bims-polyam 2020-06-14 papers

on Polyamines

Issue of 2020–06–14
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Evidence for polyamine, biogenic amine, and amino acid adduction resulting from metabolic activation of diosbulbin B.
Insights into the Mn2+ Binding Site in the Agmatinase-Like Protein (ALP): A Critical Enzyme for the Regulation of Agmatine Levels in Mammals.
Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung.
COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status.
Spermine Promotes Pulmonary Vascular Remodelling and Its Synthase is a Therapeutic Target for Pulmonary Arterial Hypertension.
Involvement of hippocampal agmatine in β1-42 amyloid induced memory impairment, neuroinflammation and BDNF signaling disruption in mice.
Spermine-priming restrained water relations and biochemical deteriorations prompted by water deficit on two soybean cultivars.
Colorimetric sensor and LDI-MS detection of biogenic amines in food spoilage based on porous PLA and graphene oxide.

Chem Res Toxicol. 2020 Jun 09.

Evidence for polyamine, biogenic amine, and amino acid adduction resulting from metabolic activation of diosbulbin B.

Zhengyu Zhang, Hui Li, Wei Li, Yukun Feng, Zixia Hu, Shenzhi Zhou, Na Zhang, Ying Peng, Jiang Zheng.

Dioscorea bulbifera L. (DBL), a traditional Chinese medicine, is a well-known herb with hepatotoxicity, and the biochemical mechanisms of the toxic action remain unknown. Diosbulbin B (DSB), a major component of DBL, can induce severer liver injury which requires cytochrome P450-catalyzed oxidation of the furan ring. It is reported that a cis-enedial reactive intermediate resulting from metabolic activation of DSB can react with thiols and amines to form pyrrole or pyrroline derivatives. In this study, we investigated the interaction of the reactive intermediate with polyamines, biogenic amines, and amino acids involved in polyamine metabolic pathway, including putrescine, spermidine, spermine, histamine, arginine, ornithine, lysine, glutamine, and asparagine. Seven DSB-derived amine adducts were detected in microsomal incubations supplemented with DSB and individual amines. Six adducts were observed in cultured rat primary hepatocytes after exposure to DSB. DSB was found to induce apoptosis and cell death in time- and concentration-dependent manners. Apparently, the observed apoptosis was associated with the detected amine adduction. The findings facilitate the understanding of the mechanisms of toxic action of DSB.

DOI: https://doi.org/10.1021/acs.chemrestox.0c00017
Int J Mol Sci. 2020 Jun 10. pii: E4132. [Epub ahead of print]21(11):

Insights into the Mn2+ Binding Site in the Agmatinase-Like Protein (ALP): A Critical Enzyme for the Regulation of Agmatine Levels in Mammals.

María-Belen Reyes, José Martínez-Oyanedel, Camila Navarrete, Erika Mardones, Ignacio Martínez, Mónica Salas, Vasthi López, María García-Robles, Estefania Tarifeño-Saldivia, Maximiliano Figueroa, David García, Elena Uribe.

  Agmatine is a neurotransmitter with anticonvulsant, anti-neurotoxic and antidepressant-like effects, in addition it has hypoglycemic actions. Agmatine is converted to putrescine and urea by agmatinase (AGM) and by an agmatinase-like protein (ALP), a new type of enzyme which is present in human and rodent brain tissues. Recombinant rat brain ALP is the only mammalian protein that exhibits significant agmatinase activity in vitro and generates putrescine under in vivo conditions. ALP, despite differing in amino acid sequence from all members of the ureohydrolase family, is strictly dependent on Mn2+ for catalytic activity. However, the Mn2+ ligands have not yet been identified due to the lack of structural information coupled with the low sequence identity that ALPs display with known ureohydrolases. In this work, we generated a structural model of the Mn2+ binding site of the ALP and we propose new putative Mn2+ ligands. Then, we cloned and expressed a sequence of 210 amino acids, here called the "central-ALP", which include the putative ligands of Mn2+. The results suggest that the central-ALP is catalytically active, as agmatinase, with an unaltered Km for agmatine and a decreased kcat. Similar to wild-type ALP, central-ALP is activated by Mn2+ with a similar affinity. Besides, a simple mutant D217A, a double mutant E288A/K290A, and a triple mutant N213A/Q215A/D217A of these putative Mn2+ ligands result on the loss of ALP agmatinase activity. Our results indicate that the central-ALP contains the active site for agmatine hydrolysis, as well as that the residues identified are relevant for the ALP catalysis.

Keywords:  ALP; manganese; ureohydrolase

DOI:  https://doi.org/10.3390/ijms21114132
Am J Physiol Lung Cell Mol Physiol. 2020 Jun 10.

Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung.

Nancy Ahrendt, Tobias Steingrüber, Alexandra Rajces, Elena Lopez-Rodriguez, Tobias Eisenberg, Christoph Magnes, Frank Madeo, Simon Sedej, Andreas Schmiedl, Matthias Ochs, Christian Mühlfeld, Julia Schipke.

  Obesity is associated with lung function impairment and respiratory diseases; however, the underlying pathophysiological mechanisms are still elusive and therapeutic options are limited. This study examined the effects of prolonged excess fat intake on lung mechanics and microstructure and tested spermidine supplementation and physical activity as intervention strategies. C57BL/6N mice fed control diet (CD, 10% fat) or high fat diet (HFD, 60% fat) were left untreated, were supplemented with 3 mM spermidine, had access to running wheels for voluntary activity or a combination of both. After 30 weeks, lung mechanics was assessed and left lungs were analyzed by design-based stereology. HFD exerted minor effects on lung mechanics, and resulted in higher body weight and elevated lung, air and septal volumes. The number of alveoli was higher in HFD-fed animals. This was accompanied by an increase in epithelial, but not endothelial surface area. Moreover, air-blood-barrier and endothelium were significantly thicker. Neither treatment affected HFD-related body weights. Spermidine lowered lung volumes as well as endothelial and air-blood barrier thicknesses towards control levels and substantially increased the endothelial surface area under HFD. Activity resulted in decreased volumes of lung, septa and septal compartments, but did not affect vascular changes in HFD-fed mice. The combination treatment showed no additive effect. In conclusion, excess fat consumption induced alveolar capillary remodeling indicative of impaired perfusion and gas diffusion. Spermidine alleviated obesity-related endothelial alterations indicating a beneficial effect, whereas physical activity reduced lung volumes apparently by other, possibly systemic effects.

Keywords:  diet-induced obesity; lung ultrastructure; physical activity; polyamine spermidine

DOI:  https://doi.org/10.1152/ajplung.00423.2019
medRxiv. 2020 May 16. pii: 2020.05.14.20102491. [Epub ahead of print]

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status.

Tiffany Thomas, Davide Stefanoni, Julie A Reisz, Travis Nemkov, Lorenzo Bertolone, Richard O Francis, Krystalyn E Hudson, James C Zimring, Kirk C Hansen, Eldad A Hod, Steven L Spitalnik, Angelo D'Alessandro.

Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is well-known to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients. Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.

DOI: https://doi.org/10.1101/2020.05.14.20102491
Eur Respir J. 2020 Jun 08. pii: 2000522. [Epub ahead of print]

Spermine Promotes Pulmonary Vascular Remodelling and Its Synthase is a Therapeutic Target for Pulmonary Arterial Hypertension.

Yang-Yang He, Yi Yan, Xin Jiang, Jun-Han Zhao, Zhe Wang, Tao Wu, Yong Wang, Shan-Shan Guo, Jue Ye, Tian-Yu Lian, Xi-Qi Xu, Jin-Lan Zhang, Kai Sun, Fu-Hua Peng, Yu-Ping Zhou, Yi-Min Mao, Xue Zhang, Ji-Wang Chen, Shu-Yang Zhang, Zhi-Cheng Jing.

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through HPLC-MS, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase (SMS) were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase (SMS) in the pathological process. Inhibition of SMS in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

DOI: https://doi.org/10.1183/13993003.00522-2020
Neurotoxicology. 2020 Jun 06. pii: S0161-813X(20)30089-9. [Epub ahead of print]

Involvement of hippocampal agmatine in β1-42 amyloid induced memory impairment, neuroinflammation and BDNF signaling disruption in mice.

Nandkishor Kotagale, Shubham Rahmatkar, Sarita Chauragade, Madhura Dixit, Milind Umekar, Chandrabhan Chopde, Brijesh Taksande.

  Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular β-amyloid (Aβ) plaques and neuronal damage. The present study investigated the effect of chronic intra-hippocampal agmatine administration on β-Amyloid (Aβ) induced memory impairment in mice. Aβ1-42peptide injected mice demonstrated impairment of cognitive abilities evaluated as reference memory error and working memory error in radial arm maze (RAM) and decreased exploration time for novel object as well as recognition index in novel object recognition (NOR) test along with elevation in Aβ1-42 peptide, β-Site APP cleaving enzyme 1 (BACE 1), microtubule-associated protein tau (MAPt), interleukin-6, tumor necrosis factor-α and reduction in neprilysin and brain derived neurotrophic factor (BDNF) immunocontent within hippocampus and prefrontal cortex. Importantly, this was associated with a reduction in the agmatine levels following Aβ1-42 peptide administration. Chronic administration of agmatine from day 8-27, prevented the memory impairment in mice and normalized the neurochemical alteration within prefrontal cortex and hippocampus induced by Aβ1-42 peptide administration. However, it did not modulate the amyloid precursor protein and BACE expression. This study suggests that agmatine improves learning and memory impairment possibly through the down regulation of neuroinflammatory pathways in AD.

Keywords:  Alzheimer's disease; Amyloid (Aβ); BDNF; Neuro-inflammation; hippocampus; memory impairment

DOI:  https://doi.org/10.1016/j.neuro.2020.06.002
Heliyon. 2020 May;6(5): e04038

Spermine-priming restrained water relations and biochemical deteriorations prompted by water deficit on two soybean cultivars.

Mona F A Dawood, Amany H A Abeed.

  The outstanding role of spermine in eliciting defense adaptation of soybean to different levels of water deficit (0, -0.1, -0.5 and -1.1 MPa) was investigated by determining the changes in growth, photosynthetic pigments, osmolytes, water relations, and antioxidants. All the studied traits clearly revealed cultivar-dependent variation in response to water deficit where cv. Giza 111 was tolerant and cv. Giza 21 was sensitive. Both cultivars came in agreement that photosynthetic limitation (chlorophylls reduction) was the troubling shot induced by water deficit. Such limitation was reflected on three directions (a) disturbances of water relations (stomatal conductance, transpiration rate, relative water content and water use efficiency), (b) down regulation of metabolites which affect osmotic adjustment and (c) elevated reactive oxygen species (increased hydrogen peroxide) and destruction of membrane stability (increment of electrolyte leakage and lipid peroxidation). The damaging impacts of water deficit on these parameters were obviously coined for sensitive cultivar compared to tolerant one. Although spermine priming did not have apparent stimulatory role on well-watered plants, unequivocal inversion from a state of down regulation to up-regulation was distinct under water stress. In this regard, spermine enhanced pigments, osmolytes accumulation, up-regulated water relations and enhanced membrane stabilization. Furthermore, spermine pre-sowing decreased oxidative stress by lowering hydrogen peroxide via activation of anthocyanins, total antioxidants and phenolic compounds.

Keywords:  Agricultural science; Antioxidants; Biochemistry; Biotechnology; Earth sciences; Ecology; Environmental science; Hydrology; Osmolyte; Physiology; Pigments; Plant biology; Spermine; Water deficit; Water relation

DOI:  https://doi.org/10.1016/j.heliyon.2020.e04038
Food Chem. 2020 May 27. pii: S0308-8146(20)31027-X. [Epub ahead of print]329 127165

Colorimetric sensor and LDI-MS detection of biogenic amines in food spoilage based on porous PLA and graphene oxide.

Tatiya Siripongpreda, Krisana Siralertmukul, Nadnudda Rodthongkum.

  Biogenic amines are the important markers for food spoilage, thus, an on-package sensor for biogenic amine detection is crucial for food quality control. A dual detection platform including colorimetry and LDI-MS was developed for screening and quantitative determining of biogenic amines. Porous PLA film, was fabricated using calcium carbonate nanoparticles to enhance film porosity leading to increased surface area of colorimetric sensor. The color intensity significantly increases depending upon the enhanced analyte concentration with a linear range of 2.0-10.0 mg/mL for putrescine, and 0.1-6.0 mg/mL for cadaverine. On another layer, graphene oxide paper was applied as an LDI-MS substrate for sensitive quantification of biogenic amines. LOD values measured on graphene oxide coated side by LDI-MS were found to be 0.07 pM and 0.02 pM for putrescine and cadaverine, respectively. This platform was successfully applied for the detection of biogenic amines in pork samples with satisfactory results.

Keywords:  Cadaverine; Calcium carbonate nanoparticles; Dual detection; Food spoilage sensor; Putrescine

DOI:  https://doi.org/10.1016/j.foodchem.2020.127165