MAT2a and AHCY Inhibition Disrupts Antioxidant Metabolism and Reduces Glioblastoma Cell Survival DOI Creative Commons
Emma Rowland, Matthew D’Antuono,

Anna Jermakowicz

et al.

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

Published: Nov. 24, 2024

Abstract Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with fatal prognosis. This due in part to metabolic reprogramming allows tumors evade treatment. We therefore must uncover the pathways mediating these adaptations develop novel and effective treatments. searched for genes are essential GBM cells as measured by whole-genome pan-cancer CRISPR screen available from DepMap identified methionine metabolism MAT2A AHCY . conducted genetic knockdown, evaluated mitochondrial respiration, performed targeted metabolomics study function of GBM. demonstrate or knockdown induces oxidative stress, hinders cellular reduces survival cells. Furthermore, selective MAT2a inhibition cell viability, impairs metabolism, changes profile towards stress death. Mechanistically, regulates spare respiratory capacity, redox buffer cystathionine, lipid amino acid prevents DNA damage Our results point pathway vulnerability Significance demonstrated maintains antioxidant production facilitate pro-tumorigenic ROS signaling survival. Importantly, targeting this can potentially reduce growth improve patients.

Language: Английский

Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival DOI Creative Commons

Elizabeth A. Rowland,

Matthew D’Antuono,

Anna Jermakowicz

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108349 - 108349

Published: Feb. 1, 2025

Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with fatal prognosis. This due in part to metabolic reprogramming allows tumors evade treatment. Therefore, we must uncover the pathways mediating these adaptations develop novel and effective treatments. We searched for genes are essential GBM cells as measured by whole-genome pan-cancer CRISPR screen available from DepMap identified methionine metabolism MAT2A AHCY. conducted genetic knockdown, evaluated mitochondrial respiration, performed targeted metabolomics study function of GBM. demonstrate or AHCY knockdown induces oxidative stress, hinders cellular reduces survival cells. Furthermore, selective MAT2a inhibition cell viability, impairs metabolism, shifts profile towards stress death. Mechanistically, regulate spare respiratory capacity, redox buffer cystathionine, lipid amino acid prevent damage Our results point pathway vulnerability Significance demonstrated maintains antioxidant production facilitate pro-tumorigenic ROS signaling survival. Importantly, targeting this has potential reduce growth improve patients.

Language: Английский

Citations

0
The dual role of microglia in Alzheimer’s disease: from immune regulation to pathological progression DOI Creative Commons
Cong He, Baojiang Chen,

Hecai Yang

et al.

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 27, 2025

Alzheimer’s disease (AD) is a widespread neurodegenerative disorder and one of the major challenges for public health. Despite extensive research, role microglia in AD remains complex dual. The aim this review to summarize most recent advances research regarding dual concerning both immunomodulation pathological progression by considering mechanisms activation microglia, effects on Aβ clearance, tau pathology, impacts due genetic variations microglial functions. Among these findings are status M1 M2 phenotypes, crucial that variants like TREM2 have modulating response microglia. This describes how modulation signaling pathway might be exploited therapeutically treatment underlines relevance personalized medicine approach.

Language: Английский

Citations

0
Regional molecular changes in chronic Lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Leandrie Pienaar,

Adalayne Ramsamy,

Aletta ME. Millen

et al.

Biological Psychiatry Global Open Science, Journal Year: 2025, Volume and Issue: unknown, P. 100515 - 100515

Published: April 1, 2025

Language: Английский

Citations

0
Pericytes mediate neuroinflammation via Fli-1 in endotoxemia and sepsis in mice DOI Creative Commons
Pengfei Li, Liu Liu,

P. V. Halushka

et al.

Inflammation Research, Journal Year: 2025, Volume and Issue: 74(1)

Published: Jan. 25, 2025

Abstract Background Sepsis-associated encephalopathy (SAE) often results from neuroinflammation. Recent studies have shown that brain platelet-derived growth factor receptor β (PDGFRβ) cells, including pericytes, may act as early sensors of infection by secreting monocyte chemoattractant protein-1 (MCP-1), which transmits inflammatory signals to the central nervous system. The erythroblast transformation-specific (ETS) transcription Friend leukemia virus integration 1 (Fli-1) plays a critical role in inflammation regulating expression key cytokines, MCP-1. However, pericyte Fli-1 neuroinflammation during sepsis remains largely unknown. Methods WT and pericyte-specific knockout mice were subjected endotoxemia through LPS injection or via cecal ligation puncture (CLP). In vitro, was knocked down using small interfering RNA cultured mouse followed stimulation. Results Elevated levels observed isolated pericytes 2 h after administration, tissues 4 CLP, stimulation vitro. endotoxemic mice, reduced MCP-1 IL-6 tissue injection. At 24 post-LPS protein IL-6, microglia activation suppressed pericyte- mice. Additionally, deficiency significantly mRNA CLP. Moreover, knockdown markedly decreased Notably, increased TLR4-Myd88 signaling, subsequently led elevated production pericytes. Conclusions serve crucial mediator directly pivotal cytokines such IL-6. Therefore, has potential therapeutic target SAE other neuroinflammatory disorders.

Language: Английский

Citations

0
MAT2a and AHCY Inhibition Disrupts Antioxidant Metabolism and Reduces Glioblastoma Cell Survival DOI Creative Commons
Emma Rowland, Matthew D’Antuono,

Anna Jermakowicz

et al.

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

Published: Nov. 24, 2024

Abstract Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with fatal prognosis. This due in part to metabolic reprogramming allows tumors evade treatment. We therefore must uncover the pathways mediating these adaptations develop novel and effective treatments. searched for genes are essential GBM cells as measured by whole-genome pan-cancer CRISPR screen available from DepMap identified methionine metabolism MAT2A AHCY . conducted genetic knockdown, evaluated mitochondrial respiration, performed targeted metabolomics study function of GBM. demonstrate or knockdown induces oxidative stress, hinders cellular reduces survival cells. Furthermore, selective MAT2a inhibition cell viability, impairs metabolism, changes profile towards stress death. Mechanistically, regulates spare respiratory capacity, redox buffer cystathionine, lipid amino acid prevents DNA damage Our results point pathway vulnerability Significance demonstrated maintains antioxidant production facilitate pro-tumorigenic ROS signaling survival. Importantly, targeting this can potentially reduce growth improve patients.

Language: Английский

Citations

0