bims-polyam 2022-11-13 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–11–13
ten papers selected by
Sebastian J. Hofer, University of Graz

Hypusinated eIF5A Promotes Ribosomal Frameshifting during Decoding of ODC Antizyme mRNA in Saccharomyces cerevisiae.
Alkaline Stress Causes Changes in Polyamine Biosynthesis in Thermus thermophilus.
The Potential Role of Polyamines in Epilepsy and Epilepsy-Related Pathophysiological Changes.
Bioengineering of Escherichia coli Nissle 1917 for Production and Excretion of Spermidine, a Key Metabolite in Human Health.
Exogenous Spermidine Promotes Germination of Aged Sorghum Seeds by Mediating Sugar Metabolism.
Spermidine inhibits high glucose-induced endoplasmic reticulum stress in HT22 cells by upregulation of growth differentiation factor 11.
Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma.
Polyamine pathways interconnect with GABA metabolic processes to mediate the low-temperature response in plants.
Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).
Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)-A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA.

Int J Mol Sci. 2022 Oct 26. pii: 12972. [Epub ahead of print]23(21):

Hypusinated eIF5A Promotes Ribosomal Frameshifting during Decoding of ODC Antizyme mRNA in Saccharomyces cerevisiae.

Kai Halwas, Lennard-Maximilian Döring, Franziska Valentina Oehlert, R Jürgen Dohmen.

  Polyamines are essential biogenic poly-cations with important roles in many cellular processes and diseases such as cancer. A rate-limiting step early in the biosynthesis of polyamines is the conversion of ornithine to putrescine by the homodimeric enzyme ornithine decarboxylase (ODC). In a conserved mechanism of posttranslational regulation, ODC antizyme (OAZ) binds to ODC monomers promoting their ubiquitin-independent degradation by the proteasome. Decoding of OAZ mRNA is unusual in that it involves polyamine-regulated bypassing of an internal translation termination (STOP) codon by a ribosomal frameshift (RFS) event. Using Saccharomyces cerevisiae, we earlier showed that high polyamine concentrations lead to increased efficiency of OAZ1 mRNA translation by binding to nascent Oaz1 polypeptide. The binding of polyamines prevents stalling of the ribosomes on OAZ1 mRNA caused by nascent Oaz1 polypeptide thereby promoting synthesis of full-length Oaz1. Polyamine depletion, however, also inhibits RFS during the decoding of constructs bearing the OAZ1 shift site lacking sequences encoding the Oaz1 parts implicated in polyamine binding. Polyamine depletion is known to impair hypusine modification of translation factor eIF5A. Using a novel set of conditional mutants impaired in the function of eIF5A/Hyp2 or its hypusination, we show here that hypusinated eIF5A is required for efficient translation across the OAZ1 RFS site. These findings identify eIF5A as a part of Oaz1 regulation, and thereby of polyamine synthesis. Additional experiments with DFMO, however, show that depletion of polyamines inhibits translation across the OAZ1 RFS site not only by reducing Hyp2 hypusination, but in addition, and even earlier, by affecting RFS more directly.

Keywords:  DFMO; Oaz1; conditional mutants; hypusination; ornithine decarboxylase antizyme; polyamines

DOI:  https://doi.org/10.3390/ijms232112972
Int J Mol Sci. 2022 Nov 04. pii: 13523. [Epub ahead of print]23(21):

Alkaline Stress Causes Changes in Polyamine Biosynthesis in Thermus thermophilus.

Teruyuki Kobayashi, Akihiko Sakamoto, Keiko Kashiwagi, Kazuei Igarashi, Toshiyuki Moriya, Tairo Oshima, Yusuke Terui.

  An extreme thermophile, Thermus thermophilus, produces 16 different polyamines including long-chain and branched-chain polyamines. The composition and content of polyamines in the thermophile cells change not only with growth temperature but also with pH changes. In particular, cell growth decreased greatly at alkaline medium together with significant changes in the composition and content of polyamines. The amounts of tetraamines (spermine and its homologs) markedly decreased at alkaline pH. Thus, we knocked out the speE gene, which is involved in the biosynthesis of tetraamines, and changes of composition of polyamines with pH changes in the mutant cells were studied. Cell growth in the ΔspeE strain was decreased compared with that of the wild-type strain for all pHs, suggesting that tetraamines are important for cell proliferation. Interestingly, the amount of spermidine decreased and that of putrescine increased in wild-type cells at elevated pH, although T. thermophilus lacks a putrescine synthesizing pathway. In addition, polyamines possessing a diaminobutane moiety, such as spermine, decreased greatly at high pH. We assessed whether the speB gene encoding aminopropylagmatine ureohydrolase (TtSpeB) is directly involved in the synthesis of putrescine. The catalytic assay of the purified enzyme indicated that TtSpeB accepts agmatine as its substrate and produces putrescine due to the change in substrate specificity at high pH. These results suggest that pH stress was exacerbated upon intracellular depletion of polyamines possessing a diaminobutane moiety induced by unusual changes in polyamine biosynthesis under high pH conditions.

Keywords:  Thermus thermophilus; alkaline stress; cell growth; polyamine

DOI:  https://doi.org/10.3390/ijms232113523
Biomolecules. 2022 Oct 29. pii: 1596. [Epub ahead of print]12(11):

The Potential Role of Polyamines in Epilepsy and Epilepsy-Related Pathophysiological Changes.

Jiayu Liu, Zhi Yu, Buajieerguli Maimaiti, Qian Meng, Hongmei Meng.

  Epilepsy is one of the most common neurological disorders and severely impacts the life quality of patients. Polyamines are ubiquitous, positively charged aliphatic amines that are present at a relatively high level and help regulate the maintenance of cell membrane excitability and neuronal physiological functions in the central nervous system. Studies have shown abnormalities in the synthesis and catabolism of polyamines in patients with epilepsy and in animal models of epilepsy. The polyamine system seems to involve in the pathophysiological processes of epilepsy via several mechanisms such as the regulation of ion permeability via interaction with ion channels, involvement in antioxidation as hydroperoxide scavengers, and the induction of cell damage via the production of toxic metabolites. In this review, we try to describe the possible associations between polyamines and epilepsy and speculate that the polyamine system is a potential target for the development of novel strategies for epilepsy treatment.

Keywords:  epilepsy; neuroprotection; neurotoxicity; pathological change; polyamine metabolism; seizure

DOI:  https://doi.org/10.3390/biom12111596
Metabolites. 2022 Nov 02. pii: 1061. [Epub ahead of print]12(11):

Bioengineering of Escherichia coli Nissle 1917 for Production and Excretion of Spermidine, a Key Metabolite in Human Health.

Clément Caffaratti, Caroline Plazy, Valérie Cunin, Bertrand Toussaint, Audrey Le Gouellec.

  Microbiota-derived metabolites have biological importance for their host. Spermidine, a metabolite described for its protective effect in age-related diseases, is now studied for its role in the resolution of inflammation and gut homeostasis. Strategies to modulate its production in the gastrointestinal tract are of interest to increase host spermidine intakes. Here, we show that metabolic engineering can be used to increase spermidine production by the probiotic Escherichia coli Nissle 1917 (EcN), used in humans. First, we found that increasing the expression of genes involved in polyamine biosynthesis, namely the S-adenosylmethionine synthase speD and the spermidine synthase speE, resulted in an increase in spermidine produced and excreted by our engineered bacteria. The major drawback of this first attempt was the production of acetylated forms of spermidine. Next, we propose to solve this problem by increasing the expression of the spermidine exporter system MdtI/MdtJ. This second strategy had a major impact on the spermidine profile found in the culture supernatant. Our results demonstrate, for the first time, the feasibility of rationally engineering bacterial probiotic strains to increase their ability to deliver the microbiota-derived metabolite, spermidine. This work illustrates how metabolomic and synthetic biology can be used to design and improve engineered Live Biotherapeutic Products that have the potential to be used in personalized medicine.

Keywords:  Live Biotherapeutic Product; immunity; metabolic engineering; metabolomics; microbiota; probiotics; spermidine

DOI:  https://doi.org/10.3390/metabo12111061
Plants (Basel). 2022 Oct 26. pii: 2853. [Epub ahead of print]11(21):

Exogenous Spermidine Promotes Germination of Aged Sorghum Seeds by Mediating Sugar Metabolism.

Min Zhang, Bang Li, Zuliang Wan, Xiaofei Chen, Chang Liu, Chunjuan Liu, Yufei Zhou.

  Starch, a substance stored in seeds, is the main source of energy for germination in sorghum seeds. However, as the seeds age, the catabolism of seed starch is affected, thereby seriously damaging germination ability. In this study, we aimed to understand how exogenous spermidine promoted germination in aged sorghum seed. Our phenotypic analysis indicated that exogenous spermidine not only significantly improved the germination rate, germination potential, germination index, and vigor index of aged seeds, but also increased the root and shoot length after germination. Further, physiological analysis showed that exogenous spermidine increased the content of soluble sugar by upregulating the activity of amylase and sucrose invertase. Exogenous spermidine also improved the activities of key enzymes in glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway of aged sorghum seeds. Interestingly, exogenous spermidine protected the mitochondrial structure of aged seeds, which was consistent with the increase in the respiration rate and ATP content during seed germination. Moreover, qRT-PCR analysis revealed that exogenous spermidine induced the expression of key genes related to starch and sugar metabolism in aged sorghum seeds. In conclusion, our study demonstrated that exogenous spermidine promoted aged sorghum seed germination by regulating starch and sugar metabolism.

Keywords:  aged sorghum seeds; germination; spermidine; starch; sugar metabolism

DOI:  https://doi.org/10.3390/plants11212853
Neuroreport. 2022 Dec 14. 33(18): 819-827

Spermidine inhibits high glucose-induced endoplasmic reticulum stress in HT22 cells by upregulation of growth differentiation factor 11.

Zhou-Zan Liao, Qi Deng, Fan Xiao, Ming Xie, Xiao-Qing Tang.

Hyperglycemia-induced neuronal endoplasmic reticulum (ER) stress is particularly important for the pathogenesis of diabetic encephalopathy. Spermidine (Spd) has neuroprotection in several nervous system diseases. Our current study to explore the potential protective role of Spd in hyperglycemia-induced neuronal ER stress and the underlying mechanisms. HT22 cells were treated with high glucose (HG) to establish an in-vitro model of hyperglycemia toxicity. The HT22 cells' activity was tested by cell counting kit-8 assay. RNA interference technology was used to silence the expression of growth differentiation factor 11 (GDF11) in HT22 cells. The GDF11 expression levels of mRNA were assessed using reverse transcription-PCR (RT-PCR). Western blotting analysis was applied to evaluate the expressions of GRP78 and cleaved caspase-12. Spd markedly abolished HG-exerted decline in cell viability as well as upregulations of GRP78 and cleaved caspase-12 in HT22 cells, indicating the protection of Spd against HG-induced neurotoxicity and ER stress. Furthermore, we showed that Spd upregulated the expression of GDF11 in HG-exposed HT22 cells. While, silenced GDF11 expression by RNA interference reversed the protective effects of Spd on HG-elicited neurotoxicity and ER stress in HT22 cells. These results indicated that Spd prevents HG-induced neurotoxicity and ER stress through upregulation of GDF11. Our findings identify Spd as a potential treatment for diabetic encephalopathy as well as ER stress-related neurologic diseases.

DOI: https://doi.org/10.1097/WNR.0000000000001853
Cell Commun Signal. 2022 Nov 08. 20(1): 175

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma.

Hong-Xiang Shi, Chao Liang, Chao-Yan Yao, Zi-Xuan Gao, Jia Qin, Jin-Lan Cao, Ming-Zhu Zhang, Ying-Ying Li, Meng-Qing Wang, Hua Sun, Song-Qiang Xie, Dong Fang.

   BACKGROUND: Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism.
METHODS: Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells.
RESULTS: Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells.
CONCLUSIONS: This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma. Video Abstract.

Keywords:  Hepatocellular carcinoma; PD-L1; STT3A; Spermine; β-Catenin

DOI:  https://doi.org/10.1186/s12964-022-00981-6
Front Plant Sci. 2022 ;13 1035414

Polyamine pathways interconnect with GABA metabolic processes to mediate the low-temperature response in plants.

Mengyun Xu, Qinwen Yang, Genxiang Bai, Ping Li, Jian Yan.

  Low temperatures are among the most commonly encountered environmental conditions that adversely affect plant growth and development, leading to substantial reductions in crop productivity. Plants have accordingly evolved coordinated mechanisms that confer low-temperature adaptation and resistance. The plant metabolic network, including polyamines (PAs) and γ-aminobutyric acid (GABA) is reprogrammed to ensure that essential metabolic homeostasis is maintained in response to cold stress conditions. Additionally, GABA might serve as a central molecule in the defense system during low-temperature tolerance in plants. However, our understanding of how these metabolites function in conferring cold tolerance is still far from complete. Here, we summarized how PAs and GABA function in conferring cold tolerance, and describe the crucial role of GABA in the mitigation of ROS during cold stress in plants.

Keywords:  GABA; ROS; cold stress; osmolytes; polyamines

DOI:  https://doi.org/10.3389/fpls.2022.1035414
Metabolites. 2022 Oct 26. pii: 1026. [Epub ahead of print]12(11):

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).

Vamsi P Guntur, Travis Nemkov, Esther de Boer, Michael P Mohning, David Baraghoshi, Francesca I Cendali, Inigo San-Millán, Irina Petrache, Angelo D'Alessandro.

  Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Keywords:  exercise intolerance; keyword post-acute sequelae of COVID-19; long COVID; metabolomics; plasma

DOI:  https://doi.org/10.3390/metabo12111026
Cancers (Basel). 2022 Oct 22. pii: 5179. [Epub ahead of print]14(21):

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)-A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA.

Vinith Yathindranath, Nura Safa, Babu V Sajesh, Kelly Schwinghamer, Magimairajan Issai Vanan, Rashid Bux, Daniel S Sitar, Marshall Pitz, Teruna J Siahaan, Donald W Miller.

  Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood-brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.

Keywords:  Spermidine/spermine N1-acetyltransferase 1 (SAT1); blood–brain barrier (BBB); brain drug delivery; cadherin peptide; gene therapy; glioblastoma (GB); lipid nanoparticles; microfluidic mixing; siRNA; transient modulation; tumor sensitization

DOI:  https://doi.org/10.3390/cancers14215179