Protective effects of spermidine levels against cardiovascular risk factors: An exploration of causality based on a bi-directional Mendelian randomization analysis.

The study investigated the causal relationships between spermidine levels and CVD risk factors using a bi-directional MR approach. Employing genetic variants from extensive GWAS datasets as IVs, the study aimed to determine whether spermidine levels can influence CVD risk factors such as blood pressure, blood glucose, and lipid profiles, and vice versa. The findings suggest a protective role of elevated spermidine levels against hypertension, elevated blood glucose, and lipid profiles (LDL-C and HDL-C). Specifically, increased spermidine levels were significantly associated with lower risk of hypertension (IVW beta = -0.0013453913, p = 0.01597648) and suppression risk of elevated blood glucose (IVW beta = -0.08061330, p = 0.02450205). Additionally, there was a notable association with lipid modulation, showing a decrease in LDL-C (IVW beta = -0.01849161, p = 0.01086728) and an increase in HDL-C (IVW beta = 0.0044608332, P = 0.01760051). Conversely, the influence of CVD risk factors on spermidine levels was minimal, with the exception that elevated blood glucose levels resulted in reduced spermidine levels. (IVW beta = -0.06714391, P = 0.01096123). These results underline the potential of spermidine as a modifiable dietary target for the prevention and management of cardiovascular diseases. Further investigations are warranted to explore the underlying biological mechanisms and the applicability of these findings in broader and diverse populations.

The longevity factor spermidine is part of a highly heritable complex erythrocyte phenotype associated with longevity.

Extreme longevity in humans is known to be a heritable trait. In a well-established twin erythrocyte metabolomics and proteomics database, we identified the longevity factor spermidine and a cluster of correlated molecules with high heritability estimates. Erythrocyte spermidine is 82% heritable and significantly correlated with 59 metabolites and 22 proteins. Thirty-eight metabolites and 19 proteins were >20% heritable, with a mean heritability of 61% for metabolites and 49% for proteins. Correlated metabolites are concentrated in energy metabolism, redox homeostasis, and autophagy pathways. Erythrocyte mean cell volume (MCV), an established heritable trait, was consistently negatively correlated with the top 25 biomolecules most strongly correlated with spermidine, indicating that smaller MCVs are associated with higher concentrations of spermidine and correlated molecules. Previous studies have linked larger MCVs with poorer memory, cognition, and all-cause mortality. Analysis of 432,682 unique patient records showed a linear increase in MCV with age but a significant deviation toward smaller than expected MCVs above age 86, suggesting that smaller MCVs are associated with extreme longevity. Consistent with previous reports, a subset of 78,158 unique patient records showed a significant skewing toward larger MCV values in a deceased cohort compared to an age-matched living cohort. Our study supports the existence of a complex, heritable phenotype in erythrocytes associated with health and longevity.

Synergistic anti-aging effect of Dendrobium officinale polysaccharide and spermidine: A metabolomics analysis focusing on the regulation of lipid, nucleotide and energy metabolism.

The importance of synergy has been underscored in recent medical research for augmenting the efficacy of therapeutic interventions, targeting multiple biological pathways simultaneously. Our prior research elucidated that Dendrobium officinale polysaccharide (DOP) has the potential to prolong the lifespan of Caenorhabditis elegans (C. elegans) via regulating gut microbiota. Concurrently, spermidine (Spd), as a mimicking caloric restriction, facilitates autophagy and exerts a pronounced anti-aging effect. To enhance the anti-aging capabilities of DOP, we conducted a comprehensive study examining the combined effects of DOP and Spd in C. elegans, incorporating metabolomics analysis to investigate the underlying mechanisms. A combination of 250 mg/L DOP and 29.0 mg/L Spd yielded the most favorable outcomes in lifespan extension, evidencing a synergistic effect with a combination index (CI) of 0.65. In oxidative and heat stress tolerance assays, the observed CIs were 0.50 and 0.33, respectively. Metabolomic analysis highlighted significant alterations in metabolites related to lipid, nucleotide and energy metabolism, notably regulating glycerol 3-phosphate, linoleoyl glycerol, docosapentaenoic acid and ß-nicotinamide mononucleotide, nicotinamide adenine dinucleotide. The effects of DS on lipid metabolism were further validated using Oil Red O staining and triglyceride level in C. elegans. The results indicated that DS may primarily be via modulating lipid metabolism. To further confirm these findings, a high-fat diet-induced mouse model was employed. Consequently, it can be inferred that the synergistic anti-aging impact of DOP and Spd is likely mediated primarily through alterations in lipid metabolic processes.

Spermidine augments salt stress resilience in rice roots potentially by enhancing OsbZIP73's RNA binding capacity.

BACKGROUND: Rice is a staple crop for over half of the global population, but soil salinization poses a significant threat to its production. As a type of polyamine, spermidine (Spd) has been shown to reduce stress-induced damage in plants, but its specific role and mechanism in protecting rice roots under salt stress require further investigation. RESULTS: This study suggested spermidine (Spd) mitigates salt stress on rice root growth by enhancing antioxidant enzyme activity and reducing peroxide levels. Transcriptomic analysis showed that salt stress caused 333 genes to be upregulated and 1,765 to be downregulated. However, adding Spd during salt treatment significantly altered this pattern: 2,298 genes were upregulated and 844 were downregulated, which indicated Spd reverses some transcriptional changes caused by salt stress. KEGG pathway analysis suggested that Spd influenced key signaling pathways, including MAPK signaling, plant hormone signal transduction, and phenylalanine metabolism. Additionally, the bZIP transcription factor OsbZIP73 was upregulated after Spd treatment, which is confirmed by Western blot. Further insights into the interaction between OsbZIP73 and Spd were gained through fluorescence polarization experiments, showing that Spd enhances protein OsbZIP73's affinity for RNA. Functional enrichment analyses revealed that OsPYL1, OsSPARK1, and various SAUR family genes involved in Spd-affected pathways. The presence of G/A/C-box elements in these genes suggests they are potential targets for OsbZIP73. CONCLUSIONS: Our findings suggest a strategy of using spermidine as a chemical alleviator for salt stress and provide insights into the regulatory function of OsbZIP73 in mitigating salt stress in rice roots.

Spermidine mitigates ferroptosis in free fatty acid-induced AML-12 cells through the ATF4/SLC7A11/GCLM/GPX4 pathway.

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease worldwide. Spermidine (SPD), a naturally occurring polyamine, has shown potential in alleviating the accumulation of hepatic lipids and reducing NAFLD symptoms in overweight mice. Nonetheless, the specific mechanisms through which SPD exerts its effects remain largely unknown. This study seeks to explore the protective effects of SPD on NAFLD and to clarify the underlying mechanisms. An in vitro model of NAFLD was established by inducing steatosis in AML-12 cells through the use of free fatty acids (FFAs). Our experimental results demonstrate that SPD significantly reduces NAFLD development induced by FFAs. This reduction is primarily achieved through the inhibition of cellular ferroptosis, as evidenced by decreased levels of Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS). Additionally, SPD was found to enhance cellular activity and ameliorate mitochondrial dysfunction and oxidative stress caused by FFA exposure. Further mechanistic studies have revealed that SPD upregulates the expression of solute transporter family 7a member 11 (SLC7A11), glutamate-cysteine ligase modifier subunit (GCLM), and glutathione peroxidase (GPX4). This upregulation is mediated by the activation of activating transcription factor 4 (ATF4). Knockdown experiments of ATF4 confirmed that its inhibition reverses the upregulation of SLC7A11, GCLM, and GPX4, thereby negating the protective effects of SPD. In conclusion, our findings suggest that SPD mitigates NAFLD by modulating the ATF4/SLC7A11/GCLM/GPX4 signaling pathway, resulting in the suppression of ferroptosis and the improvement of cellular health. These insights provide a novel molecular mechanism and identify potential therapeutic targets for the treatment of NAFLD.

Unravelling the Metabolic Underpinnings of Gestational Diabetes Mellitus: A Comprehensive Mendelian Randomisation Analysis Identifying Causal Metabolites and Biological Pathways.

BACKGROUND: Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis. OBJECTIVES: This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM. METHODS: A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites. RESULTS: MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM. CONCLUSION: This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM.

A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.

Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.

Physiological and biochemical characteristics of milk thistle (Silybum marianum (L.) Gaertn) as affected by some plant growth regulators.

Milk thistle (Silybum marianum (L.) Gaertn) is a globally and widely used medicinal plant that contains silymarin. This plant has antioxidant, antimicrobial, anticancer, hepatoprotective, cardiovascular-protective, and neuroprotective effects. Plant quality, yield, and phytochemicals, especially silymarin content, change under various conditions like drought stress. Therefore, this research studied plant growth regulators (PGRs) like salicylic acid, spermidine, and brassinosteroid to increase plant tolerance to drought stress. Experimental treatments include different levels of irrigation (25%, 50%, 75%, and 90% field capacity), and foliar spraying including salicylic acid (75 and 150 mg/L), spermine (70 and 140 mg/L), and brassinosteroid (1 and 1.2 µM), separately, and water as a control and a secondary factor. The results revealed that the highest amount of leaf phenolic compounds was observed in the highest drought stress level (25%) and 75 mg/L salicylic acid application. Furthermore, brassinosteroid at different concentrations and salicylic acid (75 mg/L) increased leaf flavonoid content compared to other treatments. In 50% field capacity, foliar application of salicylic acid (150 mg/L) significantly increased seed yield by approximately 75% compared to control under the same stress level. Brassinosteroid application (1 µM) under 75% field capacity significantly increased the seed's taxifolin amount by 159%. Additionally, salicylic acid noticeably increased the silychristin concentration. The concentration of silydianin in the seed has also been increased under drought stress and foliar spraying with PGRs. Compared to the control, using spermidine below 75% field capacity caused an increase in its concentrations by over seven times. The highest silybin A amount was obtained in 50% field capacity and foliar150 mg/L salicylic acid. Taxifolin, silychristin, silydianin, silybinin B, iso-silybinin A, and iso-silybinin B compounds were identified in the seed extract. Generally, foliar spraying using plant growth regulators increased the number of silymarin compounds under drought stress conditions and field cultivation conditions.

The Many Faces of Hypusinated eIF5A: Cell Context-Specific Effects of the Hypusine Circuit and Implications for Human Health.

The unique amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] is exclusively formed on the translational regulator eukaryotic initiation factor 5A (eIF5A) via a process coined hypusination. Hypusination is mediated by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), and hypusinated eIF5A (eIF5AHyp) promotes translation elongation by alleviating ribosome pauses at amino acid motifs that cause structural constraints, and it also facilitates translation initiation and termination. Accordingly, eIF5AHyp has diverse biological functions that rely on translational control of its targets. Homozygous deletion of Eif5a, Dhps, or Dohh in mice leads to embryonic lethality, and heterozygous germline variants in EIF5A and biallelic variants in DHPS and DOHH are associated with rare inherited neurodevelopmental disorders, underscoring the importance of the hypusine circuit for embryonic and neuronal development. Given the pleiotropic effects of eIF5AHyp, a detailed understanding of the cell context-specific intrinsic roles of eIF5AHyp and of the chronic versus acute effects of eIF5AHyp inhibition is necessary to develop future strategies for eIF5AHyp-targeted therapy to treat various human health problems. Here, we review the most recent studies documenting the intrinsic roles of eIF5AHyp in different tissues/cell types under normal or pathophysiological conditions and discuss these unique aspects of eIF5AHyp-dependent translational control.

Non-Linear Association of Dietary Polyamines with the Risk of Incident Dementia: Results from Population-Based Cohort of the UK Biobank.

Natural polyamines, including spermidine (SPD), spermine (SPM) and putrescine (PUT), are evolutionarily conserved endogenous molecules crucially involved in central cellular processes. Their physiological importance may extend to the maintenance of cognitive function during aging. However, limited population-based epidemiological studies have explored the link between dietary polyamines and dementia risk. This study was a prospective analysis of 77,092 UK Biobank participants aged ≥ 60 years without dementia at baseline. We used Cox proportional hazard regression models to explore the associations between dietary polyamines and the risk of dementia, and restricted cubic splines to test the non-linear relationships. During a median follow-up of 12 years, 1087 incidents of all-cause dementia cases occurred, including 450 Alzheimer's disease (AD) cases and 206 vascular dementia (VD) cases. The fully adjusted hazard ratios (HRs) for the upper fourth quintile of dietary SPD, in comparison with the lowest quintile of intake, were 0.68 (95% confidence interval [95% CI]: 0.66-0.83) for the risk of all-cause dementia, 0.62 (95% CI: 0.45-0.85) for AD and 0.56 (95% CI: 0.36-0.88) for VD, respectively. A 26% reduction in dementia risk [HR: 0.74, (95% CI: 0.61-0.89)] and a 47% reduction in AD [HR: 0.53, (95%CI: 0.39-0.72)] were observed comparing the third with the lowest quintiles of dietary SPM. Dietary PUT was only associated with a reduced risk of all-cause dementia in the fourth quintile [HR (95% CI): 0.82 (0.68-0.99)]. Reduced risk was not found to be significant across all quintiles. There were 'U'-shaped relationships found between dietary polyamines and all-cause dementia, AD and VD. Stratification by genetic predisposition showed no significant effect modification. Optimal intake of polyamines was linked to a decreased risk of dementia, with no modification by genetic risk. This potentially suggests cognitive benefits of dietary natural polyamines in humans.

Involvement of mammalian SoLute Carriers (SLC) in the traffic of polyamines.

Polyamines interact with different molecular targets to regulate a vast range of cellular processes. A network of enzymes and transport systems is crucial for the maintenance of polyamine homeostasis. Indeed, polyamines after synthesis must be distributed to the various tissues and some intracellular organelles. Differently from the well characterized enzymes devoted to polyamine synthesis, the transport systems are not unequivocally identified or characterized. Besides some ATPases which have been identified as polyamine transporters, much less is known about solute carriers (SLC) involved in the transport of these compounds. Only two SLCs have been unequivocally identified as polyamine transporters: SLC18B1 (VPAT) and SLC22A4 (OCTN1). Transport studies have been performed with cells transfected with the cDNAs encoding the two and other SLCs or, in the case of OCTN1, also by in vitro assay using proteoliposomes harboring the recombinant human protein. According to the role proposed for OCTN1, polyamines have been associated with prolonged and quality of life. This review provides an update on the most recent findings concerning the polyamine transporters or the prediction of the putative ones.

Polyamine Catabolism Revisited: Acetylpolyamine Oxidase Plays a Minor Role due to Low Expression.

Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines (back-conversion) or their direct efflux from the cell. PAOX is considered to catalyze a non-rate-limiting catabolic step. Here, we show that PAOX transcription levels are extremely low in various tumor- and non-tumor cell lines and, in most cases, do not change in response to altered polyamine metabolism. Its enzymatic activity is undetectable in the majority of cell lines except for neuroblastoma and low passage glioblastoma cell lines. Treatment of A549 cells with N1,N11-diethylnorspermine leads to PAOX induction, but its contribution to polyamine catabolism remains moderate. We also describe two alternative enzyme isoforms and show that isoform 4 has diminished oxidase activity and isoform 2 is inactive. PAOX overexpression correlates with the resistance of cancer cells to genotoxic antitumor drugs, indicating that PAOX may be a useful therapeutic target. Finally, PAOX is dispensable for the replication of various viruses. These data suggest that a decrease in polyamine levels is achieved predominantly by the secretion of acetylated spermine and spermidine rather than by back-conversion.

The White Clover TrMYB33-TrSAMS1 Module Contributes to Drought Tolerance by Modulation of Spermidine Biosynthesis via an ABA-Dependent Pathway.

Spermidine is well known to accumulate in plants exposed to drought, but the regulatory network associated with its biosynthesis and accumulation and the underlying molecular mechanisms remain unclear. Here, we demonstrated that the Trifolium repens TrMYB33 relayed the ABA signal to modulate drought-induced spermidine production by directly regulating the expression of TrSAMS1, which encodes an S-adenosylmethionine synthase. This gene was identified by transcriptome and expression analysis in T. repens. TrSAMS1 overexpression and its pTRV-VIGS-mediated silencing demonstrated that TrSAMS1 is a positive regulator of spermidine synthesis and drought tolerance. TrMYB33 was identified as an interacting candidate through yeast one-hybrid library screening with the TrSAMS1 promoter region as the bait. TrMYB33 was confirmed to bind directly to the predicted TAACCACTAACCA (the TAACCA MYB binding site is repeated twice in tandem) within the TrSAMS1 promoter and to act as a transcriptional activator. Additionally, TrMYB33 contributed to drought tolerance by regulating TrSAMS1 expression and modulating spermidine synthesis. Additionally, we found that spermidine accumulation under drought stress depended on ABA and that TrMYB33 coordinated ABA-mediated upregulation of TrSAMS1 and spermidine accumulation. This study elucidated the role of a T. repens MYB33 homolog in modulating spermidine biosynthesis. The further exploitation and functional characterization of the TrMYB33-TrSAMS1 regulatory module can enhance our understanding of the molecular mechanisms responsible for spermidine accumulation during drought stress.

Polyamines putrescine and spermidine as modulators of protein aggregation rate: The effect on DTT-induced aggregation of α-lactalbumin.

Protein aggregation is undesirable for cells due to its possible toxicity, and is also undesirable in biotechnology and pharmaceuticals. Polyamines are known to be capable of both suppressing and stimulating protein aggregation. In the present work polyamines (spermidine, putrescine) have been shown to alter the pathway of α-lactalbumin aggregation induced by dithiothreitol, leading to the formation of larger protein particles during the initial stages of aggregation and promoting the later stage of sticking of aggregates. According to the aggregation kinetics data, polyamines accelerate protein aggregation in a concentration-dependent manner, with a maximum at 50 mM spermidine and 100 mM putrescine. With a further increase in polyamines concentration the effect of aggregation acceleration decreased, thus, the modulation of the aggregation rate by polyamines was shown. A comparison of the aggregation kinetics and hydrodynamic radii growth data registered by dynamic light scattering with the data obtained by asymmetric flow field-flow fractionation and analytical ultracentrifugation allowed us to describe the early stages of aggregation and formation of initial α-lactalbumin clusters. Our results provide a deeper insight into the mechanism of amorphous aggregation of α-lactalbumin and polyamines action on protein aggregation and protein-protein interaction in general.

SQSTM1 improves acute lung injury via inhibiting airway epithelium ferroptosis in a vitamin D receptor/autophagy-mediated manner.

Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI.

Spermidine as an epigenetic regulator of autophagy in neurodegenerative disorders.

Autophagy is an abnormal protein degradation and recycling process that is impaired in various neurological diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. Spermidine is a natural polyamine found in various plant- and meat-based diets that can induce autophagy, and is decreased in various neurodegenerative diseases. It acts on epigenetic enzymes like E1A-binding protein p300, HAT enzymes like Iki3p and Sas3p, and α-tubulin acetyltransferase 1 that modulate autophagy. Histone modifications like acetylation, phosphorylation, and methylation could influence autophagy. Autophagy is epigenetically regulated in various neurodegenerative disorders with many epigenetic enzymes and miRNAs. Polyamine regulation plays an essential role in the disease pathogenesis of AD and PD. Therefore, in this review, we discuss various enzymes and miRNAs involved in the epigenetic regulation of autophagy in neurodegenerative disorders and the role of spermidine as an autophagy enhancer. The alterations in spermidine-mediated regulation of Beclin-1, LC3-II, and p62 genes in AD and other PD-associated enzymes could impact the process of autophagy in these neurodegenerative diseases. With the ever-growing data and such promising effects of spermidine in autophagy, we feel it could be a promising target in this area and worth further detailed studies.

Plasma Polyamines and Short-Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study.

BACKGROUND: Polyamines have been reported to be associated with neurological function, but the associations between polyamines and the prognosis of ischemic stroke remain unclear. We aimed to prospectively investigate whether elevated plasma polyamine levels are associated with adverse outcomes in patients with ischemic stroke. METHODS AND RESULTS: Plasma polyamine levels were measured at admission in 3570 patients with acute ischemic stroke, and clinical outcomes were assessed at 3 months after stroke onset. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score≥3), and secondary outcomes included the individual outcomes of death and major disability. During a 3-month follow-up period, 877 participants (25.1%) experienced the primary outcome. Increased putrescines were associated with a decreased risk of the primary outcome (the highest versus the lowest tertile: odds ratio, 0.72 [95% CI, 0.58-0.91]; P=0.005) and major disability (odds ratio, 0.59 [95% CI, 0.47-0.74]; P<0.001). Conversely, increased spermidines were associated with an increased risk of death (hazard ratio, 1.86 [95% CI, 1.10-3.14]; P=0.020), and increased spermines were associated with an increased risk of the primary outcome (odds ratio, 1.36 [95% CI, 1.08-1.71]; P=0.009) and major disability (odds ratio, 1.27 [95% CI, 1.01-1.59]; P=0.041). CONCLUSIONS: Among patients with ischemic stroke, high plasma putrescine levels were associated with a decreased risk of adverse outcomes, whereas high plasma spermidine and spermine levels were associated with an increased risk of adverse outcomes. Further studies are needed to investigate whether targeting these polyamines can improve the prognosis of patients with ischemic stroke. REGISTRATION: https://clinicaltrials.gov. Identifier: NCT01840072.

Combined assessment of lysine and N-acetyl cadaverine levels assist as a potential biomarker of the smoker periodontitis.

Periodontitis is an inflammatory condition of supporting structures of teeth leading to attachment and bone loss. Cigarette smoking is the single most important and modifiable risk factor with 5 to 20-fold susceptibility for periodontal diseases. Reverse smoking is a peculiar habit of smoking where the lit end is kept inside the mouth, which is predominant in the northern coastal districts of Andhra Pradesh. Polyamines are biologically active amines involved in tissue regeneration and modulation of inflammation. The study aimed to evaluate polyamines and check their utility as a marker in detection of periodontitis among different groups. Total polyamine levels showed significant increase in reverse smokers with periodontitis when compared to the other groups. Qualitative analysis by thin layer chromatography showed three polyamine bands with varying intensity among the different groups. Mass spectrometric and NMR analyses of the three bands identified them as N1, N8-diacetyl spermidine, N-acetyl cadaverine and lysine. Most significantly elevated levels of lysine was observed in the smoker and reverse smoker periodontitis groups when compared to healthy and non-smoker periodontitis groups. The significantly elevated levels of N-acetyl cadaverine could be responsible for the more destruction of periodontium in the reverse smoker group. Antioxidant potential decreased significantly in different smoker periodontitis groups. The present study suggests that the quantitative analysis of salivary polyamines, lysine and N-acetyl cadaverine can aid as an easy noninvasive diagnostic method for assessing the periodontal status, especially in smokers.

Plasma polyamines during pregnancy and their relationships with maternal allergies and the immune response of the neonates.

BACKGROUND: Some studies have reported that polyamine levels may influence immune system programming. The aim of this study was to evaluate the polyamine profile during gestation and its associations with maternal allergy and cytokine production in cord blood cells in response to different allergenic stimuli. METHODS: Polyamines were determined in plasma of pregnant women (24 weeks, N = 674) and in umbilical cord samples (N = 353 vein and N = 160 artery) from the Mediterranean NELA birth cohort. Immune cell populations were quantified, and the production of cytokines in response to different allergic and mitogenic stimuli was assessed in cord blood. RESULTS: Spermidine and spermine were the most prevalent polyamines in maternal, cord venous, and cord arterial plasma. Maternal allergies, especially allergic conjunctivitis, were associated with lower spermine in umbilical cord vein. Higher levels of polyamines were associated with higher lymphocyte number but lower Th2-related cells in cord venous blood. Those subjects with higher levels of circulating polyamines in cord showed lower production of inflammatory cytokines, especially IFN-α, and lower production of Th2-related cytokines, mainly IL-4 and IL-5. The effects of polyamines on Th1-related cytokines production were uncertain. CONCLUSIONS: Spermidine and spermine are the predominant polyamines in plasma of pregnant women at mid-pregnancy and also in umbilical cord. Maternal allergic diseases like allergic conjunctivitis are related to lower levels of polyamines in cord vein, which could influence the immune response of the newborn. Cord polyamine content is related to a decreased Th2 response and inflammatory cytokines production, which might be important to reduce an allergenic phenotype in the neonate.

Spermidine Synthase Localization in Retinal Layers: Early Age Changes.

Polyamine (PA) spermidine (SPD) plays a crucial role in aging. Since SPD accumulates in glial cells, particularly in Müller retinal cells (MCs), the expression of the SPD-synthesizing enzyme spermidine synthase (SpdS) in Müller glia and age-dependent SpdS activity are not known. We used immunocytochemistry, Western blot (WB), and image analysis on rat retinae at postnatal days 3, 21, and 120. The anti-glutamine synthetase (GS) antibody was used to identify glial cells. In the neonatal retina (postnatal day 3 (P3)), SpdS was expressed in almost all progenitor cells in the neuroblast. However, by day 21 (P21), the SpdS label was pronouncedly expressed in multiple neurons, while GS labels were observed only in radial Müller glial cells. During early cell adulthood, at postnatal day 120 (P120), SpdS was observed solely in ganglion cells and a few other neurons. Western blot and semi-quantitative analyses of SpdS labeling showed a dramatic decrease in SpdS at P21 and P120 compared to P3. In conclusion, the redistribution of SpdS with aging indicates that SPD is first synthesized in all progenitor cells and then later in neurons, but not in glia. However, MCs take up and accumulate SPD, regardless of the age-associated decrease in SPD synthesis in neurons.