Radioresistant cells initiate lymphocyte-dependent lung inflammation and IFNγ-dependent mortality in STING gain-of-function mice

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(25)

Published: June 13, 2022

Pediatric patients with constitutively active mutations in the cytosolic double-stranded-DNA-sensing adaptor STING develop an autoinflammatory syndrome known as STING-associated vasculopathy onset infancy (SAVI). SAVI have elevated interferon-stimulated gene expression and suffer from interstitial lung disease (ILD) lymphocyte predominate bronchus-associated lymphoid tissue (BALT). Mice harboring (STING V154M [VM]) that recapitulate human also lymphocyte-rich BALT. Ablation of either T or B lymphocytes prolongs survival mice, but immune aggregates persist, indicating cells can independently be recruited VM produced IFNγ, IFNγR deficiency prolonged mice; however, T-cell-dependent recruitment infiltrating myeloid to was IFNγ independent. Lethally irradiated recipients fully reconstituted wild type bone-marrow-derived still developed ILD, pointing a critical role for VM-expressing radioresistant parenchymal and/or stromal activation pathogenic lymphocytes. We identified endothelial express STING. Transcriptional analysis revealed up-regulation chemokines, proinflammatory cytokines, genes associated antigen presentation. Together, our data show play key initiation mice provide insights treatment patients, implications ILD other connective disorders.

Language: Английский

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Type-1 interferon-dependent and -independent mechanisms in cyclic GMP–AMP synthase–stimulator of interferon genes-driven auto-inflammation

Current Opinion in Immunology, Journal Year: 2023, Volume and Issue: 80, P. 102280 - 102280

Published: Jan. 11, 2023

Language: Английский

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Inhibition of palmitoyltransferase ZDHHC12 sensitizes ovarian cancer cells to cisplatin through ROS‐mediated mechanisms

Cancer Science, Journal Year: 2024, Volume and Issue: 115(4), P. 1170 - 1183

Published: Jan. 29, 2024

Abstract Platinum‐based therapies have revolutionized the treatment of high‐grade serous ovarian cancer (HGSOC). However, high rates disease recurrence and progression remain a major clinical concern. Impaired mitochondrial function dysregulated reactive oxygen species (ROS), hallmarks cancer, hold potential as therapeutic targets for selectively sensitizing cisplatin treatment. Here, we uncover an oncogenic role palmitoyltransferase ZDHHC12 in regulating ROS homeostasis HGSOC cells. Analysis The Cancer Genome Atlas (TCGA) data revealed significantly elevated expression, demonstrating strongest positive association with pathways among all ZDHHC enzymes. Transcriptomic analysis independent datasets SNU119 cell model corroborated this association, highlighting strong link between expression signature involving oxidative metabolism regulation. Knockdown disrupted leading to increased cellular complexity, ATP levels, activity, both ROS. This dysregulation, achieved by siRNA knockdown or general palmitoylation inhibitor 2BP fatty acid synthase C75, enhanced cytotoxicity 2D 3D spheroid models through ROS‐mediated mechanisms. Markedly, inhibition augmented anti‐tumor activity xenograft tumor model, well ascites‐derived organoid line platinum‐resistant cancer. Our suggest promising target improve outcome HGSOCs response platinum‐based chemotherapy.

Language: Английский

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Targeting the glutamine-arginine-proline metabolism axis in cancer

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 39(1)

Published: July 25, 2024

Metabolic abnormalities are an important feature of tumours. The glutamine-arginine-proline axis is node cancer metabolism and plays a major role in amino acid metabolism. This also acts as scaffold for the synthesis other nonessential acids essential metabolites. In this paper, we briefly review (1) glutamine addiction exhibited by tumour cells with accelerated transport metabolism; (2) methods regulating extracellular entry, intracellular fate glutamine; (3) glutamine, proline arginine metabolic pathways their interaction; (4) research progress therapy targeting system, focus on summarising therapeutic strategies one key enzymes P5CS (ALDH18A1). provides new basis treatments characteristics

Language: Английский

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Catalase expression is an independent prognostic marker in liver hepatocellular carcinoma

ONCOLOGIE, Journal Year: 2024, Volume and Issue: 26(1), P. 79 - 90

Published: Jan. 1, 2024

Abstract Objectives Liver hepatocellular carcinoma (LIHC) is the most common type of primary liver cancer and originates from hepatocytes, main functional cells liver. It a serious aggressive with generally poor prognosis, especially when diagnosed at advanced stages. Reactive oxygen species (ROS) have been detected in LIHC are involved carcinogenesis tumor progression. Here, comprehensive analysis was performed to evaluate effects ROS-related genes on prognosis LIHC. Methods Using bioinformatical tools including Gene Expression Profiling Interactive Analysis (GEPIA2) Q-omics, genes, superoxide dismutases (SODs), glutathione peroxidases (GPXs), peroxiredoxins (PRDXs) catalase (CAT) using The Cancer Genome Atlas (TCGA) dataset identified appropriate candidate genes. Then we further explored their cell proliferation drug selection for treatment. Results We found that CAT expression significantly downregulated late stage’s tissues compared normal or early tissues, high correlated favorable survival gene associated an inhibition “cell cycle” pathway. HepG2 Hep3B cells’ growth increased decrease by silencing its mRNA. As cells, association increase PLK1, CCNB1, CDC20, PTTG1. A comparative 426 response different expression, SU11274, Met inhibitor, could serve as therapeutic option levels low cells. Conclusions Our findings revealed inhibitors potentially control progression be used against CAT.

Language: Английский

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Genome-wide association study of hospitalized COVID-19 patients in the United Arab Emirates

EBioMedicine, Journal Year: 2021, Volume and Issue: 74, P. 103695 - 103695

Published: Nov. 11, 2021

The heterogeneity in symptomatology and phenotypic profile attributable to COVID-19 is widely unknown. objective of this manuscript conduct a trans-ancestry genome wide association study (GWAS) meta-analysis severity improve the understanding potentially causal targets for SARS-CoV-2.This cross-sectional recruited 646 participants UAE that were divided into two groups based on phenotypes, hospitalized (n=482) non-hospitalized (n=164) participants. Hospitalized patients developed acute respiratory distress syndrome (ARDS), pneumonia or progression failure required supplemental oxygen therapy mechanical ventilation support had severe complications such as septic shock multi-organ failure. We conducted GWAS European (n=302), American (n=102), South Asian (n=99), East (n=107) ancestry populations. also carried out comprehensive post-GWAS analysis, including enrichment SNP associations tissues cell-types, expression quantitative trait loci differential analysis.Eight genes demonstrated strong signal: VWA8 gene locus 13p14·11 (SNP rs10507497; p=9·54 x10-7), PDE8B 5q13·3 rs7715119; p=2·19 x10-6), CTSC 11q14·2 (rs72953026; p=2·38 THSD7B 2q22·1 (rs7605851; p=3·07x10-6), STK39 2q24·3 (rs7595310; p=4·55 FBXO34 14q22·3 (rs10140801; p=8·26 RPL6P27 18p11·31 (rs11659676; p=8·88 METTL21C 13q33·1 (rs599976; p=8·95 x10-6). are expressed lung, associated tumour progression, emphysema, airway obstruction, surface tension within well an T-cell-mediated inflammation production inflammatory cytokines.We have discovered eight highly plausible genetic with cases COVID-19. Further studies must be worldwide population genetics facilitate development specific therapeutics mitigate challenge.This review was commissioned part project host cell receptors coronaviruses funded by Khalifa University's CPRA grant (Reference number 2020-004).

Language: Английский

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Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma

OncoImmunology, Journal Year: 2022, Volume and Issue: 11(1)

Published: Jan. 3, 2022

Fibroblast growth factor receptor 1 (FGFR1) is overexpressed in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Being associated with poor prognosis, FGFR1 a potential therapeutic target for aggressive tumors. T cell-based cancer immunotherapy has played central role novel treatments. However, the antitumor targeting not been investigated. Here, we showed that FGFR-tyrosine kinase inhibitors (TKIs) augmented effects immune checkpoint an HNSCC mouse model upregulated tumoral MHC class I II expression vivo vitro. This upregulation was mitogen-activated protein signaling pathway, which crucial pathway development through FGFR signaling. Moreover, identified FGFR1-derived peptide epitope (FGFR1305-319) could elicit antigen-reactive HLA-restricted CD4+ responses. These cells direct cytotoxicity against tumor expressed FGFR1. Notably, FGFR-TKIs FGFR1-reactive human cells. results indicate combination immunotherapy, such as FGFR1-targeting vaccine or inhibitor, be robust immunologic approach treating patients FGFR1-expressing

Language: Английский

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Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Feb. 14, 2022

This study aimed to identify the mechanism of Yiqi Huayu Decoction (YQHY) induced ferroptosis in gastric cancer (GC) by using network pharmacology and experimental validation.The targets YQHY, ferroptosis-related targets, related GC were derived from databases. Following protein-protein interaction (PPI) network, hub for YQHY identified. Furthermore, gene ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) enrichment used analyze a macro perspective. We verified molecular docking, GEPIA, HPA, cBioPortal database. Finally, we performed cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, lipid peroxidation, GSH assays explore GC.We identified main active compounds targets: Quercetin, DIBP, DBP, Mipax, Phaseol TP53, ATM, SMAD4, PTGS2, ACSL4. KEGG analyses indicated that JAK2-STAT3 signaling pathway may be significant pathway. Molecular docking results showed had good binding activity with targets. The proved could induce AGS increasing MDA content reducing content. qRT-PCR Western blot can affecting expression ACSL4.This ACSL4, induction one possible mechanisms YQHY's anti-recurrence metastasis GC.

Language: Английский

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Self-supervised learning for characterising histomorphological diversity and spatial RNA expression prediction across 23 human tissue types

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 13, 2024

Abstract As vast histological archives are digitised, there is a pressing need to be able associate specific tissue substructures and incident pathology disease outcomes without arduous annotation. Here, we learn self-supervised representations using Vision Transformer, trained on 1.7 M histology images across 23 healthy tissues in 838 donors from the Genotype Tissue Expression consortium (GTEx). Using these representations, can automatically segment into their constituent proportions thousands of whole slide images, outperforming other methods (43% increase silhouette score). Additionally, detect quantify pathologies present, such as arterial calcification (AUROC = 0.93) identify missing diagnoses. Finally, link gene expression morphology, introduce RNAPath, set models types that predict spatially localise individual RNA levels directly H&E (mean genes significantly regressed 5156, FDR 1%). We validate RNAPath spatial predictions with matched ground truth immunohistochemistry for several well characterised control genes, recapitulating known specificity. Together, results demonstrate how machine learning when applied allows researchers answer questions about pathology, its organisation interplay between morphological variability expression.

Language: Английский

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The transcriptional regulation of normal and malignant blood cell development

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(5), P. 1240 - 1255

Published: Jan. 29, 2021

Development of multicellular organisms requires the differential usage our genetic information to change one cell fate into another. This process drives appearance different types that come together form specialized tissues sustaining a healthy organism. In last decade, by moving away from studying single genes toward global view gene expression control, revolution has taken place in understanding how work and cells communicate translate encoded genome body plan. The development hematopoietic long served as paradigm general. this review, we highlight transcription factors chromatin components shape regulatory networks controlling system drive blood differentiation. addition, outline goes astray cancers. We also touch upon emerging concepts these processes firmly their associated subnuclear structures adding another layer control expression.

Language: Английский

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