bims-polyam 2020-08-02 papers

on Polyamines

Issue of 2020–08–02
six papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Triggering doxorubicin release from responsive hydrogel films by polyamine uptake.
Altered brain arginine metabolism with age in the APPswe/PSEN1dE9 mouse model of Alzheimer's disease.
Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish.
Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective.
Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome.
Mechanisms by which autophagy regulates memory capacity in ageing.

Soft Matter. 2020 Jul 29.

Triggering doxorubicin release from responsive hydrogel films by polyamine uptake.

Néstor A Pérez-Chávez, Victor Nosthas Aguiar, Juan A Allegretto, Alberto G Albesa, Juan M Giussi, Gabriel S Longo.

Polyamines such as putrescine, spermidine and spermine are required in many inter- and intra-cellular processes. There is, however, evidence of anomalously high concentrations of these polyamines around cancer cells. Furthermore, high polyamine concentrations play a key role in accelerating the speed of cancer proliferation. Some current therapies target the reduction of the polyamine concentration to delay the cancer advance. In this study, we use a molecular theory to prove the concept that poly(methacrylic acid) (PMAA) hydrogels can play the dual role of incorporating and retaining polyamines as well as releasing preloaded drugs in response. Towards such a goal, we have developed a molecular model for each of the chemical species, which includes the shape, size, charge, protonation state, and configuration. Our results indicate that PMAA hydrogel films can incorporate significant amounts of polyamines; this absorption increases with the solution concentration of the polyamines. Doxorubicin was chosen as a model drug for this study, which can be successfully incorporated within the film; the optimal encapsulation conditions occur at low salt concentrations and pH values near neutral. Polyamine absorption within the film results in the desorption of the drug from the hydrogel. An increase in the concentration of the polyamines enhances the drug release. To validate our theoretical findings, poly(methacrylic acid) hydrogel thin films were synthesized by atom transfer radical polymerization. Absorption/desorption experiments followed by UV-Vis spectroscopy demonstrate doxorubicin encapsulation within these films and polyamine-dependent drug release.

DOI: https://doi.org/10.1039/d0sm00951b
Neurochem Int. 2020 Jul 22. pii: S0197-0186(20)30189-3. [Epub ahead of print] 104798

Altered brain arginine metabolism with age in the APPswe/PSEN1dE9 mouse model of Alzheimer's disease.

Pranav Kumar Vemula, Yu Jing, Jody Cicolini, Hu Zhang, Bruce G Mockett, Wickliffe C Abraham, Ping Liu.

  Amyloid-beta (Aβ) cleaved from amyloid precursor protein (APP) has been proposed to play a central and causative role in the aetiology of Alzheimer's disease (AD). APPswe/PSEN1dE9 (APP/PS1) transgenic mice display chronic Aβ accumulation and deposition in the brain. L-arginine is a semi-essential amino acid with a number of bioactive metabolites, and altered arginine metabolism has been implicated in the pathogenesis and/or the development of AD. This study systematically investigated how arginine metabolic profiles changed in the frontal cortex, hippocampus, parahippocampal region and cerebellum of male APP/PS1 mice at 4, 9 and 17 months of age relative to their sex- and age-matched wildtype controls. Immunohistochemistry demonstrated age-related Aβ deposition in the brain. High-performance liquid chromatography and mass spectrometry revealed age-related increases in glutamine, spermidine and spermine in APP/PS1 mice in a region-specific manner. Notably, genotype-related increases in spermine were found in the frontal cortex at the 9-month age point and in the frontal cortex, hippocampus and parahippocampal region at 17 months of age. Given the existing literature indicating the role of polyamines (spermine in particular) in modulating the aggregation and toxicity of Aβ oligomers, increased spermidine and spermine levels in APP/PS1 mice may be a neuroprotective mechanism to combat Aβ toxicity. Future research is required to better understand the functional significance of these changes.

Keywords:  APP/PS1 mice; arginine metabolism; frontal cortex; glutamine; hippocampus; polyamines

DOI:  https://doi.org/10.1016/j.neuint.2020.104798
Islets. 2020 Jul 25. 1-9

Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish.

Morgan A Robertson, Leah R Padgett, Jonathan A Fine, Gaurav Chopra, Teresa L Mastracci.

  Type 1 diabetes (T1D) is a disease characterized by destruction of the insulin-producing beta cells. Currently, there remains a critical gap in our understanding of how to reverse or prevent beta cell loss in individuals with T1D. Previous studies in mice discovered that pharmacologically inhibiting polyamine biosynthesis using difluoromethylornithine (DFMO) resulted in preserved beta cell function and mass. Similarly, treatment of non-obese diabetic mice with the tyrosine kinase inhibitor Imatinib mesylate reversed diabetes. The promising findings from these animal studies resulted in the initiation of two separate clinical trials that would repurpose either DFMO (NCT02384889) or Imatinib (NCT01781975) and determine effects on diabetes outcomes; however, whether these drugs directly stimulated beta cell growth remained unknown. To address this, we used the zebrafish model system to determine pharmacological impact on beta cell regeneration. After induction of beta cell death, zebrafish embryos were treated with either DFMO or Imatinib. Neither drug altered whole-body growth or exocrine pancreas length. Embryos treated with Imatinib showed no effect on beta cell regeneration; however, excitingly, DFMO enhanced beta cell regeneration. These data suggest that pharmacological inhibition of polyamine biosynthesis may be a promising therapeutic option to stimulate beta cell regeneration in the setting of diabetes.

Keywords:  Beta cell; DFMO; difluoromethylornithine; imatinib; islet; ornithine decarboxylase; polyamine biosynthesis; regeneration; type 1 diabetes; zebrafish

DOI:  https://doi.org/10.1080/19382014.2020.1791530
Int J Mol Sci. 2020 Jul 25. pii: E5291. [Epub ahead of print]21(15):

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective.

Gonçalo S Clemente, Aren van Waarde, Inês F Antunes, Alexander Dömling, Philip H Elsinga.

  Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

Keywords:  arginase; arginase inhibitors; molecular imaging; nitric oxide; positron emission tomography (PET)

DOI:  https://doi.org/10.3390/ijms21155291
J Clin Invest. 2020 Jul 28. pii: 126923. [Epub ahead of print]

Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome.

Julia Baier, Maximilian Gänsbauer, Claudia Giessler, Harald Arnold, Mercedes Muske, Ulrike Schleicher, Soeren Lukassen, Arif B Ekici, Manfred Rauh, Christoph Daniel, Arndt Hartmann, Benjamin Schmid, Philipp Tripal, Katja Dettmer, Peter J Oefner, Raja Atreya, Stefan Wirtz, Christian Bogdan, Jochen Mattner.

  Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from experimental colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells and an accumulation of intraluminal polyamines that promote epithelial healing. The pro-resolving effect of Arg1-deletion was reduced by an L-arginine-free diet, but rescued by simultaneous deletion of other L-arginine-metabolizing enzymes such as Arg2 or Nos2, demonstrating that protection from colitis requires L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wild-type recipients ameliorated intestinal inflammation while transfers from wild-type littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of L-arginine as well as altered intestinal microbiota and metabolic products account for the accelerated resolution from colitis in the absence of Arg1. Consequently, the metabolism of L-arginine may serve as target for clinical intervention in IBD patients.

Keywords:  Cellular immune response; Gastroenterology; Immunology; Polyamines

DOI:  https://doi.org/10.1172/JCI126923
Aging Cell. 2020 Jul 30. e13189

Mechanisms by which autophagy regulates memory capacity in ageing.

Maria De Risi, Giulia Torromino, Michele Tufano, Stéphanie Moriceau, Annabella Pignataro, Manon Rivagorda, Nicolò Carrano, Silvia Middei, Carmine Settembre, Martine Ammassari-Teule, Fabrizio Gardoni, Andrea Mele, Franck Oury, Elvira De Leonibus.

  Autophagy agonists have been proposed to slow down neurodegeneration. Spermidine, a polyamine that acts as an autophagy agonist, is currently under clinical trial for the treatment of age-related memory decline. How Spermidine and other autophagy agonists regulate memory and synaptic plasticity is under investigation. We set up a novel mouse model of mild cognitive impairment (MCI), in which middle-aged (12-month-old) mice exhibit impaired memory capacity, lysosomes engulfed with amyloid fibrils (β-amyloid and α-synuclein) and impaired task-induced GluA1 hippocampal post-translation modifications. Subchronic treatment with Spermidine as well as the autophagy agonist TAT-Beclin 1 rescued memory capacity and GluA1 post-translational modifications by favouring the autophagy/lysosomal-mediated degradation of amyloid fibrils. These findings provide new mechanistic evidence on the therapeutic relevance of autophagy enhancers which, by improving the degradation of misfolded proteins, slow down age-related memory decline.

Keywords:  GluA1; Spermidine; ageing; alpha-synuclein; amyloid fibrils; autophagy; mild cognitive impairment

DOI:  https://doi.org/10.1111/acel.13189