bims-polyam 2022-09-11 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–09–11
eleven papers selected by
Sebastian J. Hofer, University of Graz

Unraveling the genetics of polyamine metabolism in barley for senescence-related crop improvement.
Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway.
P5B-ATPases in the mammalian polyamine transport system and their role in disease.
Antibacterial activity of novel linear polyamines against Staphylococcus aureus.
Corrigendum for "A novel kinase subverts aluminium resistance by boosting ornithine decarboxylase-dependent putrescine biosynthesis".
Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
Targeting Myocardial Mitochondria-STING-Polyamine Axis Prevents Cardiac Hypertrophy in Chronic Kidney Disease.
Genome-Wide Identification of Polyamine Oxidase (PAO) Family Genes: Roles of CaPAO2 and CaPAO4 in the Cold Tolerance of Pepper (Capsicum annuum L.).
Physiological and biochemical bases of spermidine-induced alleviation of cadmium and lead combined stress in rice.
Metabolomic alterations in the blood plasma of older adults with mild cognitive impairment and Alzheimer's disease (from the Nakayama Study).
Metabolic regulation and function of T helper cells in neuroinflammation.

Int J Biol Macromol. 2022 Sep 05. pii: S0141-8130(22)01929-8. [Epub ahead of print]

Unraveling the genetics of polyamine metabolism in barley for senescence-related crop improvement.

Umesh Kumar Tanwar, Ewelina Stolarska, Ewelina Paluch-Lubawa, Autar K Mattoo, Magdalena Arasimowicz-Jelonek, Ewa Sobieszczuk-Nowicka.

  We explored the polyamine (PA) metabolic pathway genes in barley (Hv) to understand plant development and stress adaptation in Gramineae crops with emphasis on leaf senescence. Bioinformatics and functional genomics tools were utilized for genome-wide identification, comprehensive gene features, evolution, development and stress effects on the expression of the polyamine metabolic pathway gene families (PMGs). Three S-adenosylmethionine decarboxylases (HvSAMDCs), two ornithine decarboxylase (HvODCs), one arginine decarboxylase (HvADC), one spermidine synthase (HvSPDS), two spermine synthases (HvSPMSs), five copper amine oxidases (HvCuAO) and seven polyamine oxidases (HvPAOs) members of PMGs were identified and characterized in barley. All the HvPMG genes were found to be distributed on all chromosomes of barley. The phylogenetic and comparative assessment revealed that PA metabolic pathway is highly conserved in plants and the prediction of nine H. vulgare miRNAs (hvu-miR) target sites, 18 protein-protein interactions and 961 putative CREs in the promoter region were discerned. Gene expression of HvSAMDC3, HvCuAO7, HvPAO4 and HvSPMS1 was apparent at every developmental stage. SPDS/SPMS gene family was found to be the most responsive to induced leaf senescence. This study provides a reference for the functional investigation of the molecular mechanism(s) that regulate polyamine in plants as a tool for future breeding decision management systems.

Keywords:  Abiotic stress; Gene expression; Genome-wide identification; Gramineae; Hordeum vulgare; Leaf senescence; Model crop plant; Polyamine metabolic pathway

DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.006
Mol Med. 2022 09 04. 28(1): 103

Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway.

Xianzhi Li, Xiaojun Zhou, Xigao Liu, Xiaoyun Li, Xianzhou Jiang, Benkang Shi, Shuo Wang.

   BACKGROUND: Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive.
METHODS: We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration.
RESULTS: We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity.
CONCLUSIONS: Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.

Keywords:  Acute kidney injury; Macrophage; NLRP3; Polyamine; Spermidine

DOI:  https://doi.org/10.1186/s10020-022-00533-1
Biochim Biophys Acta Mol Cell Res. 2022 Sep 02. pii: S0167-4889(22)00146-X. [Epub ahead of print] 119354

P5B-ATPases in the mammalian polyamine transport system and their role in disease.

Mujahid Azfar, Sarah van Veen, Marine Houdou, Norin Nabil Hamouda, Jan Eggermont, Peter Vangheluwe.

  Polyamines (PAs) are physiologically relevant molecules that are ubiquitous in all organisms. The vitality of PAs to the healthy functioning of a cell is due to their polycationic nature causing them to interact with a vast plethora of cellular players and partake in numerous cellular pathways. Naturally, the homeostasis of such essential molecules is tightly regulated in a strictly controlled interplay between intracellular synthesis and degradation, uptake from and secretion to the extracellular compartment, as well as intracellular trafficking. Not surprisingly, dysregulated PA homeostasis and signaling are implicated in multiple disorders, ranging from cancer to neurodegeneration; leading many to propose rectifying the PA balance as a potential therapeutic strategy. Despite being well characterized in bacteria, fungi and plants, the molecular identity and properties of the PA transporters in animals are poorly understood. This review brings together the current knowledge of the cellular function of the mammalian PA transport system (PTS). We will focus on the role of P5B-ATPases ATP13A2-5 which are PA transporters in the endosomal system that have emerged as key players in cellular PA uptake and organelle homeostasis. We will discuss recent breakthroughs on their biochemical and structural properties as well as their implications for disease and therapy.

Keywords:  Mammalian polyamine transport system; P5B-ATPases; Polyamines

DOI:  https://doi.org/10.1016/j.bbamcr.2022.119354
Front Microbiol. 2022 ;13 948343

Antibacterial activity of novel linear polyamines against Staphylococcus aureus.

Edward J A Douglas, Abdulaziz H Alkhzem, Toska Wonfor, Shuxian Li, Timothy J Woodman, Ian S Blagbrough, Maisem Laabei.

  New therapeutic options are urgently required for the treatment of Staphylococcus aureus infections. Accordingly, we sought to exploit the vulnerability of S. aureus to naturally occurring polyamines. We have developed and tested the anti-staphylococcal activity of three novel linear polyamines based on spermine and norspermine. Using a panel of genetically distinct and clinically relevant multidrug resistant S. aureus isolates, including the polyamine resistant USA300 strain LAC, compound AHA-1394 showed a greater than 128-fold increase in inhibition against specific S. aureus strains compared to the most active natural polyamine. Furthermore, we show that AHA-1394 has superior biofilm prevention and biofilm dispersal properties compared to natural polyamines while maintaining minimal toxicity toward human HepG2 cells. We examined the potential of S. aureus to gain resistance to AHA-1394 following in vitro serial passage. Whole genome sequencing of two stable resistant mutants identified a gain of function mutation (S337L) in the phosphatidylglycerol lysyltransferase mprF gene. Inactivation of mutant mprF confirmed the importance of this allele to AHA-1394 resistance. Importantly, AHA-1394 resistant mutants showed a marked decrease in relative fitness and increased generation time. Intriguingly, mprF::S337L contributed to altered surface charge only in the USA300 background whereas increased cell wall thickness was observed in both USA300 and SH1000. Lastly, we show that AHA-1394 displays a particular proclivity for antibiotic potentiation, restoring sensitivity of MRSA and VRSA isolates to daptomycin, oxacillin and vancomycin. Together this study shows that polyamine derivatives are impressive drug candidates that warrant further investigation.

Keywords:  Staphylococcus aureus; antibacterial activity; antibiotic synergy; antimicrobial resistance (AMR); polyamines

DOI:  https://doi.org/10.3389/fmicb.2022.948343
Plant Cell Environ. 2022 Oct;45(10): 3184

Corrigendum for "A novel kinase subverts aluminium resistance by boosting ornithine decarboxylase-dependent putrescine biosynthesis".

Xiang P Liu, Li J Gao, Ben T She, Gui X Li, Yun R Wu, Ji M Xu, Zhong J Ding, Jian F Ma, Shao J Zheng.

DOI: https://doi.org/10.1111/pce.14419
Nat Commun. 2022 Sep 03. 13(1): 5202

Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.

Jin Zhou, Jeremy Pang, Madhulika Tripathi, Jia Pei Ho, Anissa Anindya Widjaja, Shamini Guna Shekeran, Stuart Alexander Cook, Ayako Suzuki, Anna Mae Diehl, Enrico Petretto, Brijesh Kumar Singh, Paul Michael Yen.

Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.

DOI: https://doi.org/10.1038/s41467-022-32788-x
JACC Basic Transl Sci. 2022 Aug;7(8): 820-840

Targeting Myocardial Mitochondria-STING-Polyamine Axis Prevents Cardiac Hypertrophy in Chronic Kidney Disease.

Wenhao Han, Changhong Du, Yingguo Zhu, Li Ran, Yue Wang, Jiachuan Xiong, Yiding Wu, Qigang Lan, Yaqin Wang, Liting Wang, Junping Wang, Ke Yang, Jinghong Zhao.

  Chronic kidney disease (CKD) is well recognized as a distinct contributor to cardiac hypertrophy, while the underlying mechanism remains incompletely understood. Here, the authors show that myocardial mitochondrial oxidative damage is early and prominent in CKD and distinctively stimulates the STING-NFκB pathway by releasing mitochondrial DNA to drive cardiac hypertrophy. Furthermore, the authors reveal that ornithine decarboxylase (ODC1)-putrescine metabolic flux is transactivated by NFκB and is required for the STING-NFκB pathway to drive cardiac hypertrophy. Finally, genetic or pharmacologic inhibition of the myocardial mitochondria-STING-NFκB-ODC1 axis significantly prevents CKD-associated cardiac hypertrophy. Therefore, targeting the myocardial mitochoandria-STING-NFκB-ODC1 axis is a promising therapeutic strategy for cardiac hypertrophy in patients with CKD.

Keywords:  ATP, adenosine triphosphate; CKD, chronic kidney disease; LV, left ventricular; MOMP, mitochondrial outer membrane permeabilization; MPTP, mitochondrial permeability transition pore; NRCM, primary neonatal rat cardiomyocyte; ODC1, ornithine decarboxylase; PUT, putrescine; ROS, reactive oxygen species; VDAC1, voltage-dependent anion channel 1; cGAS-STING pathway; cardiac hypertrophy; chronic kidney disease; mitochondria; mtDNA, mitochondrial DNA; polyamine metabolism; siRNA, small interfering RNA

DOI:  https://doi.org/10.1016/j.jacbts.2022.03.006
Int J Mol Sci. 2022 Sep 02. pii: 9999. [Epub ahead of print]23(17):

Genome-Wide Identification of Polyamine Oxidase (PAO) Family Genes: Roles of CaPAO2 and CaPAO4 in the Cold Tolerance of Pepper (Capsicum annuum L.).

Jianwei Zhang, Le Liang, Jiachang Xiao, Yongdong Xie, Li Zhu, Xinru Xue, Linyu Xu, Peihan Zhou, Jianzhao Ran, Zhi Huang, Guochao Sun, Yunsong Lai, Bo Sun, Yi Tang, Huanxiu Li.

  Polyamine oxidases (PAOs), which are flavin adenine dinucleotide-dependent enzymes, catalyze polyamine (PA) catabolism, producing hydrogen peroxide (H2O2). Several PAO family members have been identified in plants, but their expression in pepper plants remains unclear. Here, six PAO genes were identified in the 'Zunla-1' pepper genome (named CaPAO1-CaPAO6 according to their chromosomal positions). The PAO proteins were divided into four subfamilies according to phylogenetics: CaPAO1 belongs to subfamily I; CaPAO3 and CaPAO5 belong to subfamily III; and CaPAO2, CaPAO4, and CaPAO6 belong to subfamily IV (none belong to subfamily II). CaPAO2, CaPAO4, and CaPAO6 were ubiquitously and highly expressed in all tissues, CaPAO1 was mainly expressed in flowers, whereas CaPAO3 and CaPAO5 were expressed at very low levels in all tissues. RNA-seq analysis revealed that CaPAO2 and CaPAO4 were notably upregulated by cold stress. CaPAO2 and CaPAO4 were localized in the peroxisome, and spermine was the preferred substrate for PA catabolism. CaPAO2 and CaPAO4 overexpression in Arabidopsis thaliana significantly enhanced freezing-stress tolerance by increasing antioxidant enzyme activity and decreasing malondialdehyde, H2O2, and superoxide accumulation, accompanied by the upregulation of cold-responsive genes (AtCOR15A, AtRD29A, AtCOR47, and AtKIN1). Thus, we identified candidate PAO genes for breeding cold-stress-tolerant transgenic pepper cultivars.

Keywords:  PAO gene family; cold stress; overexpression; pepper; prokaryotic expression

DOI:  https://doi.org/10.3390/ijms23179999
Plant Physiol Biochem. 2022 Aug 31. pii: S0981-9428(22)00372-2. [Epub ahead of print]189 104-114

Physiological and biochemical bases of spermidine-induced alleviation of cadmium and lead combined stress in rice.

Jinyu Gu, Chunmei Hu, Xiangwei Jia, Yanfang Ren, Dongming Su, Junyu He.

  Cadmium (Cd) and lead (Pb) pollution is a major environmental issue affecting plant production. Spermidine (Spd) is involved in plant response to abiotic stress. However, the role and associated mechanism of Spd under Cd + Pb combined stress are poorly understood. The potential protective role of Spd at different concentration on rice (Oryza sativa L.) seedlings exposed to Cd + Pb treatment was investigated by a hydroponic experiment in this study. The results showed that exogenous Spd enhanced the tolerance of rice seedlings to Cd + Pb stress, resulted in an increase in plant height, root length, fresh weight and dry weight of roots and shoots. Further, application of Spd decreased the contents of hydrogen peroxide, superoxide anion, malondialdehyde, and the accumulation of Cd and Pb, and increased the contents of mineral nutrient, carotenoids, chlorophyll, proline, soluble sugar, soluble protein, total phenol, flavonoid, anthocyanin, and antioxidant enzymes activities in roots and shoots of rice seedlings under Cd + Pb stress. Particularly, 0.5 mmol L-1 Spd was the most effective to alleviate the adverse impacts on growth and physiological metabolism of rice seedlings under Cd + Pb stress. Principal component analysis and heat map clustering established correlations between physio-biochemical parameters and further revealed Spd alleviated Cd + Pb damage in rice seedling was associated with inhibition of accumulation and translocation of Cd and Pb, increasing the contents of photosynthetic pigments and mineral nutrient and stimulation of antioxidative response and osmotic adjustment. Overall, our findings provide an important prospect for use of Spd in modulating Cd + Pb tolerance in rice plants. Spd could help to alleviate Cd + Pb damage through inhibition of accumulation and translocation of Cd and Pb and stimulation of oxidant-defense system and osmotic adjustment.

Keywords:  Cd+Pb combined stress; Heat map clustering; Physio-biochemical parameters; Principal component analysis; Rice; Spermidine

DOI:  https://doi.org/10.1016/j.plaphy.2022.08.010
Sci Rep. 2022 Sep 08. 12(1): 15205

Metabolomic alterations in the blood plasma of older adults with mild cognitive impairment and Alzheimer's disease (from the Nakayama Study).

Tomoki Ozaki, Yuta Yoshino, Ayumi Tachibana, Hideaki Shimizu, Takaaki Mori, Tomohiko Nakayama, Kazuaki Mawatari, Shusuke Numata, Jun-Ichi Iga, Akira Takahashi, Tetsuro Ohmori, Shu-Ichi Ueno.

Alzheimer's disease (AD) is a progressive disease, and the number of AD patients is increasing every year as the population ages. One of the pathophysiological mechanisms of AD is thought to be the effect of metabolomic abnormalities. There have been several studies of metabolomic abnormalities of AD, and new biomarkers are being investigated. Metabolomic studies have been attracting attention, and the aim of this study was to identify metabolomic biomarkers associated with AD and mild cognitive impairment (MCI). Of the 927 participants in the Nakayama Study conducted in Iyo City, Ehime Prefecture, 106 were selected for this study as Control (n = 40), MCI (n = 26), and AD (n = 40) groups, matched by age and sex. Metabolomic comparisons were made across the three groups. Then, correlations between metabolites and clinical symptoms were examined. The blood mRNA levels of the ornithine metabolic enzymes were also measured. Of the plasma metabolites, significant differences were found in ornithine, uracil, and lysine. Ornithine was significantly decreased in the AD group compared to the Control and MCI groups (Control vs. AD: 97.2 vs. 77.4; P = 0.01, MCI vs. AD: 92.5 vs. 77.4; P = 0.02). Uracil and lysine were also significantly decreased in the AD group compared to the Control group (uracil, Control vs. AD: 272 vs. 235; P = 0.04, lysine, Control vs. AD: 208 vs. 176; P = 0.03). In the total sample, the MMSE score was significantly correlated with lysine, ornithine, thymine, and uracil. The Barthel index score was significantly correlated with lysine. The instrumental activities of daily living (IADL) score were significantly correlated with lysine, betaine, creatine, and thymine. In the ornithine metabolism pathway, the spermine synthase mRNA level was significantly decreased in AD. Ornithine was decreased, and mRNA expressions related to its metabolism were changed in the AD group compared to the Control and MCI groups, suggesting an association between abnormal ornithine metabolism and AD. Increased betaine and decreased methionine may also have the potential to serve as markers of higher IADL in elderly persons. Plasma metabolites may be useful for predicting the progression of AD.

DOI: https://doi.org/10.1038/s41598-022-19670-y
Semin Immunopathol. 2022 Sep 06.

Metabolic regulation and function of T helper cells in neuroinflammation.

Martina Spiljar, Vijay K Kuchroo.

  Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.

Keywords:  Experimental autoimmune encephalomyelitis; Immunometabolism; Multiple sclerosis; Neuroimmunology; Neuroinflammation; Th17 cells

DOI:  https://doi.org/10.1007/s00281-022-00959-z