bims-polyam 2022-07-10 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–07–10
eight papers selected by
Sebastian J. Hofer, University of Graz

Short-Term Salicylic Acid Treatment Affects Polyamine Metabolism Causing ROS-NO Imbalance in Tomato Roots.
Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.
Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells.
Arginine Catabolism and Polyamine Biosynthesis Pathway Disparities Within Francisella tularensis Subpopulations.
Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model.
Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences.
Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart.
Elevation of Serum Spermidine in Obese Patients: Results from a Cross-Sectional and Follow-Up Study.

Plants (Basel). 2022 Jun 24. pii: 1670. [Epub ahead of print]11(13):

Short-Term Salicylic Acid Treatment Affects Polyamine Metabolism Causing ROS-NO Imbalance in Tomato Roots.

Ágnes Szepesi, Péter Poór, László Bakacsy.

  The phytohormone salicylic acid (SA) can influence the polyamine metabolism in plants. Additionally, polyamines (PAs) can regulate the synthesis of SA, providing an exciting interplay between them not only in plant growth and development but also in biotic or abiotic stress conditions. The effect of SA on polyamine metabolism of leaves is well-studied but the root responses are rarely investigated. In this study, tomato roots were used to investigate the effect of short-term exposition of SA in two different concentrations, a sublethal 0.1 mM and a lethal 1 mM. To explore the involvement of SA in regulating PAs in roots, the degradation of PAs was also determined. As both SA and PAs can induce reactive oxygen species (ROS) and nitric oxide (NO) production, the balance of ROS and NO was analyzed in root tips. The results showed that 0.1 mM SA induced the production of higher PAs, spermidine (Spd), and spermine (Spm), while 1 mM SA decreased the PA contents by activating degrading enzymes. Studying the ROS and NO levels in root tips, the ROS production was induced earlier than NO, consistent with all the investigated zones of roots. This study provides evidence for concentration-dependent rapid effects of SA treatments on polyamine metabolism causing an imbalance of ROS-NO in root tips.

Keywords:  copper amine oxidase; nitric oxide; polyamines; root; salicylic acid; tomato

DOI:  https://doi.org/10.3390/plants11131670
ACS Infect Dis. 2022 Jul 05.

Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.

Vincent Mastrodomenico, Natalie J LoMascolo, Yazmin E Cruz-Pulido, Christina R Cunha, Bryan C Mounce.

  Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of polyamines in virus infection remain incompletely understood. Recent work demonstrated that polyamine metabolism supports cellular cholesterol synthesis through translation of the key transcription factor SREBP2. Here, we show that the bunyavirus Rift Valley fever virus (RVFV) relies on both cholesterol and polyamines for virus infection. Depletion of cellular cholesterol or interruption of cholesterol trafficking negatively impacts RVFV infection. Cholesterol is incorporated into RVFV virions and mediates their infectivity in a polyamine-dependent manner; we find that the virus derived from polyamine-depleted cells lacks cholesterol within the virion membrane. Conversely, we find that virion-associated cholesterol is linked to the incorporation of spermidine within the virion. Our prior work demonstrated that polyamines facilitate pH-mediated fusion and genome release, which may be a consequence of cholesterol depletion within virions. Thus, our work highlights the metabolic connection between polyamines and cholesterol synthesis to impact bunyavirus infection. These data demonstrate the connectedness between cellular metabolic pathways and reveal potential avenues of therapeutic intervention.

Keywords:  Rift Valley fever virus; bunyaviruses; cholesterol; metabolism; polyamines

DOI:  https://doi.org/10.1021/acsinfecdis.2c00071
JCI Insight. 2022 Jul 08. pii: e158457. [Epub ahead of print]7(13):

Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells.

Xianzun Tao, Yi Zhu, Zoraida Diaz-Perez, Seok-Ho Yu, Jackson R Foley, Tracy Murray Stewart, Robert A Casero, Richard Steet, R Grace Zhai.

  Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation-related diseases.

Keywords:  Genetic diseases; Genetics; Lysosomes; Polyamines; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.158457
Front Microbiol. 2022 ;13 890856

Arginine Catabolism and Polyamine Biosynthesis Pathway Disparities Within Francisella tularensis Subpopulations.

Yinshi Yue, Bhanwar Lal Puniya, Tomáš Helikar, Benjamin Girardo, Steven H Hinrichs, Marilynn A Larson.

  Francisella tularensis is a highly infectious zoonotic pathogen with as few as 10 organisms causing tularemia, a disease that is fatal if untreated. Although F. tularensis subspecies tularensis (type A) and subspecies holarctica (type B) share over 99.5% average nucleotide identity, notable differences exist in genomic organization and pathogenicity. The type A clade has been further divided into subtypes A.I and A.II, with A.I strains being recognized as some of the most virulent bacterial pathogens known. In this study, we report on major disparities that exist between the F. tularensis subpopulations in arginine catabolism and subsequent polyamine biosynthesis. The genes involved in these pathways include the speHEA and aguAB operons, along with metK. In the hypervirulent F. tularensis A.I clade, such as the A.I prototype strain SCHU S4, these genes were found to be intact and highly transcribed. In contrast, both subtype A.II and type B strains have a truncated speA gene, while the type B clade also has a disrupted aguA and truncated aguB. Ablation of the chromosomal speE gene that encodes a spermidine synthase reduced subtype A.I SCHU S4 growth rate, whereas the growth rate of type B LVS was enhanced. These results demonstrate that spermine synthase SpeE promotes faster replication in the F. tularensis A.I clade, whereas type B strains do not rely on this enzyme for in vitro fitness. Our ongoing studies on amino acid and polyamine flux within hypervirulent A.I strains should provide a better understanding of the factors that contribute to F. tularensis pathogenicity.

Keywords:  Francisella tularensis; amino acid metabolism; metabolism; polyamine biosynthesis; tularemia

DOI:  https://doi.org/10.3389/fmicb.2022.890856
J Neuroinflammation. 2022 Jul 02. 19(1): 172

Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model.

Kiara Freitag, Nele Sterczyk, Sarah Wendlinger, Benedikt Obermayer, Julia Schulz, Vadim Farztdinov, Michael Mülleder, Markus Ralser, Judith Houtman, Lara Fleck, Caroline Braeuning, Roberto Sansevrino, Christian Hoffmann, Dragomir Milovanovic, Stephan J Sigrist, Thomas Conrad, Dieter Beule, Frank L Heppner, Marina Jendrach.

   BACKGROUND: Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer's disease (AD). In recent years, impairment of autophagy has been identified as another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation.
RESULTS: Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aβ and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome.
CONCLUSIONS: Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology.

Keywords:  Alzheimer’s disease; Astrocytes; Autophagy; Dietary supplement; Liquid chromatography tandem mass spectrometry; Microglia; Neuroinflammation; Phagocytosis; Single nuclei sequencing; Spermidine

DOI:  https://doi.org/10.1186/s12974-022-02534-7
Mil Med Res. 2022 Jul 04. 9(1): 33

Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences.

Lei Pang, Xi Jiang, Xin Lian, Jie Chen, Er-Fei Song, Lei-Gang Jin, Zheng-Yuan Xia, Hai-Chun Ma, Yin Cai.

  The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease (CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction (CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas: (1) mechanisms underlying age-related cardiac remodeling; (2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women; (3) we select a few polyphenol or polyamine rich compounds as the CR-mimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.

Keywords:  Caloric restriction; Caloric restriction-mimetics; Cardiac aging; Cardiovascular disease; Clinical application; Dietary compounds; Gender difference

DOI:  https://doi.org/10.1186/s40779-022-00389-w
Autophagy. 2022 Jul 04.

Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart.

Mahmoud Abdellatif, Frank Madeo, Guido Kroemer, Simon Sedej.

  Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.

Keywords:  Heart failure; IGF1R; PI3K; human; insulin signaling; longevity; mitochondrial dysfunction; mouse

DOI:  https://doi.org/10.1080/15548627.2022.2095835
Nutrients. 2022 Jun 24. pii: 2613. [Epub ahead of print]14(13):

Elevation of Serum Spermidine in Obese Patients: Results from a Cross-Sectional and Follow-Up Study.

Hanshu Gao, Qianlong Zhang, Jiahui Xu, Wei Yuan, Ruixue Li, Hui Guo, Cuiying Gu, Wenjing Feng, Yanan Ma, Zhaoqing Sun, Liqiang Zheng.

   BACKGROUND: Spermidine, a natural polyamine, appears to be a promising intervention for the treatment of obesity in animal studies, but epidemiological studies on the association between spermidine and obesity are inadequate.
METHODS: In the cross-sectional study, a total of 4230 eligible Chinese rural participants aged ≥ 35 years at baseline were recruited, of whom 1738 completed the two-year follow-up. Serum spermidines were measured using high-performance liquid chromatography with a fluorescence detector. Obesity and change in BMI were used as outcomes. Multivariable logistic regression analysis was applied to obtain the odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: Participants who were obese had higher serum spermidine concentrations than those who were of normal weight (median (IQR), 27.2 ng/mL (14.8-53.4 ng/mL) vs. 23.8 ng/mL (12.8-46.6 ng/mL), p = 0.002). Compared with participants in the first quartile, those in the third quartile (OR 1.327, 95% CI 1.050 to 1.678) and the fourth quartile (OR 1.417, 95% CI 1.121 to 1.791) had a significantly increased risk of prevalent obesity after adjustment for confounding factors. In the follow-up study, participants in the third quartile (OR 0.712, 95% CI 0.535 to 0.946) and the fourth quartile (OR 0.493, 95% CI 0.370 to 0.657) had significantly lower risks of an increase in BMI after adjustment for confounding factors, with the lowest quartile as the reference. Meanwhile, we found a nonlinear relationship between spermidine and BMI in the follow-up study (p < 0.001).
CONCLUSIONS: Serum spermidine was positively associated with increased odds of obesity in the cross-sectional study but reduced odds of an increase in BMI in the follow-up study among Chinese adults. Future studies are warranted to determine the exact mechanism underlying the association between spermidine and obesity and the scope for interventions.

Keywords:  change in BMI; compensatory; obesity; overweight; spermidine

DOI:  https://doi.org/10.3390/nu14132613