bims-polyam 2020-04-26 papers

Biomolecules. 2020 Apr 18. pii: E628. [Epub ahead of print]10(4):

Diverse Functions of Polyamines in Virus Infection.

As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. Polyamines, comprised of putrescine, spermidine, and spermine in mammalian cells, are also critical for virus infection. Polyamines are small, positively charged molecules that function in transcription, translation, and cell cycling. Initial work on the function of polyamines in bacteriophage infection illuminated these molecules as critical to virus infection. In the decades since early virus-polyamine descriptions, work on diverse viruses continues to highlight a role for polyamines in viral processes, including genome packaging and viral enzymatic activity. On the host side, polyamines function in the response to virus infection. Thus, viruses and hosts compete for polyamines, which are a critical resource for both. Pharmacologically targeting polyamines, tipping the balance to favor the host and restrict virus replication, holds significant promise as a broad-spectrum antiviral strategy.

Keywords: host–virus interactions; metabolism; polyamines; viruses

DOI: https://doi.org/10.3390/biom10040628

Plants (Basel). 2020 Apr 16. pii: E511. [Epub ahead of print]9(4):

Plant Polyamines.

Taku Takahashi.

Polyamines are small organic compounds found in all living organisms. According to the high degree of positive charge at physiological pH, they interact with negatively charged macromolecules, such as DNA, RNA, and proteins, and modulate their activities. In plants, polyamines, some of which are presented as a conjugated form with cinnamic acids and proteins, are involved in a variety of physiological processes. In recent years, the study of plant polyamines, such as their biosynthetic and catabolic pathways and the roles they play in cellular processes, has flourished, becoming an exciting field of research. There is accumulating evidence that polyamine oxidation, the main catabolic pathway of polyamines, may have a potential role as a source of hydrogen peroxide. The papers in this Special Issue highlight new discoveries and research in the field of plant polyamine biology. The information will help to stimulate further research and make readers aware of the link between their own work and topics related to polyamines.

Keywords: copper amine oxidase; polyamine oxidase; spermidine; spermine; stress response; thermospermine

DOI: https://doi.org/10.3390/plants9040511

Free Radic Biol Med. 2020 Apr 16. pii: S0891-5849(20)30336-1. [Epub ahead of print]

Spermidine rescues the deregulated autophagic response to oxidative stress of osteoarthritic chondrocytes.

Stefania D'Adamo, Silvia Cetrullo, Serena Guidotti, Ylenia Silvestri, Manuela Minguzzi, Spartaco Santi, Luca Cattini, Giuseppe Filardo, Flavio Flamigni, Rosa Maria Borzì.

Oxidative stress (OS) contributes to Osteoarthritis (OA) pathogenesis and its effects are worsened by the impairment of homeostatic mechanisms such as autophagy in OA chondrocytes. Rescue of an efficient autophagic flux could therefore reduce the bulk of damaged molecules, and at the same time improve cell function and viability. As a promising dietary or intra-articular supplement to rescue autophagy in OA chondrocytes, we tested spermidine (SPD), known to induce autophagy and to reduce OS in several other cellular models. Chondrocytes were obtained from OA cartilage and seeded at high-density to keep their differentiated phenotype. The damaging effects of OS and the chondroprotective activity of SPD were assessed by evaluating the extent of cell death, oxidative DNA damage and caspase 3 activation. The autophagy promoting activity of SPD was evaluated by assessing pivotal autophagic effectors, i.e. Beclin-1 (BECN-1), microtubule-associated protein 1 light chain 3 II (LC3-II) and p62. BECN-1 protein expression was significantly increased by SPD and reduced by H2O2 treatment. SPD also rescued the impaired autophagic flux consequent to H2O2 exposure by increasing mRNA and protein expression of LC3-II and p62. SPD induction of mitophagy was revealed by immunofluorescent co-localization of LC3-II and TOM20. The key protective role of autophagy was confirmed by the loss of SPD chondroprotection upon autophagy-related gene 5 (ATG5) silencing. Significant SPD tuning of the H2O2-dependent induction of degradative (MMP-13) inflammatory (iNOS, COX-2) and hypertrophy markers (Runx 2 and VEGF) was revealed by Real Time PCR and pointed at the SPD ability of reducing NF-κB activation through autophagy induction. Conversely, blockage of autophagy led to parallel increases of oxidative markers and p65 nuclear translocation. SPD also increased the proliferation of slow-proliferating primary cultures. Taken together, our findings highlight the chondroprotective, anti-oxidant and anti-inflammatory activity of SPD and suggest that the protection afforded by SPD against OS is exerted through the rescue of the autophagic flux.

Keywords: Autophagy; Chondrocytes; Osteoarthritis; Oxidative stress; Spermidine

DOI: https://doi.org/10.1016/j.freeradbiomed.2020.03.029

J Am Heart Assoc. 2020 Apr 21. 9(8): e014757

Spermidine Suppresses Development of Experimental Abdominal Aortic Aneurysms.

Shuai Liu, Tingting Huang, Rui Liu, Huoying Cai, Baihong Pan, Mingmei Liao, Pu Yang, Lei Wang, Jianhua Huang, Yingbin Ge, Baohui Xu, Wei Wang.

Background The protective effects of polyamines on cardiovascular disease have been demonstrated in many studies. However, the roles of spermidine, a natural polyamine, in abdominal aortic aneurysm (AAA) disease have not been studied. In this study, we investigated the influence and potential mechanisms of spermidine treatment on experimental AAA disease. Methods and Results Experimental AAAs were induced in 8- to 10-week-old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase. Spermidine was administered via drinking water at a concentration of 3 mmol/L. Spermidine treatment prevented experimental AAA formation with preservation of medial elastin and smooth muscle cells. In immunostaining, macrophages, T cells, neutrophils, and neovessels were significantly reduced in aorta of spermidine-treated, as compared with vehicle-treated elastase-infused mice. Additionally, flow cytometric analysis showed that spermidine treatment reduced aortic leukocyte infiltration and circulating inflammatory cells. Furthermore, we demonstrated that spermidine treatment promoted autophagy-related proteins in experimental AAAs using Western blot analysis, immunostaining, and transmission electron microscopic examination. Autophagic function was evaluated for human abdominal aneurysmal and nonaneurysmal adjacent aortae from AAA patients using Western blot analysis and immunohistochemistry. Dysregulated autophagic function, as evidenced by increased SQSTM1/p62 protein and phosphorylated mTOR, was found in aneurysmal, as compared with nonaneurysmal, aortic segments. Conclusions Our results suggest that spermidine supplementation limits experimental AAA formation associated with preserved aortic structural integrity, attenuated aortic inflammatory infiltration, reduced circulating inflammatory monocytes, and increased autophagy-related proteins. These findings suggest that spermidine may be a promising treatment for AAA disease.

Keywords: abdominal aortic aneurysm; autophagy; experimental animal models; inflammation; spermidine

DOI: https://doi.org/10.1161/JAHA.119.014757

Front Chem. 2020 ;8 166

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo.

Jing Ma, Yingguang Li, Linrong Li, Kexin Yue, Hanfang Liu, Jiajia Wang, Zhuoqing Xi, Man Shi, Sihan Zhao, Qi Ma, Sitong Liu, Shudi Guo, Jianing Liu, Lili Hou, Chaojie Wang, Peng George Wang, Zhiyong Tian, Songqiang Xie.

Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

Keywords: cancer; dinitro-naphthalimide conjugate; minimized side-effects; polyamine; polyamine transporter

DOI: https://doi.org/10.3389/fchem.2020.00166

Acta Physiol (Oxf). 2020 Apr 24.

Polyamines, metabolites and metabolomics.

Tobias Sieckmann, Karin M Kirschner.

Metabolomics is now, after genomics, transcriptomics, and proteomics, one of the -omics that is beginning to expand into clinical diagnostics. This progress has been achieved by the recent development of high throughput screening methods. We are all familiar with metabolites like sugars, amino acids, lipids or nucleotides. But there are many more of these small molecules. Metabolites include all intermediates and products of cellular metabolism. Metabolome refers to the whole collection of metabolites in a biological system.

DOI: https://doi.org/10.1111/apha.13480