GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas DOI Open Access
Georgios Batsios, Suresh Udutha,

Céline Taglang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 10, 2024

Abstract Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children. The imipridones ONC201 and ONC206 induce mitochondrial dysfunction have emerged as promising therapies for DMG patients. However, efficacy monotherapy is limited, identifying a need strategies that enhance response. Another hurdle the lack of biomarkers report on drug-target engagement at an early timepoint after treatment onset. Here, using 1 H-magnetic resonance spectroscopy, which non-invasive method quantifying metabolite pool sizes, we show accumulation ψ-aminobutyric acid (GABA) metabolic biomarker can be detected within week treatment, when anatomical alterations absent, mice bearing orthotopic xenografts. Mechanistically, activate protease ClpP upregulate stress-responsive transcription factor ATF4. ATF4, turn, upregulates glutamate decarboxylase, synthesizes GABA, downregulates ABAT , degrades leading to GABA cells tumors. Functionally, secreted by imipridone-treated acts autocrine manner via GABAB receptor expression superoxide dismutase (SOD1), mitigates imipridone-induced oxidative stress and, thereby, curbs apoptosis. Importantly, blocking signaling clinical stage antagonist SGS-742 exacerbates synergistically induces apoptosis combination with tumor Collectively, identify unique adaptation leveraged assessment therapy. Clinical translation our studies has potential enable precision therapy imaging One Sentence Summary Imipridones diffuse gliomas, effect imaging.

Язык: Английский

Multiple Hits on Cerebral Folate, Tetrahydrobiopterin and Dopamine Metabolism in the Pathophysiology of Parkinson’s Disorder: A Limited Study of Post-Mortem Human Brain Tissues DOI Creative Commons

Dhruti Balakrishna Doddaballapur,

Derren J. Heyes, Jaleel A. Miyan

и другие.

Metabolites, Год журнала: 2025, Номер 15(5), С. 307 - 307

Опубликована: Май 5, 2025

Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there an urgent need to investigate upstream metabolic disruptions, including tetrahydrobiopterin (BH4) pathways, in post-mortem CSF brain tissue understand their roles PD pathogenesis. Methods: from 20 patients (mean age 84 years; 55% male; disease duration 10–30 years) controls 82 50% male) were analysed. Western Dot Blots measured proteins metabolites, spectroscopic assays assessed enzyme activities, BH4 Neopterin levels using ELISA, hydrogen peroxide, used as a proxy for reactive oxygen species, calcium quantified horseradish peroxidase flame photometry assays, respectively. ClinVar genetic data analysed variants genes encoding key enzymes. Statistical significance was unpaired t-tests (p < 0.05). Results: All enzymes significantly reduced compared 0.01) except methyltetrahydrofolate reductase (MTHFR), which elevated 0.0001). Enzymes functional control but undetectable tyrosine hydroxylase (TH). 0.0001, p 0.001) or unchanged tissue. Peroxide increased both 0.0001) selectively inhibiting TH. Calcium 40% higher than No pathogenic found searches, suggesting the observed deficiencies are physiological. Conclusions: We identified significant disruptions pathways PD, deficiencies, oxidative stress dysregulation pointing choroid plexus dysfunction. findings highlight players cerebral metabolism promote further exploration these therapeutic targets address dopaminergic dysfunction ventricular enlargement PD.

Язык: Английский

Процитировано

0
Epigallocatechin gallate with nobiletin as a novel combination therapy to induce autophagy and apoptosis in oral cancer DOI
Shuangli Zhu, Byung‐Gook Kim, Ok‐Su Kim

и другие.

Toxicology and Applied Pharmacology, Год журнала: 2025, Номер 500, С. 117380 - 117380

Опубликована: Май 9, 2025

Язык: Английский

Процитировано

0
Porcine reproductive and respiratory syndrome virus nsp2-related proteins induce host translational arrest by specifically impairing the mTOR signaling cascade DOI
Xue Jiao, Xuan Chen, Quanzhi Li

и другие.

Veterinary Microbiology, Год журнала: 2025, Номер 306, С. 110562 - 110562

Опубликована: Май 13, 2025

Язык: Английский

Процитировано

0
Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma DOI
Yuling Chi,

Shireen Chikara,

Eduardo Mere Del Aguila

и другие.

Neoplasia, Год журнала: 2025, Номер 66, С. 101188 - 101188

Опубликована: Июнь 4, 2025

Язык: Английский

Процитировано

0
eIF4E integrates into stress response DOI

Xincheng Wu,

Shu-Bing Qian

Molecular Cell, Год журнала: 2024, Номер 84(11), С. 2009 - 2010

Опубликована: Июнь 1, 2024

Язык: Английский

Процитировано

1
Prkra is the double-stranded RNA sensor to mediate an embryonic integrated stress response DOI Creative Commons
Lu Tong, Pengcheng Ma, Aijun Chen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 17, 2024

Abstract Double-stranded RNAs (dsRNAs), known as conserved pathogen-associated molecular patterns, are recognized by interferon-induced protein kinase R (PKR) to trigger an integrated stress response, characterized the inhibition of global translation. However, interferon system is inactive in pluripotent cells, thus mechanism underlying dsRNA sensing and translational control unclear. In this study, we utilized early zebrafish embryos a model cells discovered PKR-independent blockage translation initiation induced stimulation. Prkra dimer was identified genuine sensor. Upon binding dsRNAs, dimerized domain 3 becomes activated sequester eIF2 complexes from machinery, leading hindrance synthesis. This distinctive embryonic response restricts RNA virus SVCV replication but also mouse stem cells. Therefore, Prkra-mediated blocking potentially represents common strategy for reestablishing physiological homeostasis environmental stresses.

Язык: Английский

Процитировано

1
DKC1-mediated pseudouridylation of rRNA targets hnRNP A1 to sustain IRES-dependent translation and ATF4-driven metabolic adaptation DOI Open Access

Anamika Gupta,

Mohit Bansal, Jane Ding

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract The pseudouridine synthase DKC1 regulates internal ribosome entry site (IRES)-dependent translation and is upregulated in cancers by the MYC family of oncogenic transcription factors. We investigated functional significance MYCN-amplified neuroblastoma its underlying mechanisms. A key function to promote an ATF4-mediated gene expression program for amino acid metabolism stress adaptation. identified hnRNP A1, IRES trans-acting factor, as a critical downstream mediator sustaining ATF4 IRES-dependent translation. found that DKC1-mediated pseudouridylation at two specific 28S rRNA sites essential maintaining A1 protein expression. Moreover, interacts with stabilizes mRNA, significantly increasing V1 variant, which contains element mRNA. Additionally, we cellular induces required induction under such conditions. Collectively, our study reveals MYC-activated DKC1-hnRNP axis drives metabolic adaptation, supporting cancer cell survival during development.

Язык: Английский

Процитировано

1
Trading in catalytic power for sensing DOI
Zhoufei Hei, Jing Wang, Pengfei Fang

и другие.

Structure, Год журнала: 2024, Номер 32(6), С. 647 - 649

Опубликована: Июнь 1, 2024

Язык: Английский

Процитировано

0
GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas DOI Open Access
Georgios Batsios, Suresh Udutha,

Céline Taglang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 10, 2024

Abstract Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children. The imipridones ONC201 and ONC206 induce mitochondrial dysfunction have emerged as promising therapies for DMG patients. However, efficacy monotherapy is limited, identifying a need strategies that enhance response. Another hurdle the lack of biomarkers report on drug-target engagement at an early timepoint after treatment onset. Here, using 1 H-magnetic resonance spectroscopy, which non-invasive method quantifying metabolite pool sizes, we show accumulation ψ-aminobutyric acid (GABA) metabolic biomarker can be detected within week treatment, when anatomical alterations absent, mice bearing orthotopic xenografts. Mechanistically, activate protease ClpP upregulate stress-responsive transcription factor ATF4. ATF4, turn, upregulates glutamate decarboxylase, synthesizes GABA, downregulates ABAT , degrades leading to GABA cells tumors. Functionally, secreted by imipridone-treated acts autocrine manner via GABAB receptor expression superoxide dismutase (SOD1), mitigates imipridone-induced oxidative stress and, thereby, curbs apoptosis. Importantly, blocking signaling clinical stage antagonist SGS-742 exacerbates synergistically induces apoptosis combination with tumor Collectively, identify unique adaptation leveraged assessment therapy. Clinical translation our studies has potential enable precision therapy imaging One Sentence Summary Imipridones diffuse gliomas, effect imaging.

Язык: Английский

Процитировано

0