bims-polyam 2023-05-28 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–05–28
ten papers selected by
Sebastian J. Hofer, University of Graz

The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused by Plasmodium falciparum and Trypanosoma brucei.
Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice.
Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults.
Exogenous spermine alleviates the negative effects of combined salinity and paraquat in tomato plants by decreasing stress-induced oxidative damage.
Author Correction: LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages.
Carrier-Mediated Process of Putrescine Elimination at the Rat Blood-Retinal Barrier.
Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism.
Inhibiting eukaryotic initiation factor 5A (eIF5A) hypusination attenuated activation of the SIK2 (salt-inducible kinase 2)-p4E-BP1 pathway involved in ovarian cancer cell proliferation and migration.
Spermidine Retarded the Senescence of Multipotent Mesenchymal Stromal Cells In Vitro and In Vivo through SIRT3-Mediated Antioxidation.
Tumor Microenvironment Mediated Spermidine-Metal-Immunopeptide Nanocomplex for Boosting Ferroptotic Immunotherapy of Lymphoma.

Biomolecules. 2023 May 09. pii: 803. [Epub ahead of print]13(5):

The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused by Plasmodium falciparum and Trypanosoma brucei.

Annette Kaiser.

  The triamine spermidine is a key metabolite of the polyamine pathway. It plays a crucial role in many infectious diseases caused by viral or parasitic infections. Spermidine and its metabolizing enzymes, i.e., spermidine/spermine-N1-acetyltransferase, spermine oxidase, acetyl polyamine oxidase, and deoxyhypusine synthase, fulfill common functions during infection in parasitic protozoa and viruses which are obligate, intracellular parasites. The competition for this important polyamine between the infected host cell and the pathogen determines the severity of infection in disabling human parasites and pathogenic viruses. Here, we review the impact of spermidine and its metabolites in disease development of the most important, pathogenic human viruses such as SARS-CoV-2, HIV, Ebola, and in the human parasites Plasmodium and Trypanosomes. Moreover, state-of-the-art translational approaches to manipulate spermidine metabolism in the host and the pathogen are discussed to accelerate drug development against these threatful, infectious human diseases.

Keywords:  drug development; spermidine; viral and parasitic infections

DOI:  https://doi.org/10.3390/biom13050803
Sci Rep. 2023 May 23. 13(1): 8338

Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice.

Daisuke Ueno, Koji Ikeda, Ekura Yamazaki, Akiko Katayama, Ryota Urata, Satoaki Matoba.

Aging is closely associated with the increased morbidity and mortality of ischemic cardiovascular disease, at least partially through impaired angiogenic capacity. Endothelial cells (ECs) play a crucial role in angiogenesis, and their angiogenic capacity declines during aging. Spermidine is a naturally occurring polyamine, and its dietary supplementation has exhibited distinct anti-aging and healthy lifespan-extending effects in various species such as yeast, worms, flies, and mice. Here, we explore the effects of spermidine supplementation on the age-related decline in angiogenesis both in vitro and in vivo. Intracellular polyamine contents were reduced in replicative senescent ECs, which were subsequently recovered by spermidine supplementation. Our findings reveal that spermidine supplementation improved the declined angiogenic capacity of senescent ECs, including migration and tube-formation, without affecting the senescence phenotypes. Mechanistically, spermidine enhanced both autophagy and mitophagy, and improved mitochondrial quality in senescent ECs. Ischemia-induced neovascularization was assessed using the hind-limb ischemia model in mice. Limb blood flow recovery and neovascularization in the ischemic muscle were considerably impaired in aged mice compared to young ones. Of note, dietary spermidine significantly enhanced ischemia-induced angiogenesis, and improved the blood flow recovery in the ischemic limb, especially in aged mice. Our results reveal novel proangiogenic functions of spermidine, suggesting its therapeutic potential against ischemic disease.

DOI: https://doi.org/10.1038/s41598-023-35447-3
Biomedicines. 2023 May 09. pii: 1403. [Epub ahead of print]11(5):

Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults.

Hidenori Sanayama, Kiyonori Ito, Susumu Ookawara, Takeshi Uemura, Yoshio Sakiyama, Hitoshi Sugawara, Kaoru Tabei, Kazuei Igarashi, Kuniyasu Soda.

  Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher (p = 0.002) and the spermine/spermidine ratio was lower (p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression. Additionally, when the odds ratio was analyzed with spermine/spermidine instead of polyamine concentrations, only for spermine/spermidine, the odds ratio values varied in parallel with the progression of sarcopenia. Based on the present data, we believe that the blood spermine/spermidine ratio may be a diagnostic indicator of risk for sarcopenia.

Keywords:  biomarker; polyamine; sarcopenia; skeletal muscle index; spermidine; spermine

DOI:  https://doi.org/10.3390/biomedicines11051403
Front Plant Sci. 2023 ;14 1193207

Exogenous spermine alleviates the negative effects of combined salinity and paraquat in tomato plants by decreasing stress-induced oxidative damage.

Lidia S Pascual, María F López-Climent, Clara Segarra-Medina, Aurelio Gómez-Cadenas, Sara I Zandalinas.

  Plants are frequently exposed to different combinations of soil constraints including salinity and different herbicides. These abiotic conditions negatively affect photosynthesis, growth and plant development resulting in limitations in agriculture production. To respond to these conditions, plants accumulate different metabolites that restore cellular homeostasis and are key for stress acclimation processes. In this work, we analyzed the role of exogenous spermine (Spm), a polyamine involved in plant tolerance to abiotic stress, in tomato responses to the combination of salinity (S) and the herbicide paraquat (PQ). Our findings showed that application of Spm reduced leaf damage and enhanced survival, growth, photosystem II function and photosynthetic rate of tomato plants subjected to the combination of S and PQ. In addition, we revealed that exogenous Spm reduced H2O2 and malondialdehyde (MDA) accumulation in plants subjected to S+PQ, suggesting that the role of exogenous Spm in alleviating the negative effects of this stress combination could be attributed to a decrease in stress-induced oxidative damage in tomato plants. Taken together, our results identify a key role for Spm in improving plant tolerance to combined stress.

Keywords:  ROS; climate change; herbicide; polyamine; salinity; spermine; stress combination; tomato

DOI:  https://doi.org/10.3389/fpls.2023.1193207
Nature. 2023 May 25.

Author Correction: LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages.

Zheng Wei, Joonseok Oh, Richard A Flavell, Jason M Crawford.

DOI: https://doi.org/10.1038/s41586-023-06244-9
Int J Mol Sci. 2023 May 19. pii: 9003. [Epub ahead of print]24(10):

Carrier-Mediated Process of Putrescine Elimination at the Rat Blood-Retinal Barrier.

Yuma Tega, Yoshiyuki Kubo, Hiroaki Miura, Kairi Ri, Ayaka Tomise, Shin-Ichi Akanuma, Ken-Ichi Hosoya.

  Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood-retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [14C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [3H]putrescine and [14C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [3H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [3H]Putrescine transport was significantly reduced under Na+-free, Cl--free, and K+-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [3H]putrescine uptake, and CTL1 knockdown significantly reduced [3H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB.

Keywords:  blood–retinal barrier; choline transporter-like protein; polyamine; putrescine; transport

DOI:  https://doi.org/10.3390/ijms24109003
Metabolites. 2023 May 09. pii: 642. [Epub ahead of print]13(5):

Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism.

Anowarul Islam, Zeeshan Shaukat, David L Newman, Rashid Hussain, Michael G Ricos, Leanne Dibbens, Stephen L Gregory.

  Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism.

Keywords:  Drosophila; autophagy; genomic instability; reactive oxygen species (ROS); s-adenosyl methionine; spermine

DOI:  https://doi.org/10.3390/metabo13050642
Mol Biol Rep. 2023 May 23.

Inhibiting eukaryotic initiation factor 5A (eIF5A) hypusination attenuated activation of the SIK2 (salt-inducible kinase 2)-p4E-BP1 pathway involved in ovarian cancer cell proliferation and migration.

Grace Kelly Lee, Hae-Yeong Kim, Jong Hwan Park.

   BACKGROUND: Eukaryotic initiation factor 5A hypusine (eIF5AHyp) stimulates the translation of proline repeat motifs. Salt inducible kinase 2 (SIK2) containing a proline repeat motif is overexpressed in ovarian cancers, in which it promotes cell proliferation, migration, and invasion.
METHODS AND RESULTS: Western blotting and dual luciferase analyses showed that depletion of eIF5AHyp by GC7 or eIF5A-targeting siRNA downregulated SIK2 level and decreased luciferase activity in cells transfected with a luciferase-based reporter construct containing consecutive proline residues, whereas the activity of the mutant control reporter construct (replacing P825L, P828H, and P831Q) did not change. According to the MTT assay, GC7, which has a potential antiproliferative effect, reduced the viability of several ovarian cancer cell lines by 20-35% at high concentrations (ES2 > CAOV-3 > OVCAR-3 > TOV-112D) but not at low concentrations. In a pull-down assay, we identified eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP1 (p4E-BP1) phosphorylated at Ser 65 as downstream binding partners of SIK2, and we validated that the level of p4E-BP1(Ser 65) was downregulated by SIK2-targeting siRNA. Conversely, in ES2 cells overexpressing SIK2, the p4E-BP1(Ser 65) level was increased but decreased in the presence of GC7 or eIF5A-targeting siRNA. Finally, the migration, clonogenicity, and viability of ES2 ovarian cancer cells were reduced by GC7 treatment as well as by siRNA for eIF5A gene silencing and siRNA for SIK2 and 4E-BP1 gene silencing. Conversely, those activities were increased in cells overexpressing SIK2 or 4E-BP1 and decreased again in the presence of GC7.
CONCLUSION: The depletion of eIF5AHyp by GC7 or eIF5A-targeting siRNA attenuated activation of the SIK2-p4EBP1 pathway. In that way, eIF5AHyp depletion reduces the migration, clonogenicity, and viability of ES2 ovarian cancer cells.

Keywords:  4E-BP1 (Ser 65); GC7; SIK2; eIF5AHyp

DOI:  https://doi.org/10.1007/s11033-023-08510-5
Stem Cells Int. 2023 ;2023 9672658

Spermidine Retarded the Senescence of Multipotent Mesenchymal Stromal Cells In Vitro and In Vivo through SIRT3-Mediated Antioxidation.

Hua Huang, Wen Zhang, Junjie Su, Bisheng Zhou, Qingjiang Han.

Multipotent mesenchymal stromal cells (MSCs) expand in vitro and undergo replicative senescence, thereby restricting their clinical utilization. Thus, an effective strategy is required to impede MSC senescence. Since spermidine (SPD) supplementation can prolong the lifespan of yeast by inhibiting oxidative stress, spermidine is a potential option for delaying MSC senescence. In this study, to test our hypothesis, we first isolated primary human umbilical cord mesenchymal stem cells (hUCMSCs). Subsequently, the appropriate SPD dose was administered during continuous cell cultivation. Next, we evaluated the antisenescence effects by SA-β-gal staining, Ki67 expression, reactive oxygen species (ROS) levels, adipogenic or osteogenic ability, senescence-associated markers, and DNA damage markers. The results revealed that early SPD intervention significantly delays the replicative senescence of hUCMSCs and constrains premature H2O2-induced senescence. Additionally, by silencing SIRT3, the SPD-mediated antisenescence effects disappear, further demonstrating that SIRT3 is necessary for SPD to exert its antisenescence effects on hUCMSCs. Besides, the findings of this study also suggest that SPD in vivo protects MSCs against oxidative stress and delays cell senescence. Thus, MSCs maintain the ability to proliferate and differentiate efficiently in vitro and in vivo, which reflects the potential clinical utilization of MSCs in the future.

DOI: https://doi.org/10.1155/2023/9672658
ACS Nano. 2023 May 23.

Tumor Microenvironment Mediated Spermidine-Metal-Immunopeptide Nanocomplex for Boosting Ferroptotic Immunotherapy of Lymphoma.

Tianqi Nie, Hengyu Liu, Zhengwen Fang, Yilu Zheng, Ruhe Zhang, Xiaojun Xu, Sixi Liu, Jun Wu.

  Immunotherapy as an alternative treatment strategy for B-cell lymphoma is undesirable because of tumor heterogeneity and immune surveillance. Spermidine (SPM), as a regulator of the tumor microenvironment (TME), can facilitate the release of damage-associated molecular patterns (DAMPs) from cancer cells, promote immune recognition, and thus alleviate immune surveillance in the TME. Hence, in this work, self-assembled spermidine-based metal-immunopeptide nanocomplexes (APP-Fe NCs; APP is anti-programmed death ligand-1 peptide) with pH-responsive release kinetics were prepared via the flash nanocomplexation (FNC) technique based on the noncovalent interaction between APP-SPM-dextran (DEX) and sodium tripolyphosphate (TPP) and coordination between Fe3+ and TPP. An in vitro study suggested that APP-Fe NCs effectively induce strong oxidative stress and mitochondrial dysfunction and subsequently lead to ferroptosis in cells by interfering with homeostasis in lymphoma cells. Further investigation on lymphoma mice models demonstrated that APP-Fe NCs effectively inhibited the growth and liver metastasis of lymphomas. Mechanistically, by triggering ferroptosis in tumor tissues, these spermidine-containing APP-Fe NCs efficiently facilitated the release of DAMPs and ultimately reshaped TME to enhance immunotherapy efficacy in lymphoma. Combined with its good histocompatibility and facile preparation technique, this pH-responsive APP-Fe NCs with regulation on TME may hold potential for cascade amplification on the combinative immunotherapy of lymphoma in the clinic.

Keywords:  ferroptosis; immunotherapy; lymphoma; spermidine; tumor environment

DOI:  https://doi.org/10.1021/acsnano.3c02803