bims-polyam 2019-07-14 papers

on Polyamines

Issue of 2019–07–14
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Metabolic Changes in Lymphangioleiomyomatosis Patients Treated with Sirolimus and Hydroxychloroquine.
Salivary metabolomics with alternative decision tree-based machine learning methods for breast cancer discrimination.
Spermine in semen of male sea lamprey acts as a sex pheromone.
Benextramine and derivatives as novel human monoamine oxidases inhibitors: an integrated approach.
Up-regulation of HIF-1α is associated with neuroprotective effects of agmatine against rotenone-induced toxicity in differentiated SH-SY5Y cells.
The role of IP3 in NO-enhanced chilling tolerance in peach fruit.
Integrated microbiome and metabolome analysis reveals a novel interplay between commensal bacteria and metabolites in colorectal cancer.
Different tillage induces regulation in 2-acetyl-1-pyrroline biosynthesis in direct-seeded fragrant rice.

Chest. 2019 Jul 09. pii: S0012-3692(19)31310-8. [Epub ahead of print]

Metabolic Changes in Lymphangioleiomyomatosis Patients Treated with Sirolimus and Hydroxychloroquine.

Yan Tang, Souheil El-Chemaly, Angelo Taveira-Dasilva, Hilary J Goldberg, Shefali Bagwe, Ivan O Rosas, Joel Moss, Carmen Priolo, Elizabeth P Henske.

   BACKGROUND: Lymphangioleiomyomatosis (LAM), a destructive lung disease that primarily affects women, is caused by loss-of-function mutations in TSC1 or TSC2, leading to hyperactivation of mechanistic/mammalian Target of Rapamycin 1 (mTORC1). Rapamycin (sirolimus) treatment suppresses mTORC1, but also induces autophagy, which promotes the survival of TSC2-deficient cells. Based on the hypothesis that simultaneous inhibition of mTORC1 and autophagy would limit the availability of critical nutrients and inhibit LAM cells, we conducted a Phase I clinical trial of sirolimus and hydroxychloroquine for LAM. Here, we report the analyses of plasma metabolomic profiles from the clinical trial.
METHODS: We analyzed the plasma metabolome in samples obtained before, during and after six months of treatment with sirolimus and hydroxychloroquine using univariate statistical models and machine learning approaches. Metabolites and metabolic pathways were validated in LAM-patient-derived TSC2-deficient cells. Single cell RNA-Seq was employed to assess metabolic enzymes in an early passage culture from a LAM lung.
RESULTS: Metabolomic profiling revealed changes in polyamine metabolism during treatment, with 5'-methylthioadenosine (MTA) and arginine among the most highly upregulated metabolites. Similar findings were observed in TSC2-deficient LAM patient-derived cells. Single cell transcriptomic profiling of primary LAM cultured cells reavealed that mTORC1 inhibition upregulated key enzymes in the polyamine metabolism pathway, including Adenosylmethionine Decarboxylase 1 (AMD1).
CONCLUSIONS: Our data demonstrate that polyamine metabolic pathways are targeted by the combination of rapamycin and hydroxychloroquine, leading to upregulation of MTA and arginine in the plasma of LAM patients and in LAM-patient-derived cells and revealing novel candidate biomarkers of therapeutic efficacy.

Keywords:  5'-methylthioadenosine (MTA); Lymphangioleiomyomatosis; Rapamycin; Tuberous Sclerosis; angiomyolipoma; autophagy; hydroxychloroquine; metabolomics; polyamines; single cell transcriptomics; sirolimus

DOI:  https://doi.org/10.1016/j.chest.2019.05.038
Breast Cancer Res Treat. 2019 Jul 08.

Salivary metabolomics with alternative decision tree-based machine learning methods for breast cancer discrimination.

Takeshi Murata, Takako Yanagisawa, Toshiaki Kurihara, Miku Kaneko, Sana Ota, Ayame Enomoto, Masaru Tomita, Masahiro Sugimoto, Makoto Sunamura, Tetsu Hayashida, Yuko Kitagawa, Hiromitsu Jinno.

   PURPOSE: The aim of this study is to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls.
METHODS: Saliva samples were collected after 9 h fasting and were immediately stored at - 80 °C. Capillary electrophoresis and liquid chromatography with mass spectrometry were used to quantify hundreds of hydrophilic metabolites. Conventional statistical analyses and artificial intelligence-based methods were used to assess the discrimination abilities of the quantified metabolites. A multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning method were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods.
RESULTS: One hundred sixty-six unstimulated saliva samples were collected from 101 patients with invasive carcinoma of the breast (IC), 23 patients with ductal carcinoma in situ (DCIS), and 42 healthy controls (C). Of the 260 quantified metabolites, polyamines were significantly elevated in the saliva of patients with breast cancer. Spermine showed the highest area under the receiver operating characteristic curves [0.766; 95% confidence interval (CI) 0.671-0.840, P < 0.0001] to discriminate IC from C. In addition to spermine, polyamines and their acetylated forms were elevated in IC only. Two hundred each of two-fold, five-fold, and ten-fold cross-validation using different random values were conducted and the MLR model had slightly better accuracy. The ADTree with an ensemble approach showed higher accuracy (0.912; 95% CI 0.838-0.961, P < 0.0001). These prediction models also included spermine as a predictive factor.
CONCLUSIONS: These data indicated that combinations of salivary metabolomics with the ADTree-based machine learning methods show potential for non-invasive screening of breast cancer.

Keywords:  Alternative decision tree; Biomarker; Breast cancer; Metabolomics; Polyamines; Saliva

DOI:  https://doi.org/10.1007/s10549-019-05330-9
PLoS Biol. 2019 Jul;17(7): e3000332

Spermine in semen of male sea lamprey acts as a sex pheromone.

Anne M Scott, Zhe Zhang, Liang Jia, Ke Li, Qinghua Zhang, Thomas Dexheimer, Edmund Ellsworth, Jianfeng Ren, Yu-Wen Chung-Davidson, Yao Zu, Richard R Neubig, Weiming Li.

Semen is fundamental for sexual reproduction. The non-sperm part of ejaculated semen, or seminal plasma, facilitates the delivery of sperm to the eggs. The seminal plasma of some species with internal fertilization contains anti-aphrodisiac molecules that deter promiscuity in post-copulatory females, conferring fitness benefits to the ejaculating male. By contrast, in some taxa with external fertilization such as fish, exposure to semen promotes spawning behaviors. However, no specific compounds in semen have been identified as aphrodisiac pheromones. We sought to identify a pheromone from the milt (fish semen) of sea lamprey (Petromyzon marinus), a jawless fish that spawns in lek-like aggregations in which each spermiating male defends a nest, and ovulatory females move from nest to nest to mate. We postulated that milt compounds signal to ovulatory females the presence of spawning spermiating males. We determined that spermine, an odorous polyamine initially identified from human semen, is indeed a milt pheromone. At concentrations as low as 10-14 molar, spermine stimulated the lamprey olfactory system and attracted ovulatory females but did not attract males or pre-ovulatory females. We found spermine activated a trace amine-associated receptor (TAAR)-like receptor in the lamprey olfactory epithelium. A novel antagonist to that receptor nullified the attraction of ovulatory females to spermine. Our results elucidate a mechanism whereby a seminal plasma pheromone attracts ready-to-mate females and implicates a possible conservation of the olfactory detection of semen from jawless vertebrates to humans. Milt pheromones may also have management implications for sea lamprey populations.

DOI: https://doi.org/10.1371/journal.pbio.3000332
FEBS J. 2019 Jul 10.

Benextramine and derivatives as novel human monoamine oxidases inhibitors: an integrated approach.

Maria Luisa Di Paolo, Giorgio Cozza, Andrea Milelli, Francesca Zonta, Stefania Sarno, Elirosa Minniti, Fulvio Ursini, Michela Rosini, Anna Minarini.

  The two human MAO isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason are well-known and attractive pharmacological targets in neuropsychiatric and neurodegenerative diseases, for which novel pharmacological approaches are necessary. Benextramine is a tetraamine disulfide mainly known as irreversible α-adrenergic antagonist, but able to hit additional targets involved in neurodegeneration. As the molecular structures of monoamine oxidases contain nine cysteine residues, the aim of this study was to evaluate benextramine and eleven structurally related polyamine disulfides as potential MAO inhibitors. Most of the compounds were found to induce irreversible inactivation of MAOs with inactivation potency depending on both the polyamine structure and the enzyme isoform. The more effective compounds generally showed preference for MAO B. Structure-activity relationships studies revealed the key role played by the disulfide core of these molecules in the inactivation mechanism. Docking experiments pointed to Cys323, in MAO A, and Cys172, in MAO B, as target of this type of inhibitors thus suggesting that their covalent binding inside the MAO active site sterically impedes the entrance of substrate towards the FAD cofactor. The effectiveness of benextramine in inactivating MAOs was demonstrated in SH-SY5Y neuroblastoma cell line. These results demonstrated for the first time that benextramine and its derivatives can inactivate human MAOs exploiting a mechanism different from that of the classical MAO inhibitors and could be a starting point for the development of pharmacological tools in neurodegenerative diseases. This article is protected by copyright. All rights reserved.

Keywords:  benextramine; docking studies; inhibitors; monoamine oxidases; polyamines analogues

DOI:  https://doi.org/10.1111/febs.14994
Amino Acids. 2019 Jul 10.

Up-regulation of HIF-1α is associated with neuroprotective effects of agmatine against rotenone-induced toxicity in differentiated SH-SY5Y cells.

Nadia Ferlazzo, Monica Currò, Maria Laura Giunta, Domenico Longo, Valentina Rizzo, Daniela Caccamo, Riccardo Ientile.

  Agmatine, a metabolite generated by arginine decarboxylation, has been reported as neuromodulator and neuroactive substance. Several findings suggest that agmatine displays neuroprotective effects in several models of neurodegenerative disorders, such as Parkinson's disease (PD). It has been hypothesized that biogenic amines may be involved in neuroprotection by scavenging oxygen radicals, thus preventing the generation of oxidative stress. Mitochondrial dysfunction, that leads to a reduction of oxygen consumption, followed by activation of prolyl hydroxylase and decrease of hypoxia-inducible factor 1 alpha (HIF-1α) levels, has been demonstrated to play a role in PD pathogenesis. Using rotenone-treated differentiated SH-SY5Y cells as the in vitro PD model, we here investigated the molecular mechanisms underlying agmatine neuroprotective effects. Our results showed that the preliminary addition of agmatine induces HIF-1α activation, and prevents the rotenone-induced production of free radical species, and the activation of apoptotic pathways by inhibiting mitochondrial membrane potential decrease and caspase 3 as well as cytochrome c increase. Notably, these effects are mediated by HIF-1α, as indicated by experiments using a HIF-1α inhibitor. The present findings suggest that the treatment with agmatine is able to counteract the neuronal cell injury evoked by mitochondrial toxins.

Keywords:  Agmatine; Apoptosis; Hypoxia-inducible factor-1; Neuroprotective activity; Oxidative stress

DOI:  https://doi.org/10.1007/s00726-019-02759-6
J Agric Food Chem. 2019 Jul 09.

The role of IP3 in NO-enhanced chilling tolerance in peach fruit.

Caifeng Jiao, Yuquan Duan.

The role of inositol 1,4,5-trisphosphate (IP3) in nitric oxide (NO)-enhanced chilling tolerance in peach fruit was investigated. The fruit were immersed in sodium nitroprusside (SNP) (exogenous NO donor) and neomycin (IP3 inhibitor). Results showed that exogenous SNP reduced chilling injury (CI) index in postharvest peach fruit. Further, GABA accumulation in peach fruit was stimulated by SNP treatment. The up regulation of protein expression and activity for GABA biosynthetic enzymes, including glutamate decarboxylase (GAD), polyamine oxidase (PAO) and amino aldehyde dehydrogenase (AMADH) uopn SNP treatment was also observed. Also, the up regulation of △1-pyrroline-5-carboxylate synthetase (P5CS) and ornithine d-aminotransferase (OAT) and down regulation of proline dehydrogenase (PDH) were induced by SNP treatment, thereby accelating proline production. In addition, SNP treatment enhanced protein expression and activity of alternative oxidase (AOX). The above effects induced by SNP treatment were partly weakened by the addition of neomycin. Therefore, IP3 mediated NO-activated GABA and proline accumulation as well as AOX, thus inducing chilling tolerance in postharvest peach fruit.

DOI: https://doi.org/10.1021/acs.jafc.9b02871
Theranostics. 2019 ;9(14): 4101-4114

Integrated microbiome and metabolome analysis reveals a novel interplay between commensal bacteria and metabolites in colorectal cancer.

Yongzhi Yang, Biswapriya B Misra, Lei Liang, Dexi Bi, Wenhao Weng, Wen Wu, Sanjun Cai, Huanlong Qin, Ajay Goel, Xinxiang Li, Yanlei Ma.

  Rationale: Colorectal cancer (CRC) is a malignant tumor with the third highest morbidity rate among all cancers. Driven by the host's genetic makeup and environmental exposures, the gut microbiome and its metabolites have been implicated as the causes and regulators of CRC pathogenesis. We assessed human fecal samples as noninvasive and unbiased surrogates to catalog the gut microbiota and metabolome in patients with CRC. Methods: Fecal samples collected from CRC patients (CRC group, n = 50) and healthy volunteers (H group, n = 50) were subjected to microbiome (16S rRNA gene sequencing) and metabolome (gas chromatography-mass spectrometry, GC-MS) analyses. The datasets were analyzed individually and integrated for combined analysis using various bioinformatics approaches. Results: Fecal metabolomic analysis led to the identification of 164 metabolites spread across 40 metabolic pathways in both groups. In addition, there were 42 and 17 metabolites specific to the H and CRC groups, respectively. Sequencing of microbial diversity revealed 1084 operational taxonomic units (OTUs) across the two groups, and there was less species diversity in the CRC group than in the H group. Seventy-six discriminatory OTUs were identified for the microbiota of H volunteers and CRC patients. Integrated analysis correlated CRC-associated microbes with metabolites, such as polyamines (cadaverine and putrescine). Conclusions: Our results provide substantial evidence of a novel interplay between the gut microbiome and metabolome (i.e., polyamines), which is drastically perturbed in CRC. Microbe-associated metabolites can be used as diagnostic biomarkers in therapeutic explorations.

Keywords:  biomarkers; colorectal cancer; gut; metabolomics; microbiome

DOI:  https://doi.org/10.7150/thno.35186
BMC Plant Biol. 2019 Jul 12. 19(1): 308

Different tillage induces regulation in 2-acetyl-1-pyrroline biosynthesis in direct-seeded fragrant rice.

Pan Du, Haowen Luo, Jing He, Ting Mao, Bin Du, Lian Hu.

   BACKGROUND: Land preparation is an important component of fragrant rice production. However, the effect of tillage on fragrant rice production is unclear, especially regarding the biosynthesis of 2-acetyl-1-pyrroline (2-AP), which is the main compound of the unique aroma of fragrant rice. This study aimed to explore 2-AP biosynthesis in fragrant rice under different tillage regimes. Three tillage methods were applied in the present study: conventional rotary tillage (CK) as the control, plough tillage (PT), and no-tillage (NT).
RESULT: Compared with CK, the PT treatment increased 2-AP content in grain, upregulated the activity of ornithine aminotransferase (OAT) and increased contents of 1-pyrroline and pyrroline-5-carboxylic acid (P5C). Furthermore, the PT treatment increased the grain yield and nitrogen accumulation of fragrant rice. Meanwhile, the 2-AP content in the grain produced under the NT treatment was significantly higher than that in the grain produced under both the PT and CK treatments due to the enhancement of proline content and the activities of proline dehydrogenase (PDH) and △1-pyrroline-5-carboxylic acid synthetase (P5CS). However, the present study observed that the overall production of fragrant rice under NT conditions was inferior due to lower yield, nitrogen accumulation, and anti-oxidative enzymatic activities. Moreover, the organic matter content and soil microorganism quantity increased due to PT and NT treatments.
CONCLUSIONS: Compared to CK, PT improved fragrant rice grain yield and nitrogen accumulation and induced an increase in OAT activity and led to an increase in 2-AP concentration. No-tillage also produced increased 2-AP content in grain by enhancing PDH and P5CS activities but limited yields and nitrogen accumulation in fragrant rice.

Keywords:  2-acetyl-1-pyrroline; Anti-oxidative enzyme; Fragrant rice; Proline; Tillage

DOI:  https://doi.org/10.1186/s12870-019-1913-9