bims-polyam 2021-07-04 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–07–04
ten papers selected by
Sebastian J. Hofer, University of Graz

Metabolism and function of polyamines in cancer progression.
Effects of ODC on polyamine metabolism, hormone levels, cell proliferation and apoptosis in goose ovarian granulosa cells.
Novel Hemizygous Missense Variant of Spermine Synthase (SMS) Gene Causes Snyder-Robinson Syndrome in a Four-Year-Old Boy.
Polyamines: Functions, Metabolism, and Role in Human Disease Management.
Exogenous Polyamines Influence In Vitro Microbial Adhesion to Human Mucus According to the Age of Mucus Donor.
Downregulation of Polyamine and Diamine Oxidases in Silicon-Treated Cucumber.
Spermidine Inhibits Joints Inflammation and Macrophage Activation in Mice with Collagen-Induced Arthritis.
Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis, and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein.
Metabolomic Reprogramming of C57BL/6-Macrophages during Early Infection with L. amazonensis.
Urinary Spermidine Predicts and Associates with In-Hospital Acute Kidney Injury after Cardiac Surgery.

Cancer Lett. 2021 Jun 26. pii: S0304-3835(21)00305-0. [Epub ahead of print]

Metabolism and function of polyamines in cancer progression.

Ita Novita Sari, Tania Setiawan, Kwang Seock Kim, Yoseph Toni Wijaya, Kae Won Cho, Hyog Young Kwon.

  Polyamines are essential for the proliferation, differentiation, and development of eukaryotes. They include spermine, spermidine, and the diamine precursor putrescine, and are low-molecular-weight, organic polycations with more than two amino groups. Their intracellular concentrations are strictly maintained within a specific physiological range through several regulatory mechanisms in normal cells. In contrast, polyamine metabolism is dysregulated in many neoplastic states, including cancer. In various types of cancer, polyamine levels are elevated, and crosstalk occurs between polyamine metabolism and oncogenic pathways, such as mTOR and RAS pathways. Thus, polyamines might have potential as therapeutic targets in the prevention and treatment of cancer. The molecular mechanisms linking polyamine metabolism to carcinogenesis must be unraveled to develop novel inhibitors of polyamine metabolism. This overview describes the nature of polyamines, their association with carcinogenesis, the development of polyamine inhibitors and their potential, and the findings of clinical trials.

Keywords:  Cancer; Metabolism; Polyamine; Therapy

DOI:  https://doi.org/10.1016/j.canlet.2021.06.020
Poult Sci. 2021 Apr 28. pii: S0032-5791(21)00260-1. [Epub ahead of print]100(8): 101226

Effects of ODC on polyamine metabolism, hormone levels, cell proliferation and apoptosis in goose ovarian granulosa cells.

Chunyang Niu, Sujuan Zhang, Guilin Mo, Yilong Jiang, Liang Li, Hengyong Xu, Chunchun Han, Hua Zhao, Yanhong Yan, Shenqiang Hu, Jiwei Hu, Bo Kang, Dongmei Jiang.

  Ornithine decarboxylase (ODC) plays an indispensable role in the process of polyamine biosynthesis. Polyamines are a pivotal part of living cells and have diverse roles in the regulation of cell proliferation and apoptosis, aging and reproduction. However, to date, there have been no reports about ODC regulating follicular development in goose ovaries. Here, we constructed ODC siRNA and overexpression plasmids and transfected them into goose primary granulosa cells (GCs) to elucidate the effects of ODC interference and overexpression on the polyamine metabolism, hormone levels, cell apoptosis and proliferation of granulosa cells. After interfering with ODC in GCs, the mRNA and protein levels of ODC and the content of putrescine were greatly decreased (P < 0.05). When ODC was overexpressed, ODC mRNA and protein levels and putrescine content were greatly increased (P < 0.05). The polyamine-metabolizing enzyme genes ornithine decarboxylase antizyme 1 (OAZ1) and spermidine / spermine-N1-acetyltransferase (SSAT) were significantly increased, and spermidine synthase (SPDS) was significantly decreased when ODC was downregulated (P < 0.05). OAZ1, SPDS and SSAT were significantly increased when ODC was upregulated (P < 0.05). In addition, after interference with ODC, progesterone (P4) levels in the culture medium of GCs increased greatly (P < 0.05), while the overexpression of ODC caused the P4 level to decrease significantly (P < 0.05). After ODC downregulation, granulosa cell activity was significantly reduced, the apoptosis rate was significantly increased, and the BCL-2 / BAX ratio was downregulated (P < 0.05). Under ODC overexpression, the activity of GCs was notably increased, the apoptosis rate was significantly reduced, and the BCL-2 / BAX protein ratio was upregulated (P < 0.05). Our study successfully induced ODC interference and overexpression in goose ovarian GCs, and ODC regulated mainly putrescine content in GCs with a slight influence on spermidine and spermine. Moreover, ODC participated in the adjustment of P4 levels in the culture medium of GCs, promoted granulosa cell proliferation and inhibited granulosa cell apoptosis.

Keywords:  apoptosis; granulosa cells; ornithine decarboxylase; polyamine; proliferation

DOI:  https://doi.org/10.1016/j.psj.2021.101226
Mol Syndromol. 2021 Jun;12(3): 194-199

Novel Hemizygous Missense Variant of Spermine Synthase (SMS) Gene Causes Snyder-Robinson Syndrome in a Four-Year-Old Boy.

Stella Mouskou, Adamantios Katerelos, Artemis Doulgeraki, Sofia Leka-Emiri, Emmanouil Manolakos, Ioannis Papoulidis, Athina Ververi, Georgios Vartzelis, Anastasia Korona, Sotiria Mastroyanni, Konstantinos Voudris.

  Snyder-Robinson syndrome (SRS) is an extremely rare X-linked intellectual disability syndrome (MRXSSR; MIM #309583). The main clinical features of SRS include psychomotor delay, hypotonia, and asthenic-type body habitus - reduced body weight and bone abnormalities (osteoporosis, fractures, kyphoscoliosis). We report a case of SRS with a hemizygous missense variant in the SMS gene,c.334C>G (p.Pro112Ala), in a 4-year-old boy, who initially developed hypotonia, delayed motor skills, and subsequently epilepsy. This variant in SMS was found to be de novo. To the best of our knowledge, this novel SMS gene variant has never been previously reported in disease-related variation databases, such as ClinVar or HGMD.

Keywords:  Epilepsy; Osteopenia; Snyder-Robinson syndrome; Spermine synthase; de novo mutation

DOI:  https://doi.org/10.1159/000514122
Med Sci (Basel). 2021 Jun 09. pii: 44. [Epub ahead of print]9(2):

Polyamines: Functions, Metabolism, and Role in Human Disease Management.

Narashans Alok Sagar, Swarnava Tarafdar, Surbhi Agarwal, Ayon Tarafdar, Sunil Sharma.

  Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and genetic metabolism and help in transcription, translation, signaling, and post-translational modifications. At the cellular level, PA concentration may influence the condition of various diseases in the body. For instance, a high PA level is detrimental to patients suffering from aging, cognitive impairment, and cancer. The levels of PAs decline with age in humans, which is associated with different health disorders. On the other hand, PAs reduce the risk of many cardiovascular diseases and increase longevity, when taken in an optimum quantity. Therefore, a controlled diet is an easy way to maintain the level of PAs in the body. Based on the nutritional intake of PAs, healthy cell functioning can be maintained. Moreover, several diseases can also be controlled to a higher extend via maintaining the metabolism of PAs. The present review discusses the types, important functions, and metabolism of PAs in humans. It also highlights the nutritional role of PAs in the prevention of various diseases.

Keywords:  biosynthesis; disease prevention; human health; nutritional role; polyamines

DOI:  https://doi.org/10.3390/medsci9020044
Microorganisms. 2021 Jun 07. pii: 1239. [Epub ahead of print]9(6):

Exogenous Polyamines Influence In Vitro Microbial Adhesion to Human Mucus According to the Age of Mucus Donor.

Anastasia Mantziari, Enni Mannila, Maria Carmen Collado, Seppo Salminen, Carlos Gómez-Gallego.

  Adhesion to intestinal mucus is the first step for microbiota colonization in early life. Polyamines are polycations with important physiological functions in both procaryotic and eucaryotic cells. However, their role in intestinal mucus adhesion is not known. The objective of the present study was to evaluate whether exogenous polyamines (putrescine, spermidine, spermine, and their combination) would alter the adhesive properties of Lacticaseibacillus rhamnosus GG (LGG), Bifidobacterium animalis subs. lactis Bb12, Cronobacter sakazakii, and Escherichia coli. Human intestinal mucus was isolated from healthy infants (0-6-month-old and 6-12-month-old) and healthy adults (25-52 years old). Spermidine significantly increased Bb12 adhesion (p < 0.05) in the mucus of infants (0-6 months) but reduced the adhesion of LGG in adult mucus (p < 0.05) with no significant effect in any of the infant groups. Spermine was more effective than polyamine combinations in reducing C. sakazakii (p < 0.05) adhesion in early infant mucus (0-6 months). The adhesion ability of E. coli remained unaffected by exogenous polyamines at any age in the concentrations tested. Our data suggest that polyamines may modulate the bacterial adhesion to mucus depending on the bacterial strain and depending at what age the mucus has been generated.

Keywords:  Bifidobacterium; Cronobacter; Lacticaseibacillus rhamnosus; polyamines; putrescine; spermidine; spermine

DOI:  https://doi.org/10.3390/microorganisms9061239
Plants (Basel). 2021 Jun 19. pii: 1248. [Epub ahead of print]10(6):

Downregulation of Polyamine and Diamine Oxidases in Silicon-Treated Cucumber.

Anita Szegő, Iman Mirmazloum, Zsolt Pónya, Oyuntogtokh Bat-Erdene, Mohammad Omran, Erzsébet Kiss-Bába, Márta Gyöngyik, István Papp.

  Silicon (Si) is a ubiquitous element in soil with well-known beneficial effects under certain conditions, in several plant species, if supplied in available form for uptake. It may alleviate damage in various stress situations and may also promote growth when no obvious stressors are applied. Effects of Si are often linked to mitigation of oxidative stress, in particular to the induction of antioxidant defense mechanisms. In the work presented, the impact of silicon provision on pro-oxidant systems was investigated in cucumber. Plants of the F1 cultivar hybrid 'Joker' were grown under in vitro conditions in the absence of any applied external stressor. Silicon provision decreased H2O2 content and lowered lipid peroxidation in the leaves of the treated plants. This was paralleled by declining polyamine oxidase (PAO) and diamine oxidase (DAO) activities. Several PAO as well as lipoxygenase (LOX) genes were coordinately downregulated in Si-treated plants. Unlike in similar systems studied earlier, the Si effect was not associated with an increased transcript level of gene coding for antioxidant enzymes. These results suggest an inhibitory effect of Si provision on pro-oxidant amine oxidases, which may decrease the level of reactive oxygen species by retarding their production. This extends the molecular mechanisms linked to silicon effects onto redox balance in plants.

Keywords:  Cucumis sativus; diamine oxidase; polyamine oxidase; reactive oxygen species; silicate

DOI:  https://doi.org/10.3390/plants10061248
J Inflamm Res. 2021 ;14 2713-2721

Spermidine Inhibits Joints Inflammation and Macrophage Activation in Mice with Collagen-Induced Arthritis.

Hao Yuan, Si-Xian Wu, Yi-Feng Zhou, Fang Peng.

   Purpose: Spermidine (SPD) is a naturally occurring polyamine. In this study, we examined the role and possible mechanism of SPD in collagen-induced arthritis (CIA) mice.
Materials and Methods: CIA mice were intraperitoneally injected with SPD (2 and 50 mg/kg), dexamethasone (0.5 mg/kg), or saline daily for 21 days. The severity of the disease and inflammatory responses in the serum and joint tissue were assessed through macroscopic, immunohistochemical, and histological analyses.
Results: Macroscopic and histological results indicated that SPD protected against the development of CIA. SPD suppressed the levels of the pro-inflammatory cytokines IL-6 and IL-1β and increased the levels of the anti-inflammatory factor IL-10 in the serum. Immunohistochemical staining showed that 50 mg/kg SPD inhibited iNOS expression in synovial macrophages in the ankle joints of CIA mice.
Conclusion: These results suggest that SPD may protect CIA mice by inhibiting the polarization of M1 macrophages in the synovial tissue, reducing pro-inflammatory cytokines, and promoting anti-inflammatory factor release.

Keywords:  collagen-induced arthritis mice; inflammation; macrophage polarization; rheumatoid arthritis; spermidine

DOI:  https://doi.org/10.2147/JIR.S313179
Int J Mol Sci. 2021 Jun 26. pii: 6892. [Epub ahead of print]22(13):

Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis, and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein.

Ekaterina I Lesnova, Olga V Masalova, Kristina Yu Permyakova, Vyacheslav V Kozlov, Tatyana N Nikolaeva, Alexander V Pronin, Vladimir T Valuev-Elliston, Alexander V Ivanov, Alla A Kushch.

  Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.

Keywords:  CpG ODN 1826; HCV vaccine; N-acetylcysteine (NAC); adjuvants; difluoromethylornithine (DFMO); hepatitis C virus (HCV); immune response; myeloid-derived suppressor cells (MDSC); nonstructural protein NS5B; regulatory T cells (Treg)

DOI:  https://doi.org/10.3390/ijms22136892
Int J Mol Sci. 2021 Jun 26. pii: 6883. [Epub ahead of print]22(13):

Metabolomic Reprogramming of C57BL/6-Macrophages during Early Infection with L. amazonensis.

Maricruz Mamani-Huanca, Sandra Marcia Muxel, Stephanie Maia Acuña, Lucile Maria Floeter-Winter, Coral Barbas, Ángeles López-Gonzálvez.

  Leishmania survival inside macrophages depends on factors that lead to the immune response evasion during the infection. In this context, the metabolic scenario of the host cell-parasite relationship can be crucial to understanding how this parasite can survive inside host cells due to the host's metabolic pathways reprogramming. In this work, we aimed to analyze metabolic networks of bone marrow-derived macrophages from C57BL/6 mice infected with Leishmania amazonensis wild type (La-WT) or arginase knocked out (La-arg-), using the untargeted Capillary Electrophoresis-Mass Spectrometry (CE-MS) approach to assess metabolomic profile. Macrophages showed specific changes in metabolite abundance upon Leishmania infection, as well as in the absence of parasite-arginase. The absence of L. amazonensis-arginase promoted the regulation of both host and parasite urea cycle, glycine and serine metabolism, ammonia recycling, metabolism of arginine, proline, aspartate, glutamate, spermidine, spermine, methylhistidine, and glutathione metabolism. The increased L-arginine, L-citrulline, L-glutamine, oxidized glutathione, S-adenosylmethionine, N-acetylspermidine, trypanothione disulfide, and trypanothione levels were observed in La-WT-infected C57BL/6-macrophage compared to uninfected. The absence of parasite arginase increased L-arginine, argininic acid, and citrulline levels and reduced ornithine, putrescine, S-adenosylmethionine, glutamic acid, proline, N-glutamyl-alanine, glutamyl-arginine, trypanothione disulfide, and trypanothione when compared to La-WT infected macrophage. Moreover, the absence of parasite arginase leads to an increase in NO production levels and a higher infectivity rate at 4 h of infection. The data presented here show a host-dependent regulation of metabolomic profiles of C57BL/6 macrophages compared to the previously observed BALB/c macrophages infected with L. amazonensis, an important fact due to the dual and contrasting macrophage phenotypes of those mice. In addition, the Leishmania-arginase showed interference with the urea cycle, glycine, and glutathione metabolism during host-pathogen interactions.

Keywords:  arginase; bone marrow-derived macrophages; metabolites; nitric oxide synthase; polyamines pathway

DOI:  https://doi.org/10.3390/ijms22136883
Antioxidants (Basel). 2021 Jun 02. pii: 896. [Epub ahead of print]10(6):

Urinary Spermidine Predicts and Associates with In-Hospital Acute Kidney Injury after Cardiac Surgery.

Marta Martin-Lorenzo, Angeles Ramos-Barron, Paula Gutierrez-Garcia, Ariadna Martin-Blazquez, Aranzazu Santiago-Hernandez, Emilio Rodrigo Calabia, Carlos Gomez-Alamillo, Gloria Alvarez-Llamas.

  Acute Kidney Injury (AKI) affects up to 30% of the patients who undergo cardiac surgery (CVS) and is related to higher mortality. We aim to investigate molecular features associated with in-hospital AKI development and determine the predictive value of these features when analyzed preoperatively. This is a case-control study. From an initial cohort of 110 recruited subjects, a total of 60 patients undergoing cardiac surgery were included: 20 (33%) developed in-hospital AKI (CVS-AKI) and 40 did not (controls, CVS-C). Pre- and post-surgery samples were collected and a prospective study was carried out. A total of 312 serum samples and 258 urine samples were analyzed by nuclear magnetic resonance, mass spectrometry and ELISA. Six features predicted AKI development in pre-surgery samples: urinary kidney functional loss marker kidney injury molecule-1 (uKIM-1), 2-hydroxybutyric acid, 2-hydroxyphenylacetic acid, hippuric acid, phosphoethanolamine and spermidine. Two of them stood out as powerful predictors. Pre-surgery uKIM-1 levels were increased in CVS-AKI vs. CVS-C (AUC = 0.721, p-value = 0.0392) and associated strongly with the outcome (OR = 5.333, p-value = 0.0264). Spermidine showed higher concentration in CVS-AKI (p-value < 0.0001, AUC = 0.970) and had a strong association with the outcome (OR = 69.75, p-value < 0.0001). uKIM-1 and particularly spermidine predict in-hospital AKI associated with CVS in preoperative samples. These findings may aid in preventing postoperative AKI and improve prognosis of CVS.

Keywords:  KIM-1; NGAL; acute kidney injury; cardiovascular; metabolism; oxidative stress; spermidine

DOI:  https://doi.org/10.3390/antiox10060896