bims-polyam 2019-05-12 papers

on Polyamines

Issue of 2019–05–12
nine papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

PGC-1α inhibits polyamine synthesis to suppress prostate cancer aggressiveness.
Polyamine biosynthesis and biological roles in rhizobia.
Bolus Administration of Polyamines Boosts Effects on Hepatic Ischemia-Reperfusion Injury and Regeneration in Rats.
Neuroprotective Offerings by Agmatine.
Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting AMPK/mTOR signaling pathway.
Resting energy expenditure in Argininosuccinic Aciduria, and in other Urea Cycle disorders.
AMADH inhibitor optimization and its effects on GABA accumulation in soybean sprouts under NaCl-CaCl2 treatment.
Biogenic amines: Concentrations in serum and skeletal muscle from late pregnancy until early lactation in dairy cows with high versus normal body condition score.
Effect of arginine deimination and citrulline side chain length on secondary structure formation.

Cancer Res. 2019 May 07. pii: canres.2043.2018. [Epub ahead of print]

PGC-1α inhibits polyamine synthesis to suppress prostate cancer aggressiveness.

Lisa Kaminski, Stéphanie Torrino, Maeva Dufies, Zied Djabari, Romain Haider, François-René Roustan, Emilie Jaune, Kathiane Laurent, Nicolas Nottet, Jean-François Michiels, Maeva Gesson, Stéphane Rocchi, Nathalie M Mazure, Matthieu Durand, Jean François Tanti, Damien Ambrosetti, Stephan Clavel, Issam Ben-Sahra, Frédéric Bost.

Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer (PCa). Here we show that PGC-1α represses the metastatic properties of PCa cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC-1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate limiting enzyme for polyamine synthesis. Analysis of in vivo metastases and clinical data from prostate cancer patients support the proposition that the PGC-1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC-1α renders PCa cells dependent on polyamine to promote metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-18-2043
FEMS Microbiol Lett. 2019 Apr 01. pii: fnz084. [Epub ahead of print]366(7):

Polyamine biosynthesis and biological roles in rhizobia.

Victor A Becerra-Rivera, Michael F Dunn.

  Polyamines are ubiquitous molecules containing two or more amino groups that fulfill varied and often essential physiological and regulatory roles in all organisms. In the symbiotic nitrogen-fixing bacteria known as rhizobia, putrescine and homospermidine are invariably produced while spermidine and norspermidine synthesis appears to be restricted to the alfalfa microsymbiont Sinorhizobium meliloti. Studies with rhizobial mutants deficient in the synthesis of one or more polyamines have shown that these compounds are important for growth, stress resistance, motility, exopolysaccharide production and biofilm formation. In this review, we describe these studies and examine how polyamines are synthesized and regulated in rhizobia.

Keywords:   Sinorhizobium meliloti ; basic amino acid decarboxylases; nitrogen fixation; polyamines; rhizobia-legume symbiosis

DOI:  https://doi.org/10.1093/femsle/fnz084
Eur Surg Res. 2019 May 03. 60(1-2): 63-73

Bolus Administration of Polyamines Boosts Effects on Hepatic Ischemia-Reperfusion Injury and Regeneration in Rats.

Junshi Doi, Yasuhiro Fujimoto, Takumi Teratani, Naoya Kasahara, Masashi Maeda, Tatsuaki Tsuruyama, Taku Iida, Shintaro Yagi, Shinji Uemoto.

   BACKGROUND: It was demonstrated that polyamines ameliorate ischemia-reperfusion injury (IRI) and promote regeneration in the liver. An optimal protocol of polyamine treatment remains unknown in the clinical setting. We examined 2 types of administration methods using rat models.
METHODS: Experiment 1: evaluation of pharmacokinetics of polyamines. Experiment 2: for 3 days preoperatively and 5 days postoperatively, polyamines were given to male Lewis rats in the following three groups: the control group, no polyamine administration; the chow group, 0.05% polyamines mixed in chow; the bolus group, polyamines (200 μmol/kg) given by gastric tube once a day. All rats received 70% hepatectomy after 40 min of warm IRI. Postoperatively, IRI and regeneration were evaluated with assessment of serum levels of hepatic enzymes, histology and immunohistochemistry of liver tissue, and measurement of remnant liver weight.
RESULTS: The blood concentrations of polyamines in the portal vein increased at 1 h of bolus administration, while they did not increase without the bolus. The bolus group was significantly associated with lower serum levels of aspartate/alanine aminotransferases (p < 0.05), decreased hepatocyte congestion, vacuolization and necrosis in histopathological scoring (p < 0.05), a lower number of TUNEL-positive hepatocytes (p < 0.05), higher remnant liver weight at 24, 48, and 168 h (p < 0.05), and a higher Ki-67 labeling index (24 h, p < 0.01) compared with the chow group.
CONCLUSION: The bolus administration of polyamines was more effective in ameliorating IRI and promoting regeneration than chow administration. Perioperative bolus administration of polyamines might be an optimal treatment, when clinically applied.

Keywords:  Bolus administration; Hepatic ischemia-reperfusion injury; Hepatic regeneration; Polyamine; Rat

DOI:  https://doi.org/10.1159/000497434
Neurotoxicology. 2019 May 04. pii: S0161-813X(19)30037-3. [Epub ahead of print]

Neuroprotective Offerings by Agmatine.

Nandkishor Ramdas Kotagale, Brijesh Gulabrao Taksande, Nazma Najiahmad Inamdar.

  Agmatine, an endogenous polyamine in CNS, is derived from arginine by dearboxylation. Like polyamines, agmatine has been studied for its neuroprotetive effects. At present, a large body of experimental evidences has been gathered that demonstrate the neuroprotective effects of agmatine. The neuroprotective effects have been observed in various CNS cell lines and animal models against the excitotocity, oxidative damage, corticosteroidid induced neurotoxicity, ischemic/hypoxic or oxygen-glucose deprivation toxicity, spinal cord injury and traumatic brain injury. The studies have been extended to rescue of retinal ganglion cells from toxicities. The mechanistic studies suggest that neuroprotection offered by agmatine can be assigned to its multimolecular biological effects. These include its action as glutamatergic receptor antagonist, α2-adrenoceptor agonist, imidazoline binding site ligand, NOS inhibitor, ADP ribosylation inhibitor, and blocker of ATP-sensitive potassium and voltage-gated calcium channels, anti-apoptotic and antioxidant. Its action as regulator for polyamine synthesis, insulin release assists the neuroprotection. The cumulative evidences of preclinical studies support the possible use of agmatine as an agent for neuronal damage and neurodegenerative diseases. However, it will be hasty to assert and promote agmatine as a novel therapeutic agent for neuroprotection. The review is focused on the role of agmatine in different types and mechanisms of neural injuries. The aspects of concern like dose range, pharmacokinetics of exogenous agmatine, levels of endogenous agmatine during events of injury etc. has to be addressed.

Keywords:  Agmatine; excitotoxicity; ischemic toxicity; molecular targets; neuroprotection; neurotoxicity; retinal ganglions; spinal cord injury; traumatic brain injury

DOI:  https://doi.org/10.1016/j.neuro.2019.05.001
Br J Pharmacol. 2019 May 11.

Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting AMPK/mTOR signaling pathway.

Jing Yan, Jian-Yun Yan, Yu-Xi Wang, Yuan-Na Ling, Xu-Dong Song, Si-Yi Wang, Hai-Qiong Liu, Qi-Cai Liu, Ya Zhang, Ping-Zhen Yang, Xian-Bao Wang, Ai-Hua Chen.

   BACKGROUND AND PURPOSE: Spermidine (SPD), a natural polyamine, is abundant in mammalian cells and is involved in cell growth, proliferation and regeneration. A recent study found that oral SPD supplements exert a cardioprotective effect in aging-related cardiac dysfunction via enhancing autophagic flux. However, the effect of SPD on myocardial injury and cardiac dysfunction following myocardial infarction (MI) remains unknown.
EXPERIMENTAL APPROACH: In vitro and in vivo models of myocardial injury were adopted to determine the role of SPD in MI. Angiotensin II (Ang II) was used to induce cultured neonatal rat cardiomyocytes (NRCs) injury and MI model of Sprague-Dawley rats was constructed by permanent ligation of the left anterior descending artery.
KEY RESULTS: In this study, we found that SPD improved cardiomyocyte viability and decreased cell necrosis in NRCs treated with Ang II. SPD reduced infarct size and improved cardiac function as well as attenuated myocardial hypertrophy in post-MI rats. Besides, SPD suppressed the oxidative damage and inflammatory cytokines induced by MI. Moreover, SPD enhanced autophagic flux and decreased apoptosis both in vitro and in vivo. Furthermore, we found that the protective effects of SPD on the cardiomyocyte apoptosis and cardiac dysfunction were abolished by autophagy inhibitor chloroquine, indicating that SPD exerted cardioprotective effects at least partially through promoting autophagic flux. We further noted that SPD enhanced autophagic flux by activation of AMPK/mTOR signalling pathway.
CONCLUSION AND IMPLICATIONS: Conclusively, our findings suggest for the first time that SPD improves MI-induced cardiac dysfunction by promoting the AMPK/mTOR-mediated autophagic flux.

Keywords:  AMPK/mTOR; apoptosis; autophagic flux; myocardial infarction; spermidine

DOI:  https://doi.org/10.1111/bph.14706
J Inherit Metab Dis. 2019 May 06.

Resting energy expenditure in Argininosuccinic Aciduria, and in other Urea Cycle disorders.

A Brambilla, M L Bianchi, R Cancello, C Galimberti, S Gasperini, R Pretese, M Rigoldi, S Tursi, R Parini.

   BACKGROUND: No data are available on the specific energy needs of patients affected with Urea Cycle disorders (UCD) and especially Argininosuccinic Aciduria (ASA). In our experience, ASA patients tend to develop central adiposity and hypertriglyceridemia when treated with apparently adequate energy intake, while the other UCD do not.
OBJECTIVE AND METHODS: The aim of this study was to evaluate anthropometric parameters, body composition, risk of metabolic syndrome (MS) and resting energy expenditure (REE), both by indirect calorimetry (IC) and predictive equations, in UCD patients.
RESULTS: Hypertension (5/13), pathological waist circumference-to-height ratio (WtHr) (6/13), hypertriglyceridemia (12/13), reduced HDL cholesterol (12/13), and MS (5/13) were found in ASA group. In the ASA cohort, the mean and median IC-REE were 88% of what was predicted by Food and Agriculture Organization of the United Nations and Harris-Benedict equations. The "other UCD" cohort did not show hypertension, dyslipidaemia nor MS; IC-REE was similar to the REE predicted by equations. A significant difference was seen for the presence of hypertension, dyslipidaemia, pathological WtHr, MS and IC-REE/predictive equations-REE in the two cohorts.
CONCLUSIONS: ASA patients have a risk of overfeeding if their energy requirement is not assessed individually with IC. Excessive energy intake might increase the cardiovascular risk of ASA patients. We suggest to test ASA individuals with IC every year if the patient is sufficiently collaborative. We speculate that most of the features seen in ASA patients might depend on an imbalance of Krebs cycle. Further studies are needed to verify this hypothesis. This article is protected by copyright. All rights reserved.

Keywords:  Argininosuccinic aciduria; dyslipidaemia and argininosuccinic aciduria; metabolic syndrome and argininosuccinic aciduria; resting energy expenditure; resting energy expenditure and argininosuccinic aciduria; urea cycle disorders

DOI:  https://doi.org/10.1002/jimd.12108
3 Biotech. 2019 May;9(5): 184

AMADH inhibitor optimization and its effects on GABA accumulation in soybean sprouts under NaCl-CaCl2 treatment.

Runqiang Yang, Mian Wang, Xiaoyun Feng, Zhenxin Gu, Pei Wang.

   Abstract: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) was the suitable inhibitor for aminoaldehyde dehydrogenase (AMADH) compared with N-ethylmaleimide (NEE) and iodoacetamide (IAM). EDC exhibited the most obvious inhibition effect on AMADH activity, while its inhibition on glutamate decarboxylase (GAD) was insignificant. Compared with the control, AMADH activity reduced by 70.4% with 0.5 mM EDC, and γ-aminobutyric acid (GABA) content declined by 44.3% in soybean sprouts at 4 days of germination. AMADH activity reduced by 80.62, 67.61 and 72.02% in the 4-day sprouts with 1 mM EDC under NaCl, CaCl2 and NaCl + CaCl2 treatment, respectively, and GABA content decreased by 43.56, 38.84 and 35.53%, respectively. EDC is a proper inhibitor for AMADH and it could be used to quantify the contribution of polyamine degradation pathway on GABA formation. In soybean sprouts, the presence of CaCl2 under NaCl stress decreased the contribution of polyamine degradation pathway on GABA accumulation.
Graphical Abstract:

Keywords:  AMADH; GABA; Germination; Soybean sprouts

DOI:  https://doi.org/10.1007/s13205-019-1715-7
J Dairy Sci. 2019 May 02. pii: S0022-0302(19)30402-3. [Epub ahead of print]

Biogenic amines: Concentrations in serum and skeletal muscle from late pregnancy until early lactation in dairy cows with high versus normal body condition score.

M H Ghaffari, H Sadri, K Schuh, G Dusel, Dörte Frieten, C Koch, C Prehn, J Adamski, H Sauerwein.

  Biogenic amines (BA) are a class of nitrogenous compounds that are involved in a wide variety of physiological processes, but their role in transition cows is poorly understood. Our objectives were to describe the longitudinal changes of BA in serum and in skeletal muscle during the transition period and to characterize temporal responses of BA in relation to body condition score (BCS) of periparturient dairy cows. Fifteen weeks before calving, 36 multiparous Holstein cows were assigned to 2 groups (n = 18 per group) that were fed differently to reach either high [HBCS; net energy for lactation (NEL) = 7.2 MJ/kg of dry matter (DM)] or normal BCS (NBCS; NEL = 6.8 MJ/kg of DM) at dry-off. The targeted BCS and back fat thickness (BFT) at dry-off (HBCS, >3.75 and >1.4 cm; NBCS, <3.5 and <1.2 cm) were reached. Thereafter, both groups were fed identical diets. Blood samples and muscle (semitendinosus) biopsies were collected at d -49, +3, +21, and +84 relative to parturition. In serum and skeletal muscle, BA concentrations were measured using a targeted metabolomics assay. The data were analyzed as a repeated measure using the MIXED procedure of SAS. The serum concentrations of most BA (i.e., creatinine, taurine, carnosine putrescine, spermine, α-aminoadipic acid, acetylornithine, kynurenine, serotonin, hydroxyproline, asymmetric dimethylarginine, and symmetric dimethylarginine) fluctuated during the transition period, while others (i.e., spermidine, phenylethylamine) did not change with time. The muscle concentrations of BA remained unchanged over time. Creatinine had the highest concentrations in the serum, while carnosine had the highest concentration among the muscle BA. The serum concentrations of creatinine (d +21), putrescine (d +84), α-aminoadipic acid (d +3), and hydroxyproline (d +21) were or tended to be higher for HBCS compared with NBCS postpartum. The serum concentrations of symmetric dimethylarginine (d -49) and acetylornithine (d +84) were or tended to be lower for HBCS compared with NBCS, respectively. The serum kynurenine/tryptophan ratio was greater with HBCS than with NBCS (d +84). Compared with NBCS, HBCS was associated with lower muscle concentrations of carnosine, but those of hydroxyproline were higher (d -49). In both serum and muscle, the asymmetric dimethylarginine concentrations were greater with HBCS than with NBCS (d -49). No correlation was found between serum and skeletal muscle BA. This study indicates that overconditioning of dairy cows may influence serum and muscle BA concentrations in the periparturient period.

Keywords:  biogenic amines; body condition score; transition cows

DOI:  https://doi.org/10.3168/jds.2018-16034
Chembiochem. 2019 May 09.

Effect of arginine deimination and citrulline side chain length on secondary structure formation.

Po-Yi Wu, Chin-Yi Chen, Jhe-Hao Li, Jin-Kai Lin, Ting-Hsuan Chen, Shou-Ling Huang, Shing-Jong Huang, Richard Ping Cheng.

  Post-translational modifications expand the chemical functionality beyond the encoded amino acids, but studies on the structural effects of these modifications have been limited. Arginine (Arg) undergoes deimination to give citrulline (Cit), converting the positively charged guanidinium group into a neutral urea group. Herein, we present the effect of Arg deimination on secondary structure formation. To understand the reason for the number of methylenes in Cit, the effect of Cit side chain length on secondary structure formation is also presented. Ala-based peptides and β-hairpin peptides were used to study α-helix and β-sheet formation, respectively. Peptides containing Cit analogues were prepared by an orthogonal protecting group strategy coupled with solid phase ureidylation. The CD data for the Ala-based peptides was analysed based on modified Lifson-Roig theory, showing that the helix propensity of Arg decreased upon deimination and either shortening or lengthening Cit decreased helix propensity. The hairpin peptides were analysed by NMR methods, showing minimal change in strand formation energetics upon Arg deimination and altering the Cit side chain length did not affect strand formation energetics either. These results should be useful for the preparation of urea-bearing molecules and the design of peptides with urea-bearing residues with varying side chain length.

Keywords:  Citrulline; Peptide; α-Helix; β-Hairpin

DOI:  https://doi.org/10.1002/cbic.201900231