bims-polyam 2019-10-27 papers

on Polyamines

Issue of 2019–10–27
ten papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Dual role of polyamines in heart ischemia/reperfusion injury through regulation of mitochondrial permeability transition pore.
Acrolein is involved in ischemic stroke-induced neurotoxicity through spermidine/spermine-N1-acetyltransferase activation.
Altered plasma levels of arginine metabolites in depression.
The effects of oral arginine on its metabolic pathways in Sprague Dawley rats.
The potential therapeutic effect of NG-hydroxy-nor-L-arginine in 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats.
Structure, Function, and Evolution of the Pseudomonas aeruginosa Lysine Decarboxylase LdcA.
Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors.
Arginase Deficiency Presenting as Acute Encephalopathy.
Agmatine Protects Against the Progression of Sepsis Through the Imidazoline I2 Receptor-Ribosomal S6 Kinase 2-Nuclear Factor-κB Signaling Pathway.
Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells.

Sheng Li Xue Bao. 2019 Oct 25. 71(5): 681-688

Dual role of polyamines in heart ischemia/reperfusion injury through regulation of mitochondrial permeability transition pore.

Hui-Ying Chen, Xiao-Li Jia, Shu-Qin Zhao, Wei-Hong Zheng, Zhi-Gang Mei, Hong-Wei Yang, Shi-Zhong Zhang.

Polyamines (putrescine, spermidine, and spermine) are essential polycations that play important roles in various physiological and pathophysiological processes in mammalian cells. The study was to investigate their role in cardioprotection against ischemia/reperfusion (I/R) injury and the underlying mechanism. Isolated hearts from male Sprague-Dawley rats were Langendorff-perfused and cardiac I/R was achieved by 30 min of global ischemia followed by 120 min of reperfusion. Different concentrations of polyamines (0.1, 1, 10, and 15 μmol/L of putrescine, spermidine, and spermine), cyclosporin A (0.2 μmol/L), or atractyloside (20 μmol/L) were given 10 min before the onset of reperfusion. The hemodynamics were monitored; the lactate dehydrogenase (LDH) levels in the coronary effluent were measured spectrophotometrically; infarct size was determined by the 2,3,5-triphenyltetrazolium chloride staining method; and mitochondrial permeability transition pore (MPTP) opening was determined spectrophotometrically by the Ca2+-induced swelling of isolated cardiac mitochondria. The results showed that compared to I/R alone, 0.1 and 1 μmol/L polyamines treatment improved heart function, reduced LDH release, decreased infarct size, and these effects were inhibited by atractyloside (MPTP activator). In isolated mitochondria from normal rats, 0.1 and 1 μmol/L polyamines treatment inhibited MPTP opening. However, 10 and 15 μmol/L polyamines treatment had the opposite effects, and these effects were inhibited by cyclosporin A (MPTP inhibitor). Our findings showed that polyamines may have either protective or damaging effects on hearts suffering from I/R by inhibiting or activating MPTP opening.
Exp Neurol. 2019 Oct 17. pii: S0014-4886(19)30215-8. [Epub ahead of print]323 113066

Acrolein is involved in ischemic stroke-induced neurotoxicity through spermidine/spermine-N1-acetyltransferase activation.

Jin-Hui Liu, Tse-Wen Wang, Yung-Yang Lin, Wen-Chien Ho, Hong-Chieh Tsai, Shih-Pin Chen, Anya Maan-Yuh Lin, Tsung-Yun Liu, Hsiang-Tsui Wang.

   BACKGROUND AND PURPOSE: Ischemic stroke is the most common type of cerebrovascular event and is responsible for approximately 85% of all strokes in Taiwan. Neurons contain high concentrations of polyamines, which are prone to various pathological states in the brain and are perturbed after cerebral ischemia. Acrolein, an α,β-unsaturated aldehyde, has been suggested as the primary culprit of neuronal damage in stroke patients. However, the mechanism by which acrolein induces neuronal damage during ischemic stroke is not clear.
METHODS: Urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione (GSH) metabolite, plasma acrolein-protein conjugates (Acr-PC) and plasma GSH levels were analyzed to correlate disease severity and prognosis of stroke patients compared with control subjects. In vivo middle cerebral artery occlusion (MCAO) animal models and an in vitro oxygen glucose deprivation (OGD) stroke model were used to investigate the mechanisms of acrolein-induced neuronal damage.
RESULTS: A deregulated acrolein metabolism, including significantly increased plasma Acr-PC levels, decreased urinary 3-HPMA levels and decreased plasma GSH levels, was found in stroke patients compared to control subjects. We further observed that acrolein was produced during ischemia resulting in brain damage in in vivo MCAO animal model. The induction of acrolein in neuronal cells during OGD occurred due to the increased expression of spermidine/spermine N1-acetyltransferase (SSAT) by NF-kB pathway activation. In addition, acrolein elicited a vicious cycling of oxidative stress resulting in neurotoxicity. Finally, N-acetylcysteine effectively prevented OGD-induced neurotoxicity by scavenging acrolein.
CONCLUSION: Overall, our current results demonstrate that acrolein is a culprit of neuronal damage through GSH depletion in stroke patients. The mechanism underlying the role of acrolein in stroke-related neuronal damage occurs through SSAT-induced polyamine oxidation by NF-kB pathway activation. These results provide a novel mechanism of neurotoxicity in stroke patients, aid in the development of neutralizing or preventive measures, and further our understanding of neural protection.

Keywords:  3-HPMA; Acrolein; Glutathione; Ischemic stroke; Neurotoxicity; SSAT

DOI:  https://doi.org/10.1016/j.expneurol.2019.113066
J Psychiatr Res. 2019 Oct 07. pii: S0022-3956(19)30900-8. [Epub ahead of print]120 21-28

Altered plasma levels of arginine metabolites in depression.

Arisoy Ozden, Halaris Angelos, Aricioglu Feyza, Wild Elizabeth, Piletz John.

  L-Arginine pathway metabolites appear to play differential roles in the pathogenesis of major depressive disorder (MDD). Studies have revealed an antidepressant and anxiolytic effect of agmatine and putrescine. Possible mechanisms of these effects include inhibition of nitric oxide synthase and N-methyl-D-aspartate receptors. The present study sought to determine whether MDD is associated with altered levels of arginine metabolites and whether these metabolites are associated with depression, anxiety and stress severity. Seventy seven MDD patients 21-65 years of age with a minimum score of 18 on the Hamilton Depression Scale, and 27 age and sex matched healthy controls (HC) were included. Patients with uncontrolled physical diseases, abnormal routine lab tests, other psychiatric diagnoses, or under psychotropic medication were excluded. HC subjects were recruited from the community. Rating instruments included Hamilton Depression and Anxiety Scales, Beck Depression and Anxiety Inventory and Perceived Stress Scale. Fasting blood was drawn between 8:30 and 11:00 a.m. and High Performance Liquid Chromatography (HPLC) was used to measure plasma arginine metabolites. ADMA (Asymmetrical dimethylarginine) and putrescine were significantly lower while SDMA (Symmetric dimethylarginine), agmatine and ornithine were significantly higher in MDD patients (p˂0.05). Depression, anxiety and stress severity were negatively correlated with ADMA and putrescine (p˂0.05). Stress was positively correlated with citrulline, NOHA (N-omega-hydroxy-nor-l-arginine), SDMA, agmatine and ornithine (p˂0.05). Lower putrescine levels predicted depression diagnosis (p = 0.039) and depression severity (p = 0.003). Low ADMA level predicted depression severity as well. Arginine pathway metabolites are associated with the pathophysiology of depression. Putrescine may be a biomarker to predict MDD.

Keywords:  ADMA (Asymmetric dimethyl arginine); Agmatine; Arginine metabolites; Major depression; Putrescine; Stress

DOI:  https://doi.org/10.1016/j.jpsychires.2019.10.004
Br J Nutr. 2019 Oct 24. 1-32

The effects of oral arginine on its metabolic pathways in Sprague Dawley rats.

Sarah Martin, Kaushik Desai.

  Oral arginine supplements are popular mainly for their presumed vasodilatory benefit. Arginine is a substrate for at least four enzymes including nitric oxide synthase and arginase, but the impact of oral supplements on its different metabolic pathways is not clear. Deficiencies of arginine metabolizing enzymes are associated with conditions such as hyperammonemia, endothelial dysfunction, CNS and muscle dysfunction, which complicates the use of oral arginine supplements. We examined the effect of L-arginine and D-arginine, each at 500 mg/kg/day in drinking water administered for 4 weeks to separate groups of 9 week old male Sprague-Dawley rats. We quantified the expression of enzymes and plasma, urine and organ levels of various metabolites of arginine. L-arginine significantly decreased cationic transporter-1 expression in the liver and the ileum, and increased endothelial nitric oxide synthase expression in the aorta and the kidney and plasma nitrite levels, but did not affect the mean arterial pressure. L-arginine also decreased expression of arginase II in the ileum, arginine:glycine amidinotransferase in the liver and the kidney, and glyoxalase I in the liver, ileum and the brain, but increased the expression of arginine decarboxylase and polyamines levels in the liver. D-arginine, the supposedly inert isomer, also unexpectedly affected the expression of some enzymes and metabolites. In conclusion, both L- and D-arginine significantly affected enzymes and metabolites in several pathways that use arginine as a substrate and further studies with different doses and treatment duration are planned to establish their safety or adverse effects to guide their use as oral supplements.

Keywords:  Arginine supplements; D-arginine; arginase; creatine; nitric oxide

DOI:  https://doi.org/10.1017/S0007114519002691
Exp Mol Pathol. 2019 Oct 17. pii: S0014-4800(19)30160-1. [Epub ahead of print] 104316

The potential therapeutic effect of NG-hydroxy-nor-L-arginine in 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats.

Nikolay Avtandilyan, Hayarpi Javrushyan, Anahit Mamikonyan, Anna Grigoryan, Armen Trchounian.

  Advances in our understanding of the metabolism and molecular functions of arginine and their alterations in cancer have led to resurgence in the interest of targeting arginine catabolism as an anticancer strategy. Therefore, arginase inhibitors have been proposed as a way to treat cancer. In this study, the anti-tumor potential of the arginase inhibition by NG-hydroxy-nor-L-arginine (nor-NOHA) (3 mg/kg/day, i.p.), administered for 5 weeks (parallel tumors development, every 3th day) against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats has been investigated. Treatment by nor-NOHA has obvious inhibition effects on development of carcinogenesis in rats was shown. That was seen in downregulation of rats' tumors size and number, mortality rate, in stopped alteration of tissue histopathology, in decrease of polyamines, NO and MDA (malondialdeide) concentrations (in blood). Results have shown arginase and NO-synthase can cooperate to restrain quantities of polyamines and NO for cancer progression. The results obtained can serve as a base to use this model for determination of productive, noncytotoxic antitumor and immune modulating concentration of anticancer agents. Perspectives of targeting arginase and NOS in cancer management can ground application in clinical medicine.

Keywords:  7,12-dimethylbenz(a)anthracene induced, anti-tumor potential; Arginase; Breast cancer; NO-synthase; Nor-NOHA

DOI:  https://doi.org/10.1016/j.yexmp.2019.104316
Structure. 2019 Oct 21. pii: S0969-2126(19)30344-2. [Epub ahead of print]

Structure, Function, and Evolution of the Pseudomonas aeruginosa Lysine Decarboxylase LdcA.

Eaazhisai Kandiah, Diego Carriel, Pierre Simon Garcia, Jan Felix, Manuel Banzhaf, George Kritikos, Maria Bacia-Verloop, Céline Brochier-Armanet, Sylvie Elsen, Irina Gutsche.

  The only enzyme responsible for cadaverine production in the major multidrug-resistant human pathogen Pseudomonas aeruginosa is the lysine decarboxylase LdcA. This enzyme modulates the general polyamine homeostasis, promotes growth, and reduces bacterial persistence during carbenicillin treatment. Here we present a 3.7-Å resolution cryoelectron microscopy structure of LdcA. We introduce an original approach correlating phylogenetic signal with structural information and reveal possible recombination among LdcA and arginine decarboxylase subfamilies within structural domain boundaries. We show that LdcA is involved in full virulence in an insect pathogenesis model. Furthermore, unlike its enterobacterial counterparts, LdcA is regulated neither by the stringent response alarmone ppGpp nor by the AAA+ ATPase RavA. Instead, the P. aeruginosa ravA gene seems to play a defensive role. Altogether, our study identifies LdcA as an important player in P. aeruginosa physiology and virulence and as a potential drug target.

Keywords:  LdcA; Pseudomonas aeruginosa; amino acid decarboxylases; bacteria; cryo-EM structure; defense island; evolution; phylogenetic analysis; ppGpp; virulence

DOI:  https://doi.org/10.1016/j.str.2019.10.003
Amino Acids. 2019 Oct 25.

Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors.

Pamela Martinis, Silvia Grancara, Yuta Kanamori, Aída Nelly García-Argáez, Elena Pacella, Lisa Dalla Via, Antonio Toninello, Enzo Agostinelli.

  Agmatine (AGM) produces a dual effect on the mitochondrial permeability transition (MPT) mechanism in rat liver mitochondria: at low concentrations, it induces the phenomenon, at high ones, inhibits it. The prevention at high concentrations is evidenced by the significant inhibition of mitochondrial swelling induced by Ca2+ and phosphate; in this condition, AGM both prevents the release of Apoptosis Inducing Factor (AIF) and enhances the release of other pro-apoptotic factors, such as cytochrome c (cyt c) and Smac/DIABLO. As these factors are released without MPT induction, the involvement of mitochondrial outer membrane permeabilization (MOMP) could be hypothesized. Cyclosporin A (CsA), a powerful inhibitor of MPT, enhanced the AGM-mediated inhibition of swelling, and surprisingly, prevented the release of cyt c and Smac/DIABLO. In the presence of Ca2+, AGM also activated the Bcl-2 family protein Bax, a key factor in inducing MOMP, which is inactivated by CsA. Together with the voltage-dependent anion channel (VDAC), Bax forms channels in the outer membrane further supporting the involvement of MOMP in the release of pro-apoptotic factors. In view of the fact that VDAC was inactivated by ruthenium red, which in turn inhibited the release of cyt c, it can be hypothesized that, on the one hand, AGM inhibits MPT induction and, on the other, it selectively permeabilizes the outer membrane via MOMP induction.

Keywords:  Agmatine; Apoptotic factors; Membrane permeabilization; Mitochondria

DOI:  https://doi.org/10.1007/s00726-019-02791-6
J Pediatr Neurosci. 2019 Jul-Sep;14(3):14(3): 133-136

Arginase Deficiency Presenting as Acute Encephalopathy.

Leema Pauline Cornelius, Vivekasaravanan Raju, Asir Julin.

  Urea cycle disorders are rare metabolic disorders that present as encephalopathy with hyperammonemia. Arginase deficiency causing hyperargininemia is one among the urea cycle disorders, which usually presents as spastic diplegia. Hyperammonemic encephalopathy is rare in arginase deficiency. We present a rare case of arginase deficiency presenting as acute encephalopathy in a child.

Keywords:  Arginase deficiency; encephalopathy; hyperammonemia

DOI:  https://doi.org/10.4103/jpn.JPN_36_19
Crit Care Med. 2019 Oct 21.

Agmatine Protects Against the Progression of Sepsis Through the Imidazoline I2 Receptor-Ribosomal S6 Kinase 2-Nuclear Factor-κB Signaling Pathway.

Xuanfei Li, Junyu Zhu, Lixing Tian, Xiaoyuan Ma, Xia Fan, Li Luo, Jing Yu, Yu Sun, Xue Yang, Wanqi Tang, Wei Ma, Jun Yan, Xiang Xu, Huaping Liang.

OBJECTIVES: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis.
DESIGN: Clinical/laboratory investigations.
SETTING: Medical centers/University-based research laboratory.
SUBJECTS: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g.
INTERVENTIONS: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation.
MEASUREMENTS AND MAIN RESULTS: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα.
CONCLUSIONS: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.

DOI: https://doi.org/10.1097/CCM.0000000000004065
Antioxidants (Basel). 2019 Oct 23. pii: E505. [Epub ahead of print]8(11):

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells.

López Grueso María José, Tarradas Valero Rosa María, Carmona Hidalgo Beatriz, Lagal Ruiz Daniel, Peinado José, McDonagh Brian, Requejo Aguilar Raquel, Bárcena José Antonio, Padilla C Alicia.

  Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the roles and mechanisms of multifunctional Prdx6 in several pathologies and on its sensitivity to, and influence on, the redox environment. We have down-regulated Prdx6 with specific siRNA in hepatoblastoma HepG2 cells to study its role in cell proliferation, redox homeostasis, and metabolic programming. Cell proliferation and cell number decreased while cell volume increased; import of glucose and nucleotide biosynthesis also diminished while polyamines, phospholipids, and most glycolipids increased. A proteomic quantitative analysis suggested changes in membrane arrangement and vesicle trafficking as well as redox changes in enzymes of carbon and glutathione metabolism, pentose-phosphate pathway, citrate cycle, fatty acid metabolism, biosynthesis of aminoacids, and Glycolysis/Gluconeogenesis. Specific redox changes in Hexokinase-2 (HK2), Prdx6, intracellular chloride ion channel-1 (CLIC1), PEP-carboxykinase-2 (PCK2), and 3-phosphoglycerate dehydrogenase (PHGDH) are compatible with the metabolic remodeling toward a predominant gluconeogenic flow from aminoacids with diversion at 3-phospohglycerate toward serine and other biosynthetic pathways thereon and with cell cycle arrest at G1/S transition.

Keywords:  Peroxiredoxin; cell cycle; lipid metabolism; redox homeostasis; redox proteome; thiol redox regulation

DOI:  https://doi.org/10.3390/antiox8110505