bims-polyam 2024-01-07 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2024‒01‒07
seven papers selected by
Sebastian J. Hofer, University of Graz

Antizyme inhibitor family: biological and translational research implications.
A toxicological assessment of spermidine trihydrochloride produced using an engineered strain of Saccharomyces cerevisiae.
Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds.
VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.
Thermospermine is an evolutionarily ancestral phytohormone required for organ development and stress responses in Marchantia polymorpha.
Putrescine promotes MMP9-induced angiogenesis in skeletal muscle through hydrogen peroxide/METTL3 pathway.
Human trials exploring anti-aging medicines.

Cell Commun Signal. 2024 Jan 02. 22(1): 11

Antizyme inhibitor family: biological and translational research implications.

Qiaohui Feng, Huijie Wang, Youcheng Shao, Xiaoyan Xu.

  Metabolism of polyamines is of critical importance to physiological processes. Ornithine decarboxylase (ODC) antizyme inhibitors (AZINs) are capable of interacting with antizymes (AZs), thereby releasing ODC from ODC-AZs complex, and promote polyamine biosynthesis. AZINs regulate reproduction, embryonic development, fibrogenesis and tumorigenesis through polyamine and other signaling pathways. Dysregulation of AZINs has involved in multiple human diseases, especially malignant tumors. Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post-transcriptional nucleotide modification in humans. Additionally, the high frequencies of RNA-edited AZIN1 in human cancers correlates with increase of cancer cell proliferation, enhancement of cancer cell stemness, and promotion of tumor angiogenesis. In this review, we summarize the current knowledge on the various contribution of AZINs related with potential cancer promotion, cancer stemness, microenvironment and RNA modification, especially underlying molecular mechanisms, and furthermore explored its promising implication for cancer diagnosis and treatment.

Keywords:  Antizyme inhibitors (AZINs); Microenvironment; Polyamine; RNA editing; Therapy

DOI:  https://doi.org/10.1186/s12964-023-01445-1
Food Chem Toxicol. 2023 Dec 30. pii: S0278-6915(23)00831-1. [Epub ahead of print] 114428

A toxicological assessment of spermidine trihydrochloride produced using an engineered strain of Saccharomyces cerevisiae.

Paola P Chrysostomou, Elaine L Freeman, Mary M Murphy, Rui Pereira, David J Esdaile, Patrick Keohane.

  Spermidine is a polyamine consumed in the diet, endogenously biosynthesized in most cells, and produced by the intestinal microbiome. A variety of foods contribute to intake of spermidine along with other polyamines. Spermidine trihydrochloride (spermidine-3HCl) of high purity can be produced using an engineered strain of Saccharomyces cerevisiae. Spermidine has a demonstrated history of safe use in the diet; however, limited information is available in the public literature to assess the potential toxicity of spermidine-3HCl. To support a safety assessment for this spermidine-3HCl as a dietary source of spermidine, authoritative guideline and good laboratory practice (GLP) compliant in vitro genotoxicity assays (bacterial reverse mutation and mammalian micronucleus assays) and a 90-day oral (dietary) toxicity study in rats were conducted with spermidine-3HCl. Spermidine-3HCl was non-genotoxic in the in vitro assays, and no adverse effects were reported in the 90-day oral toxicity study up to the highest dose tested, 12500 ppm, equivalent to 728 mg/kg bw/day for males and 829 mg/kg bw/day for females. The subchronic no observed adverse effect level (NOAEL) is 728 mg/kg bw/day.

Keywords:  90-Day oral; In vitro genotoxicity; Spermidine trihydrochloride; Subchronic toxicity; Toxicology

DOI:  https://doi.org/10.1016/j.fct.2023.114428
Front Pharmacol. 2023 ;14 1327603

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds.

Lucy O Ojomoko, Elena V Kryukova, Natalya S Egorova, Arthur I Salikhov, Lyubov A Epifanova, Daria A Denisova, Alex R Khomutov, Dmitry A Sukhov, Alexander A Vassilevski, Maxim A Khomutov, Victor I Tsetlin, Irina V Shelukhina.

  Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed "cyclo"R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), C-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. "Cyclo"R8 showed similar activity to that of R8 against α9α10 nAChR (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.

Keywords:  acylpolyamine; argiopin; calcium imaging; electrophysiology; nicotinic acetylcholine receptor; oligoarginine; polyamines; radioligand analysis

DOI:  https://doi.org/10.3389/fphar.2023.1327603
Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01672-8. [Epub ahead of print]43(1): 113661

VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.

Keman Zhang, Amin Zakeri, Tyler Alban, Juan Dong, Hieu M Ta, Ajay H Zalavadia, Andrelie Branicky, Haoxin Zhao, Ivan Juric, Hanna Husich, Prerana B Parthasarathy, Amit Rupani, Judy A Drazba, Abhishek A Chakraborty, Stanley Ching-Cheng Huang, Timothy Chan, Stefanie Avril, Li Lily Wang.

  Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.

Keywords:  CP: Cancer; CP: Immunology; GM-CSF; IL-6; MDSC differentiation; STAT3; VISTA; mitochondrial function; myeloid-derived suppressor cells; polyamine; tumor-associated myeloid cells

DOI:  https://doi.org/10.1016/j.celrep.2023.113661
Plant Cell Physiol. 2024 Jan 05. pii: pcae002. [Epub ahead of print]

Thermospermine is an evolutionarily ancestral phytohormone required for organ development and stress responses in Marchantia polymorpha.

Takuya Furumoto, Shohei Yamaoka, Takayuki Kohchi, Hiroyasu Motose, Taku Takahashi.

  Thermospermine suppresses auxin-inducible xylem differentiation, whereas its structural isomer, spermine, is involved in stress responses in angiosperms. The thermospermine synthase, ACAULIS5 (ACL5), is conserved from algae to land plants, but its physiological functions remain elusive in non-vascular plants. Here, we focused on MpACL5, a gene in the liverwort Marchantia polymorpha, that rescued the dwarf phenotype of the acl5 mutant in Arabidopsis. In the Mpacl5 mutants generated by genome editing, severe growth retardation was observed in the vegetative organ, thallus, and the sexual reproductive organ, gametangiophore. The mutant gametangiophores exhibited remarkable morphological defects such as short stalks, fasciation, and indeterminate growth. Two gametangiophores fused together and new gametangiophores were often initiated from the old ones. Furthermore, Mpacl5 showed altered responses to heat and salt stresses. Given the absence of spermine in bryophytes, these results suggest that thermospermine has a dual primordial function in organ development and stress responses in M. polymorpha. The stress response function may have eventually been assigned to spermine during land plant evolution.

Keywords:   Marchantia polymorpha ; ACAULIS5; polyamine; sexual organ; stress response; thermospermine

DOI:  https://doi.org/10.1093/pcp/pcae002
Free Radic Biol Med. 2023 Dec 28. pii: S0891-5849(23)01203-0. [Epub ahead of print]

Putrescine promotes MMP9-induced angiogenesis in skeletal muscle through hydrogen peroxide/METTL3 pathway.

Chengjun Hu, Fengjie Ji, Renlong Lv, Hanlin Zhou, Guanyu Hou, Tieshan Xu.

  Blood vessels play a crucial role in the development of skeletal muscle, ensuring the supply of nutrients and oxygen. Putrescine, an essential polyamine for eukaryotic cells, has an unclear impact on skeletal muscle angiogenesis. In this study, we observed lower vessel density and reduced putrescine level in the muscle of low-birth-weight piglet models, and identified a positive correlation between putrescine content and muscle vessel density. Furthermore, putrescine was found to promote angiogenesis in skeletal muscle both in vitro and in vivo by targeting matrix metalloproteinase 9 (MMP9). On a mechanistic level, putrescine augmented the expression of methyltransferase like 3 (METTL3) by attenuating hydrogen peroxide production, thereby increasing the level of N6-methyladenosine (m6A)-modified MMP9 mRNA. This m6A-modified MMP9 mRNA was subsequently recognized and bound by the YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), enhancing the stability of MMP9 mRNA and its protein expression, consequently accelerating angiogenesis in skeletal muscle. In summary, our findings suggest that putrescine enhances MMP9-mediated angiogenesis in skeletal muscle via the hydrogen peroxide/METTL3 pathway.

Keywords:  Hydrogen peroxide; METTL3; MMP9; Putrescine; Skeletal muscle angiogenesis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.041
Cell Metab. 2023 Dec 22. pii: S1550-4131(23)00458-8. [Epub ahead of print]

Human trials exploring anti-aging medicines.

Leonard Guarente, David A Sinclair, Guido Kroemer.

  Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.

Keywords:  age-related disease; autophagy; metformin; nicotinamide mononucleotide/NAD(+)/sirtuins; senescence

DOI:  https://doi.org/10.1016/j.cmet.2023.12.007