bims-polyam 2021-09-05 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–09–05
eight papers selected by
Sebastian J. Hofer, University of Graz

Polyamine homeostasis-based strategies for cancer: The role of combination regimens.
Overexpression of EiKCS confers paraquat-resistance in rice (Oryza sativa L.) by promoting the polyamine pathway.
Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.
Investigating how amine structure influences drug-amine ion-pair formation and uptake via the polyamine transporter in A549 lung cells.
Ornithine decarboxylase of the fungal pathogen Colletotrichum higginsianum plays an important role in regulating global metabolic pathways and virulence.
Effect of calcium-sensing receptor on the migration and proliferation of porcine intestinal epithelial cells.
Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.
Immunometabolic signatures predict risk of progression to sepsis in COVID-19.

Eur J Pharmacol. 2021 Aug 28. pii: S0014-2999(21)00610-5. [Epub ahead of print] 174456

Polyamine homeostasis-based strategies for cancer: The role of combination regimens.

Qi-Zhang Li, Zan-Wen Zuo, Ze-Rong Zhou, Yan Ji.

  Spermine, spermidine and putrescine polyamines are naturally occurring ubiquitous positively charged amines and are essential metabolites for biological functions in our life. These compounds play a crucial role in many cell processes, including cellular proliferation, growth, and differentiation. Intracellular levels of polyamines depend on their biosynthesis, transport and degradation. Polyamine levels are high in cancer cells, which leads to the promotion of tumor growth, invasion and metastasis. Targeting polyamine metabolism as an anticancer strategy is considerably rational. Due to compensatory mechanisms, a single strategy does not achieve satisfactory clinical effects when using a single agent. Combination regimens are more clinically promising for cancer chemoprevention because they work synergistically with causing little or no adverse effects due to each individual agent being used at lower doses. Moreover, bioactive substances have advantages over single chemical agents because they can affect multiple targets. In this review, we discuss anticancer strategies targeting polyamine metabolism and describe how combination treatments and effective natural active ingredients are promising therapies. The existing research suggests that polyamine metabolic enzymes are important therapeutic targets and that combination therapies can be more effective than monotherapies based on polyamine depletion.

Keywords:  Antitumor; Combination; Natural products; Polyamine metabolism; Small molecules

DOI:  https://doi.org/10.1016/j.ejphar.2021.174456
Pest Manag Sci. 2021 Sep 03.

Overexpression of EiKCS confers paraquat-resistance in rice (Oryza sativa L.) by promoting the polyamine pathway.

Qiyu Luo, Shu Chen, Jiazheng Zhu, Laihua Ye, Nathan Daniel Hall, Suma Basak, J Scott McElroy, Yong Chen.

   BACKGROUND: Paraquat is used widely as one of the bipyridine herbicides, which generates reactive oxygen species to cause cell death. With a growing number of paraquat-resistant weeds, the mechanism of paraquat-resistance in plants remains unclear. This research verified the functions of a previously confirmed putative paraquat-resistant gene, EiKCS, from paraquat-resistant goosegrass by genetic engineering in a single overexpressing line in rice.
RESULTS: Overexpression of EiKCS improved paraquat resistance in transgenic rice (KCSox). Pre-applied (12 h) exogenous spermidine (1.5 mmol/L), alleviated the injury of paraquat in rice. Paraquat induced injury in KCSox was 19.57%, which was lower than 32.22% injury it induced in WT rice. The paraquat-resistant mechanism was through the increased activity of antioxidant enzymes and the overproduction of endogenous polyamines. The spermine content in KCSox was more than 30 μg/mL, while that in WT rice was less than 5 μg/mL. Quantitative proteomics showed that β-Ketoacyl-CoA synthase (51.81 folds) encoded by the transgenic EiKCS gene promoted the synthesis of the proteins involved with the polyamine pathway. The synthesized putrescine was promoted by the arginine decarboxylase (ADC) pathway. The spermidine synthase I (1.10 folds) and three eceriferum cofactors (CERs) were responsive to the paraquat stress. We validated putrescine (C18 H20 N2 O2 ) spermidine (C28 H31 N3 O3 ), and spermine (C38 H42 N4 O4 ) in this study.
CONCLUSION: EiKCS encoding β-ketoacyl-CoA synthase from goosegrass has been shown as an ideal candidate gene for engineering genetically modified organism (GMO) crops, as its overexpression does not only bring paraquat-resistance, but also have potential benefits without decreasing yield and rice grain quality. This article is protected by copyright. All rights reserved.

Keywords:  GMO crops; goosegrass (Eleusine indica L.); paraquat resistance; polyamines; rice (Oryza sativa L.)

DOI:  https://doi.org/10.1002/ps.6628
Am J Med Genet A. 2021 Sep 03.

Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.

Elizabeth A VanSickle, Julianne Michael, André S Bachmann, Surender Rajasekaran, Jeremy W Prokop, Ruben Kuzniecky, Floris C Hofstede, Katharina Steindl, Anita Rauch, Mark H Lipson, Caleb P Bupp.

  Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

Keywords:  Bachmann-Bupp syndrome; DFMO; ODC1; alopecia; macrocephaly; polyamines

DOI:  https://doi.org/10.1002/ajmg.a.62473
Eur J Pharm Biopharm. 2021 Aug 26. pii: S0939-6411(21)00207-1. [Epub ahead of print]

Investigating how amine structure influences drug-amine ion-pair formation and uptake via the polyamine transporter in A549 lung cells.

Zarif M Sofian, Norsyifa Harun, Mohd Muzamir Mahat, Nikman Adli Nor Hashim, Stuart A Jones.

  Transiently associating amines with therapeutic agents through the formation of ion-pairs has been established both in vitro and in vivo as an effective means to systemically direct drug delivery to the lung via the polyamine transport system (PTS). However, there remains a need to better understand the structural traits required for effective PTS uptake of drug ion-pairs. This study aimed to use a structurally related series of amine counterions to investigate how they influenced the stability of theophylline ion-pairs and their active uptake in A549 cells. Using ethylamine (mono-amine), ethylenediamine (di-amine), spermidine (tri-amine) and spermine (tetra-amine) as counterions the ion-pair affinity was shown to increase as the number of protonated amine groups in the counterion structure increased. The mono and diamines generated a single hydrogen bond and the weakest ion-pair affinities (pKFTIR: 1.32 ± 0.04 and 1.43 ± 0.02) whereas the polyamines produced two hydrogen bonds and thus the strongest ion-pair affinities (pKFTIR: 1.93 ± 0.05 and 1.96 ± 0.04). In A549 cells depleted of endogenous polyamines using α-difluoromethylornithine (DFMO), the spermine-theophylline uptake was significantly increased (p < 0.05) compared to non-amine depleted cells and this evidenced the active PTS sequestering of the ion-pair. The mono-amine and di-amine failed to enhance theophylline uptake in these A549 cells, but the tri-amine and tetra-amine both almost doubled the theophylline uptake into the cells when compared to the uptake of free drug. As the data indicated that polyamines with at least 3 amines were required to form ion-pairs that could enhance A549 cell uptake, it suggested that at least two amines were required to physically stabilise the ion-pair and one to interact with the PTS.

Keywords:  active uptake; ion-pairing; lung; polyamines; targeted delivery

DOI:  https://doi.org/10.1016/j.ejpb.2021.08.003
Environ Microbiol. 2021 Sep 01.

Ornithine decarboxylase of the fungal pathogen Colletotrichum higginsianum plays an important role in regulating global metabolic pathways and virulence.

Yaqin Yan, Jintian Tang, Qinfeng Yuan, Hao Liu, Junbin Huang, Tom Hsiang, Chonglai Bao, Lu Zheng.

  Colletotrichum higginsianum is an important fungal pathogen causing anthracnose disease of cruciferous plants. In this study, we characterized a putative ortholog of yeast SPE1 in C. higginsianum, named ChODC. Deletion mutants of ChODC were defective in hyphal and conidial development. Importantly, deletion of ChODC significantly affected appressorium-mediated penetration in C. higginsianum. However, polyamines partially restore appressorium function and virulence indicating that loss of ChODC caused significantly decreased virulence by the crosstalk between polyamines and other metabolic pathways. Subsequently, transcriptomic and metabolomic analyses demonstrated that ChODC played an important role in metabolism of various carbon and nitrogen compounds including amino acids, carbohydrates and lipids. Along with these clues, we found deletion of ChODC affected glycogen and lipid metabolism, which were important for conidial storage utilization and functional appressorium formation. Loss of ChODC affected the mTOR signaling pathway via modulation of autophagy. Interestingly, cAMP treatment restored functional appressoria to the ΔChODC mutant, and rapamycin treatment also stimulated formation of functional appressoria in the ΔChODC mutant. Overall, ChODC was associated with the polyamine biosynthesis pathway, as a mediator of cAMP and mTOR signaling pathways to regulate appressorium function. Our study provides evidence of a link between ChODC and the cAMP signaling pathway and defines a novel mechanism by which ChODC regulates infection-associated autophagy and plant infection by fungi. This article is protected by copyright. All rights reserved.

Keywords:  Polyamines; appressorium function; autophagy; metabolome, transcriptome; ornithine decarboxylase

DOI:  https://doi.org/10.1111/1462-2920.15755
Anim Biotechnol. 2021 Aug 30. 1-10

Effect of calcium-sensing receptor on the migration and proliferation of porcine intestinal epithelial cells.

Jie Zheng, Guangmang Liu, Caimei Wu, Gang Jia, Hua Zhao, Xiaoling Chen, Jing Wang.

  The rapid healing of impaired intestinal surface plays a role in maintaining intestinal homeostasis. This study investigated the effect of calcium-sensing receptor (CaSR) on the migration and proliferation of intestinal porcine epithelial cells (IPEC-J2). Results showed that cell migration area and width were increased by R568 (CaSR activator) and decreased by NPS2143 (CaSR inhibitor). The protein level of GTP-rac1 and the phosphorylation of phospholipase C gamma 1 (PLCγ1) were increased by 2 µM R568. Furthermore, R568 + 120 µM NSC23766 (Rac1 inhibitor) and R568 + 1 µM U73122 (PLCγ1 inhibitor) decreased the protein level of GTP-rac1 and the phosphorylated PLCγ1, respectively, and both inhibited cell migration compared with R568. In addition, spermine increased the protein expression levels of CaSR and the levels of GTP-rac1 and the phosphorylated PLCγ1 and thereby promoted the migration of IPEC-J2 cells. Moreover, R568 improved the proliferation of the IPEC-J2 cells. Spermine increased cell proliferation, but NPS2143 incubated with spermine decreased cell proliferation compared with the spermine group. This study suggests that CaSR activation increased cell migration by activating Rac1 and PLCγ1 signaling and improved cell proliferation, and both effects were regulated by spermine by activating CaSR.

Keywords:  Calcium-sensing receptor; Rac1/PLCγ1 signaling pathway; cell migration; cell proliferation; spermine

DOI:  https://doi.org/10.1080/10495398.2021.1968885
Sci Rep. 2021 Aug 31. 11(1): 17463

Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.

João Fadista, Victor Yakimov, Urmo Võsa, Christine S Hansen, Silva Kasela, Line Skotte, Frank Geller, Julie Courraud, Tõnu Esko, Viktorija Kukuškina, Alfonso Buil, Mads Melbye, Thomas M Werge, David M Hougaard, Lili Milani, Jonas Bybjerg-Grauholm, Arieh S Cohen, Bjarke Feenstra.

Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10-49) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10-28) and adults (P = 2.748 × 10-8) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention.

DOI: https://doi.org/10.1038/s41598-021-97069-x
PLoS One. 2021 ;16(8): e0256784

Immunometabolic signatures predict risk of progression to sepsis in COVID-19.

Ana Sofía Herrera-Van Oostdam, Julio E Castañeda-Delgado, Juan José Oropeza-Valdez, Juan Carlos Borrego, Joel Monárrez-Espino, Jiamin Zheng, Rupasri Mandal, Lun Zhang, Elizabeth Soto-Guzmán, Julio César Fernández-Ruiz, Fátima Ochoa-González, Flor M Trejo Medinilla, Jesús Adrián López, David S Wishart, José A Enciso-Moreno, Yamilé López-Hernández.

Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).

DOI: https://doi.org/10.1371/journal.pone.0256784