25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 19, 2024

Abstract Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation response to different inflammatory stimuli overexpress a proinflammatory signature genes. Among these, Ch25h is gene overexpressed brain tissue from Alzheimer’s disease as well various mouse models neuroinflammation. encodes cholesterol 25-hydroxylase, an enzyme upregulated activated microglia under conditions neuroinflammation, hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant for leukocytes. We have previously shown that increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (CKO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. WT females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among CKO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1b IL-6 strongly correlated levels. Our results suggest role following peripheral administration

Язык: Английский

Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity DOI Creative Commons

Liming Gui,

Kaiwen W. Chen, Jingjing Yan

и другие.

Cell Reports Medicine, Год журнала: 2025, Номер unknown, С. 101913 - 101913

Опубликована: Янв. 1, 2025

The induction of immunogenic cell death (ICD) impedes tumor progression via both cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as potential target. ICD-provoking effect NUAK1 inhibition depends on the production reactive oxygen species (ROS), consequent downregulation nuclear factor erythroid 2-related 2 (NRF2)-mediated antioxidant gene expression. Moreover, mevalonate pathway/cholesterol biosynthesis, activated by spliced form X-box binding protein (XBP1s) downstream ICD-induced endoplasmic reticulum (ER) stress, functions negative feedback mechanism. Targeting pathway with CRISPR knockout or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies inhibition-mediated ICD antitumor activity, while cholesterol dampens ROS ICD, therefore also suppression. combination statin enhances efficacy anti-PD-1 therapy. Collectively, our study unveils promise blocking mevalonate-cholesterol in conjunction immunotherapy.

Язык: Английский

Процитировано

2
25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

и другие.

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Окт. 5, 2024

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation and, response to different inflammatory stimuli, overexpress a proinflammatory signature genes. Among these, Ch25h is gene overexpressed brain tissue from Alzheimer's disease as well various mouse models neuroinflammation. encodes cholesterol 25-hydroxylase, an enzyme upregulated activated microglia under conditions neuroinflammation, that hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant leukocytes. We have previously shown increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (KO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among KO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1β IL-6 strongly correlated levels. Our results suggest role for following peripheral administration

Язык: Английский

Процитировано

3
A combination of dietary cholesterol and cholic acid induces hepatic expression of proinflammatory genes accompanied by changes in sterol metabolism and redox status DOI
W. Iwasaki,

H. Soma,

Hiromichi Yamazaki

и другие.

Drug Metabolism and Disposition, Год журнала: 2025, Номер unknown, С. 100095 - 100095

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 19, 2024

Abstract Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation response to different inflammatory stimuli overexpress a proinflammatory signature genes. Among these, Ch25h is gene overexpressed brain tissue from Alzheimer’s disease as well various mouse models neuroinflammation. encodes cholesterol 25-hydroxylase, an enzyme upregulated activated microglia under conditions neuroinflammation, hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant for leukocytes. We have previously shown that increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (CKO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. WT females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among CKO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1b IL-6 strongly correlated levels. Our results suggest role following peripheral administration

Язык: Английский

Процитировано

0