bims-polyam 2022-10-30 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–10–30
thirteen papers selected by
Sebastian J. Hofer, University of Graz

Autophagic flux restoration enhances the antitumor efficacy of tumor infiltrating lymphocytes.
Autophagy-inducing nutritional interventions in experimental and clinical oncology.
Oral Supplementation with the Polyamine Spermidine Affects Hepatic but Not Pulmonary Lipid Metabolism in Lean but Not Obese Mice.
Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice.
Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription.
CsPAO2 Improves Salt Tolerance of Cucumber through the Interaction with CsPSA3 by Affecting Photosynthesis and Polyamine Conversion.
Structural analysis of carboxyspermidine dehydrogenase from Helicobacter pylori.
Polyamines from myeloid-derived suppressor cells promote Th17 polarization and disease progression.
METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification.
Signaling pathways involved in paraquat-induced pulmonary toxicity: Molecular mechanisms and potential therapeutic drugs.
Disruption of three polyamine uptake transporter genes in rice by CRISPR/Cas9 gene editing confers tolerance to herbicide paraquat.
Practical Synthesis of Polyamine Succinamides and Branched Polyamines.
Metabolic Regulation and Lipidomic Remodeling in Relation to Spermidine-induced Stress Tolerance to High Temperature in Plants.

J Immunother Cancer. 2022 Oct;pii: e004868. [Epub ahead of print]10(10):

Autophagic flux restoration enhances the antitumor efficacy of tumor infiltrating lymphocytes.

Chaoting Zhang, Yizhe Sun, Shance Li, Luyan Shen, Xia Teng, Yefei Xiao, Nan Wu, Zheming Lu.

   BACKGROUND: Although adoptive cell therapy with tumor infiltrating lymphocytes (TILs) has mediated effective antitumor responses in several cancers, dysfunction and exhaustion of TILs significantly impair the therapeutic effect of TILs. Thus, it is essential to elucidate the exhausted characteristics of TILs and improve the antitumor effect of TILs by reversing their exhaustion. Here, we focused on the influence of autophagy on TILs in terms of T-cell activation, proliferation, and differentiation in vitro and in vivo.
METHODS: We first evaluated autophagy level of TILs and influence of spermidine treatment on autophagy levels of TILs. Furthermore, we assessed the proliferative potential, phenotypical characteristics, T cell receptor (TCR) repertoire and antitumor activity of TILs with and without spermidine treatment.
RESULTS: We found that autophagic flux of TILs, especially exhausted TILs that express inhibitory immunoreceptors and have impaired proliferative capacity and decreased production of cytotoxic effector molecules, was significantly impaired. The restoration of autophagic flux via spermidine treatment resulted in increased diversity of the TCR repertoire, reduced expression of inhibitory immunoreceptors (PD1, TIM3, or LAG3), enhanced proliferation and effector functions, which subsequently demonstrated the superior in vitro and in vivo antitumor activity of TILs. Our findings unveil that spermidine, as an autophagy inducer, reverses dysfunction and exhaustion of TILs and subsequently improves the antitumor activity of TILs.
CONCLUSIONS: These data suggest that spermidine treatment presents an opportunity to improve adoptive TIL therapy for the treatment of solid tumors.

Keywords:  Immunotherapy, Adoptive; T-Lymphocytes

DOI:  https://doi.org/10.1136/jitc-2022-004868
Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00111-3. [Epub ahead of print]373 125-158

Autophagy-inducing nutritional interventions in experimental and clinical oncology.

Sebastian J Hofer, Guido Kroemer, Oliver Kepp.

  Numerous pro-autophagic dietary interventions are being investigated for their potential cancer-preventive or therapeutic effects. This applies to different fasting regimens, methionine restriction and ketogenic diets. In addition, the supplementation of specific micronutrients such as nicotinamide (vitamin B3) or spermidine induces autophagy. In humans, leanness, plant-based diets (that may lead to partial methionine restriction) and high dietary uptake of spermidine are associated with a low incidence of cancers. Moreover, clinical trials have demonstrated the capacity of nicotinamide to prevent non-melanoma skin carcinogenesis. Multiple interventional trials are evaluating the capacity of autophagy-inducing regimens to improve the outcome of chemotherapy and immunotherapy. Here, we discuss the mechanistic underpinnings of autophagy induction by nutritional interventions, as well as the mechanisms through which autophagy induction in malignant or immune cells improves anticancer immunosurveillance.

Keywords:  Checkpoint blockade; Dietary restriction; Immunogenic cell death; Immunotherapy

DOI:  https://doi.org/10.1016/bs.ircmb.2022.08.003
Nutrients. 2022 Oct 15. pii: 4318. [Epub ahead of print]14(20):

Oral Supplementation with the Polyamine Spermidine Affects Hepatic but Not Pulmonary Lipid Metabolism in Lean but Not Obese Mice.

Sophia Pankoke, Christiane Pfarrer, Silke Glage, Christian Mühlfeld, Julia Schipke.

  The polyamine spermidine is discussed as a caloric restriction mimetic and therapeutic option for obesity and related comorbidities. This study tested oral spermidine supplementation with regard to the systemic, hepatic and pulmonary lipid metabolism under different diet conditions. Male C57BL/6 mice were fed a purified control (CD), high sucrose (HSD) or high fat (HFD) diet with (-S) or without spermidine for 30 weeks. In CD-fed mice, spermidine decreased body and adipose tissue weights and reduced hepatic lipid content. The HSD induced hepatic lipid synthesis and accumulation and hypercholesterolemia. This was not affected by spermidine supplementation, but body weight and blood glucose were lower in HSD-S compared to HSD. HFD-fed mice showed higher body and fat depot weights, prediabetes, hypercholesterolemia and severe liver steatosis, which were not altered by spermidine. Within the liver, spermidine diminished hepatic expression of lipogenic transcription factors SREBF1 and 2 under HSD and HFD and affected the expression of other lipid-related enzymes. In contrast, diet and spermidine exerted only minor effects on pulmonary parameters. Thus, oral spermidine supplementation affects lipid metabolism in a diet-dependent manner, with significant reductions in body fat and weight under physiological nutrition and positive effects on weight and blood glucose under high sucrose intake, but no impact on dietary fat-related parameters.

Keywords:  caloric restriction mimetic; diet-induced obesity; high fat diet; high sucrose diet; liver lipid metabolism; lung lipid metabolism; spermidine

DOI:  https://doi.org/10.3390/nu14204318
Science. 2022 Oct 28. 378(6618): eabj3510

Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice.

Muna Al-Habsi, Kenji Chamoto, Ken Matsumoto, Norimichi Nomura, Baihao Zhang, Yuki Sugiura, Kazuhiro Sonomura, Aprilia Maharani, Yuka Nakajima, Yibo Wu, Yayoi Nomura, Rosemary Menzies, Masaki Tajima, Koji Kitaoka, Yasuharu Haku, Sara Delghandi, Keiko Yurimoto, Fumihiko Matsuda, So Iwata, Toshihiko Ogura, Sidonia Fagarasan, Tasuku Honjo.

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and β subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.

DOI: https://doi.org/10.1126/science.abj3510
Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2214900119

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription.

Vincent Peng, Siyan Cao, Tihana Trsan, Jennifer K Bando, Julian Avila-Pacheco, John L Cleveland, Clary Clish, Ramnik J Xavier, Marco Colonna.

  Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against Citrobacter rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.

Keywords:  IL-22; enteritis; innate lymphoid cells; ornithine decarboxylase; polyamines

DOI:  https://doi.org/10.1073/pnas.2214900119
Int J Mol Sci. 2022 Oct 17. pii: 12413. [Epub ahead of print]23(20):

CsPAO2 Improves Salt Tolerance of Cucumber through the Interaction with CsPSA3 by Affecting Photosynthesis and Polyamine Conversion.

Jianqiang Wu, Mengliang Zhu, Weikang Liu, Mohammad Shah Jahan, Qinsheng Gu, Sheng Shu, Jin Sun, Shirong Guo.

  Polyamine oxidases (PAOs) are key enzymes in polyamine metabolism and are related to the tolerance of plants to abiotic stresses. In this study, overexpression of cucumber (Cucumis sativus L.) PAO2 (CsPAO2) in Arabidopsis resulted in increased activity of the antioxidant enzyme and accelerated conversion from Put to Spd and Spm, while malondialdehyde content (MDA) and electrolyte leakage (EL) was decreased when compared with wild type, leading to enhanced plant growth under salt stress. Photosystem Ⅰ assembly 3 in cucumber (CsPSA3) was revealed as an interacting protein of CsPAO2 by screening yeast two-hybrid library combined with in vitro and in vivo methods. Then, CsPAO2 and CsPSA3 were silenced in cucumber via virus-mediated gene silencing (VIGS) with pV190 as the empty vector. Under salt stress, net photosynthetic rate (Pn) and transpiration rate (Tr) of CsPAO2-silencing plants were lower than pV190-silencing plants, and EL in root was higher than pV190-silencing plants, indicating that CsPAO2-silencing plants suffered more serious salt stress damage. However, photosynthetic parameters of CsPSA3-silencing plants were all higher than those of CsPAO2 and pV190-silencing plants, thereby enhancing the photosynthesis process. Moreover, CsPSA3 silencing reduced the EL in both leaves and roots when compared with CsPAO2-silencing plants, but the EL only in leaves was significantly lower than the other two gene-silencing plants, and conversion from Put to Spd and Spm in leaf was also promoted, suggesting that CsPSA3 interacts with CsPAO2 in leaves to participate in the regulation of salt tolerance through photosynthesis and polyamine conversion.

Keywords:  cucumber; photosynthesis; polyamine; protein interaction; salt stress

DOI:  https://doi.org/10.3390/ijms232012413
Biochem Biophys Res Commun. 2022 Oct 18. pii: S0006-291X(22)01449-8. [Epub ahead of print]635 210-217

Structural analysis of carboxyspermidine dehydrogenase from Helicobacter pylori.

Kyung Yeol Ko, Sun Cheol Park, So Yeon Cho, Sung-Il Yoon.

  Spermidine is a cationic polyamine that plays key roles in diverse biological processes, including biofilm formation and cell viability in bacteria. In some human gastrointestinal bacteria, such as Helicobacter pylori and Campylobacter jejuni, spermidine is biosynthesized using carboxyspermidine dehydrogenase (CASDH) and carboxyspermidine decarboxylase through an alternative pathway rather than the classical pathway found in most bacteria and eukaryotes. CASDH condenses putrescine and aspartate β-semialdehyde into carboxyspermidine in an NADPH-dependent manner. Because structural information on CASDH is not available, the exact enzymatic mechanism of CASDH has not been elucidated. To reveal the structural features of CASDH required for cofactor and substrate recruitment, we determined the crystal structures of the H. pylori CASDH protein alone and in complex with NADP. CASDH consists of three domains (D1, D2, and D3) and assembles into a homodimer exclusively using the D3 domain. The CASDH structure harbors a dent between the D1 and D3 domains. The NADP cofactor is inserted into the interdomain dent and induces structural rearrangements in CASDH, including dent closure and local structural changes in the D1 and D3 domains. A comparative analysis suggests that the substrate of CASDH binds in a cavity near the nicotinamide moiety of NADPH for the condensation reaction.

Keywords:  Carboxyspermidine dehydrogenase; Crystal structure; Helicobacter pylori; NADP; Spermidine

DOI:  https://doi.org/10.1016/j.bbrc.2022.10.049
Mol Ther. 2022 Oct 28. pii: S1525-0016(22)00625-6. [Epub ahead of print]

Polyamines from myeloid-derived suppressor cells promote Th17 polarization and disease progression.

Cong Hu, Yu Zhen, Zhanchuan Ma, Li Zhao, Hao Wu, Chang Shu, Bo Pang, Jinyu Yu, Ying Xu, Xin Zhang, Xiang-Yang Wang, Huanfa Yi.

  Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells that play an important role in diseases. MDSCs promote Th17 differentiation and aggravate systemic lupus erythematosus (SLE) progression by producing arginase-1 to metabolize arginine. However, the metabolic regulators remain unknown. Here, we report that MDSC derivative polyamines can promote Th17 differentiation via miR-542-5p in vitro. Th17 polarization was enhanced in response to polyamine treatment or upon miR-542-5p overexpression. The TGF-β/SMAD3 pathway was shown to be involved in miR-542-5p-facilitated Th17 differentiation. Furthermore, miR-542-5p expression positively correlated with the levels of polyamine synthetases in peripheral blood mononuclear cells of patients with SLE as well as disease severity. In humanized SLE model mice, MDSC depletion decreased the levels of Th17 cells, accompanied by reduced expression of miR-542-5p and these polyamine synthetases. In addition, miR-542-5p expression positively correlated with the Th17 level and disease severity in both patients and humanized SLE mice. Together, our data reveal a novel molecular pathway by which MDSC-derived polyamine metabolism enhances Th17 differentiation and aggravates SLE.

Keywords:  Myeloid-derived suppressor cells; TGF-β/SMAD3; Th17; miR-542-5p; polyamine; systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.ymthe.2022.10.013
Front Oncol. 2022 ;12 962204

METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification.

Zhenyun Guo, Xiang Zhang, Chengjie Lin, Yue Huang, Yun Zhong, Hailing Guo, Zhou Zheng, Shangeng Weng.

  Spermine synthase (SMS) is an enzyme participating in polyamine synthesis; however, its function and role in pancreatic cancer remains elusive. Here we report that SMS is upregulated in pancreatic cancer and predicts a worse overall survival and significantly promotes the proliferation and migration of pancreatic cancer cells. Excessive SMS reduces the accumulation of spermidine by converting spermidine into spermine, which activates the phosphorylation of serine/threonine kinase (AKT) and epithelial-mesenchymal transition (EMT) signaling pathway, thereby inhibiting pancreatic cancer cell proliferation and invasion. Moreover, SMS was identified as the direct target of both methyltransferase like 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly bind to the m6A modification sites of SMS and inhibit mRNA degradation. Knockdown of METTL3 or IGF2BP3 significantly reduced the SMS protein expression and inhibited the migration of pancreatic cancer. We propose a novel regulatory mechanism in which the METTL3-IGF2BP3 axis mediates the mRNA degradation of SMS in an m6A-dependent manner to regulate spermine/spermidine conversion, which regulates AKT phosphorylation and EMT activation, thereby inducing tumor progression and migration in pancreatic cancer.

Keywords:  AKT; EMT; m6A; pancreatic cancer; polyamine; spermine synthase

DOI:  https://doi.org/10.3389/fonc.2022.962204
Int Immunopharmacol. 2022 Oct 21. pii: S1567-5769(22)00785-8. [Epub ahead of print]113(Pt A): 109301

Signaling pathways involved in paraquat-induced pulmonary toxicity: Molecular mechanisms and potential therapeutic drugs.

Xianbo Liu, He Yang, Zhenning Liu.

  Paraquat poisoning is a severe health problem globally, particularly in developing countries. Due to its severe toxicity, the mortality rate of paraquat poisoning is greatly higher than other pesticide poisoning. Paraquat accumulates in the lung by specific polyamine uptake and causes a great amount of reactive oxygen species generation induced by redox cycling. Free radicals can further cause cellular damage via lipid peroxidation, mitochondrial damage, inflammatory response, and apoptosis in many organs including lung, liver, and kidney. The potential mechanisms of paraquat toxicity in the lung are extremely complicated. In this review, the biochemical mechanisms and pathophysiological process of paraquat-induced pulmonary toxicity are systematically elaborated based on previous studies. Furthermore, the signaling pathways including Nrf2/ARE, NF-κB, NLRP3 inflammasome, TLRs, PPAR-γ, MAPKs, AMPK, Rho/ROCK, PI3K/Akt/mTOR, TGF-β/Smad, and Wnt/β-catenin and the potential therapeutic drugs are comprehensively summarized. Further studies are still required to evaluate the efficacy of these drugs in the future.

Keywords:  Oxidative stress; Paraquat; Pulmonary toxicity; Signaling pathways; Therapeutic drug

DOI:  https://doi.org/10.1016/j.intimp.2022.109301
Abiotech. 2022 Jun;3(2): 140-145

Disruption of three polyamine uptake transporter genes in rice by CRISPR/Cas9 gene editing confers tolerance to herbicide paraquat.

Yu-Shu Lyu, Li-Miao Cao, Wen-Qian Huang, Jian-Xiang Liu, Hai-Ping Lu.

  Weeds are a major biotic constraint that can cause dramatic crop production losses. Herbicide technology has been widely used by farmers as the most cost-effective weed control measure, and development of new strategy to improve herbicide tolerance in plants is urgently needed. The CRISPR/Cas9-based genome editing tool has been used in diverse applications related to agricultural technology for crop improvement. Here we identified three polyamine uptake transporter (PUT) genes in rice that are homologous to the Arabidopsis AtRMV1. We successfully demonstrate that CRISPR/Cas9-targeted mutagenesis of OsPUT1/2/3 greatly improves paraquat resistance in rice without obvious yield penalty. Therefore, manipulation of these loci could be valuable for producing transgene-free rice with improved herbicide resistance in future.
Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-022-00075-4.

Keywords:  CRISPR/Cas9; OsPUTs; Paraquat; Rice

DOI:  https://doi.org/10.1007/s42994-022-00075-4
ChemistryOpen. 2022 Oct;11(10): e202200147

Practical Synthesis of Polyamine Succinamides and Branched Polyamines.

Abdulaziz H Alkhzem, Maisem Laabei, Timothy J Woodman, Ian S Blagbrough.

  Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram-positive and Gram-negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4-Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo- and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram-negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo- and hetero-dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram-positive or Gram-negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16-32 μg mL-1 .

Keywords:  antibiotics; polyamines; spermine; succinic anhydride; thermine

DOI:  https://doi.org/10.1002/open.202200147
Int J Mol Sci. 2022 Oct 13. pii: 12247. [Epub ahead of print]23(20):

Metabolic Regulation and Lipidomic Remodeling in Relation to Spermidine-induced Stress Tolerance to High Temperature in Plants.

Zhou Li, Bizhen Cheng, Yue Zhao, Lin Luo, Yan Zhang, Guangyan Feng, Liebao Han, Yan Peng, Xinquan Zhang.

  Beneficial effects of spermidine (Spd) on alleviating abiotic stress damage have been explored in plants for hundreds of years, but limited information is available about its roles in regulating lipids signaling and metabolism during heat stress. White clover (Trifolium repens) plants were pretreated with 70 μM Spd and then subjected to high temperature (38/33 °C) stress for 20 days. To further investigate the effect of Spd on heat tolerance, transgenic Arabidopsisthaliana overexpressing a TrSAMS encoding a key enzyme involved in Spd biosynthesis was exposed to high temperature (38/33 °C) stress for 10 days. A significant increase in endogenous Spd content in white clover by exogenous application of Spd or the TrSAMS overexpression in Arabidopsisthaliana could effectively mitigate heat-induced growth retardation, oxidative damage to lipids, and declines in photochemical efficiency and cell membrane stability. Based on the analysis of metabolomics, the amino acids and vitamins metabolism, biosynthesis of secondary metabolites, and lipids metabolism were main metabolic pathways regulated by the Spd in cool-season white clover under heat stress. Further analysis of lipidomics found the TrSAMS-transgenic plants maintained relatively higher accumulations of total lipids, eight phospholipids (PC, phosphatidylcholine; PG, phosphatidylglycerol; PS, phosphatidylserine; CL, cardiolipin; LPA, lysophosphatidic acid; LPC, lyso phosphatidylcholine; LPG, lyso phosphatidylglycerol; and LPI, lyso phosphatidylinositol), one glycoglycerolipid (DGDG, digalactosyl diacylglycerol), and four sphingolipids (Cer, ceramide; CerG2GNAc1, dihexosyl N-acetylhexosyl ceramide; Hex1Cer, hexosyl ceramide; and ST, sulfatide), higher ratio of DGDG: monogalactosyl diacylglycerol (MGDG), and lower unsaturation level than wild-type Arabidopsisthaliana in response to heat stress. Spd-induced lipids accumulation and remodeling could contribute to better maintenance of membrane stability, integrity, and functionality when plants underwent a long period of heat stress. In addition, the Spd significantly up-regulated PIP2 and PA signaling pathways, which was beneficial to signal perception and transduction for stress defense. Current findings provide a novel insight into the function of Spd against heat stress through regulating lipids signaling and reprograming in plants.

Keywords:  glycoglycerolipids; heat stress; metabolomics; phospholipids; signaling pathway; sphingolipids; unsaturation index

DOI:  https://doi.org/10.3390/ijms232012247