bims-polyam 2023-01-29 papers

Issue of 2023–01–29
five papers selected by
Sebastian J. Hofer, University of Graz

Nat Commun. 2023 Jan 25. 14(1): 399

Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.

S S Mahalingam, S Jayaraman, N Bhaskaran, E Schneider, F Faddoul, A Paes da Silva, M M Lederman, R Asaad, K Adkins-Travis, L P Shriver, P Pandiyan.

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

DOI: https://doi.org/10.1038/s41467-023-36163-2

Int Immunopharmacol. 2023 Jan 25. pii: S1567-5769(23)00062-0. [Epub ahead of print]116 109739

Putrescine accelerates the differentiation of bone marrow derived dendritic cells via inhibiting phosphorylation of STAT3 at Tyr705.

Panpan Huang, Mengyang Wang, Zixuan Lu, Shaojie Shi, Xia Wei, Chenxiao Bi, Guoyan Wang, Hong Liu, Tao Hu, Bin Wang.

Dendritic cells (DCs) play pivotal roles in immune responses. The differentiation and function of DCs are regulated by environmental metabolites. Putrescine is ubiquitous in various metabolic microenvironments and its immunoregulation has been of increasing interest. However, the mechanisms associated with its DC-induced immunoregulation remain unclear. In this study, we found putrescine promoted induction of immature bone marrow derived DCs (BMDCs), along with the increased phagocytosis and migration, and altered cytokine secretion in immature BMDCs. Transcriptomic profiles indicated significantly impaired inflammatory-related pathways, elevated oxidative phosphorylation, and decreased p-STAT3 (Tyr705) expression. Additionally, putrescine performed minor influence on the lipopolysaccharide (LPS)-induced maturation of BMDCs but significantly impaired LPS-induced DC-elicited allogeneic T-cell proliferation as well as the cytokine secretion. Furthermore, molecular docking and dynamics on the conjugation between putrescine and STAT3 revealed that putrescine could be stably bound to the hydrophilic cavity in STAT3 and performed significant influence on the Tyr705 phosphorylation. CUT&Tag analysis uncovered altered motifs, downregulated IFN-γ response, and upregulated p53 pathway in Putrescine group compared with Control group. In summary, our results demonstrated for the first time that putrescine might accelerate the differentiation of BMDCs by inhibiting the phosphorylation of STAT3 at Tyr705. Given that both DCs and putrescine have ubiquitous and distinct roles in various immune responses and pathogeneses, our findings may provide more insights into polyamine immunoregulation on DCs, as well as distinct strategies in the clinical utilization of DCs by targeting polyamines.

Keywords: DC; Mitochondrial respiratory activity; Putrescine; STAT3; Th2 response

DOI: https://doi.org/10.1016/j.intimp.2023.109739

Commun Chem. 2021 Nov 19. 4(1): 160

Chain length of bioinspired polyamines affects size and condensation of monodisperse silica particles.

Sai Prakash Maddala, Wei-Chih Liao, Rick R M Joosten, Mohammad Soleimani, Remco Tuinier, Heiner Friedrich, Rolf A T M van Benthem.

Polyamines play a major role in biosilicification reactions in diatoms and sponges. While the effects of polyamines on silicic acid oligomerization and precipitation are well known, the impact of polyamines chain length on silica particle growth is unclear. We studied the effects of polyamine chain length on silica particle growth and condensation in a known, simple, and salt-free biphasic reaction system; with tetraethyl orthosilicate as organic phase and polyamine dissolved in the aqueous phase. The particles at various growth stages were characterized by Cryo- Transmission Electron Microscopy, Scanning Electron Microscopy, Thermogravimetric Analysis, Zeta Potential, and solid-state NMR analysis. Polyamines were found co-localized within silica particles and the particle diameter increased with an increase in polyamine chain length, whereas silica condensation showed the opposite trend. Particle growth is proposed to progress via a coacervate intermediate while the final particles have a core shell structure with an amine-rich core and silica-rich shell. The results presented in this paper would of interest for researchers working in the field of bioinspired materials.

DOI: https://doi.org/10.1038/s42004-021-00595-y

Int Immunopharmacol. 2023 Jan;pii: S1567-5769(22)01042-6. [Epub ahead of print]114 109557

Effect of spermidine on radiation-induced long-term bone marrow cell injury.

Bowen Guan, Chengcheng Li, Yin Yang, Yanhua Lu, Yuhang Sun, Lulu Su, Guiying Shi, Lin Bai, Jiangning Liu, Aimin Meng.

OBJECTIVE: Spermidine, a natural polyamine, possesses anti-oxidant, autophagy-regulation, and anti-aging properties. Elevated levels of oxidative stress, which was mediated the senescence of hematopoietic stem cells (HSCs) induced by radiation exposure, may further contribute to long-term myelosuppression. Therefore, this study investigated the protective effect of spermidine on the long-term damage of the hematopoietic system caused by radiation exposure.
METHODS: In vitro experiments, bone marrow mononuclear cells (BMMNCs) of C57BL/6 mice were isolated and incubated with 5 mM spermidine for 30 min, then irradiated by 2 Gy X ray. The survival rate, proliferation, and differentiation ability of BMMNCs were detected. In vivo experiment, mice received 4 Gy total body irradiation (TBI), 3 mM spermidine were administered in the drinking water every day for 14 days prior to irradiation and then continued for 30 days after irradiation. Peripheral blood, bone marrow cell typing, level of reactive oxygen species (ROS), colony-forming ability of HSC, and transplantation-reconstitution capability were detected.
RESULTS: In vitro experiments, spermidine significantly improved the survival rate of BMMNCs as well as the proliferation and differentiation ability of HSCs exposure to ionizing radiation (IR). In vivo, spermidine reduced levels of ROS in HSCs; spermidine attenuated long-term myeloid differentiation deviation induced by TBI. Spermidine promoted the proliferation and differentiation ability of stem cells, but failed to ameliorate the decreased engraftment capacity of bone marrow cells in mice exposed to TBI.
CONCLUSION: This study demonstrated that spermidine could promote the recovery of IR-induced inhibition of proliferation and differentiation ability of HSCs, partly through antioxidant effects. Whether combining spermidine with other radioprotectants could further increase protective efficacy and reduce the long-term bone marrow injury needs further investigation.

Keywords: Hematopoietic stem cells; Ionizing radiation; Reactive oxygen species; Spermidine

DOI: https://doi.org/10.1016/j.intimp.2022.109557

Mol Biol Rep. 2023 Jan 23.

Eukaryotic initiation factor 5A hypusine as a negative regulator of adenosine 2B receptor (A2bAR) through interaction with stem loop sequences within the A2bAR 3'-untranslated region.

Grace Kelly Lee, Chang Wook Kim, Ik-Hyun Cho, Hae-Yeong Kim, Jong Hwan Park.

PURPOSE: The aim of this study was to investigate whether eIF5A hypusine (eIF5AHyp) reduces adenosine 2b receptor (A2bAR) gene expression through interaction with highly structured stem-loop sequences within the A2bAR 3'UTR.
METHODS AND RESULTS: Based on real-time PCR and western blotting, expression of A2bAR mRNA was significantly decreased upon treatment with eIF5AHyp in mouse embryonic fibroblasts of eIF5A (eIF5A-MEF) and 3T3-L1 cells. Target Scan software and RNAfold web server predicted two different structures formed by stem-loop sequences with overlapping microRNA 27 seed sequences and mutations. The EMSA results showed significantly impaired formation of the wild type (WT) biotin-labeled A2bAR probe (27 base) containing stem loop sequences-eIF5AHyp complex by mutation of stem-loop sequences or by eIF5A non-hypusine (eIF5ALys). The luciferase reporter assay showed that GC7-induced eIF5ALys accumulation increased the activity of pMIR-A2bAR WT containing the same stem-loop sequence in 3T3-L1 cells, whereas the activity with pMIR-A2bAR Mut was increased compared to WT control without dependence on GC7. Oil Red O staining showed that suppression of A2bAR expression (A2bAR siRNA and eIF5AHyp) increased the amount of lipid droplet formation and the mRNA levels of lipid droplet-related genes (C/EBP-β, PPAR-γ, FABP4, SREBP-1, and Perilipin). In contrast, overexpression of A2bAR (A2bAR vector, eIF5ALys vector, and GC7) significantly decreased the expression of lipid droplet-associated genes and lipid droplet formation.
CONCLUSIONS: eIF5AHyp acts as a negative regulator of A2bAR gene expression through stem loop sequences in A2bAR 3'UTR, allowing differentiation of adipocytes.

Keywords: Adenosine 2B receptor; C/EBP-β; GC7; Lipid droplet; eIF5A hypusine

DOI: https://doi.org/10.1007/s11033-023-08252-4