bims-polyam 2023-03-12 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–03–12
eight papers selected by
Sebastian J. Hofer, University of Graz

The upregulation of peripheral blood polyamine metabolites spermidine and spermine in children with hand, foot, mouth disease is related to enterovirus 71 capsid protein VP1, but not VP4.
Exploring the effect of polyamines on NK cell function in colorectal cancer process based on glycolysis.
Combined inhibition of polyamine metabolism and eIF5A hypusination suppresses colorectal cancer growth through a converging effect on MYC translation.
Transcriptional Basis of Ca2+ Remodeling Reversal Induced by Polyamine Synthesis Inhibition in Colorectal Cancer Cells.
Spermidine suppresses the activation of hepatic stellate cells to cure liver fibrosis through autophagy activator MAP1S.
CaSPDS, a Spermidine Synthase Gene from Pepper (Capsicum annuum L.), Plays an Important Role in Response to Cold Stress.
Interactions of Polyamines and Phytohormones in Plant Response to Abiotic Stress.
Circular RNA protein tyrosine kinase 2 aggravates pyroptosis and inflammation in septic lung tissue by promoting microRNA-766/eukaryotic initiation factor 5A axis-mediated ATP efflux.

Transl Pediatr. 2023 Feb 28. 12(2): 194-207

The upregulation of peripheral blood polyamine metabolites spermidine and spermine in children with hand, foot, mouth disease is related to enterovirus 71 capsid protein VP1, but not VP4.

Cong Li, Weijian Zhang, Xiaodan Chang, Xiaohua Di, Qi Xie, Bihua Lin, Hui Zhang, Ziyu Ye, Minsheng Lan, Jiachun Lian, Hailiang Zhang, Xianxiu Qiu, Jincheng Zeng, Mingyuan Huang.

   Background: Hand, foot, and mouth disease (HFMD) is a common viral childhood illness caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16. The pathogenesis of EV71 has been extensively studied, and the regulation of the host immune response is suspected to aggravate the serious complications induced by EV71. Our previous research showed that EV71 infection significantly increased the release of circulating interleukin (IL)-6, IL-10, IL-13, and IL-27. Notably, these cytokines are related to the EV71 infection risk and clinical stage. Polyamines are compounds that are ubiquitous in mammalian cells and play a key role in various cellular processes. Several studies have shown that targeting polyamine metabolic pathways can reduce infections caused by viruses. However, the significance of polyamine metabolism in EV71 infection remains largely unknown.
Methods: Serum samples from 82 children with HFMD and 70 healthy volunteers (HVs) were collected to determine the polyamine metabolites spermidine (SPD) and spermine (SPM), and IL-6 levels. In addition, peripheral blood mononuclear cells (PBMCs) were treated with EV71 viral protein 1 (VP1) and EV71 VP4, and the cells and supernatant were then collected to analyze the expression of polyamine metabolism-related enzymes by western blot. The data were analyzed using GraphPad Prism 7.0 software (USA).
Results: The serum polyamine metabolites SPD and SPM were elevated in the HFMD patients, especially in the EV71-infected children. Further, a positive correlation was found between serum SPD and IL-6 levels in the EV71-infected children. We also found that the upregulation of peripheral blood polyamine metabolites in the EV71-infected HFMD children was related to EV71 capsid protein VP1, but not VP4. VP1 may promote the expression of polyamine metabolism-related enzymes and promote the production of polyamine metabolites, thereby upregulating the SPD/nuclear factor kappa B/IL-6 signaling pathway. However, VP4 has the opposite effect in this process.
Conclusions: Our results suggest that EV71 capsid protein may regulate the polyamine metabolic pathways of infected cells in a variety of ways. This study provides insights into the mechanism of EV71 infection and polyamine metabolism and has good reference value for the development of EV71 vaccine.

Keywords:  Hand, foot, and mouth disease (HFMD); enterovirus 71 (EV71); polyamine; spermidine; spermine

DOI:  https://doi.org/10.21037/tp-23-41
Int Immunopharmacol. 2023 Mar 03. pii: S1567-5769(23)00264-3. [Epub ahead of print]117 109944

Exploring the effect of polyamines on NK cell function in colorectal cancer process based on glycolysis.

Huan He, Zijing Song, Siqi Lin, Yu Wang, Guixiang Wang.

  Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Myc is a key regulator of immune cell activity and function, but little is known about how Myc controls NK cell activation and function. In this study, we found that c-Myc is involved in the regulation of NK cell immune activity. In the development of colon cancer, the energy generation disorder of tumor cells promotes the plunder of polyamines of NK cells by tumor cells, resulting in the inhibition of NK cell c-Myc. After inhibition of c-Myc, glycolysis of NK cells was impaired, resulting in decreased killing activity. There are three main types of polyamines: putrescine (Put), spermidine (Spd) and spermine (Spm). We found that the NK cells could reverse the inhibition state of c-Myc and glycolysis energy supply disorder and recover the killing activity of NK cells after giving certain spermidine. These results suggest that polyamine content and glycolysis supply under the regulation of c-Myc play a crucial role in the immune activity of NK cells.

Keywords:  Co-culture; Glycolysis; MYC pathway; NK cell; Polyamine

DOI:  https://doi.org/10.1016/j.intimp.2023.109944
Cancer Lett. 2023 Mar 07. pii: S0304-3835(23)00071-X. [Epub ahead of print] 216120

Combined inhibition of polyamine metabolism and eIF5A hypusination suppresses colorectal cancer growth through a converging effect on MYC translation.

Sonia Coni, Rosa Bordone, Devon Michael Ivy, Zuleyha Nihan Yurtsever, Laura Di Magno, Rodrigo D'Amico, Bianca Cesaro, Alessandro Fatica, Francesca Belardinilli, Francesca Bufalieri, Marella Maroder, Enrico De Smaele, Lucia Di Marcotullio, Giuseppe Giannini, Enzo Agostinelli, Gianluca Canettieri.

  A key mechanism driving colorectal cancer (CRC) development is the upregulation of MYC and its targets, including ornithine decarboxylase (ODC), a master regulator of polyamine metabolism. Elevated polyamines promote tumorigenesis in part by activating DHPS-mediated hypusination of the translation factor eIF5A, thereby inducing MYC biosynthesis. Thus, MYC, ODC and eIF5A orchestrate a positive feedback loop that represents an attractive therapeutic target for CRC therapy. Here we show that combined inhibition of ODC and eIF5A induces a synergistic antitumor response in CRC cells, leading to MYC suppression. We found that genes of the polyamine biosynthesis and hypusination pathways are significantly upregulated in colorectal cancer patients and that inhibition of ODC or DHPS alone limits CRC cell proliferation through a cytostatic mechanism, while combined ODC and DHPS/eIF5A blockade induces a synergistic inhibition, accompanied to apoptotic cell death in vitro and in mouse models of CRC and FAP. Mechanistically, we found that this dual treatment causes complete inhibition of MYC biosynthesis in a bimodal fashion, by preventing translational elongation and initiation. Together, these data illustrate a novel strategy for CRC treatment, based on the combined suppression of ODC and eIF5A, which holds promise for the treatment of CRC.

Keywords:  DFMO; GC7; Mouse models; Polyamines; Synergy

DOI:  https://doi.org/10.1016/j.canlet.2023.216120
Cancers (Basel). 2023 Mar 04. pii: 1600. [Epub ahead of print]15(5):

Transcriptional Basis of Ca2+ Remodeling Reversal Induced by Polyamine Synthesis Inhibition in Colorectal Cancer Cells.

Enrique Pérez-Riesgo, Elena Hernando-Pérez, Verónica Feijóo, Sendoa Tajada, Lucía Núñez, Carlos Villalobos.

  Colorectal cancer (CRC) is associated with mutations in APC/Wnt leading to c-myc activation and the overexpression of ODC1, the limiting step in polyamine synthesis. CRC cells also display a remodeling of intracellular Ca2+ homeostasis that contributes to cancer hallmarks. As polyamines may modulate Ca2+ homeostasis during epithelial tissue repair, we investigated whether polyamine synthesis inhibition may reverse Ca2+ remodeling in CRC cells and, if so, the molecular basis for this reversal. To this end, we used calcium imaging and transcriptomic analysis in normal and CRC cells treated with DFMO, an ODC1 suicide inhibitor. We found that polyamine synthesis inhibition partially reversed changes in Ca2+ homeostasis associated with CRC, including a decrease in resting Ca2+ and SOCE along with an increased Ca2+ store content. We also found that polyamine synthesis inhibition reversed transcriptomic changes in CRC cells without affecting normal cells. Specifically, DFMO treatment enhanced the transcription of SOCE modulators CRACR2A; ORMDL3; and SEPTINS 6, 7, 8, 9, and 11, whereas it decreased SPCA2, involved in store-independent Orai1 activation. Therefore, DFMO treatment probably decreased store-independent Ca2+ entry and enhanced SOCE control. Conversely, DFMO treatment decreased the transcription of the TRP channels TRPC1 and 5, TRPV6, and TRPP1 while increasing TRPP2, thus probably decreasing Ca2+ entry through TRP channels. Finally, DFMO treatment enhanced the transcription of the PMCA4 Ca2+ pump and mitochondrial channels MCU and VDAC3 for enhanced Ca2+ extrusion through the plasma membrane and mitochondria. Collectively, these findings suggested the critical role of polyamines in Ca2+ remodeling in colorectal cancer.

Keywords:  DFMO; TRP channels; colorectal cancer; intracellular calcium; mitochondria; polyamines; store-operated calcium entry; transcriptomic analysis

DOI:  https://doi.org/10.3390/cancers15051600
Liver Int. 2023 Mar 09.

Spermidine suppresses the activation of hepatic stellate cells to cure liver fibrosis through autophagy activator MAP1S.

Boyun Shi, Wei Wang, Mengting Ye, Min Liang, Ziyu Yu, Yingying Zhang, Zhaoyu Liu, Xue Liang, Jian Ao, Fengfeng Xu, Guibin Xu, Xianhan Jiang, Xinke Zhou, Leyuan Liu.

   BACKGROUND & AIMS: Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already-developed liver fibrosis.
METHODS: We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild-type and MAP1S knockout mice with CCl4 -induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis.
RESULTS: Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after one month of CCl4 induction for an additional three months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells.
CONCLUSIONS: Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients.

Keywords:  MAP1S; autophagy; extracellular matrix; hepatic stellate cells; liver fibrosis; spermidine

DOI:  https://doi.org/10.1111/liv.15558
Int J Mol Sci. 2023 Mar 06. pii: 5013. [Epub ahead of print]24(5):

CaSPDS, a Spermidine Synthase Gene from Pepper (Capsicum annuum L.), Plays an Important Role in Response to Cold Stress.

Jianwei Zhang, Minghui Xie, Guofeng Yu, Dong Wang, Zeping Xu, Le Liang, Jiachang Xiao, Yongdong Xie, Yi Tang, Guochao Sun, Bo Sun, Zhi Huang, Yunsong Lai, Huanxiu Li.

  Spermidine synthase (SPDS) is a key enzyme in the polyamine anabolic pathway. SPDS genes help regulate plant response to environmental stresses, but their roles in pepper remain unclear. In this study, we identified and cloned a SPDS gene from pepper (Capsicum annuum L.), named CaSPDS (LOC107847831). Bioinformatics analysis indicated that CaSPDS contains two highly conserved domains: an SPDS tetramerisation domain and a spermine/SPDS domain. Quantitative reverse-transcription polymerase chain reaction results showed that CaSPDS was highly expressed in the stems, flowers, and mature fruits of pepper and was rapidly induced by cold stress. The function of CaSPDS in cold stress response was studied by silencing and overexpressing it in pepper and Arabidopsis, respectively. Cold injury was more serious and reactive oxygen species levels were greater in the CaSPDS-silenced seedlings than in the wild-type (WT) seedlings after cold treatment. Compared with the WT plants, the CaSPDS-overexpression Arabidopsis plants were more tolerant to cold stress and showed higher antioxidant enzyme activities, spermidine content, and cold-responsive gene (AtCOR15A, AtRD29A, AtCOR47, and AtKIN1) expression. These results indicate that CaSPDS plays important roles in cold stress response and is valuable in molecular breeding to enhance the cold tolerance of pepper.

Keywords:  cold stress; overexpression; pepper; spermidine synthase; virus-induced gene silencing

DOI:  https://doi.org/10.3390/ijms24055013
Plants (Basel). 2023 Mar 03. pii: 1159. [Epub ahead of print]12(5):

Interactions of Polyamines and Phytohormones in Plant Response to Abiotic Stress.

Natalia Napieraj, Małgorzata Janicka, Małgorzata Reda.

  Numerous environmental conditions negatively affect plant production. Abiotic stresses, such as salinity, drought, temperature, and heavy metals, cause damage at the physiological, biochemical, and molecular level, and limit plant growth, development, and survival. Studies have indicated that small amine compounds, polyamines (PAs), play a key role in plant tolerance to various abiotic stresses. Pharmacological and molecular studies, as well as research using genetic and transgenic approaches, have revealed the favorable effects of PAs on growth, ion homeostasis, water maintenance, photosynthesis, reactive oxygen species (ROS) accumulation, and antioxidant systems in many plant species under abiotic stress. PAs display a multitrack action: regulating the expression of stress response genes and the activity of ion channels; improving the stability of membranes, DNA, and other biomolecules; and interacting with signaling molecules and plant hormones. In recent years the number of reports indicating crosstalk between PAs and phytohormones in plant response to abiotic stresses has increased. Interestingly, some plant hormones, previously known as plant growth regulators, can also participate in plant response to abiotic stresses. Therefore, the main goal of this review is to summarize the most significant results that represent the interactions between PAs and plant hormones, such as abscisic acid, brassinosteroids, ethylene, jasmonates, and gibberellins, in plants under abiotic stress. The future perspectives for research focusing on the crosstalk between PAs and plant hormones were also discussed.

Keywords:  abiotic stress; abscisic acid; brassinosteroids; ethylene; gibberellins; jasmonates; plant hormones; polyamines

DOI:  https://doi.org/10.3390/plants12051159
Acta Cir Bras. 2023 ;pii: S0102-86502023000100201. [Epub ahead of print]38 e380323

Circular RNA protein tyrosine kinase 2 aggravates pyroptosis and inflammation in septic lung tissue by promoting microRNA-766/eukaryotic initiation factor 5A axis-mediated ATP efflux.

FuYan Ding, JiaLu Zhu, YanLei Hu.

PURPOSE: Sepsis is characterized by an acute inflammatory response to infection, often with multiple organ failures, especially severe lung injury. This study was implemented to probe circular RNA (circRNA) protein tyrosine kinase 2 (circPTK2)-associated regulatory mechanisms in septic acute lung injury (ALI).
METHODS: A cecal ligation and puncture-based mouse model and an lipopolysaccharides (LPS)-based alveolar type II cell (RLE-6TN) model were generated to mimic sepsis. In the two models, inflammation- and pyroptosis-related genes were measured.
RESULTS: The degree of lung injury in mice was analyzed by hematoxylin and eosin (H&E) staining and the apoptosis was by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. In addition, pyroptosis and toxicity were detected in cells. Finally, the binding relationship between circPTK2, miR-766, and eukaryotic initiation factor 5A (eIF5A) was detected. Data indicated that circPTK2 and eIF5A were up-regulated and miR-766 was down-regulated in LPS-treated RLE-6TN cells and lung tissue of septic mice. Lung injury in septic mice was ameliorated after inhibition of circPTK2.
CONCLUSIONS: It was confirmed in the cell model that knockdown of circPTK2 effectively ameliorated LPS-induced ATP efflux, pyroptosis, and inflammation. Mechanistically, circPTK2 mediated eIF5A expression by competitively adsorbing miR-766. Taken together, circPTK2/miR-766/eIF5A axis ameliorates septic ALI, developing a novel therapeutic target for the disease.

DOI: https://doi.org/10.1590/acb380323