bims-polyam 2023-10-01 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–10–01
eight papers selected by
Sebastian J. Hofer, University of Graz

Spermidine suppresses oxidative stress and ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway to alleviate ovarian damage.
Exogenous Putrescine Modulates Nitrate Reductase-Dependent NO Production in Cucumber Seedlings Subjected to Salt Stress.
Indomethacin Induces Spermidine/Spermine-N1-Acetyltransferase-1 via the Nucleolin-CDK1 Axis and Synergizes with the Polyamine Oxidase Inhibitor Methoctramine in Lung Cancer Cells.
Investigation of the Influence of Polyamines on Mature Embryo Culture and DNA Methylation of Wheat (Triticum aestivum L.) Using the Machine Learning Algorithm Method.
Spermidine suppresses oral carcinogenesis through autophagy induction, DNA damage repair and oxidative stress reduction.
Nitric Oxide Induces Autophagy in Triticum aestivum Roots.
Synthesis and application of spermine-based amphiphilic poly(β-amino ester)s for siRNA delivery.
Urine spermine and multiparametric magnetic resonance imaging for prediction of prostate cancer in Japanese men.

Life Sci. 2023 Sep 21. pii: S0024-3205(23)00744-0. [Epub ahead of print]332 122109

Spermidine suppresses oxidative stress and ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway to alleviate ovarian damage.

Chunyang Niu, Dongmei Jiang, Yongni Guo, Zelong Wang, Qian Sun, Xin Wang, Weikang Ling, Xiaoguang An, Chengweng Ji, Shuo Li, Hua Zhao, Bo Kang.

   AIMS: Oxidative stress is considered to be one of the culprits of ovarian dysfunction. Spermidine (SPD) is a natural aliphatic polyamine that is widely present in living organisms and has been shown to exert preventive effects on various ageing-related diseases. This study seeks to investigate the potential preventive and protective effects of SPD on ovarian oxidative damage.
MAIN METHODS: Ovarian oxidative stress model in C57BL/6 mice was established by 3-nitropropionic acid. Female mice were administrated 10 mg/kg or 15 mg/kg SPD. The estrous cycle, serum hormone levels and mating test were measured to evaluate ovarian function. Follicle counts and AMH levels to assess ovarian reserve. Masson's trichrome to assess ovarian fibrosis. TUNEL analysis to evaluate follicular granulosa cells (GCs) apoptosis. Oxidative stress and autophagy indicators (Nrf2, HO-1, GPX4, LC3B, P62) were measured in vivo and in vitro. RNA-sequencing was performed on SPD-treated GC to study the effects of SPD on Akt and FHC/ACSL4 signaling.
KEY FINDINGS: SPD supplementation improved ovarian endocrine function and reproductive capacity in oxidative stress mice. SPD regularized the estrous cycle and alleviated oxidative stress. Furthermore, SPD increased the ovarian reserve, reducing GC apoptosis by activating the Nrf2/HO-1/GPX4 pathway. RNA-sequencing showed that SPD induced 230 genes changes in porcine GC, which were mainly involved in oocyte meiosis, arginine biosynthesis and glutathione metabolism pathways. SPD attenuated H2O2-induced ferroptosis by regulating Akt/FHC/ACSL4 signaling.
SIGNIFICANCE: SPD alleviates oxidative stress and ferroptosis by regulating the Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway, which may be a novel potential strategy to protect ovarian oxidative damage.

Keywords:  Autophagy; Ferroptosis; GPX4 signaling; Ovary; Oxidative stress; Spermidine

DOI:  https://doi.org/10.1016/j.lfs.2023.122109
Metabolites. 2023 Sep 21. pii: 1030. [Epub ahead of print]13(9):

Exogenous Putrescine Modulates Nitrate Reductase-Dependent NO Production in Cucumber Seedlings Subjected to Salt Stress.

Natalia Napieraj, Małgorzata Janicka, Beata Augustyniak, Małgorzata Reda.

  Polyamines (PAs) are small aliphatic compounds that participate in the plant response to abiotic stresses. They also participate in nitric oxide (NO) production in plants; however, their role in this process remains unknown. Therefore, the study aimed to investigate the role of putrescine (Put) in NO production in the roots of cucumber seedlings subjected to salt stress (120 mM NaCl) for 1 and 24 h. In salinity, exogenous Put can regulate NO levels by managing NO biosynthesis pathways in a time-dependent manner. In cucumber roots exposed to 1 h of salinity, exogenous Put reduced NO level by decreasing nitrate reductase (NR)-dependent NO production and reduced nitric oxide synthase-like (NOS-like) activity. In contrast, during a 24 h salinity exposure, Put treatment boosted NO levels, counteracting the inhibitory effect of salinity on the NR and plasma membrane nitrate reductase (PM-NR) activity in cucumber roots. The role of endogenous Put in salt-induced NO generation was confirmed using Put biosynthesis inhibitors. Furthermore, the application of Put can modulate the NR activity at the genetic and post-translational levels. After 1 h of salt stress, exogenous Put upregulated CsNR1 and CsNR2 expression and downregulated CsNR3 expression. Put also decreased the NR activation state, indicating a reduction in the level of active dephosphorylated NR (dpNR) in the total enzyme pool. Conversely, in the roots of plants subjected to 24 h of salinity, exogenous Put enhanced the NR activation state, indicating an enhancement of the dpNR form in the total NR pool. These changes were accompanied by a modification of endogenous PA content. Application of exogenous Put led to an increase in the amount of Put in the roots and reduced endogenous spermine (Spm) content in cucumber roots under 24 h salinity. The regulatory role of exogenous Put on NO biosynthesis pathways may link with plant mechanisms of response to salt stress.

Keywords:  nitrate reductase (NR); nitric oxide; nitric oxide synthase-like activity; polyamines; putrescine; salt stress

DOI:  https://doi.org/10.3390/metabo13091030
Biomolecules. 2023 Sep 12. pii: 1383. [Epub ahead of print]13(9):

Indomethacin Induces Spermidine/Spermine-N1-Acetyltransferase-1 via the Nucleolin-CDK1 Axis and Synergizes with the Polyamine Oxidase Inhibitor Methoctramine in Lung Cancer Cells.

Neudo Buelvas, Isidora Ugarte-Vio, Laura Asencio-Leal, Matías Muñoz-Uribe, Antonia Martin-Martin, Alejandro Rojas-Fernández, José A Jara, Julio C Tapia, María Elena Arias, Rodrigo A López-Muñoz.

  Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin's primary action mechanism, COX-independent ways are associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) is related to the increase in spermidine/spermine-N1-acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells; however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-γ on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-γ with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.

Keywords:  cancer; indomethacin; non-steroidal anti-inflammatory drugs; polyamines

DOI:  https://doi.org/10.3390/biom13091383
Plants (Basel). 2023 Sep 13. pii: 3261. [Epub ahead of print]12(18):

Investigation of the Influence of Polyamines on Mature Embryo Culture and DNA Methylation of Wheat (Triticum aestivum L.) Using the Machine Learning Algorithm Method.

Barış Eren, Aras Türkoğlu, Kamil Haliloğlu, Fatih Demirel, Kamila Nowosad, Güller Özkan, Gniewko Niedbała, Alireza Pour-Aboughadareh, Henryk Bujak, Jan Bocianowski.

  Numerous factors can impact the efficiency of callus formation and in vitro regeneration in wheat cultures through the introduction of exogenous polyamines (PAs). The present study aimed to investigate in vitro plant regeneration and DNA methylation patterns utilizing the inter-primer binding site (iPBS) retrotransposon and coupled restriction enzyme digestion-iPBS (CRED-iPBS) methods in wheat. This investigation involved the application of distinct types of PAs (Put: putrescine, Spd: spermidine, and Spm: spermine) at varying concentrations (0, 0.5, 1, and 1.5 mM). The subsequent outcomes were subjected to predictive modeling using diverse machine learning (ML) algorithms. Based on the specific polyamine type and concentration utilized, the results indicated that 1 mM Put and Spd were the most favorable PAs for supporting endosperm-associated mature embryos. Employing an epigenetic approach, Put at concentrations of 0.5 and 1.5 mM exhibited the highest levels of genomic template stability (GTS) (73.9%). Elevated Spd levels correlated with DNA hypermethylation while reduced Spm levels were linked to DNA hypomethylation. The in vitro and epigenetic characteristics were predicted using ML techniques such as the support vector machine (SVM), extreme gradient boosting (XGBoost), and random forest (RF) models. These models were employed to establish relationships between input variables (PAs, concentration, GTS rates, Msp I polymorphism, and Hpa II polymorphism) and output parameters (in vitro measurements). This comparative analysis aimed to evaluate the performance of the models and interpret the generated data. The outcomes demonstrated that the XGBoost method exhibited the highest performance scores for callus induction (CI%), regeneration efficiency (RE), and the number of plantlets (NP), with R2 scores explaining 38.3%, 73.8%, and 85.3% of the variances, respectively. Additionally, the RF algorithm explained 41.5% of the total variance and showcased superior efficacy in terms of embryogenic callus induction (ECI%). Furthermore, the SVM model, which provided the most robust statistics for responding embryogenic calluses (RECs%), yielded an R2 value of 84.1%, signifying its ability to account for a substantial portion of the total variance present in the data. In summary, this study exemplifies the application of diverse ML models to the cultivation of mature wheat embryos in the presence of various exogenous PAs and concentrations. Additionally, it explores the impact of polymorphic variations in the CRED-iPBS profile and DNA methylation on epigenetic changes, thereby contributing to a comprehensive understanding of these regulatory mechanisms.

Keywords:  DNA methylation; genomic template stability; iPBS; machine learning

DOI:  https://doi.org/10.3390/plants12183261
Am J Pathol. 2023 Sep 21. pii: S0002-9440(23)00361-9. [Epub ahead of print]

Spermidine suppresses oral carcinogenesis through autophagy induction, DNA damage repair and oxidative stress reduction.

Fernanda Borchers Coeli-Lacchini, Gabriel da Silva, Monica Belentani, Jovelina Samara Ferreira Alves, Tatiane Resende Ushida, Glauce Trevisan Lunardelli, Cristiana Bernadelli Garcia, Tarcília Aparecida Silva, Norberto Peporine Lopes, Andréia Machado Leopoldino.

  In cancer, autophagy has been proposed to play a dual role. In this study, we investigated the role of autophagy in oral carcinogenesis using the model of oral squamous cell carcinoma (OSCC) induced by carcinogen 4-nitroquinoline 1-oxide (4NQO), mimicking molecular and histopathological aspects of human OSCC. The induction of autophagy by spermidine (SPD) treatment reduced the severity of lesions and the incidence of OSCC in mice exposed to 4NQO. On the other hand, autophagy inhibition by chloroquine treatment had no protection. Using the comet assay, we identified that SPD reduced 4NQO-induced DNA damage, likely related to the activation of DNA repair and decreasing reactive oxygen species. As sphingolipid alterations have been reported in OSCC, we analyzed sphingolipids in the tongue and plasma of animals and verified that plasma C16 ceramide levels increase proportionally to lesion severity, indicating its potential as a biomarker. Mice exposed to 4NQO plus spermidine had lower levels of C16 ceramide than the 4NQO group, which means spermidine's ability to prevent the 4NQO-induced carcinogenesis. Therefore, we conclude that activation of autophagy has a tumor suppressor role during the early stages of oral carcinogenesis. Due to its ability to induce autophagy accompanied by reduced oxidative stress and DNA damage, spermidine seems to have a protective action against chemically induced oral cancer.

Keywords:  4NQO; C16 Ceramide; DNA damage response; autophagy; ceramides; glucosylceramide; head and neck cancer; oral carcinoma; spermidine; sphingolipids

DOI:  https://doi.org/10.1016/j.ajpath.2023.09.005
Antioxidants (Basel). 2023 Aug 22. pii: 1655. [Epub ahead of print]12(9):

Nitric Oxide Induces Autophagy in Triticum aestivum Roots.

Farida Minibayeva, Anastasia Mazina, Natalia Gazizova, Svetlana Dmitrieva, Anastasia Ponomareva, Daniya Rakhmatullina.

  Autophagy is a highly conserved process that degrades damaged macromolecules and organelles. Unlike animals, only scant information is available regarding nitric oxide (NO)-induced autophagy in plants. Such lack of information prompted us to study the roles of the NO donors' nitrate, nitrite, and sodium nitroprusside in this catabolic process in wheat roots. Furthermore, spermine, a polyamine that is found in all eukaryotic cells, was also tested as a physiological NO donor. Here, we show that in wheat roots, NO donors and spermine can trigger autophagy, with NO and reactive oxygen species (ROS) playing signaling roles based on the visualization of autophagosomes, analyses of the levels of NO, ROS, mitochondrial activity, and the expression of autophagic (ATG) genes. Treatment with nitrite and nitroprusside causes an energy deficit, a typical prerequisite of autophagy, which is indicated by a fall in mitochondrial potential, and the activity of mitochondrial complexes. On the contrary, spermine sustains energy metabolism by upregulating the activity of appropriate genes, including those that encode glyceraldehyde 3-phosphate dehydrogenase GAPDH and SNF1-related protein kinase 1 SnRK1. Taken together, our data suggest that one of the key roles for NO in plants may be to trigger autophagy via diverse mechanisms, thus facilitating the removal of oxidized and damaged cellular constituencies.

Keywords:  autophagy; energy metabolism; nitric oxide; plant; spermine

DOI:  https://doi.org/10.3390/antiox12091655
Nanoscale Adv. 2023 Sep 26. 5(19): 5256-5262

Synthesis and application of spermine-based amphiphilic poly(β-amino ester)s for siRNA delivery.

Yao Jin, Friederike Adams, Anny Nguyen, Sebastian Sturm, Simone Carnerio, Knut Müller-Caspary, Olivia M Merkel.

Small interfering RNA (siRNA) can trigger RNA interference (RNAi) to therapeutically silence disease-related genes in human cells. The approval of siRNA therapeutics by the FDA in recent years generated a new hope in novel and efficient siRNA therapeutics. However, their therapeutic application is still limited by the lack of safe and efficient transfection vehicles. In this study, we successfully synthesized a novel amphiphilic poly(β-amino ester) based on the polyamine spermine, hydrophobic decylamine and 1,4-butanediol diacrylate, which was characterized by 1H NMR spectroscopy and size exclusion chromatography (SEC, Mn = 6000 Da). The polymer encapsulated siRNA quantitatively from N/P 5 on as assessed by fluorescence intercalation while maintaining optimal polyplex sizes and zeta potentials. Biocompatibility and cellular delivery efficacy were also higher than those of the commonly used cationic, hyperbranched polymer polyethylenimine (PEI, 25 kDa). Optimized formulations mediated around 90% gene silencing in enhanced green fluorescence protein expressing H1299 cells (H1299-eGFP) as determined by flow cytometry. These results suggest that spermine-based, amphiphilic poly(β-amino ester)s are very promising candidates for efficient siRNA delivery.

DOI: https://doi.org/10.1039/d3na00272a
Prostate Int. 2023 Sep;11(3): 180-185

Urine spermine and multiparametric magnetic resonance imaging for prediction of prostate cancer in Japanese men.

Shuji Isotani, Peter Ka-Fung Chiu, Takeshi Ashizawa, Yan-Ho Fung, Takeshi Ieda, Toshiyuki China, Haruna Kawano, Fumitaka Shimizu, Masayoshi Nagata, Yuki Nakagawa, Satoru Muto, Ka-Leung Wong, Chi-Fai Ng, Shigeo Horie.

   Objectives: To investigate the role of urine spermine and spermine risk score in predicting prostate cancer (PCa) diagnoses in combination with multiparametric magnetic resonance imaging (mpMRI).
Methods: Three hundred forty seven consecutive men with elevated prostate-specific antigen (PSA) with mpMRI examination were prospectively enrolled in this study. In 265 patients with PSA levels between 4 and20 ng/ml, pre-biopsy urine samples were analyzed for spermine levels with ultra-high performance liquid chromatography (UPLC-MS/MS). Transperineal image-guided prostate biopsies with 16-18 cores were performed. Logistic regressions were used to form different models for the prediction of the PCa, and the performances were compared using the area under the curve (AUC).
Results: The median serum PSA level and prostate volume were 7.4 ng/mL and 33.9 mL, respectively. PCa and high-grade PCa (ISUP group ≥2, HGPCa) were diagnosed in 66.0% (175/265) and 132/265 (49.8%) cases, respectively. The urine spermine levels were significantly lower in men with PCa (0.87 vs. 2.20, P < 0.001). Multivariate analyses showed that age, PSA, PV, urine spermine level, and Prostate Imaging Reporting and Data System (PI-RADS) findings were independent predictors for PCa. The Spermine Risk Score is a multivariable model including PSA, age, prostate volume, and urine spermine. Adding the Spermine Risk Score to PI-RADS improved the AUC from 0.73 to 0.86 in PCa and from 0.72 to 0.83 in high grade PCa (HGPCa) prediction (both P < 0.001). At 90% sensitivity for HGPCa prediction using Spermine Risk Score, 31.1% of unnecessary biopsies could be avoided. In men with equivocal MRI PI-RADS score 3, the AUC for HGPCa prediction was 0.58, 0.79, and 0.87 for PSA, PSA density, and Spermine Risk Score, respectively.
Conclusion: Urine Spermine Risk Score, including mpMRI could accurately identify men at high risk of HGPCa and reduce unnecessary prostate biopsies. Spermine Risk Score could more accurately predict HGPCa than PSA density in men with MRI showing equivocal PI-RADS 3 lesions.

Keywords:  Biomarker; Multiparametric MRI; Prostate cancer; Urine spermine

DOI:  https://doi.org/10.1016/j.prnil.2023.07.003