bims-polyam 2020-08-30 papers

on Polyamines

Issue of 2020–08–30
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome.
Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway.
Fluorescent nanoprobe array based on carbon nanodots for qualitative and quantitative determination of biogenic polyamine.
Study on the interaction of polyamine transport (PAT) and 4-Chloro-naphthalimide-homospermidine conjugate (4-ClNAHSPD) by molecular docking and dynamics.
Changes in polyamine pattern mediates sex differentiation and unisexual flower development in monoecious cucumber (Cucumis sativus L.).
Putrescine elicits ROS - dependent activation of the salicylic acid pathway in Arabidopsis thaliana.
Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals.
Mitochondrial Calcium Uniporter Complex Activation Protects Against Calcium Alternans in Atrial Myocytes.

BMC Med Genet. 2020 Aug 24. 21(1): 168

Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome.

Talal J Qazi, Qiao Wu, Ailikemu Aierken, Daru Lu, Ihtisham Bukhari, Hafiz M J Hussain, Jingmin Yang, Asif Mir, Hong Qing.

   BACKGROUND: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood.
METHODS: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features.
RESULTS: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C > T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity.
CONCLUSION: A novel missense variant in the SMS, c.905C > T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

Keywords:  Gait abnormalities; Intellectual disability; SMS; Snyder-Robinson syndrome; X-linked mental retardation

DOI:  https://doi.org/10.1186/s12881-020-01095-x
Brain Res Bull. 2020 Aug 25. pii: S0361-9230(20)30607-9. [Epub ahead of print]

Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway.

Shaiana Beck Fabbrin, Bruna Amanda Girardi, Arithane de Lorena Wendel, Carolina Valin, Micheli Mainardi Pillat, Fernanda Tibolla Viero, Carlos Fernando Mello, Maribel Antonello Rubin.

  Spermidine (SPD) is an endogenous polyamine that plays a facilitatory role in memory acquisition and consolidation. Memory consolidation occurs immediately after learning and again around 3-6 hours later. Current evidence indicates that the polyamine binding site at the NMDA receptor (NMDAr) mediates the effects of SPD on memory. While NMDAr activation increases brain-derived neurotrophic factor (BDNF) release, no study has investigated whether BDNF-activated signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway play a role in SPD-induced improvement of memory consolidation. Therefore, the aim of the current study was to evaluate whether the TrkB receptor and the PI3K/Akt pathway are involved in the facilitatory effect of SPD on memory consolidation. Male Wistar rats were trained in the contextual conditioned fear task. SPD, ANA-12 (TrkB antagonist), and LY294002 (PI3K inhibitor) were administered immediately after training. The animals were tested 24 h after training. We found that SPD improved fear memory consolidation and that both ANA-12 and LY294002 prevented the facilitatory effect of SPD on memory. These results suggest that SPD-induced improvement of memory consolidation involves the activation of the TrkB receptor and PI3K/Akt pathway.

Keywords:  Akt; BDNF; Memory; consolidation; hippocampus; polyamines

DOI:  https://doi.org/10.1016/j.brainresbull.2020.08.018
Mikrochim Acta. 2020 Aug 27. 187(9): 522

Fluorescent nanoprobe array based on carbon nanodots for qualitative and quantitative determination of biogenic polyamine.

Na Du, Zhi Dou, Yapei Wu, Qiuhua Wu, Guolin Zhang, Xue Liu.

  A nanoprobe array based on fluorescent nitrogen-rich carbon dots (N-CDs) and Ag+ was constructed for simultaneous qualitative and quantitative determination of seven kinds of biogenic polyamines (BAs), including tryptamine (Try), histamine (His), putrescine (Put), cadaverine (Cad), spermine (Spm), spermidine (Spd), and agmatine (Agm). Ag+ can specifically bind to the N-CDs and quench the fluorescence of the N-CDs through a static mechanism. BAs further statically quench the fluorescence of the N-CD@Ag+ composite by bridging two Ag+ centers of the N-CD@Ag+. The nanoprobe array was constructed based on the differential fluorescence response arising from the differential binding affinity of various BAs. BAs can be differentiated and analyzed by the nanoprobe array within the concentration range 0.5-500 μM. The preliminary diluted and artificially spiked commercial human serum was utilized to simulate the serum environment for assessing the performance of the nanoprobe array in real samples. The N-CD@Ag+ system can recognize BAs with 100% accuracy in simulated human serum samples. The quantitative determination of BAs - no matter in a one-component system or a three-component system - was also realized by using the N-CD@Ag+ system even in the simulated serum environment. The recovery rates from spiked serum samples were higher 99%, and the relative standard deviation (RSD) was less than 3%. Based on the excellent multi-BA determination performance, a BA-related disease model about cerebral ischemia was constructed. Healthy cases as well as mild, moderate, and severe cerebral ischemia cases can be well identified from the disease model based on the N-CD@Ag+ nanoprobe array. Schematic representation of fluorescent nanoprobe array constructed by carbon nanodots (N-CDs) and Ag+ for qualitative and quantitative analyses of biogenic polyamines (BAs) and diagnosis of cerebral ischemia (CI) through linear discriminant analysis (LDA) and support vector machine (SVM).

Keywords:  Cerebral ischemia diagnosis; Fluorometric analysis; Indicator displacement assay; Linear discriminant analysis; Multi-channel analysis; Single indicator; Support vector machine

DOI:  https://doi.org/10.1007/s00604-020-04492-4
J Biomol Struct Dyn. 2020 Aug 28. 1-7

Study on the interaction of polyamine transport (PAT) and 4-Chloro-naphthalimide-homospermidine conjugate (4-ClNAHSPD) by molecular docking and dynamics.

Zhiyong Tian, Luyao Tian, Sihan Zhao, Man Shi, Shudi Guo, Chaojie Wang, Zhihui Tian, Xiaohui He.

  Polyamine transporter (PAT) is a protein that can deliver "drug-polyamine" conjugates to tumor cells. 4-Chloro-naphthalimide- homospermidine (4-ClNAHSPD) displayed good antitumor activity and excellent cell selectivity via PAT pathway. In this paper, 4-ClNAHSPD and spermidine (SPD) were docked against PAT. The results showed that 4-ClNAHSPD could bind to PAT through hydrogen bond, Van der Waals, salt bridge or attractive charge and hydrophobic interaction. The interaction of SPD and PAT, however, was hydrogen bond and Van der Waals interaction. Moreover, their binding sites were also different. The primary binding sites of 4-ClNAHSPD with PAT are the residues of VAL59, HIS222, ASP61, ASP179 and GLU64, while SPD interacts with PAT in the sites of ASP37, ASP244, APS275 and SER36. The docked ligand-protein complexes were simulated for 5000ps. In simulations, various binding sites further resulted in the diverse root-mean-square deviation (RMSD) and root-mean-square deviation fluctuation (RMSF) values. The RMSD and RMSF values of 4-ClNAHSPD-PAT indicated that 4-ClNAHSPD caused a weak conformational change of PAT in a different style from SPD. More importantly, the interaction force numbers of 4-ClNAHSPD-PAT were also changed after the simulation. These results supported that 4-ClNAHSPD harnesses PAT pathway for cellular entrance. Communicated by Ramaswamy H. Sarma.

Keywords:  4-ClNAHSPD; PAT; dynamics; molecular docking

DOI:  https://doi.org/10.1080/07391102.2020.1813199
Physiol Plant. 2020 Aug 25.

Changes in polyamine pattern mediates sex differentiation and unisexual flower development in monoecious cucumber (Cucumis sativus L.).

Agnieszka Kiełkowska, Michał Dziurka.

Changes in the levels of polyamines are associated with fundamental physiological processes such as embryogenesis, induction of flowering, fruit development and ripening, senescence, and responses to environmental stresses, but the role of polyamines in sex differentiation and unisexual flower development has not been deeply studied. To extend the knowledge on the regulatory mechanisms of flowering in monoecious plant (producing unisexual flowers), we investigated the morphogenesis and free polyamine levels in Cucumis sativus during sex differentiation and unisexual flower development in vitro using histo-cytological and biochemical methods. As shown in our study, floral development in vitro was undisturbed and flowers of both sexes were produced. Sex differentiation relied on preventing the development of generative organs of the opposite sex, as we observed carpel repression in male flowers and stamen repression in female flowers. Pollen viability was negatively correlated with female flower development on the same node. Biochemical analysis revealed increased accumulation of aliphatic amines (tri, tetra-amines) in generative (flower buds and flowers) compare to vegetative (axillary buds and leaves) organs. Undifferentiated floral buds contained elevated levels of agmatine, cadaverine, spermidine and spermine. Sex differentiation was associated with significantly decreased levels of agmatine and cadaverine. Our results showed that female flowers contained higher levels of total polyamine than male flowers. The increased level of cadaverine was associated with macrogametogenesis and female flower maturation. Putrescine was important for male flower development. Such results support the hypothesis that aliphatic amines are involved in unisexual flower development. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/ppl.13197
Plant Cell Environ. 2020 Aug 24.

Putrescine elicits ROS - dependent activation of the salicylic acid pathway in Arabidopsis thaliana.

Changxin Liu, Kostadin E Atanasov, Nazanin Arafaty, Ester Murillo, Antonio F Tiburcio, Jürgen Zeier, Rubén Alcázar.

  Polyamines are small amines that accumulate during stress and contribute to disease resistance through as yet unknown signaling pathways. Using a comprehensive RNA-sequencing analysis, we show that early transcriptional responses triggered by each of the most abundant polyamines (putrescine, spermidine, spermine, thermospermine and cadaverine) exhibit specific quantitative differences, suggesting that polyamines (rather than downstream metabolites) elicit defense responses. Signaling by putrescine, which accumulates in response to bacteria that trigger effector triggered immunity (ETI) and systemic acquired resistance (SAR), is largely dependent on the accumulation of hydrogen peroxide, and is partly dependent on salicylic acid (SA), the expression of ENHANCED DISEASE SUSCEPTIBILITY (EDS1) and NONEXPRESSOR of PR GENES1 (NPR1). Putrescine elicits local SA accumulation as well as local and systemic transcriptional reprogramming that overlaps with SAR. Loss-of-function mutations in arginine decarboxylase 2 (ADC2), which is required for putrescine synthesis and copper amine oxidase (CuAO), which is involved in putrescine oxidation, compromise basal defenses, as well as putrescine and pathogen - triggered systemic resistance. These findings confirm that putrescine elicits ROS-dependent SA pathways in the activation of plant defenses. This article is protected by copyright. All rights reserved.

Keywords:  Polyamines; defense; putrescine; salicylic acid; systemic acquired resistance

DOI:  https://doi.org/10.1111/pce.13874
Brain Res Bull. 2020 Aug 25. pii: S0361-9230(20)30609-2. [Epub ahead of print]

Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals.

Yati Sharma, Debapriya Garabadu.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal features of cognitive dysfunction in an individual. Recently, the blockade of mitochondrial calcium uniporter (MCU) exhibits neuroprotective activity in experimental animals. However, the therapeutic potential of MCU has not yet been established in the management of AD. Therefore, the present study explored the therapeutic potential of either Ruthenium red (RR), a MCU blocker, or Spermine, a MCU opener, on the extent of mitochondrial calcium accumulation, function, integrity and bioenergetics in hippocampus, pre-frontal cortex and amygdale of ICV-STZ challenged rats. Experimental AD was induced in male rats by intracerebroventricular injection of streptozotocin (ICV-STZ) on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. RR attenuated ICV-STZ-induced memory-related behavioral abnormalities in Morris water maze and Y-maze tests. RR also attenuated ICV-STZ-induced decrease in the level of acetylcholine and activity of choline acetyltransferase and, increase in the activity of acetylcholinestarase in memory-sensitive rat brain regions. Further, RR attenuated mitochondrial toxicity in terms of reducing mitochondrial calcium accumulation and improving the mitochondrial function, integrity and bioenergetics in memory-sensitive brain regions of ICV-STZ challenged rats. Furthermore, RR attenuated the percentage of apoptotic cells in ICV-STZ challenged rat brain regions. However, Spermine did not alter ICV-STZ-induced behavioral, biochemical and molecular observations in any of the brain regions. These observations indicate the fact that the MCU blockage could be a potential therapeutic option in the management of sporadic type of AD.

Keywords:  Apoptosis; Memory; Mitochondrial calcium uniporter; Ruthenuim red; Spermine; Streptozotocin

DOI:  https://doi.org/10.1016/j.brainresbull.2020.08.020
Am J Physiol Heart Circ Physiol. 2020 Aug 28.

Mitochondrial Calcium Uniporter Complex Activation Protects Against Calcium Alternans in Atrial Myocytes.

Yuriana Oropeza-Almazan, Lothar A Blatter.

  Cardiac alternans, defined as beat-to-beat alternations in action potential duration, cytosolic Ca transient (CaT) amplitude and cardiac contraction, is associated with atrial fibrillation (AF) and sudden cardiac death. At the cellular level, cardiac alternans is linked to abnormal intracellular calcium handling during excitation-contraction coupling. We investigated how pharmacological activation or inhibition of cytosolic Ca sequestration via mitochondrial Ca uptake and mitochondrial Ca retention affects the occurrence of pacing-induced CaT alternans in isolated rabbit atrial myocytes.Cytosolic CaTs were recorded using Fluo-4 fluorescence microscopy. Alternans was quantified as the alternans ratio (AR=1-CaTSmall/CaTLarge; CaTSmalland CaTLargeare the amplitudes of the small and large CaTs of a pair of alternating CaTs). Inhibition of mitochondrial Ca sequestration via mitochondrial Ca uniporter complex (MCUC) with Ru360 enhanced the severity of CaT alternans (AR increase) and lowered the pacing frequency threshold for alternans. In contrast, stimulation of MCUC mediated mitochondrial Ca uptake with spermine rescued alternans (AR decrease) and increased the alternans pacing threshold. Direct measurement of mitochondrial [Ca] in membrane permeabilized myocytes with Fluo-4 loaded mitochondria revealed that spermine enhanced and accelerated mitochondrial Ca uptake. Stimulation of mitochondrial Ca retention by preventing mitochondrial Ca efflux through the mitochondrial permeability transition pore with cyclosporin A also protected from alternans and increased the alternans pacing threshold. Pharmacological manipulation of MCUC activity did not affect sarcoplasmic reticulum Ca load. Our results suggest that activation of Ca sequestration by mitochondria protects from CaT alternans and could be a potential therapeutic target for cardiac alternans and AF prevention.

Keywords:  Ca alternans; atrial fibrillation; mitochondrial calcium uniporter complex; mitochondrial calcium uptake

DOI:  https://doi.org/10.1152/ajpheart.00375.2020