bims-polyam 2021-01-10 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–01–10
fiveteen papers selected by
Sebastian J. Hofer, University of Graz

Epibrassinolide activates AKT to trigger autophagy with polyamine metabolism in SW480 and DLD-1 colon cancer cell lines.
Polyamine homeostasis modulates plasma membrane- and tonoplast-associated aquaporin expression in etiolated salt-stressed sunflower (Helianthus annuus L.) seedlings.
tpo3 and dur3, Aspergillus fumigatus Plasma Membrane Regulators of Polyamines, Regulate Polyamine Homeostasis and Susceptibility to Itraconazole.
Polyamines Influence Mouse Sperm Channels Activity.
Combined ability of salicylic acid and spermidine to mitigate the individual and interactive effects of drought and chromium stress in maize (Zea mays L.).
Inhibition of ornithine decarboxylase restores hypoxic pulmonary vasoconstriction in endotoxemic mice.
Reduction of oxidative stress and ornithine decarboxylase expression in a human prostate cancer cell line PC-3 by a combined treatment with α-tocopherol and naringenin.
Quantitative Analysis of Biogenic Amines in Different Cheese Varieties Obtained from the Korean Domestic and Retail Markets.
ODC (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains MerTK (MER Tyrosine-Protein Kinase) Expression to Drive Resolution.
Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange.
Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation.
Identification of Potential Radiation Responsive Metabolic Biomarkers in Plasma of Rats Exposed to Different Doses of Cobalt-60 Gamma Rays.
Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities: Investigating Sex-Differences.
Arginine metabolism: a potential target in pancreatic cancer therapy.
Urine spermine and multivariable Spermine Risk Score predict high-grade prostate cancer.

Turk J Biol. 2020 ;44(6): 417-426

Epibrassinolide activates AKT to trigger autophagy with polyamine metabolism in SW480 and DLD-1 colon cancer cell lines.

Kaan Adacan, Pınar Obakan Yerlİkaya.

  Epibrassinolide (EBR), a plant-derived polyhydroxylated derivative of 5α-cholestane, structurally shows similarities to animal steroid hormones. According to the present study, EBR treatment triggered a significant stress response via activating ER stress, autophagy, and apoptosis in cancer cells. EBR could also increase Akt phosphorylation in vitro. While the activation of Akt resulted in cellular metabolic activation in normal cells to proceed with cell survival, a rapid stress response was induced in cancer cells to reduce survival. Therefore, Akt as a mediator of cellular survival and death decision pathways is a crucial target in cancer cells. In this study, we determined that EBR induces stress responses through activating Akt, which reduced the mTOR complex I (mTORC1) activation in SW480 and DLD-1 colon cancer cells. As a consequence, EBR triggered macroautophagy and led to lipidation of LC3 most efficiently in SW480 cells. The cotreatment of spermidine (Spd) with EBR increased lipidation of LC3 synergistically in both cell lines. We also found that EBR promoted polyamine catabolism in SW480 cells. The retention of polyamine biosynthesis was remarkable following EBR treatment. We suggested that EBR-mediated Akt activation might determine the downstream cellular stress responses to induce autophagy related to polyamines.

Keywords:  Autophagy; LC3; epibrassinolide; polyamines; spermidine

DOI:  https://doi.org/10.3906/biy-2005-37
Protoplasma. 2021 Jan 06.

Polyamine homeostasis modulates plasma membrane- and tonoplast-associated aquaporin expression in etiolated salt-stressed sunflower (Helianthus annuus L.) seedlings.

Aditi Tailor, Satish C Bhatla.

  Salt stress adversely affects plants by causing osmotic and ionic imbalance. Cellular osmotic adjustment occurs by modulation of water fluxes. Polyamines (PAs) are often advocated to be involved in osmoregulation during stressful conditions, and thus, they serve as potential "osmolytes." Aquaporins (AQPs), the water-transporting channels, are expected to play crucial roles in osmoregulation. Present investigations on etiolated sunflower seedlings demonstrate a possible correlation between PA homeostasis and maintenance of water balance, as a function of modulation of the abundance of two major AQP subfamilies: PIP2 (plasma membrane intrinsic protein 2) and TIP1 (tonoplast intrinsic protein 1). Salt stress (120 mM NaCl) restricts growth of sunflower seedlings and induces reduction in relative water content (RWC). This accompanies enhanced abundance of PIP2s and TIP1s in seedling roots and that of TIP1s in cotyledons, as revealed by Western blot analysis of AQP isoforms and also their imaging by confocal laser scanning microscopy (CLSM). Raising seedlings in the presence of 500 μM of DFMA (DL-α-difluoromethylarginine) or DFMO (DL-α-difluoromethylornithine), which are potent inhibitors of PA biosynthesis enzymes (arginine decarboxylase (ADC) and ornithine decarboxylase (ODC), respectively), significantly promotes root extension, irrespective of NaCl stress, and results in further lowering of salt-induced reduction in RWC in roots and cotyledons. This correlates with enhanced accumulation of both PIP2s and TIP1s in seedling roots, but not in cotyledons. Present work, therefore, implicates PA homeostasis in the maintenance of water status of sunflower seedlings, possibly via regulation of abundance and distribution of AQP isoforms associated with the plasma membrane and tonoplast.

Keywords:  Aquaporins; Osmoregulation; Polyamine; Salt stress; Sunflower seedlings

DOI:  https://doi.org/10.1007/s00709-020-01589-8
Front Microbiol. 2020 ;11 563139

tpo3 and dur3, Aspergillus fumigatus Plasma Membrane Regulators of Polyamines, Regulate Polyamine Homeostasis and Susceptibility to Itraconazole.

Mingcong Chen, Guowei Zhong, Sha Wang, Jun Zhu, Lei Tang, Lei Li.

  Aspergillus fumigatus is a well-known opportunistic pathogen that causes invasive aspergillosis (IA) infections, which have high mortality rates in immunosuppressed individuals. Long-term antifungal drug azole use in clinical treatment and agriculture results in loss of efficacy or drug resistance. Drug resistance is related to cellular metabolites and the corresponding gene transcription. In this study, through untargeted metabolomics and transcriptomics under itraconazole (ITC) treatment, we identified two plasma membrane-localized polyamine regulators tpo3 and dur3, which were important for polyamine homeostasis and susceptibility to ITC in A. fumigatus. In the absence of tpo3 and/or dur3, the levels of cytoplasmic polyamines had a moderate increase, which enhanced the tolerance of A. fumigatus to ITC. In comparison, overexpression of tpo3 or dur3 induced a drastic increase in polyamines, which increased the sensitivity of A. fumigatus to ITC. Further analysis revealed that polyamines concentration-dependently affected the susceptibility of A. fumigatus to ITC by scavenging reactive oxygen species (ROS) at a moderate concentration and promoting the production of ROS at a high concentration rather than regulating drug transport. Moreover, inhibition of polyamine biosynthesis reduced the intracellular polyamine content, resulted in accumulation of ROS and enhanced the antifungal activity of ITC. Interestingly, A. fumigatus produces much lower levels of ROS under voriconazole (VOC) treatment than under ITC-treatment. Accordingly, our study established the link among the polyamine regulators tpo3 and dur3, polyamine homeostasis, ROS content, and ITC susceptibility in A. fumigatus.

Keywords:  Aspergillus fumigatus; itraconazole susceptibility; polyamine; polyamine homeostasis; reactive oxygen species

DOI:  https://doi.org/10.3389/fmicb.2020.563139
Int J Mol Sci. 2021 Jan 04. pii: E441. [Epub ahead of print]22(1):

Polyamines Influence Mouse Sperm Channels Activity.

Lorena Rodríguez-Páez, Charmina Aguirre-Alvarado, Norma Oviedo, Verónica Alcántara-Farfán, Edgar E Lara-Ramírez, Guadalupe Elizabeth Jimenez-Gutierrez, Joaquín Cordero-Martínez.

  Polyamines are ubiquitous polycationic compounds that are highly charged at physiological pH. While passing through the epididymis, sperm lose their capacity to synthesize the polyamines and, upon ejaculation, again come into contact with the polyamines contained in the seminal fluid, unleashing physiological events that improve sperm motility and capacitation. In the present work, we hypothesize about the influence of polyamines, namely, spermine, spermidine, and putrescine, on the activity of sperm channels, evaluating the intracellular concentrations of chloride [Cl-]i, calcium [Ca2+]i, sodium [Na+]i, potassium [K+]i, the membrane Vm, and pHi. The aim of this is to identify the possible regulatory mechanisms mediated by the polyamines on sperm-specific channels under capacitation and non-capacitation conditions. The results showed that the presence of polyamines did not directly influence the activity of calcium and chloride channels. However, the results suggested an interaction of polyamines with sodium and potassium channels, which may contribute to the membrane Vm during capacitation. In addition, alkalization of the pHi revealed the possible activation of sperm-specific Na+/H+ exchangers (NHEs) by the increased levels of cyclic AMP (cAMP), which were produced by soluble adenylate cyclase (sAC) and interact with the polyamines, evidence that is supported by in silico analysis.

Keywords:  channels; polyamines; soluble adenylate cyclase; spermatozoa

DOI:  https://doi.org/10.3390/ijms22010441
Plant Physiol Biochem. 2021 Jan 05. pii: S0981-9428(20)30645-8. [Epub ahead of print]159 285-300

Combined ability of salicylic acid and spermidine to mitigate the individual and interactive effects of drought and chromium stress in maize (Zea mays L.).

Rabia Naz, Amina Sarfraz, Zahid Anwar, Humaira Yasmin, Asia Nosheen, Rumana Keyani, Thomas H Roberts.

  Application of the growth regulator salicylic acid (SA) and the polyamine spermidine (Spd) can be used to manage various plant abiotic stresses. We aimed to evaluate the sole and combined effects of SA and Spd on maize (Zea mays) under individual and combined drought and chromium (Cr) stress. Drought, Cr, and drought + Cr treatments caused oxidative stress by inducing higher production of reactive oxygen species (H2O2, O2-), enhanced malondialdehyde content and increased relative membrane permeability. Increased oxidative stress and higher Cr uptake in the host plant reduced the content of carotenoids, other photosynthetic pigments and protein, and changed carbohydrate metabolism. Combined drought + Cr stress was more damaging for the growth of maize plants than the individual stresses. Exogenous treatments of SA and Spd alleviated the adverse effects of drought and Cr toxicity, reflected by accumulations of osmolytes, antioxidants and endogenous polyamines. Single applications of Spd (0.1 mM) increased plant height, shoot fresh weight, leaf area, above-ground dry matter accumulation and polyamine content under drought, Cr, and drought + Cr stress conditions. However, the combined treatment SA + Spd (0.25 mM + 0.05 mM) was more effective in increasing protein and water contents, photosynthetic pigments, and carotenoids. The same treatment increased Cr tolerance in the maize plants by decreasing uptake of this heavy metal from root to shoot. The SA + Spd treatment also decreased oxidative stress by promoting antioxidant enzyme activities, and enhanced levels of proline, soluble sugars, and carbohydrate contents under individual and combined stress conditions. Results indicate that the combined half-dose application of SA + Spd may be utilized to boost the tolerance in maize under individual as well as combined drought and Cr stress conditions.

Keywords:  Antioxidants; Osmolytes; Oxidative stress; Polyamines; Salicylic acid; Spermidine; Zea mays

DOI:  https://doi.org/10.1016/j.plaphy.2020.12.022
Pulm Circ. 2020 Oct-Dec;10(4):10(4): 2045894020915831

Inhibition of ornithine decarboxylase restores hypoxic pulmonary vasoconstriction in endotoxemic mice.

P H Gebauer, M Turzo, F Lasitschka, M A Weigand, C J Busch.

  Endotoxemia impairs hypoxic pulmonary vasoconstriction which leads to systemic hypoxemia. This derogation is attributable to increased activity of nitric oxide synthase 2 and arginase metabolism. Gene expression analysis has shown increased expression of ornithine decarboxylase in lungs of endotoxemic mice, a downstream enzyme of arginase metabolism. The aim of this study was to investigate whether inhibition of ornithine decarboxylase increases hypoxic pulmonary vasoconstriction in lungs of endotoxemic mice. Mice received lipopolysaccharides or saline intraperitoneal, and hypoxic pulmonary vasoconstriction was measured using an isolated perfused mouse lung model. Additional mice with and without endotoxemia were pretreated with the ornithine decarboxylase-inhibitor difluoromethylornithine before examination of hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction was defined as the difference of pulmonary arterial pressure between normoxic and hypoxic ventilation. In addition, lung tissue was analyzed using real-time quantitative polymerase chain reaction, Western blot and immunohistochemistry. Lipopolysaccharides caused an up-regulation of ornithine decarboxylase mRNA level (2.73 ± 0.19-fold increase, p < 0.05) as well as ornithine decarboxylase protein level (4.05 ± 0.37-fold increase, p < 0.05). Endotoxemia attenuated hypoxic pulmonary vasoconstriction when compared with untreated control mice (26.3 ± 9.7% vs. 67.0 ± 17.5%). Difluoromethylornithine (20, 100, 500 mg kg-1 body weight intraperitoneal) restored hypoxic pulmonary vasoconstriction in lungs of endotoxemic mice in a dose-dependent way (25.8 ± 9.9%, 57.3 ± 17.2%, 62.3 ± 12.4%) and decreased hypoxic pulmonary vasoconstriction in control mice (53.6 ± 13.6%, 40.0 ± 14.9%, 35.9 ± 12.4%). These results show that endotoxemia induces ornithine decarboxylase expression and suggest that ornithine decarboxylase contributes to the endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction. Inhibition of ornithine decarboxylase might be a target in the therapy of diseases with inflammation impaired hypoxic pulmonary vasoconstriction, like the sepsis-associated acute respiratory distress syndrome (ARDS).

Keywords:  hypoxic pulmonary vasoconstriction; mouse; ornithine decarboxylase; sepsis

DOI:  https://doi.org/10.1177/2045894020915831
Amino Acids. 2021 Jan 04.

Reduction of oxidative stress and ornithine decarboxylase expression in a human prostate cancer cell line PC-3 by a combined treatment with α-tocopherol and naringenin.

Piera Torricelli, Antonia Concetta Elia, Gabriele Magara, Giordana Feriotto, Cinzia Forni, Ilaria Borromeo, Angelo De Martino, Claudio Tabolacci, Carlo Mischiati, Simone Beninati.

  Differentiation of a human aggressive PC-3 cancer cell line was obtained, in a previous investigation, by the synergic effect of α-tocopherol (α-TOC) and naringenin (NG). This combined treatment induced apoptosis and subsequent reduction of the PC-3 cell proliferation and invasion, by a pro-differentiating action. Since one of the peculiar characteristics of NG and α-TOC is their strong antioxidant activity, this study aimed to investigate their potential effect on the activity of the main enzymes involved in the antioxidant mechanism in prostate cancer cells. NG and α-TOC administered singularly or combined in the PC-3 cell line, affected the activity of several enzymes biomarkers of the cellular antioxidant activity, as well as the concentration of total glutathione (GSH + GSSG) and thiobarbituric acid reactive substances (TBARS). The combined treatment increased the TBARS levels and superoxide dismutase (SOD) activity, while decreased the glutathione S-transferase (GST), glutathione reductase (GR), and glyoxalase I (GI) activities. The results obtained indicate that a combined treatment with these natural compounds mitigated the oxidative stress in the human PC-3 cell line. In addition, a significant reduction of both ornithine decarboxylase (ODC) expression and intracellular levels of polyamines, both well-known positive regulators of cell proliferation, accompanied the reduction of oxidative stress observed in the combined α-TOC and NG treatment. Considering the established role of polyamines in cell differentiation, the synergism with NG makes α-TOC a potential drug for further study on the differentiation therapy in prostate cancer patients.

Keywords:  Antioxidant biomarkers; NG; ODC; PC-3 cell line; Polyamines; Prostate cancer; α-TOC

DOI:  https://doi.org/10.1007/s00726-020-02925-1
Metabolites. 2021 Jan 04. pii: E31. [Epub ahead of print]11(1):

Quantitative Analysis of Biogenic Amines in Different Cheese Varieties Obtained from the Korean Domestic and Retail Markets.

Sujatha Kandasamy, Jayeon Yoo, Jeonghee Yun, Han Byul Kang, Kuk-Hwan Seol, Jun-Sang Ham.

  To evaluate the safety and risk assessment of cheese consumption in the Republic of Korea, sixty cheese samples purchased from the farmstead and retails markets (imported) were analyzed for their biogenic amine (BA) contents. The BA profiles and quantities of eight amines (tryptamine, 2-phenylethylamine, putrescine, cadaverine, histamine, tyramine, spermidine, and spermine) were determined using high-performance liquid chromatography (HPLC). Spermine was the only amine detectable in all the samples. The BAs of fresh cheeses from both farmstead and retail markets were mostly undetectable, and comparatively at lower levels (<125 mg/kg) than ripened samples. Putrescine was undetectable in all the domestic ripened cheeses. The sum of BA levels in the imported ripened cheeses of Pecorino Romano (1889.75 mg/kg) and Grana Padano (1237.80 mg/kg) exceeds >1000 mg/kg, of which histamine accounts nearly 86 and 77% of the total levels, respectively. The tolerable limits of the potential toxic amines, histamine and tyramine surpassed in four and three imported ripened samples, respectively. Furthermore, the presence of potentiators (putrescine and cadaverine) together in samples even with a lower level of toxic amines alarms the risk in consumption. Therefore, adoption of strict hygienic practices during the entire chain of cheese production, along with obligatory monitoring and regulation of BA in cheeses seems to be mandatory to ensure the safety of the consumers.

Keywords:  HPLC-DAD; biogenic amines; cheese; risk assessment; toxicity

DOI:  https://doi.org/10.3390/metabo11010031
Arterioscler Thromb Vasc Biol. 2021 Jan 06. ATVBAHA120315622

ODC (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains MerTK (MER Tyrosine-Protein Kinase) Expression to Drive Resolution.

Arif Yurdagul, Na Kong, Brennan D Gerlach, Xiaobo Wang, Patrick Ampomah, George Kuriakose, Wei Tao, Jinjun Shi, Ira Tabas.

   OBJECTIVE: ODC (ornithine decarboxylase)-dependent putrescine synthesis promotes the successive clearance of apoptotic cells (ACs) by macrophages, contributing to inflammation resolution. However, it remains unknown whether ODC is required for other arms of the resolution program. Approach and Results: RNA sequencing of ODC-deficient macrophages exposed to ACs showed increases in mRNAs associated with heightened inflammation and decreases in mRNAs related to resolution and repair compared with WT (wild type) macrophages. In zymosan peritonitis, myeloid ODC deletion led to delayed clearance of neutrophils and a decrease in the proresolving cytokine, IL (interleukin)-10. Nanoparticle-mediated silencing of macrophage ODC in a model of atherosclerosis regression lowered IL-10 expression, decreased efferocytosis, enhanced necrotic core area, and reduced fibrous cap thickness. Mechanistically, ODC deletion lowered basal expression of MerTK (MER tyrosine-protein kinase)-an AC receptor-via a histone methylation-dependent transcriptional mechanism. Owing to lower basal MerTK, subsequent exposure to ACs resulted in lower MerTK-Erk (extracellular signal-regulated kinase) 1/2-dependent IL-10 production. Putrescine treatment of ODC-deficient macrophages restored the expression of both MerTK and AC-induced IL-10.
CONCLUSIONS: These findings demonstrate that ODC-dependent putrescine synthesis in macrophages maintains a basal level of MerTK expression needed to optimally resolve inflammation upon subsequent AC exposure.

Keywords:  atherosclerosis; histones; inflammation; macrophages; putrescine

DOI:  https://doi.org/10.1161/ATVBAHA.120.315622
Nat Commun. 2021 Jan 08. 12(1): 163

Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange.

Andrea Canal-Martín, Ruth Pérez-Fernández.

Dynamic combinatorial chemistry applied to biological environments requires the exchange chemistry of choice to take place under physiological conditions. Thiol-disulfide exchange, one of the most popular dynamic combinatorial chemistries, usually needs long equilibration times to reach the required equilibrium composition. Here we report selenocystine as a catalyst mimicking Nature's strategy to accelerate thiol-disulfide exchange at physiological pH and low temperatures. Selenocystine is able to accelerate slow thiol-disulfide systems and to promote the correct folding of an scrambled RNase A enzyme, thus broadening the practical range of pH conditions for oxidative folding. Additionally, dynamic combinatorial chemistry target-driven self-assembly processes are tested using spermine, spermidine and NADPH (casting) and glucose oxidase (molding). A non-competitive inhibitor is identified in the glucose oxidase directed dynamic combinatorial library.

DOI: https://doi.org/10.1038/s41467-020-20415-6
Virulence. 2021 Dec;12(1): 217-230

Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation.

Juan Shen, RenYi Lu, Qing Cai, LingZhi Fan, WanNian Yan, ZhenYu Zhu, LianJuan Yang, YingYing Cao.

  The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.

Keywords:   C. albicans ; Caspofungin; ROS; SPE1; mangiferin; polyamines

DOI:  https://doi.org/10.1080/21505594.2020.1870079
Dose Response. 2020 Oct-Dec;18(4):18(4): 1559325820979570

Identification of Potential Radiation Responsive Metabolic Biomarkers in Plasma of Rats Exposed to Different Doses of Cobalt-60 Gamma Rays.

Hua Zhao, Cong Xi, Mei Tian, Xue Lu, Tian-Jing Cai, Shuang Li, Xue-Lei Tian, Ling Gao, Hai-Xiang Liu, Ke-Hui Liu, Qing-Jie Liu.

  Metabolomics has great potential to process accessible biofluids through high-throughput and quantitative analysis for radiation biomarker screening. This study focused on the potential radiation responsive metabolites in rat plasma and the dose-response relationships. In the discovery stage, 20 male Sprague-Dawley rats were exposed to 0, 1, 3 and 5 Gy of cobalt-60 gamma rays at a dose rate of 1 Gy/min. Plasma samples were collected at 72 h after exposure and analyzed using liquid chromatography mass spectrometry based on non-targeted metabolomics. In the verification stage, 50 additional rats were exposed to 0, 1, 2, 3, 5 and 8 Gy of gamma rays. The concentrations of candidate metabolites were then analyzed using targeted metabolomics methods. Fifteen candidate radiation responsive metabolites were identified as potential radiation metabolite biomarkers. Metabolic pathways, such as linoleic acid metabolism and glycerophospholipid metabolism pathways, were changed after irradiation. Six radiation responsive metabolites, including LysoPC(20:2), LysoPC(20:3), PC(18:0/22:5), L-palmitoylcarnitine, N-acetylornithine and butyrylcarnitine, had good dose-response relationships (R 2 > 0.80). The area under the curve of the panel of the 6 radiation responsive metabolites was 0.923. The radiation exposure metabolomics biomarkers and dose-response curves may have potential for rapid dose assessment and triage in nuclear and radiation accidents.

Keywords:  LC-MS; biomarker; dose-response; ionizing radiation; metabolomics

DOI:  https://doi.org/10.1177/1559325820979570
Front Psychiatry. 2020 ;11 579538

Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities: Investigating Sex-Differences.

Jennie Sotelo-Orozco, Leonard Abbeduto, Irva Hertz-Picciotto, Carolyn M Slupsky.

  Background: Developmental disabilities are defined by delays in learning, language, and behavior, yet growing evidence has revealed disturbances in metabolic systems that may also be present. Little is known about whether these metabolic issues contribute to the symptoms or severity of these disabilities, or whether sex plays a role in these associations, given that boys are disproportionately affected by some developmental disabilities. Here we sought to investigate the correlation between psychometric scores, sex, and the plasma metabolome. Methods: The plasma metabolomes of children with autism spectrum disorder (ASD; n = 167), idiopathic developmental delay (i-DD; n = 51), Down syndrome (DS; n = 31), and typically developing controls (TD; n = 193) were investigated using NMR spectroscopy. Spearman rank correlations and multiple linear regression models (adjusted for child's neurodevelopmental diagnosis, child's sex, child's age, child's race/ethnicity, maternal age at child's birth, and parental homeownership) were used to examine the association between plasma metabolites and sex in relation to psychometric measures of cognitive skills, adaptive behavior, and maladaptive behavior in our study population. Results: Higher levels of metabolites involved in cellular energy and mitochondrial function among children with ASD (fumarate and cis-aconitate), DS (lactate), and TD (pyruvate) are associated with poorer cognitive and adaptive subscales. Similarly, higher o-acetylcarnitine associated with deficits in cognitive subscales among all DS cases and TD boys, and carnitine correlated with increased maladaptive behavior among girls with ASD and girls with DS. Among children with DS, elevated myo-inositol, ornithine, and creatine correlated with poorer scores across several subscales. Even among TD cases, elevated 3-hydroxybutyrate correlated with decreased receptive language. In contrast, higher levels of glutamate were associated with better socialization skills among ASD cases. Even after adjusting for the child's neurodevelopmental diagnosis, sex, and other possible confounders, key metabolites including glycolysis metabolites (lactate and pyruvate), ketone bodies (3-hydroxybutyrate and acetoacetate), TCA cycle metabolites (cis-aconitate and fumarate), as well as ornithine were associated with deficits in multiple domains of cognitive function, adaptive skills, and aberrant behaviors. Conclusions: Our results highlight that some plasma metabolites may relate to specific functional subdomains within cognitive, adaptive, and behavioral development with some variation by diagnosis and sex.

Keywords:  adaptive behavior; autism spectrum disorder; cognitive scores; down syndrome; maladaptive behavior; metabolites; metabolomics; sex-differences

DOI:  https://doi.org/10.3389/fpsyt.2020.579538
Chin Med J (Engl). 2020 Nov 04. 134(1): 28-37

Arginine metabolism: a potential target in pancreatic cancer therapy.

Jin-Shou Yang, Cheng-Cheng Wang, Jiang-Dong Qiu, Bo Ren, Lei You.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant disease, which has an extremely low survival rate of <9% in the United States. As a new hallmark of cancer, metabolism reprogramming exerts crucial impacts on PDAC development and progression. Notably, arginine metabolism is altered in PDAC cells and participates in vital signaling pathways. In addition, arginine and its metabolites including polyamine, creatine, agmatine, and nitric oxide regulate the proliferation, growth, autophagy, apoptosis, and metastasis of cancer cells. Due to the loss of argininosuccinate synthetase 1 (ASS1) expression, the key enzyme in arginine biosynthesis, arginine deprivation is regarded as a potential strategy for PDAC therapy. However, drug resistance develops during arginine depletion treatment, along with the re-expression of ASS1, metabolic dysfunction, and the appearance of anti-drug antibody. Additionally, arginase 1 exerts crucial roles in myeloid-derived suppressor cells, indicating its potential targeting by cancer immunotherapy. In this review, we introduce arginine metabolism and its impacts on PDAC cells. Also, we discuss the role of arginine metabolism in arginine deprivation therapy and immunotherapy for cancer.

DOI: https://doi.org/10.1097/CM9.0000000000001216
Prostate Cancer Prostatic Dis. 2021 Jan 06.

Urine spermine and multivariable Spermine Risk Score predict high-grade prostate cancer.

Peter Ka-Fung Chiu, Yan-Ho Fung, Jeremy Yuen-Chun Teoh, Chun-Hong Chan, Ka-Lun Lo, Kai-Man Li, Ryan Tsz-Hei Tse, Chi-Ho Leung, Yim-Ping Wong, Monique J Roobol, Ka-Leung Wong, Chi-Fai Ng.

BACKGROUND: To investigate the role of urine spermine and Spermine Risk Score in prediction of high-grade prostate cancer (HGPCa, ISUP grade group ≥2).
METHODS: Nine hundred and five consecutive men with elevated PSA were prospectively recruited from two hospitals. Core analyses focused on consecutive men with PSA 4-20 ng/mL (n = 600). Pre-biopsy urine without prior prostatic massage was analyzed for spermine level with ultra-high performance liquid chromatography with triple quadrupole mass spectrometer (UPLC-MS/MS). The proportions of PCa and HGPCa were compared across different spermine ranges. Logistic regressions were used to form different models, and their performances were compared using area under curve (AUC) and decision curve analysis (DCA).
RESULTS: PCa and HGPCa were diagnosed in 30.8% (185/600) and 17.2% (103/600) men, respectively, and were significantly associated with lower urine spermine levels. Between the lowest and highest quartiles of spermine results, a threefold increase in PCa risk (49.3% vs. 16.7%) and 3.5-fold increase in ISUP grade group ≥2 PCa risk (31.3% vs. 8.7%) were observed. Multivariate analysis showed PSA, prostate volume (PV), digital rectal examination (DRE), and spermine, which were independent predictors for PCa and HGPCa, and a Spermine Risk Score with these factors achieved the highest AUC of 0.78 for PCa and 0.82 for HGPCa. At 90% sensitivity for HGPCa, 36.7% biopsies and 24.4% ISUP grade group 1 diagnoses could have been avoided, with a negative predictive value of 95.4%. DCA revealed net clinical benefit of the Spermine Risk Score. Internal validation with bootstrapping showed good discrimination and calibration.
CONCLUSION: Urine spermine and Spermine Risk Score identified men at higher risk of HGPCa and reduced unnecessary biopsies.

DOI: https://doi.org/10.1038/s41391-020-00312-1