics-Enabled De Novo Proteolysis Targeting Chimera Discovery Platform Identifies a Metallothionein Degrader to Probe Its Role in Cancer

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7817 - 7828

Published: Feb. 24, 2025

Proteolysis targeting chimeras (PROTACs) represent powerful tools to modulate the activity of classically "undruggable" proteins, but their application has been limited known ligands and a few select protein classes. Herein, we present our chemoproteomic strategy for simultaneous de novo discovery novel degraders challenging previously targets. Using comparative PROTAC versus ligand global proteomics analyses, rapidly identify proteins selectively downregulated by several "untargeted" PROTACs containing VHL E3 ligase recruiter various covalent noncovalent ligands. We showcase approach identifying first-in-class metallothionein 2A (MT2A), small, cysteine-rich, metal-binding implicated in heavy metal detoxification, zinc homeostasis, cellular invasion. Notably, isoform-specific MT overexpression shown augment migration invasion across cancer cell lines, although precise mechanisms are unknown due insufficient study MTs. show that optimized AA-BR-157 covalently binds conserved C44, degrades overexpressed MT2A with nanomolar potency, reduces MDA-MB-231 cells. further demonstrate time-dependent increase intracellular levels following degradation as well downregulation diaphanous homolog 3 (DIAPH3), positive regulator actin motility. Super-resolution imaging cells shows DIAPH3 inhibits polarization thereby migration, suggesting may regulate motility via DIAPH3-dependent cytoskeletal remodeling. In summary, enables disease-related targets lays groundwork expansion druggable proteome.

Language: Английский

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Bee Pollen Potential to Modulate Ferroptosis: Phytochemical Insights for Age-Related Diseases

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 265 - 265

Published: Feb. 25, 2025

Bee pollen (BP) is one of the richest known natural resources micronutrients and bioactive phytochemicals. Some captivating bioactivities BP compounds, although being largely investigated for latter as individual molecules, remain very scarcely or completely uninvestigated in bee a whole product. Among most intriguing these bioactivities, we identified ferroptosis major one. Ferroptosis, recently discovered form cell death (connecting oxidative stress inflammation), complex pathophysiological process crucial perplexing events current challenging human diseases such cancer, neurodegeneration, general aging diseases. Many compounds were found to intricately modulate depending on cellular context by inducing this mechanism malignant cells preventing it non-malignant cells. Since research both fields, i.e., ferroptosis, still recent, deemed necessary undertake review figure out extent potential modulating mechanisms. Our proved that wide range (polyphenols, phenolamides, carotenoids, vitamins, minerals, others) substantially diverse Accordingly, phytochemicals nutrients showed interesting preclinical studies lead ferroptosis-mediated outcomes important processes, including many aging-related disorders. One paramount challenges be resolved determine how different act biological contexts, either through synergistic antagonistic behaviors. We hope our work constitutes valuable incentive future investigations promising relevant avenue.

Language: Английский

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Identification of a cisplatin resistant-based prognostic immune related gene signature in MIBC

Translational Oncology, Journal Year: 2024, Volume and Issue: 44, P. 101942 - 101942

Published: March 30, 2024

Language: Английский

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DIAPH3 in Cancer: Role and Mechanism

Published: Feb. 25, 2025

Diaphanous-related formin 3 (DIAPH3) is a pivotal member of the family and serves as crucial regulator actin filament assembly. As such, DIAPH3 plays an integral role in variety cellular processes including cytokinesis, cell migration, intracellular transport. Given its fundamental importance maintaining cytoskeletal dynamics, functionally associated with numerous physiological pathological conditions, particularly cancer. In this review, we explore structural functional characteristics investigate mutational transcriptional landscape human cancers. By focusing on DIAPH3's controlling metastasis tumor microenvironment, aim to provide new insights into how contributes development progression. Altogether, believe that enhanced understanding signalosome will facilitate more precise clinical decision-making novel therapeutics against aggressive

Language: Английский

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The antioxidant effects of coenzyme Q10 on albino rat testicular toxicity and apoptosis triggered by bisphenol A

Environmental Science and Pollution Research, Journal Year: 2023, Volume and Issue: 30(14), P. 42339 - 42350

Published: Jan. 17, 2023

Language: Английский

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Recent advances in the application of metallomics in diagnosis and prognosis of human cancer

Metallomics, Journal Year: 2022, Volume and Issue: 14(7)

Published: Jan. 1, 2022

Abstract Metals play a critical role in human health and diseases. In recent years, metallomics has been introduced extensively applied to investigate the distribution, regulation, function, crosstalk of metal(loid) ions various physiological pathological processes. Based on high-throughput multielemental analytical techniques bioinformatics methods, it is possible elucidate correlation between metabolism homeostasis diverse metals complex diseases, particular for cancer. This review aims provide an overview progress made application cancer research. We mainly focuses studies about metallomic profiling different biological samples several major types cancer, which reveal distinct dynamic patterns metal ion contents potential benefits using such information detection prognosis these malignancies. Elevated levels copper appear be significant risk factor cancers, each type unique distribution biofluids, hair/nails, tumor-affected tissues. Furthermore, associations genetic variations representative metalloprotein genes susceptibility have also demonstrated. Overall, not only offers better understanding relationship dyshomeostasis development but facilitates discovery new diagnostic prognostic markers translational medicine.

Language: Английский

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Dietary Selenium Intake and Kidney Stones in Old Adults: an Analysis from NHANES 2011 to 2018

Biological Trace Element Research, Journal Year: 2022, Volume and Issue: 201(4), P. 1588 - 1595

Published: June 10, 2022

The association between dietary selenium intake and kidney stones remains unclear. purpose of this study was to explore the correlation in older adults. A total 6669 adults aged ≥ 60 years who had participated National Health Nutrition Examination Survey (NHANES) during 2011-2018 were enrolled current study. assessed by logistic regression analysis. Smooth curve fitting used potential non-linear relationship subgroup analyses further adopted. After adjustment for multiple confounding factors, odds ratio (OR) with 95% confidence interval (CI) per standard deviation increment 0.92 (0.85, 1.00) overall. Compared lowest quartile, ORs (95% CIs) increasing quartiles 0.88 (0.71, 1.08), 0.82 (0.66, 1.02), 0.79 (0.64, 0.97). In addition, smooth stratified showed that there a stable occurrence respectively. For over 60, inversely correlated stones, remained after adjusting other variables. Further researches are needed mechanism stones.

Language: Английский

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