bims-polyam 2024-03-17 papers

Issue of 2024–03–17
six papers selected by
Sebastian J. Hofer, University of Graz

Int J Mol Sci. 2024 Feb 20. pii: 2463. [Epub ahead of print]25(5):

Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase.

Amin Cressman, David Morales, Zhenyang Zhang, Bryan Le, Jackson Foley, Tracy Murray-Stewart, Damian C Genetos, Fernando A Fierro.

Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder-Robinson syndrome (SRS), as the presenting skeletal defects-associated with SMS deficiency-could potentially be ameliorated by treatment with DFMO.

Keywords: MSCs; Snyder–Robinson syndrome; osteogenesis; polyamines; spermine synthase

DOI: https://doi.org/10.3390/ijms25052463

Vavilovskii Zhurnal Genet Selektsii. 2024 Feb;28(1): 24-32

Effects of polyamines and indole on the expression of ribosome hibernation factors in Escherichia coli at the translational level.

E A Khaova, A G Tkachenko.

Polyamines and indole are small regulatory molecules that are involved in the adaptation to stress in bacteria, including the regulation of gene expression. Genes, the translation of which is under the regulatory effects of polyamines, form the polyamine modulon. Previously, we showed that polyamines upregulated the transcription of genes encoding the ribosome hibernation factors RMF, RaiA, SRA, EttA and RsfS in Escherichia coli. At the same time, indole affected the expression at the transcriptional level of only the raiA and rmf genes. Ribosome hibernation factors reversibly inhibit translation under stress conditions, including exposure to antibiotics, to avoid resource waste and to conserve ribosomes for a quick restoration of their functions when favorable conditions occur. In this work, we have studied the influence of indole on the expression of the raiA and rmf genes at the translational level and regulatory effects of the polyamines putrescine, cadaverine and spermidine on the translation of the rmf, raiA, sra, ettA and rsfS genes. We have analyzed the mRNA primary structures of the studied genes and the predicted mRNA secondary structures obtained by using the RNAfold program for the availability of polyamine modulon features. We have found that all of the studied genes contain specific features typical of the polyamine modulon. Furthermore, to investigate the influence of polyamines and indole on the translation of the studied genes, we have constructed the translational reporter lacZ-fusions by using the pRS552/λRS45 system. According to the results obtained, polyamines upregulated the expression of the rmf, raiA and sra genes, the highest expression of which was observed at the stationary phase, but did not affect the translation of the ettA and rsfS genes, the highest expression of which took place during the exponential phase. The stimulatory effects were polyamine-specific and observed at the stationary phase, when bacteria are under multiple stresses. In addition, the data obtained demonstrated that indole significantly inhibited translation of the raiA and rmf genes, despite the stimulatory effect on their transcrip- tion. This can suggest the activity of a posttranscriptional regulatory mechanism of indole on gene expression.

Keywords: adaptation to stress; gene expression; indole; polyamine modulon; polyamines; reporter gene fusions; ribosome hibernation factors

DOI: https://doi.org/10.18699/vjgb-24-04

Int J Mol Sci. 2024 Feb 22. pii: 2576. [Epub ahead of print]25(5):

Bactericidal Biodegradable Linear Polyamidoamines Obtained with the Use of Endogenous Polyamines.

Natalia Śmigiel-Gac, Anna Smola-Dmochowska, Katarzyna Jelonek, Monika Musiał-Kulik, Renata Barczyńska-Felusiak, Piotr Rychter, Kamila Lewicka, Piotr Dobrzyński.

The work presents the synthesis of a series of linear polyamidoamines by polycondensation of sebacoyl dichloride with endogenous polyamines: putrescine, spermidine, spermine, and norspermidine-a biogenic polyamine not found in the human body. During the synthesis carried out via interfacial reaction, hydrophilic, semi-crystalline polymers with an average viscosity molecular weight of approximately 20,000 g/mol and a melting point of approx. 130 °C were obtained. The structure and composition of the synthesized polymers were confirmed based on NMR and FTIR studies. The cytotoxicity tests performed on human fibroblasts and keratinocytes showed that the polymers obtained with spermine and norspermidine were strongly cytotoxic, but only in high concentrations. All the other examined polymers did not show cytotoxicity even at concentrations of 2000 µg/mL. Simultaneously, the antibacterial activity of the obtained polyamides was confirmed. These polymers are particularly active against E. Coli, and virtually all the polymers obtained demonstrated a strong inhibitory effect on the growth of cells of this strain. Antimicrobial activity of the tested polymer was found against strains like Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. The broadest spectrum of bactericidal action was demonstrated by polyamidoamines obtained from spermine, which contains two amino groups in the repeating unit of the chain. The obtained polymers can be used as a material for forming drug carriers and other biologically active compounds in the form of micro- and nanoparticles, especially as a component of bactericidal creams and ointments used in dermatology or cosmetology.

Keywords: amines; antibacterial polymers; biodegradable polymers; biomaterials; polyamides

DOI: https://doi.org/10.3390/ijms25052576

Dis Model Mech. 2024 Mar 11. pii: dmm.050639. [Epub ahead of print]

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson Syndrome.

Oluwaseun Akinyele, Anushe Munir, Marie A Johnson, Megan S Perez, Yuan Gao, Jackson R Foley, Ashley Nwafor, Yijen Wu, Tracy Murray-Stewart, Robert A Casero, Hulya Bayir, Dwi U Kemaladewi.

Snyder-Robinson Syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene encoding spermine synthase and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia, and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human mutations and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model carrying a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature, and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility, and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts, and Sms-null hippocampal cells, and may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.

Keywords: Mouse model; Neurological functions; Pathogenesis; Rare disease; Spermine; Spermine synthase

DOI: https://doi.org/10.1242/dmm.050639

Med Res Rev. 2024 Mar 14.

Enhancing healthy aging with small molecules: A mitochondrial perspective.

Xiujiao Qin, Hongyuan Li, Huiying Zhao, Le Fang, Xiaohui Wang.

The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Keywords: aging; mitochondrial; mitophagy; redox homeostasis; unfolded protein response

DOI: https://doi.org/10.1002/med.22034

Biochemistry (Mosc). 2024 Jan;89(1): 1-26

Natural Activators of Autophagy.

Julia A Pavlova, Ekaterina A Guseva, Olga A Dontsova, Petr V Sergiev.

Autophagy is the process by which cell contents, such as aggregated proteins, dysfunctional organelles, and cell structures are sequestered by autophagosome and delivered to lysosomes for degradation. As a process that allows the cell to get rid of non-functional components that tend to accumulate with age, autophagy has been associated with many human diseases. In this regard, the search for autophagy activators and the study of their mechanism of action is an important task for treatment of many diseases, as well as for increasing healthy life expectancy. Plants are rich sources of autophagy activators, containing large amounts of polyphenolic compounds in their composition, which can be autophagy activators in their original form, or can be metabolized by the intestinal microbiota to active compounds. This review is devoted to the plant-based autophagy activators with emphasis on the sources of their production, mechanism of action, and application in various diseases. The review also describes companies commercializing natural autophagy activators.

Keywords: autophagy activators; curcumin; lipophagy; mTOR; mitophagy; resveratrol; spermidine; urolithin A

DOI: https://doi.org/10.1134/S0006297924010012