bims-polyam 2022-02-06 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–02–06
eight papers selected by
Sebastian J. Hofer, University of Graz

Profiling the metabolic landscape of AD.
The metabolic landscape of brain alterations in Alzheimer's disease.
Pharmacological targeting of polyamine and hypusine biosynthesis reduces tumor activity of endometrial cancer.
Progesterone and interferon tau regulate expression of polyamine enzymes during the ovine peri-implantation period.
Conjugated Polyamines in Root Plasma Membrane Enhanced the Tolerance of Plum Seedling to Osmotic Stress by Stabilizing Membrane Structure and Therefore Elevating H+-ATPase Activity.
Comparative study on the influence of silicon and selenium to mitigate arsenic induced stress by modulating TCA cycle, GABA, and polyamine synthesis in rice seedlings.
Spermine-mediated polyamine metabolism enhances arsenic-stress tolerance in Phaseolus vulgaris by expression of zinc-finger proteins related genes and modulation of mineral nutrient homeostasis and antioxidative system.
Spermidine Regulates Mitochondrial Function by Enhancing eIF5A Hypusination and Contributes to Reactive Oxygen Species Production and Ganoderic Acids Biosynthesis in Ganoderma lucidum.

Alzheimers Dement. 2021 Dec;17 Suppl 3 e050086

Profiling the metabolic landscape of AD.

Dominantly Inherited Alzheimer Network

BACKGROUND: Metabolic dysfunction, including perturbations in lipid, neurotransmitter, and polyamine metabolism, is an early indicator of cognitive impairment and Alzheimer disease (AD) risk. Further investigation is needed to elucidate the role of genetic heterogeneity in these metabolic disturbances. Here, we interrogate metabolomic signatures in the brains of carriers of pathological mutations in APP, PSEN1, and PSEN2 (Autosomal Dominant AD; ADAD), risk variants in TREM2, non-carrier sporadic AD cases (sAD), individuals with neuropathology but without clinical symptoms (Presymptomatic), and neuropathology-free controls (CO).
METHOD: Metabolomic data from parietal brain tissue of donors to the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network (ADAD, n=25; TREM2, n=21; sAD, n=305; Presymptomatic, n=15; CO, n=27) were generated using the Metabolon global metabolomics platform. A total of 627 metabolites passed our QC process. Differential abundance between AD strata and controls was tested using linear regression corrected for sex, age, and post-mortem interval. Age was excluded from ADAD models. Benjamini-Hochberg multiple testing correction was applied, and pathway analysis was performed with MetaboAnalyst and IMPaLA.
RESULT: In total, we identified 138 metabolites associated with distinct genetic strata (FDR q-value<0.05). For sAD, these included tryptophan betaine (β=-0.55) and N-acetylputrescine (β=-0.14). Metabolites associated with both sAD and ADAD were ergothioneine (β=-0.22 and -0.26 respectively) and serotonin (β=-0.34 and -0.57). TREM2 and ADAD showed association with α-tocopherol (β=-0.12 and -0.12). β-citrylglutamate abundance decreased in sAD, ADAD, and TREM2 versus controls (β=-0.14; -0.22; and -0.29). Pathways identified included glutamate, vitamin, and antioxidant metabolism. A 16-metabolite subset showed consistent direction of effect among the genetic strata with the magnitude of effect of ADAD greater than that of TREM2, in turn greater than sAD. A representation of these (eigengene) is associated with disease duration in sAD (p=5.65x10-03 ), possibly driven by tau accumulation. Hierarchical clustering identified 41 "early stage" sAD individuals with Braak tau stage similar to Presymptomatic (p=0.35), but lower than other sAD individuals (β=-0.56, p=3.09x10-04 ) (Figure 1).
CONCLUSION: Our findings suggest distinct and characteristic metabolic perturbations in ADAD and TREM2 brains. Investigation of these differentially abundant metabolites may lead to greater insight into the metabolic etiology of AD and its impact on clinical presentation.

DOI: https://doi.org/10.1002/alz.050086
Alzheimers Dement. 2021 Dec;17 Suppl 3 e054793

The metabolic landscape of brain alterations in Alzheimer's disease.

Richa Batra, Matthias Arnold, Gabi Kastenmüller, Mariet Allen, Xue Wang, David A Bennett, Nilüfer Ertekin-Taner, Rima F Kaddurah-Daouk, Jan Krumsiek.

BACKGROUND: Impairment of brain glucose metabolism has been frequently described in Alzheimer's disease (AD). Moreover, the strongest predictor of the lifetime incidence of AD is the ε4 allele of APOE, a protein involved in lipid metabolism. These connections between AD and metabolism provide motivation to perform an in-depth metabolic profiling of human brain tissue for different stages of AD pathophysiology.
METHOD: Brain tissue samples were obtained from the Religious Orders Study and Memory and Aging Project (ROS/MAP) at the Rush Alzheimer's Disease Center. Furthermore, ROS/MAP collects extensive phenotyping of the participants' cognitive trajectories as well as postmortem pathology. Metabolic profiling was performed on Metabolon's untargeted platform, yielding 1,055 quantified metabolites. Generalized linear models with appropriate linkage functions for continuous or categorical AD-related phenotypes were used to discover the association of metabolic profiles with AD-related phenotypes, such as amount of amyloid and tangles in brain, global burden of pathology, NIA-Reagan score, diagnosis (derived from Braak and CERAD scores), clinical diagnosis at the time of death, global cognition assessed during the visit before death, estimated decline of global cognition over lifetime. The models included confounder correction for age, gender, body mass index, years of education, post mortem interval, number of APOEε4 alleles, and medications.
RESULT: We found 263 metabolites to be significantly associated (adjusted p-value <0.05) with one of the AD phenotypes. 137 of these metabolites were significantly associated with three or more phenotypes. Of these, nine could be replicated using an independent autopsy cohort from Mayo Clinic, five could also be replicated using a published study based on Baltimore Longitudinal Study of Aging cohort. The associated metabolites are involved in various metabolic processes known to be involved in AD pathogenesis, such as amino acid metabolism, urea cycle, and polyamine metabolism. In addition, we have identified several novel associations that could uncover the interdependence of different AD-associated metabolic processes.
CONCLUSION: We have generated a comprehensive landscape of AD-associated metabolites and associated processes. These will be instrumental to fill the gap in our understanding of the metabolic components of AD pathophysiology.

DOI: https://doi.org/10.1002/alz.054793
J Drug Target. 2022 Feb 01. 1-28

Pharmacological targeting of polyamine and hypusine biosynthesis reduces tumor activity of endometrial cancer.

Hong Im Kim, Chad R Schultz, Gadisetti V R Chandramouli, Dirk Geerts, John I Risinger, André S Bachmann.

  Endometrial cancer (EC) is a common and deadly cancer in women and novel therapeutic approaches are urgently needed. Polyamines (putrescine, spermidine, spermine) are critical for mammalian cell proliferation and MYC coordinately regulates polyamine metabolism through ornithine decarboxylase (ODC). ODC is a MYC target gene and rate-limiting enzyme of polyamine biosynthesis and the FDA-approved anti-protozoan drug α-difluoromethylornithine (DFMO) inhibits ODC activity and induces polyamine depletion that leads to tumor growth arrest. Spermidine is required for the hypusine-dependent activation of eukaryotic translation initiation factors 5A1 (eIF5A1) and 5A2 (eIF5A2) and connects the MYC/ODC-induced deregulation of spermidine to eIF5A1/2 protein translation, which is increased during cancer cell proliferation. We show that the eIF5A1 is significantly upregulated in EC cells compared to control cells (p = 0.000038) and that combined pharmacological targeting of ODC and eIF5A hypusination with cytostatic drugs DFMO and N1-guanyl-1,7-diaminoheptane (GC7), respectively, reduces eIF5A1 activation and synergistically induces apoptosis in EC cells. In vivo, DFMO/GC7 suppressed xenografted EC tumor growth in mice more potently than each drug alone compared to control (p = 0.002) and decreased putrescine (p = 0.045) and spermidine levels in tumor tissues. Our data suggest DFMO and GC7 combination therapy may be useful in the treatment or prevention of EC.

Keywords:  Cell death; DFMO; DHPS; Endometrial cancer; GC7; Hypusine; In vivo tumor xenografts; ODC; Polyamines; eIF5A1

DOI:  https://doi.org/10.1080/1061186X.2022.2036164
Biol Reprod. 2022 Jan 29. pii: ioac022. [Epub ahead of print]

Progesterone and interferon tau regulate expression of polyamine enzymes during the ovine peri-implantation period.

Katherine M Halloran, Claire Stenhouse, Robyn M Moses, Heewon Seo, Gregory A Johnson, Guoyao Wu, Fuller W Bazer.

  Progesterone (P4) and interferon tau (IFNT) are important for establishment and maintenance of pregnancy in ruminants. Agmatine and polyamines (putrescine, spermidine, and spermine) have important roles in the survival, growth, and development of mammalian conceptuses. This study tested the hypothesis that P4 and/or IFNT stimulate expression of genes and proteins involved in the metabolism and transport of polyamines in the ovine endometrium. Rambouillet ewes (n = 24) were surgically fitted with intrauterine catheters on Day 7 of the estrous cycle. They received daily intramuscular injections of 50 mg P4 in corn oil vehicle and/or 75 mg progesterone receptor antagonist (RU486) in corn oil vehicle from Days 8-15, and twice daily intrauterine injections (25 μg/uterine horn/day) of either control serum proteins (CX) or IFNT from Days 11-15, resulting in four treatment groups: 1) P4 + CX; 2) P4 + IFNT; 3) RU486 + P4 + CX; or 4) RU486 + P4 + IFNT. On Day 16, ewes were hysterectomized. The total amounts of arginine, citrulline, ornithine, agmatine, and putrescine in uterine flushings were affected (P < 0.05) by P4 and/or IFNT. P4 increased endometrial expression of SLC22A2 (P < 0.01) and SLC22A3 (P < 0.05) mRNAs. IFNT affected endometrial expression of MAT2B (P < 0.001), SAT1 (P < 0.01), and SMOX (P < 0.05) mRNAs, independent of P4. IFNT increased the abundance of SRM protein in uterine luminal (LE), superficial glandular (sGE), and glandular epithelia (GE), as well as MAT2B protein in uterine LE and sGE. These results indicate that P4 and IFNT act synergistically to regulate expression of key genes required for cell-specific metabolism and transport of polyamines in the ovine endometrium during the peri-implantation period of pregnancy.

Keywords:  agmatine; amino acids; endometrium; gene expression; interferon tau; polyamines; progesterone

DOI:  https://doi.org/10.1093/biolre/ioac022
Front Plant Sci. 2021 ;12 812360

Conjugated Polyamines in Root Plasma Membrane Enhanced the Tolerance of Plum Seedling to Osmotic Stress by Stabilizing Membrane Structure and Therefore Elevating H+-ATPase Activity.

Hongyang Du, Benxue Chen, Qiang Li, Huaipan Liu, Ronald Kurtenbach.

  Polyamines are small positively charged molecules in plants and play important functions in many biological processes under various environmental stresses. One of the most confounding problems relating to polyamines (PAs) in stresses is the lack of understanding of the mechanisms underlying their function(s). Furthermore, a limited number of studies have addressed this issue at the sub-cellular level, especially in tree plants under drought stress. Therefore, in this research, by simulating natural drought stress with polyethylene glycol (PEG) osmotic stress, the relationship between the levels of conjugated polyamines and the activity of H+-ATPase in the plasma membrane was elucidated with the roots of two plum (Prunus salicina L.) cultivars, which were different in drought tolerance, as experimental materials. Furthermore, free PA levels and the activities of S-adenosylmethionine decarboxylase (SAMDC) and transglutaminase (TGase), which were closely associated with the levels of free and conjugated PAs, were also detected. Results showed that under osmotic stress, the increases of the levels of non-covalently conjugated (non-CC) spermidine (Spd) and spermine (Spm), covalently conjugated (CC) putrescine (Put) and Spd in the plasma membrane of drought-tolerant Ganli No. 5 were more significant than those of drought-sensitive Suli No. 3, indicating that these conjugated PAs might be involved in the tolerance of plum seedlings to stress. Furthermore, the conjugated PAs were closely correlated with plum seedling growth, water retention capacity, plasma membrane damage degree, and hydrogen (H+)-ATPase activity in the plasma membrane. To get more complementary pieces of evidence, we subjected plum seedlings to combined treatments of PEG and exogenous PA (Spd and Spm), and an inhibitor of SAMDC [methylglyoxal-bis (guanylhydrazone), (MGBG)] or TGase (o-phenanthroline). These results collectively suggested that non-CC Spd and Spm, CC Put and Spd in plasma membrane might function in enhancing the tolerance of plum seedlings to osmotic stress by stabilizing membrane structure and therefore elevating H+-ATPase activity.

Keywords:  H+-ATPase; conjugated polyamines; osmotic stress; plasma membrane; plum (Prunus salicina L.)

DOI:  https://doi.org/10.3389/fpls.2021.812360
Ecotoxicology. 2022 Feb 05.

Comparative study on the influence of silicon and selenium to mitigate arsenic induced stress by modulating TCA cycle, GABA, and polyamine synthesis in rice seedlings.

Susmita Das, Barsha Majumder, Asok K Biswas.

  Arsenic contamination of groundwater is a major concern for its usage in crop irrigation in many regions of the world. Arsenic is absorbed by rice plants mainly from arsenic contaminated water during irrigation. It hampers growth and agricultural productivity. The aim of the study was to mitigate the toxic effects of arsenate (As-V) [25 μM, 50 μM, and 75 μM] by silicon (Si) [2 mM] and selenium (Se) [5 μM] amendments on the activity of the TCA cycle, synthesis of γ-aminobutyric acid (GABA) and polyamines (PAs) in rice (Oryza sativa L. cv. MTU-1010) seedlings and to identify which chemical was more potential to combat this threat. As(V) application decreased the activities of tested respiratory enzymes and increased the levels of organic acids (OAs) in the test seedlings. Application of Si with As(V) and Se with As(V) increased the activities of respiratory enzymes and the levels of OAs. The effects were more pronounced during Si amendments. The activities of GABA synthesizing enzymes along with accumulation of GABA were increased under As(V) stress. During joint application of Si with As(V) and Se with As(V) the activity and the level of said parameters were decreased that indicating defensive role of these chemicals to resist As(V) toxicity in rice and Si amendments showed greater potential to reduce As(V) induced damages in the test seedlings. PAs trigger tolerance mechanism against As(V) in plants. PAs such as putrescine, spermidine and spermine were synthesized more during Si and Se amendments in As(V) contaminated rice seedlings to combat the toxic effects of As(V). Si amendments substantially modulated the toxic effects caused by As(V) over Se amendments in the As(V) challenged test seedlings. Thus, in future application of Si enriched fertilizer will be beneficial to grow rice plants with normal vigor in arsenic contaminated soil.

Keywords:  Arsenic; GABA; Polyamine; Respiration; Selenium; Silicon

DOI:  https://doi.org/10.1007/s10646-022-02524-8
Environ Pollut. 2022 Feb 01. pii: S0269-7491(22)00155-5. [Epub ahead of print] 118941

Spermine-mediated polyamine metabolism enhances arsenic-stress tolerance in Phaseolus vulgaris by expression of zinc-finger proteins related genes and modulation of mineral nutrient homeostasis and antioxidative system.

Anis Ali Shah, Luqman Riaz, Manzer H Siddiqui, Rabia Nazar, Shakil Ahmed, Nasim Ahmad Yasin, Aamir Ali, Soumya Mukherjee, Muhammad Hussaan, Sumera Javad, Ozair Chaudhry.

  The contamination of groundwater and agricultural land by metalloids especially arsenic (As) is one of the most serious threats to people and plants worldwide. Therefore, the present study was design to explore the role of spermine (Spm)- mediated polyamine metabolism in the alleviation of arsenic (As) toxicity in common bean (Phaseolus vulgaris L.). It was noted that As stress caused reduction in the intracellular CO2 concentration, stomatal conductivity and transpiration rate as compared to the control treatment and also impairedplant growth attributes and mineral nutrient homeostasis (sulfur, phosphorus, potassium and calcium). However, the exogenous application of Spm resulted in a considerable enhance in the content of glutathione and nitric oxide, and the activity of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione-reductase (GR), ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR) in P. vulgaris seedlings grown As-contaminated soil. In addition, Spm application significantly improved the endogenous production of putrescine and spermidine accompanied along with reduction in malondialdehyde, electrolyte leakage, hydrogen peroxide, superoxide level besides enhanced methylglyoxal (MG) detoxification. Moreover, Spm treatment elevated the expression level of zinc-finger proteins related genes (PvC3H24, PvC3H25, PvC3H26 and PvC3H27) involved in abiotic stress response. The study concluded that Spm acted as an enhancing agent and improved tolerance to As-toxicity by upregulating the expression of zinc-finger proteins related genes, polyamine metabolism, Mg detoxification and antioxidant system in P. vulgaris.

Keywords:  Antioxidant enzymes; Arsenic; Common bean; Stress; Zing-finger proteins

DOI:  https://doi.org/10.1016/j.envpol.2022.118941
Appl Environ Microbiol. 2022 Feb 02. AEM0203721

Spermidine Regulates Mitochondrial Function by Enhancing eIF5A Hypusination and Contributes to Reactive Oxygen Species Production and Ganoderic Acids Biosynthesis in Ganoderma lucidum.

Xiaofei Han, Jiaolei Shangguan, Zi Wang, Yu Li, Junpei Fan, Ang Ren, Mingwen Zhao.

Spermidine, a kind of polycation and one important member in the polyamine family, is essential for survival in many kinds of organisms and participates in the regulation of cell growth and metabolism. To explore the mechanism by which spermidine regulates ganoderic acids (GAs) biosynthesis in Ganoderma lucidum, the effects of spermidine on GAs and reactive oxygen species (ROS) contents were examined. Our data suggested that spermidine promoted the production of mitochondrial ROS and positively regulated GAs biosynthesis. Further research revealed that spermidine promoted the translation of mitochondrial complexes I and II and subsequently influenced their activity. With the reduction in eukaryotic translation initiation factor 5A (eIF5A) hypusination by over 50% in spermidine synthase gene (spds) knockdown strains, the activity of mitochondrial complexes I and II was reduced by nearly 60% and 80%, respectively, and the protein content was reduced by over 50%, suggesting that the effect of spermidine in mitochondrial complexes I and II was mediated through its influence on eIF5A hypusination. Furthermore, after knocking down eIF5A, the deoxyhypusine synthase gene (dhs) and the deoxyhypusine hydroxylase gene (dohh), mitochondrial ROS level was reduced by nearly 50%, and GAs content was reduced by over 40%, suggesting that eIF5A hypusination contributed to mitochondrial ROS production and GAs biosynthesis. In summary, spermidine maintains mitochondrial ROS homeostasis by regulating the translation and subsequent activity of complexes I and II via eIF5A hypusination and promotes GAs biosynthesis via mitochondrial ROS signaling. The present findings provide new insight into spermidine-mediated biosynthesis of secondary metabolites. IMPORTANCE: Spermidine is necessary for organism survival and is involved in the regulation of various biological processes. However, the specific mechanisms underlying the various physiological functions of spermidine are poorly understood, especially in microorganisms. In this study, we found that spermidine hypusinates eIF5A to promote the production of mitochondrial ROS and subsequently regulate secondary metabolism in microorganisms. Our study provides a better understanding of the mechanism by which spermidine regulates mitochondrial function and provides new insight into spermidine-mediated biosynthesis of secondary metabolites.

DOI: https://doi.org/10.1128/AEM.02037-21