bims-polyam 2023-06-25 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–06–25
twelve papers selected by
Sebastian J. Hofer, University of Graz

Polyamine catabolism is concentrated in tumor-associated histiocytes in diffuse large B-cell lymphoma and classic Hodgkin lymphoma.
Lack of polyamines leads to co-translational degradation of the general stress factor RpoS in Escherichia coli.
Maybe the various forms of kidney disease are not so mechanistically different?
Genetic portrait of polyamine transporters in barley: insights in the regulation of leaf senescence.
Polyamine as a microenvironment factor in resistance to antibiotics.
Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
Exogenous Spermidine Alleviates Diabetic Myocardial Fibrosis Via Suppressing Inflammation and Pyroptosis in db/db Mice.
Purification and characterization of tomato arginine decarboxylase and its inhibition by the bacterial small molecule phevamine A.
Bifidobacterium animalis subsp. lactis and arginine mixture intake improves cognitive flexibility in mice.
Targeting eIF5A2 reduces invasion and reverses chemoresistance in SCC-9 cells in vitro.
Development and validation of polyamines metabolism-associated gene signatures to predict prognosis and immunotherapy response in lung adenocarcinoma.
Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex.

Pathol Res Pract. 2023 Jun 17. pii: S0344-0338(23)00327-8. [Epub ahead of print]248 154627

Polyamine catabolism is concentrated in tumor-associated histiocytes in diffuse large B-cell lymphoma and classic Hodgkin lymphoma.

Adam S Bronson, Cullen M Lilley, Mathew Zleczewski, Kamran M Mirza.

  Polyamines are cationic molecules necessary for cell survival, growth, and replication [1-5]. Polyamines come in a variety of structural forms and are principally regulated by two enzymes, spermine/spermidine acetyltransferase-1 (SAT1) and ornithine decarboxylase-1 (ODC1). SAT1 targets the polyamines spermidine and spermine for degradation via acetylation, while ODC1 is involved in converting the polyamine precursor molecule to more complex polyamines [6-8]. Polyamines and their regulatory enzymes have been implicated in tumor metastasis [9,10] and in crosstalk between oncogenes [11-13] in numerous types of cancer, but their role has never been evaluated in B-cell malignancies. In this study, we examine the expression of SAT1 in diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). We found that SAT1 is expressed in all examined cases of DLBCL (n = 15) and HL (n = 5), though the levels of expression across cases vary. We also note that SAT1 expression appears to be concentrated in tumor-associated histiocytes, rather than tumor cells in both DLBCL and HL. We propose that these findings indicate that the polyamine catabolic enzyme, SAT1, plays an unappreciated role in the pathogenesis of B-cell neoplasms.

Keywords:  Classic Hodgkin Lymphoma; Diffuse Large B-cell Lymphoma; Polyamine; Spermine/Spermidine Acetyltransferase-1

DOI:  https://doi.org/10.1016/j.prp.2023.154627
J Biol Chem. 2023 Jun 19. pii: S0021-9258(23)01971-3. [Epub ahead of print] 104943

Lack of polyamines leads to co-translational degradation of the general stress factor RpoS in Escherichia coli.

Nadim Majdalani, Manas Chattopadhyay, Christopher Keller, Susan Gottesman.

  The specialized sigma factor RpoS mediates a general stress response in Escherichia coli and related bacteria, activating promoters that allow cells to survive stationary phase and many stresses. RpoS synthesis and stability are regulated at multiple levels. Translation of RpoS is positively regulated by multiple small RNAs (sRNAs) in response to stress. Degradation of RpoS, dependent upon the adaptor protein RssB, is rapid during exponential growth, and ceases upon starvation or other stresses, increasing accumulation of RpoS. E. coli carrying mutations that block the synthesis of polyamines were previously found to have low levels of RpoS, while levels increased rapidly when polyamines were added. We have used a series of reporters to examine the basis for the lack of RpoS in polyamine-deficient cells. The polyamine requirement was independent of sRNA-mediated positive regulation of RpoS translation. Mutations in rssB stabilize RpoS and significantly bypassed the polyamine deficit, suggesting that polyamines might lead to rapid RpoS degradation. However, rates of degradation of mature RpoS were unaffected by polyamine availability. Codon optimization in rpoS partially relieved the polyamine dependence, suggesting a defect in RpoS translation in the absence of polyamines. Consistent with this, a hyper-proofreading allele of ribosomal protein S12, encoded by rpsL, showed a decrease in RpoS levels, and this decrease was also suppressed by either codon optimization or blocking RpoS degradation. We suggest that rpoS codon usage leads it to be particularly sensitive to slowed translation, due to either lack of polyamines or hyperproofreading, leading to co-translational degradation.

Keywords:  RssB; response regulator; ribosomal proofreading; rpsL; sRNA; sigma factor; stress response

DOI:  https://doi.org/10.1016/j.jbc.2023.104943
Kidney Int. 2023 Jul;pii: S0085-2538(23)00329-0. [Epub ahead of print]104(1): 31-33

Maybe the various forms of kidney disease are not so mechanistically different?

Roger G Evans.

Sieckmann and colleagues provide evidence of a common abnormality in polyamine metabolism in 11 different rodent models of acute kidney injury and chronic kidney disease, and in human renal transplantation. The abnormality is characterized by downregulation of enzymes involved in polyamine synthesis and/or upregulation of enzymes involved in polyamine metabolism. Therefore, polyamine metabolism is a potential target for development of pharmacotherapies for a broad range of kidney diseases.

DOI: https://doi.org/10.1016/j.kint.2023.04.014
Front Plant Sci. 2023 ;14 1194737

Genetic portrait of polyamine transporters in barley: insights in the regulation of leaf senescence.

Ewelina Stolarska, Umesh Kumar Tanwar, Yufeng Guan, Magda Grabsztunowicz, Magdalena Arasimowicz-Jelonek, Otto Phanstiel, Ewa Sobieszczuk-Nowicka.

  Nitrogen (N) is one of the most expensive nutrients to supply, therefore, improving the efficiency of N use is essential to reduce the cost of commercial fertilization in plant production. Since cells cannot store reduced N as NH3 or NH4 +, polyamines (PAs), the low molecular weight aliphatic nitrogenous bases, are important N storage compounds in plants. Manipulating polyamines may provide a method to increase nitrogen remobilization efficiency. Homeostasis of PAs is maintained by intricate multiple feedback mechanisms at the level of biosynthesis, catabolism, efflux, and uptake. The molecular characterization of the PA uptake transporter (PUT) in most crop plants remains largely unknown, and knowledge of polyamine exporters in plants is lacking. Bi-directional amino acid transporters (BATs) have been recently suggested as possible PAs exporters for Arabidopsis and rice, however, detailed characterization of these genes in crops is missing. This report describes the first systematic study to comprehensively analyze PA transporters in barley (Hordeum vulgare, Hv), specifically the PUT and BAT gene families. Here, seven PUTs (HvPUT1-7) and six BATs (HvBAT1-6) genes were identified as PA transporters in the barley genome and the detailed characterization of these HvPUT and HvBAT genes and proteins is provided. Homology modeling of all studied PA transporters provided 3D structures prediction of the proteins of interest with high accuracy. Moreover, molecular docking studies provided insights into the PA-binding pockets of HvPUTs and HvBATs facilitating improved understanding of the mechanisms and interactions involved in HvPUT/HvBAT-mediated transport of PAs. We also examined the physiochemical characteristics of PA transporters and discuss the function of PA transporters in barley development, and how they help barley respond to stress, with a particular emphasis on leaf senescence. Insights gained here could lead to improved barley production via modulation of polyamine homeostasis.

Keywords:  barley; bi-directional amino acid transporters; polyamine uptake transporters; polyamines; senescence

DOI:  https://doi.org/10.3389/fpls.2023.1194737
Crit Rev Microbiol. 2023 Jun 20. 1-10

Polyamine as a microenvironment factor in resistance to antibiotics.

Amrita C Bhagwat, Sunil D Saroj.

  One of the main issues in modern medicine is the decrease in the efficacy of antibiotic therapy against resistant microorganisms. The advent of antimicrobial resistance has added significantly to the impact of infectious diseases, in number of infections, as well as added healthcare costs. The development of antibiotic tolerance and resistance is influenced by a variety of environmental variables, and it is important to identify these environmental factors as part of any strategy for combating antibiotic resistance. The review aims to emphasize that biogenic polyamines are one of such environmental cues that impacts the antibiotic resistance in bacteria. The biogenic polyamines can help bacteria acquire resistance to antibiotics either by regulating the level of number of porin channels in the outer membrane, by modifying the outer membrane liposaccharides or by protecting macromolecule from antibiotic stress. Thus, understanding the way polyamines function in bacteria can thus be beneficial while designing the drugs to combat diseases.

Keywords:  Polyamines; antibiotic resistance; polyamine transporters; porins

DOI:  https://doi.org/10.1080/1040841X.2023.2223277
HGG Adv. 2023 07 13. 4(3): 100206

Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.

Leah R Padgett, Mollie R Shinkle, Spencer Rosario, Tracy Murray Stewart, Jackson R Foley, Robert A Casero, Myung Hee Park, Wendy K Chung, Teresa L Mastracci.

  DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the Deoxyhypusine synthase (DHPS) gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures. Therefore, to increase our understanding of this rare disease, it is critical to determine the mechanisms by which mutations in DHPS alter neurodevelopment. In this study, we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function. Moreover, we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP). Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function. This study reveals new insight into the biological consequences and molecular impact of human DHPS deficiency and provides valuable information toward the goal of developing treatment strategies for this rare disease.

Keywords:  DHPS; DHPS deficiency; eIF5A; hypusination; hypusine; mRNA translation; neurodevelopment; rare disease

DOI:  https://doi.org/10.1016/j.xhgg.2023.100206
Balkan Med J. 2023 Jun 23.

Exogenous Spermidine Alleviates Diabetic Myocardial Fibrosis Via Suppressing Inflammation and Pyroptosis in db/db Mice.

Can Wei, Jiyu Xu, Yong Liu, Javeria Qadir, Shumin Zhang, Hui Yuan.

Background: The main pathological feature of diabetic cardiomyopathy (DCM) caused by diabetes mellitus is myocardial fibrosis. According to recent studies in cardiology, it has been suggested that spermidine (SPD) has cardioprotective properties.
Aims: To explore the role and mechanism of SPD in alleviating myocardial fibrosis of DCM.
Study Design: In vivo and in vitro study.
Methods: Type 2 diabetic mice and primary neonatal mouse cardiac fibroblasts (CFs) were selected. Measurements of serum-related markers, echocardiographic analysis, and immunohistochemistry were used to evaluate myocardial fibrosis injury and the effects of SPD. The proliferation and migration of CFs undergoing different treatments were studied. Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction were used to demonstrate molecular mechanisms.
Results: In vivo immunoblotting analysis indicated a downregulation of ornithine decarboxylase and an upregulation of SPD/spermine N1-acetyltransferase. We observed cardiac dysfunction in diabetic mice after 12 weeks. However, the administration of exogenous SPD improved cardiac function, decreased collagen deposition, and reduced myocardial tissue damage. mRNA expression levels of NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-17A, and IL-18 were increased and suppressed in the myocardium of db/db mice upon treatment with SPD. SPD inhibited the proliferation, migration, and collagen secretion of high-glucose-treated fibroblasts in vitro. SPD inhibits the activation of the TGF-β1/Smad signaling pathway and decreases collagen deposition by reducing pyroptosis and Smad-7 ubiquitination levels.
Conclusion: Based on our findings, SPD may have potential applications in protecting against the deterioration of cardiac function in patients with DCM due to a significant new mechanism for diabetic myocardial fibrosis that we discovered.

DOI: https://doi.org/10.4274/balkanmedj.galenos.2023.2023-3-102
Protein Expr Purif. 2023 Jun 20. pii: S1046-5928(23)00097-9. [Epub ahead of print] 106326

Purification and characterization of tomato arginine decarboxylase and its inhibition by the bacterial small molecule phevamine A.

Qiang Guo, Xiaoyan Chen, Bo Li.

  Polyamines play essential roles in plant growth and survival. Arginine decarboxylase (ADC), which converts arginine to agmatine, catalyzes the first step in polyamine biosynthesis from arginine. However, few biochemical studies with purified plant ADCs have been conducted to evaluate their catalytic efficiency. Tomato genome encodes two arginine decarboxylases: SlADC1 and SlADC2, which are critical for growth, development, and immune responses against bacterial pathogens. We expressed and purified soluble SlADC1 as a recombinant protein fused with maltose-binding protein tag from E. coli Rosetta 2(DE3) cells. Using the purified fusion protein, we characterized the biochemical properties of SlADC1 in vitro and explored it as a target of the bacterial small molecule phevamine A. We confirmed that the activity of SlADC1 depends on the cofactor pyridoxal 5'-phosphate. SlADC1 is specific towards l-arginine and its kinetic parameters were measured using a liquid chromatography coupled-mass spectrometry method. Phevamine A is a competitive inhibitor of SlADC1 and reduces the activity of SlADC1 at high micromolar concentrations. Our purification and biochemical characterization of SlADC1 sets the stage for inhibition studies of this enzyme.

Keywords:  Arginine decarboxylase; Bacterial small molecules; Phevamine A; Polyamines

DOI:  https://doi.org/10.1016/j.pep.2023.106326
Front Nutr. 2023 ;10 1164809

Bifidobacterium animalis subsp. lactis and arginine mixture intake improves cognitive flexibility in mice.

Kayo Ikuta, Daisuke Joho, Masaki Kakeyama, Mitsuharu Matsumoto.

  The relationship between intestinal microbiota and cognitive function has been investigated as one of the major topics within the intestinal microbiota-gut-brain axis. Although an increasing number of studies have demonstrated an improvement in learning and memory when using probiotics or prebiotics, to date, there are no studies that target the cognitive flexibility observed in the early stages of several neuropsychiatric diseases, including dementia. We have recently developed a novel behavioral task using the touchscreen operant system to assess cognitive flexibility. We found that the disruption of the intestinal microbiota in mice induced a decline in cognitive flexibility. In the present study, we investigated the effects of treatments consisting of Bifidobacterium animalis subsp. lactis and arginine (Bifal + Arg), which promote the production of intestinal bacterial polyamine, on cognitive flexibility in the mouse model. Male C57BL6 mice orally treated with Bifal + Arg three times a week gradually decreased the 1st-choice incorrect diagonal rate with repeated reversals compared with the control group. Furthermore, in serial reversal phases, Bifal + Arg-treated mice shifted to the behavior of choosing a new correct spot more quickly after the reversal, and this was faster with repeated reversals. These results indicate that this treatment adapts to change and improves cognitive flexibility. This is the first report to show that intestinal environmental control, including probiotics and prebiotics, improves cognitive flexibility in mice.

Keywords:  functional food; learning-set; microbiota-gut-brain axis; polyamines; reversal learning; touchscreen operant system

DOI:  https://doi.org/10.3389/fnut.2023.1164809
Histol Histopathol. 2023 Jun 06. 18637

Targeting eIF5A2 reduces invasion and reverses chemoresistance in SCC-9 cells in vitro.

Jinbo Gao, Peng Li.

BACKGROUND AND AIMS: Eukaryotic translation initiation factor 5A2 (EIF5A2) has been reported to be involved in metastasis and chemotherapy resistance in many human cancers. However, the effect and mechanism of EIF5A2 in oral cancer cells are unknown. Here, we investigated the effects of targeting EIF5A2 on chemotherapy resistance in oral cancer cells in vitro.
METHODS: By using a lentiviral system, we investigated the effects of targeting EIF5A2 on the invasion, migration, growth, and chemosensitivity of SCC-9 cells to CDDP in vitro. Through the method of gene intervention, we explore the role of pro-apoptotic Bim and epithelial and mesenchymal marker E-cadherin protein in this process and the regulation of EIF5A2 on Bim and E-cadherin.
RESULTS: Targeting EIF5A2 reduces invasion and migration in SCC-9 cells partly through upregulation of E-cadherin expression; Targeting EIF5A2 promotes cell apoptosis and inhibits cell survival as well as increasing chemosensitivity in SCC-9 cells through upregulation of Bim expression.
CONCLUSION: EIF5A2 may be a novel potential therapeutic target for oral cancer by upregulation of Bim and E-cadherin.

DOI: https://doi.org/10.14670/HH-18-637
Front Immunol. 2023 ;14 1070953

Development and validation of polyamines metabolism-associated gene signatures to predict prognosis and immunotherapy response in lung adenocarcinoma.

Ning Wang, Mengyu Chai, Lingye Zhu, Jingjing Liu, Chang Yu, Xiaoying Huang.

   Background: Polyamines metabolism is closely related to tumor development and progression, as well as tumor microenvironment (TME). In this study, we focused on exploring whether polyamines metabolism-associated genes would provide prognosis and immunotherapy response prediction in lung adenocarcinoma (LUAD).
Methods: The expression profile data of polyamines metabolism-associated genes were acquired from the Cancer Genome Atlas (TCGA) database. Utilizing the least absolute shrinkage and selection operator (LASSO) algorithm, we created a risk score model according to polyamines metabolism-associated gene signatures. Meanwhile, an independent cohort (GSE72094) was employed to validate this model. Through the univariate and multivariate Cox regression analyses, the independent prognostic factors were identified. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect their expression in LUAD cells. By consensus clustering analysis, polyamines metabolism-associated subgroups were determined in LUAD patients, with differential gene expression, prognosis, and immune characteristics analyses explored.
Results: A total of 59 polyamines metabolism genes were collected for this study, of which 14 genes were identified for the construction of risk score model using LASSO method. High- and low- risk groups of LUAD patients in TCGA cohort were distinguished via this model, and high-risk group presented dismal clinical outcomes. The same prognostic prediction of this model had been also validated in GSE72094 cohort. Meanwhile, three independent prognostic factors (PSMC6, SMOX, SMS) were determined for constructing the nomogram, and they were all upregulated in LUAD cells. In addition, two distinct subgroups (C1 and C2) were identified in LUAD patients. Comparing the two subgroups, 291 differentially expressed genes (DEGs) were acquired, mainly enriching in organelle fission, nuclear division, and cell cycle. Comparing to C1 subgroup, the patients in C2 subgroup had favorable clinical outcomes, increased immune cells infiltration, and effective immunotherapy response.
Conclusion: This study identified polyamines metabolism-associated gene signatures for predicting the patients' survival, and they were also linked to immune cells infiltration and immunotherapy response in LUAD patients.

Keywords:  immunotherapy response; lung adenocarcinoma; polyamines metabolism; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1070953
bioRxiv. 2023 Jun 06. pii: 2023.06.06.543936. [Epub ahead of print]

Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex.

Yung-Chi Tu, Fan-Yi Chao, Ming-Feng Tsai.

The mitochondrial Ca 2+ uniporter mediates the crucial cellular process of mitochondrial Ca 2+ uptake, which regulates cell bioenergetics, intracellular Ca 2+ signaling, and cell death initiation. The uniporter contains the pore-forming MCU subunit, an EMRE protein that binds to MCU, and the regulatory MICU1 subunit, which can dimerize with MICU1 or MICU2 and under resting cellular [Ca 2+ ] occludes the MCU pore. It has been known for decades that spermine, which is ubiquitously present in animal cells, can enhance mitochondrial Ca 2+ uptake, but the underlying mechanisms remain unclear. Here, we show that spermine exerts dual modulatory effects on the uniporter. In physiological concentrations of spermine, it enhances uniporter activity by breaking the physical interactions between MCU and the MICU1-containing dimers to allow the uniporter to constitutively take up Ca 2+ even in low [Ca 2+ ] conditions. This potentiation effect does not require MICU2 or the EF-hand motifs in MICU1. When [spermine] rises to millimolar levels, it inhibits the uniporter by targeting the pore region in a MICU-independent manner. The MICU1-dependent spermine potentiation mechanism proposed here, along with our previous finding that cardiac mitochondria have very low MICU1, can explain the puzzling observation in the literature that mitochondria in the heart show no response to spermine.

DOI: https://doi.org/10.1101/2023.06.06.543936