Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Tzou, Fei-Yang; Su, Tsu-Yi; Lin, Wan-Syuan; Kuo, Han-Chun; Yu, Yu‐Lian; Yeh, Yu-Han; Liu, Chung‐Chih; Kuo, Ching‐Hua; Huang, Shu‐Yi; Chan, Chih‐Chiang

doi:10.1016/j.celrep.2021.108972

Cited by 16 publications

(6 citation statements)

References 51 publications

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“…Studies in different cell lines have shown that the stimulation of oxidative stress by H 2 O 2 leads to dhCer accumulation, indicating inhibition of DEGS that is directly related to oxidative stress ( Idkowiak-Baldys et al, 2010 ). Furthermore, DEGS mutation ( DEGS1 H132R ) resulting in gene inactivation provokes mislocalization of Rac1 to the endolysosomes, where it forms the NOX complex with NADPH-oxidase, promoting cytosolic ROS generation ( Tzou et al, 2021 ). In addition, hypoxic conditions lead to apoptosis-mediated dhCer accumulation due to an inhibition of DEGS.…”

Section: Stroke and Ceramide Metabolismmentioning

confidence: 99%

Involvement of Ceramide Metabolism in Cerebral Ischemia

Ouro

Correa-Paz²,

Maqueda³

et al. 2022

Front. Mol. Biosci.

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Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in worldwide. Although reperfusion therapies have shown efficacy in a limited number of patients with acute ischemic stroke, neuroprotective drugs and recovery strategies have been widely assessed, but none of them have been successful in clinical practice. Therefore, the search for new therapeutic approaches is still necessary. Sphingolipids consist of a family of lipidic molecules with both structural and cell signaling functions. Regulation of sphingolipid metabolism is crucial for cell fate and homeostasis in the body. Different works have emphasized the implication of its metabolism in different pathologies, such as diabetes, cancer, neurodegeneration, or atherosclerosis. Other studies have shown its implication in the risk of suffering a stroke and its progression. This review will highlight the implications of sphingolipid metabolism enzymes in acute ischemic stroke.

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Section: Stroke and Ceramide Metabolismmentioning

confidence: 99%

Involvement of Ceramide Metabolism in Cerebral Ischemia

Ouro

Correa-Paz²,

Maqueda³

et al. 2022

Front. Mol. Biosci.

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“…Since cysteine residues can form disulfide bonds in response to oxidative stress ( 30 ), we wondered whether C291 and C322 are involved in the effects of oxidative stress on tau metabolism. To test the effect of antioxidant, 4Rtau wt or 4Rtau C291/322A was co-expressed with UAS-SOD1 ( 31 , 32 ). We found that co-expression of SOD1 reduced the abundance of 4Rtau wt protein by more than 40% ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo

Saito

Chiku

Oka

et al. 2021

Human Molecular Genetics

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Accumulation of microtubule-associated tau protein is thought to cause neuron loss in a group of neurodegenerative diseases called tauopathies. In diseased brains, tau molecules adopt pathological structures that propagate into insoluble forms with disease-specific patterns. Several types of posttranslational modifications in tau are known to modulate its aggregation propensity in vitro, but their influence on tau accumulation and toxicity at the whole-organism level has not been fully elucidated. Herein, we utilized a series of transgenic Drosophila models to compare systematically the toxicity induced by five tau constructs with mutations or deletions associated with aggregation, including substitutions at seven disease-associated phosphorylation sites (S7A and S7E), deletions of PHF6 and PHF6* sequences (ΔPHF6 and ΔPHF6*), and substitutions of cysteine residues in the microtubule binding repeats (C291/322A). We found that substitutions and deletions resulted in different patterns of neurodegeneration and accumulation, with C291/322A having a dramatic effect on both tau accumulation and neurodegeneration. These cysteines formed disulfide bonds in mouse primary cultured neurons and in the fly retina, and stabilized tau proteins. Additionally, they contributed to tau accumulation under oxidative stress. We also found that each of these cysteine residues contributes to the microtubule polymerization rate and microtubule levels at equilibrium, but none of them affected tau binding to polymerized microtubules. Since tau proteins expressed in the Drosophila retina are mostly present in the early stages of tau filaments self-assembly, our results suggest that disulfide bond formation by these cysteine residues could be attractive therapeutic targets.

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“…Moreover, sphingolipids and their metabolites are a class of very important active molecules that are involved in many important signal transduction processes, such as the regulation of inflammation, oxidative stress, cell growth and programmed cell death 32,33 . Degs1 is a key gene encoding enzyme in the sphingolipid metabolism pathway that can regulate sphingolipid homeostasis 34 . Inhibition of Degs1 expression is hypothesized to benefit hepatic steatosis, which may provide a means of treating hepatic steatosis and metabolic disorders 35 .…”

Section: Discussionmentioning

confidence: 99%

“…32,33 Degs1 is a key gene encoding enzyme in the sphingolipid metabolism pathway that can regulate sphingolipid homeostasis. 34 Inhibition of Degs1 expression is hypothesized to benefit hepatic steatosis, which may provide a means of treating hepatic steatosis and metabolic disorders. 35 However, no studies have reported on the specific role of Degs1 in liver injury.…”

Section: Discussionmentioning

confidence: 99%

Asiatic acid ameliorates rifampicin‐ and isoniazid‐induced liver injury in vivo by regulating sphingolipid metabolism and mitogen‐activated protein kinase signalling pathways

Zhu

Wei

et al. 2023

Basic Clin Pharma Tox

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In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)‐ and isoniazid (INH)‐induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen‐activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4‐desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH‐induced liver injury.

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Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Cited by 16 publications

References 51 publications

Involvement of Ceramide Metabolism in Cerebral Ischemia

Involvement of Ceramide Metabolism in Cerebral Ischemia

Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo

Asiatic acid ameliorates rifampicin‐ and isoniazid‐induced liver injury in vivo by regulating sphingolipid metabolism and mitogen‐activated protein kinase signalling pathways

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