Spermine oxidase promotes Helicobacter pylori-mediated gastric carcinogenesis through acrolein production
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PROVIDER: PRJNA1108754 | ENA |
REPOSITORIES: ENA
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Project description:Helicobacter pylori is the primary cause of gastric cancer and there is a need to discover new molecular targets for therapeutic intervention in H. pylori disease progression. We have previously shown that spermine oxidase (SMOX), the enzyme that catabolizes the back-conversion of the polyamine spermine to spermidine, is upregulated during infection and is associated with increased cancer risk in humans. We sought to determine the direct role of SMOX in gastric carcinogenesis during H. pylori infection. In this study, we demonstrate that transgenic FVB/N insulin-gastrin (INS-GAS) mice that develop gastric carcinoma with H. pylori infection were protected from cancer development with Smox deletion. RNA sequencing revealed that genes associated with the immune system and cancer were downregulated in the infected Smox–/– mice. Furthermore, there was a decrease in cell proliferation and DNA damage in infected Smox–/– animals. There was significant generation of adducts of the highly reactive electrophile acrolein, a byproduct of SMOX activity, in tissues from H. pylori-infected WT mice and humans. Genetic deletion of Smox or chemical inhibition of SMOX in murine organoids and human gastric epithelial cells and organoids, respectively, significantly reduced generation of acrolein induced by H. pylori. Furthermore, acrolein induced DNA damage in gastric epithelial cells, which was ablated with the electrophile scavenger 2-hydroxybenzylamine (2-HOBA). Infected 2-HOBA treated INS-GAS WT mice with reduced gastric carcinoma had attenuated gastric acrolein adduct formation. These findings implicate SMOX and acrolein in H. pylori-induced carcinogenesis in gastric epithelial cells, thus indicating potential therapeutic targets.
2025-02-05 | GSE266944 | GEO
Project description:For additional details see Bongers et al, Spermine Oxidase Maintains Basal Skeletal Muscle Gene Expression and Fiber Size, and Is Strongly Repressed by Conditions that Cause Skeletal Muscle Atrophy . Am J Physiol Endocrinol Metab. 2014 [under review] Bilateral tibialis anterior muscles of C57BL/6 mice were harvested seven days after transfection with spermine oxidase or control plasmid.
2014-12-04 | E-GEOD-63006 | biostudies-arrayexpress
Project description:For additional details see Bongers et al, Spermine Oxidase Maintains Basal Skeletal Muscle Gene Expression and Fiber Size, and Is Strongly Repressed by Conditions that Cause Skeletal Muscle Atrophy . Am J Physiol Endocrinol Metab. 2014 [under review]
2014-12-04 | GSE63006 | GEO
Project description:Spermine oxidase (SMOX) catalyzes oxidation of spermine to generate spermidine, hydrogen peroxide (H2O2) and 3-aminopropanal, which is spontaneously converted to acrolein. SMOX is induced by a variety of stimuli including bacterial infection, polyamine analogues and acetaldehyde exposure. However, the physiological functions of SMOX are not yet fully understood. We investigated the physiological role of SMOX in liver cells using human hepatocellular carcinoma cell line HepG2. SMOX localized to the bile canalicular lumen, as determined by F-actin staining. Knockdown of SMOX reduced the formation of bile canalicular lumen. We also found that phospho-Akt (phosphorylated protein kinase B) was localized to canalicular lumen. Treatment with Akt inhibitor significantly reduced the formation of bile canalicular lumen. Acrolein scavenger also inhibited the formation of bile canalicular lumen. PTEN, phosphatase and tensin homolog and an inhibitor of Akt, was alkylated in a SMOX-dependent manner. Our results suggest that SMOX plays a central role in the formation of bile canalicular lumen in liver cells by activating Akt pathway through acrolein production.
| S-EPMC5665972 | biostudies-literature
Project description:Acrolein is a major reactive component of vehicle exhaust, cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high throughput technology, we have thus characterized the effects of acrolein exposure on miRNA expression in human umbilical vein endothelial cells (HUVEC).
2014-06-03 | GSE56782 | GEO
Project description:Acrolein is a major reactive component of vehicle exhaust, cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high throughput technology, we have thus characterized the effects of acrolein exposure on miRNA expression in human umbilical vein endothelial cells (HUVEC). 2 condition, acrolein-exposed and vehicle exposed; 4 replicates of each
2014-06-03 | E-GEOD-56782 | biostudies-arrayexpress
Project description:Acute acrolein inhalation in male rats resulted in multi-tissue transcriptomic alterations that were observed through Illumina mRNA sequencing. Specifically, site-specific respiratory expression profile differences were noted between air- and acrolein-exposed groups. Nasal epithelial tissue demonstrated 452 differentially expressed genes (DEGs) (310 up-regulated and 142 down-regulated)and lung tissue demonstrated 95 DEGs (80 up-regulated and 15 down-regulated). Notable transcriptomic alterations were also observed in liver tissue of acrolein-exposed rats, with 1699 identified DEGs (788 up-regulated and 911 down-regulated). A variety of mRNA expression profile differences resulting from acute acrolein inhalation was observed in other peripheral tissues, including adipose, muscle, adrenals, hippocamus, and hypothalamus. Gene changes were largely representative of oxidative and inflammatory response in the nose, as well as xenobiotic metabolism changes in the lung. Liver changes, which were most numerous, included alterated metabolic signaling (Sirtuin and FXR signaling), as well as alterated oxidoreductive, GPCR, and glucocorticoid pathways. Together, these data demonstrate acrolein, a well-characterized respiratory irritant, induces systemic neuroendocrine immunological and metabolic stress.
2023-11-16 | GSE247698 | GEO
Project description:Our previous experiments showed the function of Akr1a1a was related to insulin resistance. The knockout of Akr1a1a led to poor acrolein detoxification and accumulated acrolein inhibits insulin receptors (insra/insrb) expression. To understand how the loss of Akr1a1a and acrolein reflects at the transcriptome level, we performed full genome RNA-Seq between akr1a1a+/+, akr1a1a-/- and akr1a1a+/+ with acrolein treatment zebrafish larvae at 120 hpf. An overview of RNA-Seq, including quality control, principal component analysis (PCA), and volcano plots of regulated genes showed comparable properties between akr1a1a mutants, wild type and acrolein treated wild type zebrafish larvae. We found the insulin receptor signaling pathway was down-regulated significantly in akr1a1a mutants and acrolein treated wild type larvae as compared to wild type larvae via gene set enrichment analysis (normalized enrichment score, -1.888, p=0.028; -1.93, p=0.019). Intriguingly, downstream signaling pathways including MAPK, signal transduction by protein phosphorylation and transmembrane receptor protein tyrosine kinase signaling pathway were also significantly down-regulated in akr1a1a mutants and acrolein treated wild type larvae. Taken together, these results further suggest akr1a1a and acrolein as an important regulator in insulin receptor signaling transduction. Furthermore, we offer a comprehensive and more detailed evaluation of mRNA content within zebrafish larvae. We conclude that RNA-seq based transcriptome would clearly illustrate genetic network and clarify complex biological functions.
2021-09-05 | GSE168786 | GEO
Project description:Combining metabolomics analyses with an IFN-stimulated response elements reporter system, we identify spermine as a cellular metabolite brake for JAK1 signaling. Spermine directly binds to FERM and SH2 domains of JAK1 to impair IFNAR2-JAK1 interaction. Spermine suppresses JAK1 phosphorylation triggered by types I and II cytokines, including IFN-I/II, IL-2, and IL-6. Spermine treatment attenuates autoimmune pathogenesis in a SLE murine model and reduces IFN-I signaling in monocytes from SLE patients, which have reduced spermine levels.
2024-06-21 | GSE218731 | GEO