bims-polyam 2024-07-14 papers

Issue of 2024‒07‒14
three papers selected by
Sebastian J. Hofer, University of Graz

Cells. 2024 Jul 01. pii: 1134. [Epub ahead of print]13(13):

Polyamine Catabolism Revisited: Acetylpolyamine Oxidase Plays a Minor Role due to Low Expression.

Olga N Ivanova, Anna V Gavlina, Inna L Karpenko, Martin A Zenov, Svetlana S Antseva, Natalia F Zakirova, Vladimir T Valuev-Elliston, George S Krasnov, Irina T Fedyakina, Pavel O Vorobyev, Birke Bartosch, Sergey N Kochetkov, Anastasiya V Lipatova, Dmitry V Yanvarev, Alexander V Ivanov.

Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines (back-conversion) or their direct efflux from the cell. PAOX is considered to catalyze a non-rate-limiting catabolic step. Here, we show that PAOX transcription levels are extremely low in various tumor- and non-tumor cell lines and, in most cases, do not change in response to altered polyamine metabolism. Its enzymatic activity is undetectable in the majority of cell lines except for neuroblastoma and low passage glioblastoma cell lines. Treatment of A549 cells with N1,N11-diethylnorspermine leads to PAOX induction, but its contribution to polyamine catabolism remains moderate. We also describe two alternative enzyme isoforms and show that isoform 4 has diminished oxidase activity and isoform 2 is inactive. PAOX overexpression correlates with the resistance of cancer cells to genotoxic antitumor drugs, indicating that PAOX may be a useful therapeutic target. Finally, PAOX is dispensable for the replication of various viruses. These data suggest that a decrease in polyamine levels is achieved predominantly by the secretion of acetylated spermine and spermidine rather than by back-conversion.

Keywords: N1,N11-diethylnorspermine; acetylpolyamine oxidase; doxorubicin; polyamines; spermidine; spermine; virus replication

DOI: https://doi.org/10.3390/cells13131134

Free Radic Biol Med. 2024 Jul 10. pii: S0891-5849(24)00555-0. [Epub ahead of print]

SQSTM1 improves acute lung injury via inhibiting airway epithelium ferroptosis in a vitamin D receptor / autophagy-mediated manner.

Youjing Yang, Tao Zhang, Qianmin Li, Yi Ling, Yu Ma, Shasha Tao.

Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI.

Keywords: Acute lung injury; Ferroptosis; SQSTM1; Spermidine

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.07.009

Front Immunol. 2024 ;15 1407035

Impaired arginine/ornithine metabolism drives severe HFMD by promoting cytokine storm.

Yaozhong Zhang, Qingqing Yang, Qi Peng, Zhihua Tian, Fen Lv, Xiaomei Zeng, Zaixue Jiang, Qingqiu Cheng, Lijun Yang, Baimao Zhong, Xiaomei Lu, Yinghua Zhu.

Introduction: The Hand, Foot and Mouth Disease (HFMD), caused by enterovirus 71 infection, is a global public health emergency. Severe HFMD poses a significant threat to the life and well-being of children. Numerous studies have indicated that the occurrence of severe HFMD is associated with cytokine storm. However, the precise molecular mechanism underlying cytokine storm development remains elusive, and there are currently no safe and effective treatments available for severe HFMD in children.Methods: In this study, we established a mouse model of severe HFMD to investigate the molecular mechanisms driving cytokine storm. We specifically analyzed metabolic disturbances, focusing on arginine/ornithine metabolism, and assessed the potential therapeutic effects of spermine, an ornithine metabolite.
Results: Our results identified disturbances in arginine/ornithine metabolism as a pivotal factor driving cytokine storm onset in severe HFMD cases. Additionally, we discovered that spermine effectively mitigated the inflammatory injury phenotype observed in mice with severe HFMD.
Discussion: In conclusion, our findings provide novel insights into the molecular mechanisms underlying severe HFMD from a metabolic perspective while offering a promising new strategy for its safe and effective treatment.

Keywords: EV71; cytokine storm; macrophage; ornithine; severe HFMD

DOI: https://doi.org/10.3389/fimmu.2024.1407035