bims-polyam 2022-03-13 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–03–13
ten papers selected by
Sebastian J. Hofer, University of Graz

ATP13A3 facilitates polyamine transport in human pancreatic cancer cells.
Polyamines Metabolism Interacts with γ-Aminobutyric Acid, Proline and Nitrogen Metabolisms to Affect Drought Tolerance of Creeping Bentgrass.
Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity.
The Spermidine Synthase Gene SPD1: A Novel Auxotrophic Marker for Chlamydomonas reinhardtii Designed by Enhanced CRISPR/Cas9 Gene Editing.
The Complex Metabolomics Crosstalk Triggered by Four Molecular Elicitors in Tomato.
The Role of Plant Growth Promoting Rhizosphere Microbiome as Alternative Biofertilizer in Boosting Solanum melongena L. Adaptation to Salinity Stress.
Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway.
Targeted Metabolomic Analysis in Alzheimer's Disease Plasma and Brain Tissue in Non-Hispanic Whites.
Widely-Targeted Metabolic Profiling in Lyciumbarbarum Fruits under Salt-Alkaline Stress Uncovers Mechanism of Salinity Tolerance.
Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.

Sci Rep. 2022 Mar 08. 12(1): 4045

ATP13A3 facilitates polyamine transport in human pancreatic cancer cells.

Vandana Sekhar, Thomas Andl, Otto Phanstiel.

The purpose of this study is to provide an increased understanding of the molecular mechanisms responsible for mammalian polyamine transport, a process that has been a long-standing 'black box' for the polyamine field. Here, we describe how ATP13A3, a P-type ATPase, functions as a polyamine transporter in response to different polyamine stimuli and polyamine-targeted therapies in highly proliferating pancreatic cancer cells. We assessed the expression, cellular localization and the response of the human ATP13A3 protein to polyamine treatments in different pancreatic cancer cell lines using Western blot and immunofluorescence microscopy. Using CRISPR mutagenesis and radiolabeled polyamine uptake assays, we investigated the role of ATP13A3 protein in polyamine transport. Highly metastatic cancer cells with high polyamine import express higher levels of the full-length ATP13A3 compared to cells with slow proliferation and low import activity. Highlighting its role in polyamine trafficking, the localization of ATP13A3 is altered in the presence of polyamine stimuli and polyamine-targeted therapies in these cells. Using CRISPR mutagenesis, we demonstrate that the first membrane-associated domain of this protein is critical and indispensable for its function as a spermidine and spermine transporter in cells. Further analysis of existing databases revealed that pancreatic cancer patients with high expression of ATP13A3 have decreased overall survival consistent with the role of intracellular polyamines in supporting tumor growth. Our studies shed light on the mysterious polyamine transport process in human cells and clearly establishes ATP13A3 as an intrinsic component of the spermidine and spermine transport system in humans.

DOI: https://doi.org/10.1038/s41598-022-07712-4
Int J Mol Sci. 2022 Mar 03. pii: 2779. [Epub ahead of print]23(5):

Polyamines Metabolism Interacts with γ-Aminobutyric Acid, Proline and Nitrogen Metabolisms to Affect Drought Tolerance of Creeping Bentgrass.

Meng Tan, Muhammad Jawad Hassan, Yan Peng, Guangyan Feng, Linkai Huang, Lin Liu, Wei Liu, Liebao Han, Zhou Li.

  Due to increased global warming and climate change, drought has become a serious threat to horticultural crop cultivation and management. The purpose of this study was to investigate the effect of spermine (Spm) pretreatment on metabolic alterations of polyamine (PAs), γ-aminobutyric acid (GABA), proline (Pro), and nitrogen associated with drought tolerance in creeping bentgrass (Agrostis stolonifera). The results showed that drought tolerance of creeping bentgrass could be significantly improved by the Spm pretreatment, as demonstrated by the maintenance of less chlorophyll loss and higher photosynthesis, gas exchange, water use efficiency, and cell membrane stability. The Spm pretreatment further increased drought-induced accumulation of endogenous PAs, putrescine, spermidine, and Spm, and also enhanced PAs metabolism through improving arginine decarboxylases, ornithine decarboxylase, S-adenosylmethionine decarboxylase, and polyamine oxidase activities during drought stress. In addition, the Spm application not only significantly improved endogenous GABA content, glutamate content, activities of glutamate decarboxylase and α-ketoglutarase, but also alleviated decline in nitrite nitrogen content, nitrate reductase, glutamine synthetase, glutamate synthetase, and GABA aminotransferase activities under drought stress. The Spm-pretreated creeping bentgrass exhibited significantly lower ammonia nitrogen content and nitrite reductase activity as well as higher glutamate dehydrogenase activity than non-pretreated plants in response to drought stress. These results indicated beneficial roles of the Spm on regulating GABA and nitrogen metabolism contributing towards better maintenance of Tricarboxylic acid (TCA) cycle in creeping bentgrass. Interestingly, the Spm-enhanced Pro metabolism rather than more Pro accumulation could be the key regulatory mechanism for drought tolerance in creeping bentgrass. Current findings provide a comprehensive understanding of PAs interaction with other metabolic pathways to regulate drought tolerance in grass species.

Keywords:  TCA cycle; energy metabolism; nitrogen assimilation; photosynthesis; water balance

DOI:  https://doi.org/10.3390/ijms23052779
Cells. 2022 Mar 05. pii: 896. [Epub ahead of print]11(5):

Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity.

Tzu-Yi Chia, Andrew Zolp, Jason Miska.

  Polyamines are ubiquitous, amine-rich molecules with diverse processes in biology. Recent work has highlighted that polyamines exert profound roles on the mammalian immune system, particularly inflammation and cancer. The mechanisms by which they control immunity are still being described. In the context of inflammation and autoimmunity, polyamine levels inversely correlate to autoimmune phenotypes, with lower polyamine levels associated with higher inflammatory responses. Conversely, in the context of cancer, polyamines and polyamine biosynthetic genes positively correlate with the severity of malignancy. Blockade of polyamine metabolism in cancer results in reduced tumor growth, and the effects appear to be mediated by an increase in T-cell infiltration and a pro-inflammatory phenotype of macrophages. These studies suggest that polyamine depletion leads to inflammation and that polyamine enrichment potentiates myeloid cell immune suppression. Indeed, combinatorial treatment with polyamine blockade and immunotherapy has shown efficacy in pre-clinical models of cancer. Considering the efficacy of immunotherapies is linked to autoimmune sequelae in humans, termed immune-adverse related events (iAREs), this suggests that polyamine levels may govern the inflammatory response to immunotherapies. This review proposes that polyamine metabolism acts to balance autoimmune inflammation and anti-tumor immunity and that polyamine levels can be used to monitor immune responses and responsiveness to immunotherapy.

Keywords:  autoimmunity; cancer; myeloid cells; polyamines

DOI:  https://doi.org/10.3390/cells11050896
Cells. 2022 Feb 28. pii: 837. [Epub ahead of print]11(5):

The Spermidine Synthase Gene SPD1: A Novel Auxotrophic Marker for Chlamydomonas reinhardtii Designed by Enhanced CRISPR/Cas9 Gene Editing.

Robert A Freudenberg, Luisa Wittemeier, Alexander Einhaus, Thomas Baier, Olaf Kruse.

  Biotechnological application of the green microalga Chlamydomonas reinhardtii hinges on the availability of selectable markers for effective expression of multiple transgenes. However, biological safety concerns limit the establishment of new antibiotic resistance genes and until today, only a few auxotrophic markers exist for C. reinhardtii. The recent improvements in gene editing via CRISPR/Cas allow directed exploration of new endogenous selectable markers. Since editing frequencies remain comparably low, a Cas9-sgRNA ribonucleoprotein (RNP) delivery protocol was strategically optimized by applying nitrogen starvation to the pre-culture, which improved successful gene edits from 10% to 66% after pre-selection. Probing the essential polyamine biosynthesis pathway, the spermidine synthase gene (SPD1) is shown to be a potent selectable marker with versatile biotechnological applicability. Very low levels of spermidine (0.75 mg/L) were required to maintain normal mixotrophic and phototrophic growth in newly designed spermidine auxotrophic strains. Complementation of these strains with a synthetic SPD1 gene was achieved when the mature protein was expressed in the cytosol or targeted to the chloroplast. This work highlights the potential of new selectable markers for biotechnology as well as basic research and proposes an effective pipeline for the identification of new auxotrophies in C. reinhardtii.

Keywords:  CRISPR/Cas9; SPD1; auxotrophy; gene editing; microalgae; selectable marker; spermidine

DOI:  https://doi.org/10.3390/cells11050837
Plants (Basel). 2022 Mar 01. pii: 678. [Epub ahead of print]11(5):

The Complex Metabolomics Crosstalk Triggered by Four Molecular Elicitors in Tomato.

Giusy Iula, Begoña Miras-Moreno, Youssef Rouphael, Luigi Lucini, Marco Trevisan.

  The elicitation of plant secondary metabolism may offer interesting opportunities in the framework of sustainable approaches in plant science and in terms of their ability to prime resistance to biotic and abiotic stressors. The broad metabolic reprogramming triggered by different molecular elicitors, namely salicylate (SA), polyamines (PAs), and chitosan, was comprehensively investigated using a metabolomics approach and the tomato (Solanum lycopersicum L.) as the model crop. Six different treatments were compared: a negative control (no treatments), a second negative control treated with 1 M acetic acid (the reference for chitosan, since chitosan was solubilized in acetic acid), and four molecular elicitors, 1 mM 2,1,3-benzothiadiazole (BTH, a positive control), 10 mg/mL chitosan, 0.01 mM SA, and a 0.1 mM PA (putrescine, spermidine, and spermine). All treatments determined a slight increase in biomass, in particular following PA treatment. A broad reprogramming of secondary metabolism could be observed, including membrane lipid remodeling, phenylpropanoid antioxidants, and phytohormone crosstalk. Overall, our results suggest that PAs, SA, and BTH shared a systemic acquired resistance (SAR)-related response, whereas chitosan induced a more distinct induced systemic resistance (ISR)-like jasmonate-related response. These results pave the way towards the possible use of elicitors as a sustainable tool in plant science and agriculture by increasing crop resilience to biotic and abiotic stressors without detrimental effects on plant biomass.

Keywords:  Solanum lycopersicum L.; biotic and abiotic stressors; chitosan; metabolomics; phenylpropanoids; phytohormones; polyamines; sustainable agriculture

DOI:  https://doi.org/10.3390/plants11050678
Plants (Basel). 2022 Feb 28. pii: 659. [Epub ahead of print]11(5):

The Role of Plant Growth Promoting Rhizosphere Microbiome as Alternative Biofertilizer in Boosting Solanum melongena L. Adaptation to Salinity Stress.

Souhair Mokabel, Zakia Olama, Safaa Ali, Rehab El-Dakak.

  Recent ecological perturbations are presumed to be minimized by the application of biofertilizers as a safe alternative to chemical fertilizers. The current study aims to use bioinoculum (I) as an alternative biofertilizer and to alleviate salinity stress in the cultivar Solanum melongena L. Baldi. The salinity drench was 200 mM NaCl (S), which was used with different treatments (0; I; S; S + I) in pots prefilled with clay and sand (1:2). Results showed that salinity stress inhibited both plant fresh and dry weights, water content, and photosynthetic pigments. The content of root spermine (Spm), spermidine (Spd), and puterscine (Put) decreased. However, addition of the bioinoculum to salt-treated plants increased pigment content (80.35, 39.25, and 82.44% for chl a, chl b, and carotenoids, respectively). Similarly, K+, K+/Na+, Ca2+, P, and N contents were significantly enhanced. Increases were recorded for Spm + Spd and Put in root and shoot (8.4-F, 1.6-F and 2.04-F, 2.13-F, respectively). RAPD PCR showed gene expression upregulation of photosystem II D2 protein, glutathione reductase, glutathione-S-transferase, protease I, and protease II. The current work recommends application of the selected bioinoculum as a green biofertilizer and biopesticide. Additionally, the studied eggplant cultivar can be regarded as a source of salt tolerance genes in agricultural fields.

Keywords:  Solanum melongena; biofertilizer; biopesticide; eggplant; gene expression; physiological traits; polyamines; salinity; stress

DOI:  https://doi.org/10.3390/plants11050659
Reprod Biol Endocrinol. 2022 Mar 07. 20(1): 45

Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway.

Jin-Yuan Wang, Duo Ma, Min Luo, Yong-Peng Tan, Ou Zhong, Ge Tian, Yong-Ting Lv, Mei-Xiang Li, Xi Chen, Zhi-Han Tang, Lin-Lin Hu, Xiao-Can Lei.

  Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM's effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM's protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What's more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP's positive effect on moderating spermatogenic disorder in T1DM mice's testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway's activation.

Keywords:  Diabetes; Glycolytic pathway; Sertoli cells; Spermatogenic dysfunction; Spermidine

DOI:  https://doi.org/10.1186/s12958-022-00890-w
J Alzheimers Dis. 2022 Feb 28.

Targeted Metabolomic Analysis in Alzheimer's Disease Plasma and Brain Tissue in Non-Hispanic Whites.

Karel Kalecký, Dwight C German, Albert A Montillo, Teodoro Bottiglieri.

   BACKGROUND: Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer's disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis.
OBJECTIVE: In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers.
METHODS: This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer's Research and Care Consortium - TARCC) and 71 postmortem cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500).
RESULTS: We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95 = 75-88%); for females specifically, AUC = 88% (CI95 = 80-95%). A reduced model using 20 features achieves AUC = 79% (CI95 = 71-85%); for females AUC = 84% (CI95 = 74-92%).
CONCLUSION: Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis.

Keywords:  Alzheimer’s disease; antioxidants; bacterial toxins; biomarkers; human microbiome; hyperlipidemia; lipidomics; metabolic pathways; metabolomics; polyamines

DOI:  https://doi.org/10.3233/JAD-215448
Molecules. 2022 Feb 26. pii: 1564. [Epub ahead of print]27(5):

Widely-Targeted Metabolic Profiling in Lyciumbarbarum Fruits under Salt-Alkaline Stress Uncovers Mechanism of Salinity Tolerance.

Xiaojie Liang, Yajun Wang, Yuekun Li, Wei An, Xinru He, Yanzhen Chen, Zhigang Shi, Jun He, Ru Wan.

  Wolfberry (Lycium barbarum L.) is an important economic crop widely grown in China. The effects of salt-alkaline stress on metabolites accumulation in the salt-tolerant Ningqi1 wolfberry fruits were evaluated across 12 salt-alkaline stress gradients. The soil pH, Na+, K+, Ca2+, Mg2+, and HCO3- contents decreased at a gradient across the salt-alkaline stress gradients. Based on the widely-targeted metabolomics approach, we identified 457 diverse metabolites, 53% of which were affected by salt-alkaline stress. Remarkably, soil salt-alkaline stress enhanced metabolites accumulation in wolfberry fruits. Amino acids, alkaloids, organic acids, and polyphenols contents increased proportionally across the salt-alkaline stress gradients. In contrast, nucleic acids, lipids, hydroxycinnamoyl derivatives, organic acids and derivatives and vitamins were significantly reduced by high salt-alkaline stress. A total of 13 salt-responsive metabolites represent potential biomarkers for salt-alkaline stress tolerance in wolfberry. Specifically, we found that constant reductions of lipids and chlorogenic acids; up-regulation of abscisic acid and accumulation of polyamines are essential mechanisms for salt-alkaline stress tolerance in Ningqi1. Overall, we provide for the first time some extensive metabolic insights into salt-alkaline stress tolerance and key metabolite biomarkers which may be useful for improving wolfberry tolerance to salt-alkaline stress.

Keywords:  abiotic stress; goji berry; metabolomics; nutritional quality

DOI:  https://doi.org/10.3390/molecules27051564
Sci Adv. 2022 Mar 11. 8(10): eabi4797

Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.

Alexander S Häusl, Thomas Bajaj, Lea M Brix, Max L Pöhlmann, Kathrin Hafner, Meri De Angelis, Joachim Nagler, Frederik Dethloff, Georgia Balsevich, Karl-Werner Schramm, Patrick Giavalisco, Alon Chen, Mathias V Schmidt, Nils C Gassen.

The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD)-induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.

DOI: https://doi.org/10.1126/sciadv.abi4797