bims-polyam 2021-07-25 papers

Issue of 2021–07–25
four papers selected by
Sebastian J. Hofer, University of Graz

Pharmacol Res Perspect. 2021 Aug;9(4): e00837

Spermidine and spermine exert protective effects within the lung.

Marcin Wawrzyniak, David Groeger, Remo Frei, Ruth Ferstl, Paulina Wawrzyniak, Krzysztof Krawczyk, Benoit Pugin, Weronika Barcik, Patrick Westermann, Anita Dreher, Michael Scharl, Marek Jutel, Cezmi A Akdis, Liam O Mahony.

Asthma is a heterologous disease that is influenced by complex interactions between multiple environmental exposures, metabolism, and host immunoregulatory processes. Specific metabolites are increasingly recognized to influence respiratory inflammation. However, the role of protein-derived metabolites in regulating inflammatory responses in the lung are poorly described. The aims of the present study were to quantify polyamine levels in bronchoalveolar lavages (BALs) from healthy volunteers and asthma patients, and to evaluate the impact of each polyamine on inflammatory responses using in vitro models and in a house dust mite (HDM)-induced respiratory allergy model. Spermidine levels were decreased, while cadaverine levels were increased in BALs from asthma patients compared to healthy controls, using Ultra Performance Liquid Chromatography (UPLC). Both spermine and spermidine inhibit lipopolysaccharide (LPS)-induced cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in vitro. In addition, oral gavage with spermine or spermidine modulate HDM-induced cell infiltration, cytokine secretion, and epithelial cell tight junction expression in murine models. Spermidine also reduces airway hyper-responsiveness. These results suggest that modulation of polyamine metabolism, in particular spermidine, is associated with respiratory inflammation and these molecules and pathways should be further explored as biomarkers of disease and potential targets for novel therapies.

Keywords: asthma; mouse models; polyamines; spermidine; spermine

DOI: https://doi.org/10.1002/prp2.837

Elife. 2021 Jul 20. pii: e67097. [Epub ahead of print]10

Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.

Surender Rajasekaran, Caleb P Bupp, Mara Leimanis-Laurens, Ankit Shukla, Christopher Russell, Joseph Junewick, Emily Gleason, Elizabeth A VanSickle, Yvonne Edgerly, Bryan M Wittmann, Jeremy W Prokop, André S Bachmann.

Background: Polyamine levels are intricately controlled by biosynthetic, catabolic enzymes and antizymes. The complexity suggests that minute alterations in levels lead to profound abnormalities. We described the therapeutic course for a rare syndrome diagnosed by whole exome sequencing caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC), characterized by neurological deficits and alopecia.
Methods: N-acetylputrescine levels with other metabolites were measured using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores established against a reference cohort of 866 children.
Results: From previous studies and metabolic profiles, eflornithine was identified as potentially beneficial with therapy initiated on FDA approval. Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support.
Conclusions: This work highlights the strategy of repurposing drugs to treat a rare disease.
Funding: No external funding was received for this work.

Keywords: genetics; genomics; global metabolomics; human; repurposing drugs; whole exome sequencing

DOI: https://doi.org/10.7554/eLife.67097

Cancers (Basel). 2021 Jul 15. pii: 3541. [Epub ahead of print]13(14):

Arginine Signaling and Cancer Metabolism.

Chia-Lin Chen, Sheng-Chieh Hsu, David K Ann, Yun Yen, Hsing-Jien Kung.

Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, and is a direct activator of mTOR, a nutrient-sensing kinase strongly implicated in carcinogenesis. Yet, it is also considered as a non- or semi-essential amino acid, due to normal cells' intrinsic ability to synthesize arginine from citrulline and aspartate via ASS1 (argininosuccinate synthase 1) and ASL (argininosuccinate lyase). As such, arginine can be used as a dietary supplement and its depletion as a therapeutic strategy. Strikingly, in over 70% of tumors, ASS1 transcription is suppressed, rendering the cells addicted to external arginine, forming the basis of arginine-deprivation therapy. In this review, we will discuss arginine as a signaling metabolite, arginine's role in cancer metabolism, arginine as an epigenetic regulator, arginine as an immunomodulator, and arginine as a therapeutic target. We will also provide a comprehensive summary of ADI (arginine deiminase)-based arginine-deprivation preclinical studies and an update of clinical trials for ADI and arginase. The different cell killing mechanisms associated with various cancer types will also be described.

Keywords: ADI; arginase; arginine; arginine-deprivation therapy; cancer metabolism; epigenetics

DOI: https://doi.org/10.3390/cancers13143541

Int J Phytoremediation. 2021 Jul 20. 1-9

Role of magnesium oxide nanoparticles in the mitigation of lead-induced stress in Daucus carota: modulation in polyamines and antioxidant enzymes.

Samia Faiz, Nasim Ahmad Yasin, Waheed Ullah Khan, Anis Ali Shah, Waheed Akram, Aqeel Ahmad, Aamir Ali, Naima Huma Naveed, Luqman Riaz.

During the current study, the effects of magnesium oxide nanoparticles (5 mmol/L) were observed on the growth and mineral nutrients of Daucus carota under lead (Pb) stress. The results demonstrated that Pb stress decreased the growth and photosynthetic rate of D. carota plants. Furthermore, Pb stressed plants showed decreased uptake of mineral nutrients including Zn, Na, Fe, K, Ca, Mg, K, and Cu. Similarly, Pb stressed plants showed enhanced electrolyte leakage (EL) and malondialdehyde (MDA) content. However, magnesium oxide nanoparticles detoxified ROS to mitigate Pb stress and improved the growth of plants. Magnesium oxide nanoparticles also escalated the activity of antioxidant enzymes including superoxide dismutase (SOD) and Catalase (CAT). A higher amount of Pb content was observed in the roots as compared to the shoot of plants. Lead toxicity reduced manganese accumulation in D. carota plants. The increased concentration of iron, manganese, copper, and zinc advocates stress the ameliorative role of Pb stress in plants. Novelty statementThe role of MgONPs in the alleviation of Pb-toxicity in Daucus carota has never been exploited. In addition, the potential of MgONPs to enhance nutritional content in D. carota via modulation in antioxidant system and polyamines have never been reported.

Keywords: Antioxidant; carrot; nanoparticles; stress

DOI: https://doi.org/10.1080/15226514.2021.1949263