bims-polyam Biomed News
on Polyamines
Issue of 2022–06–12
six papers selected by
Sebastian J. Hofer, University of Graz
  1. Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study.
  2. Functions of polyamines in growth and development of Phycomyces blakesleeanus wild-type and mutant strains.
  3. The Association between Spermidine/Spermine N1-Acetyltransferase (SSAT) and Human Malignancies.
  4. Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections.
  5. Metabolomics Analysis Reveals Alterations in Cochlear Metabolic Profiling in Mice with Noise-Induced Hearing Loss.
  6. Polyamine synthesis enzyme AMD1 is closely related to the tumorigenesis and prognosis of human breast cancer.
  1. Int J Mol Sci. 2022 May 27. pii: 6039. [Epub ahead of print]23(11):
    Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study.
    Hannah Mein, Yu Jing, Faraz Ahmad, Hu Zhang, Ping Liu.
      Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the MAPT P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system.
    Keywords:  PS19 mice; arginine; hippocampus; polyamine; polyamine stress response; spermine; tau; tauopathy
    DOI:  https://doi.org/10.3390/ijms23116039
  2. Fungal Biol. 2022 Jun-Jul;126(6-7):pii: S1878-6146(22)00048-4. [Epub ahead of print]126(6-7): 429-437
    Functions of polyamines in growth and development of Phycomyces blakesleeanus wild-type and mutant strains.
    Humberto R Medina, Beatriz Morera, Rafael Flores, José Ruiz-Herrera, Enrique Cerdá-Olmedo.
      Polyamines are ubiquitous polycationic molecules with multiple effects. Spermidine was present in all the life stages of Phycomyces blakesleeanus, fulfilled the physiological requirement for polyamines during germination, and became most abundant at the emergence of germinating tubes. Putrescine was not found in resting spores or in stationary cultures, but was synthesized during apical growth and greatly exceeded spermidine in fast-growing stages of the vegetative and sexual life cycles. Changes in the polyamines did not correlate with the various stages of sporulation. Ornithine decarboxylase was so strongly inhibited in vitro by its product, putrescine, that it would completely block the enzyme if not compartmentalized away. 1,4-Diamino-2-butanone inhibited mycelial growth throughout the vegetative cycle without killing the cells. The inhibition was counteracted very effectively by putrescine, which acts as a close analog of the inhibitor, and very little by spermidine. Four independent spe mutants were obtained by a procedure that selected for resistance to diaminobutanone among functionally-uninucleate spores that survived exposure to N-methyl-N'-nitro-N-nitrosoguanidine. The stability of the enzyme, in vivo and in vitro, and its inhibition by diaminobutanone in vitro were the same in the wild type and in the mutants. Two of these were hypomorph mutants, with lower affinity of their ornithine decarboxylase for its substrate, ornithine, and lower maximal velocity. The other two were hypermorph transport mutants; we propose that they are affected in a protein that binds putrescine and its analogs for transport across the plasmalemma and sequestration away from the active enzyme. The transport mutants concentrated the exogenous diaminobutanone and the endogenous putrescine in inactive compartments; the highest enzyme activity was reached when the plasmalemma of the mutants was permeabilized with diethylaminoethyl dextran.
    Keywords:  Diaminobutanone; Mucorales; Ornithine decarboxylase; Permeation; Polyamines
    DOI:  https://doi.org/10.1016/j.funbio.2022.04.009
  3. Int J Mol Sci. 2022 May 25. pii: 5926. [Epub ahead of print]23(11):
    The Association between Spermidine/Spermine N1-Acetyltransferase (SSAT) and Human Malignancies.
    Ryan Tsz-Hei Tse, Xiaofan Ding, Christine Yim-Ping Wong, Carol Ka-Lo Cheng, Peter Ka-Fung Chiu, Chi-Fai Ng.
      Spermidine/spermine N1-acetyltransferase (SSAT) functions as a critical enzyme in maintaining the homeostasis of polyamines, including spermine, spermidine, and putrescine, in mammalian cells. SSAT is a catalytic enzyme that indirectly regulates cellular physiologies and pathways through interaction with endogenous and exogenous polyamines. Normally, SSAT exhibits only at a low cellular level, but upon tumorigenesis, the expression, protein level, and activities of SSAT are altered. The alterations induce cellular damages, including oxidative stress, cell cycle arrest, DNA dynamics, and proliferation by influencing cellular mechanisms and signaling pathways. The expression of SSAT has been reported in various studies to be altered in different cancers, and it has been correlated with tumor development and progression. Tumor grades and stages are associated with the expression levels of SSAT. SSAT can be utilized as a target for substrate binding, and excreted metabolites may be used as a novel cancer biomarker. There is also potential for SSAT to be developed as a therapeutic target. Polyamine analogs could increase SSAT expression and increase the cytotoxicity of chemotherapy to tumor cells. Drugs targeting polyamines and SSAT expression have the potential to be developed into new cancer treatments in the future.
    Keywords:  SSAT; cancers development; mechanisms; polyamines
    DOI:  https://doi.org/10.3390/ijms23115926
  4. Molecules. 2022 May 26. pii: 3425. [Epub ahead of print]27(11):
    Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections.
    Francesca Truzzi, Anne Whittaker, Eros D'Amen, Camilla Tibaldi, Antonella Abate, Maria Chiara Valerii, Enzo Spisni, Giovanni Dinelli.
      Impaired autophagy, responsible for increased inflammation, constitutes a risk factor for the more severe COVID-19 outcomes. Spermidine (SPD) is a known autophagy modulator and supplementation for COVID-19 risk groups (including the elderly) is recommended. However, information on the modulatory effects of eugenol (EUG) is scarce. Therefore, the effects of SPD and EUG, both singularly and in combination, on autophagy were investigated using different cell lines (HBEpiC, SHSY5Y, HUVEC, Caco-2, L929 and U937). SPD (0.3 mM), EUG (0.2 mM) and 0.3 mM SPD + 0.2 mM EUG, significantly increased autophagy using the hallmark measure of LC3-II protein accumulation in the cell lines without cytotoxic effects. Using Caco-2 cells as a model, several crucial autophagy proteins were upregulated at all stages of autophagic flux in response to the treatments. This effect was verified by the activation/differentiation and migration of U937 monocytes in a three-dimensional reconstituted intestinal model (Caco-2, L929 and U937 cells). Comparable benefits of SPD, EUG and SPD + EUG in inducing autophagy were shown by the protection of Caco-2 and L929 cells against lipopolysaccharide-induced inflammation. SPD + EUG is an innovative dual therapy capable of stimulating autophagy and reducing inflammation in vitro and could show promise for COVID-19 risk groups.
    Keywords:  SARS-CoV-2; autophagy; eugenol; human cell lines; inflammation; spermidine
    DOI:  https://doi.org/10.3390/molecules27113425
  5. Biomed Res Int. 2022 ;2022 9548316
    Metabolomics Analysis Reveals Alterations in Cochlear Metabolic Profiling in Mice with Noise-Induced Hearing Loss.
    Long Miao, Juan Zhang, Lihong Yin, Yuepu Pu.
      Noise-induced hearing loss (NIHL) has always been an important occupational hazard, but the exact etiopathogenesis underlying NIHL remains unclear. Herein, we aimed to find metabolic biomarkers involved in the development of NIHL based on a mouse model using a gas chromatography coupled with mass spectrometry (GC-MS) metabolomics technique. We showed that the auditory brainstem response (ABR) thresholds at the frequencies of 4, 8, 12, 16, 24, and 32 kHz were all significantly elevated in the noise-exposed mice. Noise could cause outer hair cell (OHC) loss in the base of the cochlea. A total of 17 differential metabolites and 9 metabolic pathways were significantly affected following noise exposure. Spermidine acting as an autophagy modulator was found to be 2.85-fold higher in the noise-exposed group than in the control group and involved in β-alanine metabolism and arginine and proline metabolism pathways. Additionally, we demonstrated that LC3B and Beclin1 were expressed in the spiral ganglion neurons (SGNs), and their mRNA levels were increased after noise. We showed that SOD activity was significantly decreased in the cochlea of noise-exposed mice. Further experiments suggested that SOD1 and SOD2 proteins in the SGNs were all decreased following noise exposure. The upregulation of spermidine may induce LC3B- and Beclin1-mediated autophagy in the cochlear hair cells (HCs) through β-alanine metabolism and arginine and proline metabolism and be involved in the NIHL. ROS-mediated oxidative damage may be a pivotal molecular mechanism of NIHL. Taken together, spermidine can be regarded as an important metabolic marker for the diagnosis of NIHL.
    DOI:  https://doi.org/10.1155/2022/9548316
  6. Exp Cell Res. 2022 Jun 04. pii: S0014-4827(22)00228-2. [Epub ahead of print] 113235
    Polyamine synthesis enzyme AMD1 is closely related to the tumorigenesis and prognosis of human breast cancer.
    Hongyu Gao, Hanjun Li, Jingjie Wang, Cheng Xu, Yueyun Zhu, Dilihumaer Tuluhong, Xinfang Li, Shaohua Wang, Jieshou Li.
      Adenosylmethionine decarboxylase 1 (AMD1) has been implicated in carcinogenesis and tumor progression. However, the potential biomechanism and biological implications of AMD1 in breast cancer (BC) remain unclear. The purpose of this study was to investigate the effect of abnormal expression of AMD1 in BC. The expression of AMD1 in different human BC cell lines was studied by using western blotting and qRT-PCR. In vitro cell proliferation, clone formation, cell cycle and apoptosis assays were performed to explore the effect of AMD1 on cellular proliferation. Xenograft mouse models were established to elucidate the role of AMD1 in BC growth. The expression profiles of AMD1 in 28 pairs of BC tissues and adjacent noncancerous tissues (ANTs) were investigated by using western blotting and immunohistochemistry. The clinical implication and prognostic evaluation of AMD1 in BC were examined by excavating the online database. We found that the expression levels of AMD1 in BC cell lines were significantly higher than those in the normal human breast epithelial cell line MCF-10A. In addition, AMD1 potentiated proliferation, induced cell cycle progression and inhibited apoptosis in BC cells. Subcutaneous tumor xenografts also supported the promotive role of AMD1 in BCBC growth. We discovered that the level of AMD1 in BC tissues was significantly higher than that in ANTs. Using the online database, increased AMD1 was found to be associated with clinical indicators and predicted a poor prognosis in patients with BC. Our findings indicate that AMD1 elicits potent oncogenic effects on the malignant progression of BC. AMD1 might serve as a promising diagnostic biomarker and therapeutic target for patients with BC.
    Keywords:  AMD1; Biomarker; Breast cancer; Proliferation; Therapeutic target
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113235
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