bims-bramad 2020-10-04 papers

bims-bramad

Biomed News

on Branched chain amino acid catabolism in metabolic diseases

Issue of 2020–10–04
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet, Dalhousie University

Huangjinya Black Tea Alleviates Obesity and Insulin Resistance via Modulating Fecal Metabolome in High-Fat Diet-Fed Mice.
Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates.
Excessive ROS Production and Enhanced Autophagy Contribute to Myocardial Injury Induced by Branched-chain Amino Acids: Roles for the AMPK-ULK1 Signaling Pathway and α7nAChR.
Metabolomics in Sleep, Insomnia and Sleep Apnea.
Effect of very low-protein diets supplemented with branched-chain amino acids on energy balance, plasma metabolomics and fecal microbiome of pigs.
A pathogen branched-chain amino acid catabolic pathway subverts host survival by impairing energy metabolism and the mitochondrial UPR.
A route to decreasing N pollution from livestock: Use of Festulolium hybrids improves efficiency of N flows in rumen simulation fermenters.
Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population.
Hydrolyzed peptides from purple perilla (Perilla frutescens L. Britt.) seeds improve muscle synthesis and exercise performance in mice.
The impact of L-branched-chain amino acids and L-leucine on malnutrition, sarcopenia, and other outcomes in patients with chronic liver disease.
Interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection.
Genome-scale metabolic modelling predicts biomarkers and therapeutic targets for neuropsychiatric disorders.
Herbicides that target acetohydroxyacid synthase are potent inhibitors of the growth of drug resistant Candida auris.
Unveiling the Pharmacological Mechanisms of Eleutheroside E Against Postmenopausal Osteoporosis Through UPLC-Q/TOF-MS-Based Metabolomics.

Mol Nutr Food Res. 2020 Oct 01. e2000353

Huangjinya Black Tea Alleviates Obesity and Insulin Resistance via Modulating Fecal Metabolome in High-Fat Diet-Fed Mice.

Jialin Xu, Mingxi Li, Yi Zhang, Suo Chu, Yan Huo, Jie Zhao, Chunpeng Wan.

   SCOPE: Huangjinya is a light-sensitive tea mutant containing low levels of tea polyphenols. Currently, most studies focused on characteristics formation, free amino acids metabolism and phytochemicals purification. The biological activity of Huangjinya black tea (HJBT) on metabolic syndrome regarding fecal metabolome modulation is unavailable and studied herein.
METHODS AND RESULTS: High-fat diet (HFD)-fed mice were treated with HJBT for 9 weeks, various metabolic biomarkers and fecal metabolites were determined. HJBT reduced adipogenic and lipogenic genes expression, enhanced lipolytic genes expression, decreased adipocyte expansion and prevented the development of obesity. HJBT reduced lipogenic genes expression, increased fatty acid oxidation-related genes expression, which alleviated liver steatosis. HJBT enhanced glucose/insulin tolerance, increased insulin/Akt signaling, attenuated hyperlipidemia and hyperglycemia, prevented the onset of insulin resistance. HJBT modulated bile acid metabolism, promoted secondary / primary bile acid ratio; increased short-chain fatty acids production, promoted saturated and polyunsaturated fatty acids content; reduced carnitines and phosphocholines, but increased myo-inositol content; decreased branched-chain and aromatic amino acids content; increased the metabolite content related to pentose phosphate pathway.
CONCLUSION: This study reported the association between fecal metabolome modulation and metabolism improvement due to HJBT administration, proposed that HJBT as a dietary intervention for preventing obesity and metabolic disorders. This article is protected by copyright. All rights reserved.

Keywords:  Black tea; Fecal metabolome; Huangjinya; Lipolysis; Liver steatosis; Obesity

DOI:  https://doi.org/10.1002/mnfr.202000353
Cochrane Database Syst Rev. 2020 Oct 02. 10 CD012273

Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates.

Shoichiro Amari, Sadequa Shahrook, Fumihiko Namba, Erika Ota, Rintaro Mori.

BACKGROUND: Branched-chain amino acids (BCAAs) play a vital role in neonatal nutrition. Optimal BCAA supplementation might improve neonatal nutrient storage, leading to better physical and neurological development and other outcomes.
OBJECTIVES: To determine the effect of BCAA supplementation on physical growth and neurological development in term and preterm neonates. We planned to make the following comparisons: parenteral nutrition with and without BCAA supplementation; enteral BCAA supplementation versus no supplementation; and any type of supplementation including enteral, parenteral and both ways versus no supplementation. To investigate the supplementation effectiveness for different dosages assessed in the eligible trials.
SEARCH METHODS: We conducted comprehensive searches using Cochrane Neonatal's standard search strategies: Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 6), MEDLINE, Embase and CINAHL (up to July 2016). We updated the search with CENTRAL (2019, Issue 8), MEDLINE, Embase and CINAHL (up to August 2019). We also searched clinical trials registries and reference lists of retrieved articles.
SELECTION CRITERIA: We planned to include individual and cluster-randomised and quasi-randomised controlled trials comparing BCAA supplementation versus placebo or no supplementation in term and preterm neonates. We excluded trials presented only as abstracts and cross-over trials.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of all potential studies identified from the search strategy. We planned to extract data using a pilot-tested standard data extraction form and assess risk of bias of the included studies following the methods described in the Cochrane Handbook for Systematic Reviews of Interventions. We planned to analyse treatment effects and report their effect estimates as per dichotomous or continuous data with 95% confidence intervals. We planned to conduct subgroup analysis to investigate heterogeneity, and perform sensitivity analysis where possible. We planned to use fixed-effect meta-analysis to combine data wherever appropriate. We planned to assess evidence quality using the GRADE approach.
MAIN RESULTS: We did not identify any potentially eligible studies that met the inclusion criteria in this review.
AUTHORS' CONCLUSIONS: We found no trial data to support or refute the idea that BCAA supplementation affects physical and neurological development and other outcomes in term and preterm neonates.

DOI: https://doi.org/10.1002/14651858.CD012273.pub2
Biochim Biophys Acta Mol Basis Dis. 2020 Sep 24. pii: S0925-4439(20)30328-8. [Epub ahead of print] 165980

Excessive ROS Production and Enhanced Autophagy Contribute to Myocardial Injury Induced by Branched-chain Amino Acids: Roles for the AMPK-ULK1 Signaling Pathway and α7nAChR.

Yu-Jie Jiang, Si-Jia Sun, Wen-Xiang Cao, Xiu-Ting Lan, Min Ni, Hui Fu, Dong-Jie Li, Pei Wang, Fu-Ming Shen.

  Backgrounds and Aims Leucine, isoleucine, and valine are diet derived and essential amino acids that are termed branched-chain amino acids (BCAA). BCAA are widely used as dietary supplements to boost muscle growth and enhance exercise performance. However, the effects of BCAA on myocardial function are largely unknown. This study was designed to investigate whether BCAA affect heart function and, if so, to further explore the underlying molecular basis for the observed effects. Methods and Results C57BL/6J mice were randomly divided into two groups, the control group received solvent (water) and the BCAA group received 2% BCAA dissolved in water, for a successive period of 12 weeks. Compared with control, BCAA treatment significantly increased water consumption without changing body weight or diet consumption. Heart tissue BCAA levels were increased. Markers representative of myocardial injury were found in heart tissue including C-reactive protein and cardiac muscle troponin. Creatine kinase, creatine kinase-MB, and lactate dehydrogenase were increased in serum. Severe myocardial fibrosis was observed by Masson staining, which was accompanied by increased reactive oxygen species (ROS) production and decreased superoxide dismutase activity in heart tissue. Both p-AMPK and p-ULK1 were significantly increased as was autophagy, judged by the presence of LC3 by western blotting and immunofluorescence. Increased numbers of autophagosomes were found by transmission electron microscopy in the BCAA group. In vitro, 20 mmol/L BCAA significantly decreased cell viability and increased the production of ROS, as well as the expression of p-AMPK/AMPK and p-ULK1/ULK1 in cultured H9C2 cells. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) improved cell viability and reversed ROS changes. Decreased H9C2 cell viability induced with 20 mmol/L BCAA was reversed by either blocking AMPK or inhibition of ULK1. Furthermore, blocking AMPK significantly decreased p-ULK1/ULK1, while inhibition of ULK1 reversed the enhanced expression of LC3-II/LC3-I induced by BCAA. Excessive ROS production and decreased cell viability induced by BCAA were further confirmed in primary cultured murine cardiomyocytes. Pharmacological activation of α7nAChR with PNU-282987 attenuated BCAA-induced injury in primary murine cardiomyocytes. However, this compound failed to suppress BCAA activation of AMPK and autophagy (LC3-II/I ratio). CONCLUSION: These results provide the first evidence that treatment of mice with BCAA induced myocardial injury by triggering excessive ROS production and by enhancing AMPK-ULK1 pathway-dependent autophagy. These findings suggested that inhibition of either ROS production or autophagy may alleviate myocardial injury induced by BCAA.

Keywords:  AMPK-ULK1; Autophagy; BCAA; Myocardial Injury; Oxidative Stress; α7nAChR

DOI:  https://doi.org/10.1016/j.bbadis.2020.165980
Int J Mol Sci. 2020 Sep 30. pii: E7244. [Epub ahead of print]21(19):

Metabolomics in Sleep, Insomnia and Sleep Apnea.

Elke Humer, Christoph Pieh, Georg Brandmayr.

  Sleep-wake disorders are highly prevalent disorders, which can lead to negative effects on cognitive, emotional and interpersonal functioning, and can cause maladaptive metabolic changes. Recent studies support the notion that metabolic processes correlate with sleep. The study of metabolite biomarkers (metabolomics) in a large-scale manner offers unique opportunities to provide insights into the pathology of diseases by revealing alterations in metabolic pathways. This review aims to summarize the status of metabolomic analyses-based knowledge on sleep disorders and to present knowledge in understanding the metabolic role of sleep in psychiatric disorders. Overall, findings suggest that sleep-wake disorders lead to pronounced alterations in specific metabolic pathways, which might contribute to the association of sleep disorders with other psychiatric disorders and medical conditions. These alterations are mainly related to changes in the metabolism of branched-chain amino acids, as well as glucose and lipid metabolism. In insomnia, alterations in branched-chain amino acid and glucose metabolism were shown among studies. In obstructive sleep apnea, biomarkers related to lipid metabolism seem to be of special importance. Future studies are needed to examine severity, subtypes and treatment of sleep-wake disorders in the context of metabolite levels.

Keywords:  insomnia; mental disorders; metabolomics; sleep; sleep apnea

DOI:  https://doi.org/10.3390/ijms21197244
Sci Rep. 2020 Sep 28. 10(1): 15859

Effect of very low-protein diets supplemented with branched-chain amino acids on energy balance, plasma metabolomics and fecal microbiome of pigs.

Shelby Spring, Hasitha Premathilake, Chloe Bradway, Cedrick Shili, Udaya DeSilva, Scott Carter, Adel Pezeshki.

Feeding pigs with very-low protein (VLP) diets while supplemented with limiting amino acids (AA) results in decreased growth. The objective of this study was to determine if supplementing VLP diets with branched-chain AA (BCAA) would reverse the negative effects of these diets on growth and whether this is associated with alterations in energy balance, blood metabolomics and fecal microbiota composition. Twenty-four nursery pigs were weight-matched, individually housed and allotted into following treatments (n = 8/group): control (CON), low protein (LP) and LP supplemented with BCAA (LP + BCAA) for 4 weeks. Relative to CON, pigs fed with LP had lower feed intake (FI) and body weight (BW) throughout the study, but those fed with LP + BCAA improved overall FI computed for 4 weeks, tended to increase the overall average daily gain, delayed the FI and BW depression for ~ 2 weeks and had transiently higher energy expenditure. Feeding pigs with LP + BCAA impacted the phenylalanine and protein metabolism and fatty acids synthesis pathways. Compared to CON, the LP + BCAA group had higher abundance of Paludibacteraceae and Synergistaceae and reduced populations of Streptococcaceae, Oxyphotobacteria_unclassified, Pseudomonadaceae and Shewanellaceae in their feces. Thus, supplementing VLP diets with BCAA temporarily annuls the adverse effects of these diets on growth, which is linked with alterations in energy balance and metabolic and gut microbiome profile.

DOI: https://doi.org/10.1038/s41598-020-72816-8
PLoS Pathog. 2020 Sep 30. 16(9): e1008918

A pathogen branched-chain amino acid catabolic pathway subverts host survival by impairing energy metabolism and the mitochondrial UPR.

Siraje Arif Mahmud, Mohammed Adnan Qureshi, Madhab Sapkota, Mark W Pellegrino.

The mitochondrial unfolded protein response (UPRmt) is a stress-activated pathway promoting mitochondrial recovery and defense against infection. In C. elegans, the UPRmt is activated during infection with the pathogen Pseudomonas aeruginosa-but only transiently. As this may reflect a pathogenic strategy to target a pathway required for host survival, we conducted a P. aeruginosa genetic screen to uncover mechanisms associated with this temporary activation. Here, we find that loss of the P. aeruginosa acyl-CoA dehydrogenase FadE2 prolongs UPRmt activity and extends host survival. FadE2 shows substrate preferences for the coenzyme A intermediates produced during the breakdown of the branched-chain amino acids valine and leucine. Our data suggests that during infection, FadE2 restricts the supply of these catabolites to the host hindering host energy metabolism in addition to the UPRmt. Thus, a metabolic pathway in P. aeruginosa contributes to pathogenesis during infection through manipulation of host energy status and mitochondrial stress signaling potential.

DOI: https://doi.org/10.1371/journal.ppat.1008918
Food Energy Secur. 2020 Aug;9(3): e209

A route to decreasing N pollution from livestock: Use of Festulolium hybrids improves efficiency of N flows in rumen simulation fermenters.

Stephen Kamau, Alejandro Belanche, Teri Davies, Pauline Rees Stevens, Mike Humphreys, Alison H Kingston-Smith.

  Ruminant agriculture suffers from inefficient capture of forage protein and consequential release of N pollutants to land. This is due to proteolysis in the rumen catalyzed by both microbial but initially endogenous plant proteases. Plant breeding-based solutions are sought to minimize these negative environmental impacts. The aim of this study was to perform an integrated study of rumen N metabolism using semi-continuous rumen simulation fermenters (Rusitec) to explore the extent to which swards containing Festulolium populations (interspecific hybrids between Lolium and Festuca grass species) with decreased rates of endogenous protein degradation conferred advantageous protein utilization in comparison with a National Listed perennial ryegrass. An in vitro experiment was conducted using three Festulolium hybrids (Lolium perenne × Festuca arundinacea var. glaucescens, LpFg; Lolium perenne × Festuca mairei, LpFm; and Lolium multiflorum × Festuca arundinacea var. glaucescens, LmFg) and a Lolium perenne, Lp control. LpFm and LmFg demonstrated significantly lower plant-mediated proteolysis than the control. Fresh forage was incubated in Rusitec with rumen fluid from four donor cows. Feed disappearance and production of gas, methane, and volatile fatty acids were similar across cultivars. Whereas no differences in microbial protein synthesis were noted across treatments during early fermentation (0-6 hr after feeding), an increased microbial N flow in LpFm (+30%) and LmFg hybrids (+41%) was observed during late fermentation (6-24 hr after feeding), with higher overall microbial N flows (+13.5% and + 20.2%, respectively) compared with the control (Lp). We propose an underpinning mechanism involving the partitioning of amino acid catabolism toward branched-chain amino acids and microbial protein synthesis in grasses with slow plant-mediated proteolysis instead of accumulation of rumen ammonia in grasses with fast plant-mediated proteolysis. These observations indicate the potential of Festulolium hybrids with a slow plant-mediated proteolysis trait to improve the efficiency of capture of forage protein and decrease the release of N pollutants onto the land.

Keywords:  Festuca; Festulolium; Lolium; nitrogen‐use efficiency; protein; proteolysis; rumen

DOI:  https://doi.org/10.1002/fes3.209
BMJ Open Diabetes Res Care. 2020 Oct;pii: e001315. [Epub ahead of print]8(1):

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population.

Samuel H Gunther, Chin Meng Khoo, E-Shyong Tai, Xueling Sim, Jean-Paul Kovalik, Jianhong Ching, Jeannette J Lee, Rob M van Dam.

   INTRODUCTION: We evaluated whether concentrations of serum acylcarnitines and amino acids are associated with risk of type 2 diabetes and can improve predictive diabetes models in an Asian population.
RESEARCH DESIGN AND METHODS: We used data from 3313 male and female participants from the Singapore Prospective Study Program cohort who were diabetes-free at baseline. The average age at baseline was 48.0 years (SD: 11.9 years), and participants were of Chinese, Malay, and Indian ethnicity. Diabetes cases were identified through self-reported physician diagnosis, fasting glucose and glycated hemoglobin concentrations, and linkage to national disease registries. We measured fasting serum concentrations of 45 acylcarnitines and 14 amino acids. The association between metabolites and incident diabetes was modeled using Cox proportional hazards regression with adjustment for age, sex, ethnicity, height, and parental history of diabetes, and correction for multiple testing. Metabolites were added to the Atherosclerosis Risk in Communities (ARIC) predictive diabetes risk model to assess whether they could increase the area under the receiver operating characteristic curve (AUC).
RESULTS: Participants were followed up for an average of 8.4 years (SD: 2.1 years), during which time 314 developed diabetes. Branched-chain amino acids (HR: 1.477 per SD; 95% CI 1.325 to 1.647) and the alanine to glycine ratio (HR: 1.572; 95% CI 1.426 to 1.733) were most strongly associated with diabetes risk. Additionally, the acylcarnitines C4 and C16-OH, and the amino acids alanine, combined glutamate/glutamine, ornithine, phenylalanine, proline, and tyrosine were significantly associated with higher diabetes risk, and the acylcarnitine C8-DC and amino acids glycine and serine with lower risk. Adding selected metabolites to the ARIC model resulted in a significant increase in AUC from 0.836 to 0.846.
CONCLUSIONS: We identified acylcarnitines and amino acids associated with risk of type 2 diabetes in an Asian population. A subset of these modestly improved the prediction of diabetes when added to an established diabetes risk model.

Keywords:  Asia; risk predictors; type 2 diabetes

DOI:  https://doi.org/10.1136/bmjdrc-2020-001315
J Food Biochem. 2020 Sep 28. e13461

Hydrolyzed peptides from purple perilla (Perilla frutescens L. Britt.) seeds improve muscle synthesis and exercise performance in mice.

Yixiang Liu, Donghui Li, Ying Wei, Yu Ma, Yuchen Wang, Ling Huang, Yanbo Wang.

  The purple perilla (Perilla frutescens L. Britt.) seed peptides (PPSP) were obtained and their improvement of muscle synthesis and exercise performance was investigated in this work. Results showed that the weight-average molecular weight of the PPSP was 869 Dalton. The PPSP were rich in branched-chain amino acids (18.82 g/100 g) and anti-fatigue amino acids, including glutamate (Glu), aspartic acid (Asp), and arginine (Arg). After the administration of PPSP at 1.2 g kg-1 day-1 for 4 weeks, the muscle coefficient and muscle fiber thickness in mice displayed a distinct (p < .05) increase via the upregulation of myogenic differentiation (MyoD) and myogenin (MyoG). The improved muscle strength and exercise tolerance were also observed. Simultaneously, the levels of the biochemical blood markers associated with fatigue and the glycogen degradation in liver and muscle were significantly (p < .05) suppressed. These results suggested that PPSP could effectively promote muscle synthesis and ameliorate exercise fatigue. PRACTICAL APPLICATIONS: Purple perilla is an annual herbal plant and widely grown in Asian countries as an important crop and food. It is believed that the protein content of purple perilla seeds can reach 23.7%, and the protein is rich in essential amino acids. However, the information about the beneficial effects of their proteins or peptides on muscle synthesis and anti-exercise fatigue were still limited. The present results discovered that the PPSP can effectively promote the growth of muscle tissue and improve exercise tolerance. It is indicated that PPSP may have a potential application value in partly or completely replacing animal proteins such as whey protein.

Keywords:  exercise fatigue; muscle growth; myogenic factor; peptides; purple perilla

DOI:  https://doi.org/10.1111/jfbc.13461
Expert Rev Gastroenterol Hepatol. 2020 Sep 30.

The impact of L-branched-chain amino acids and L-leucine on malnutrition, sarcopenia, and other outcomes in patients with chronic liver disease.

Ana Luiza Soaresdos Santos, Lucilene Rezende Anastacio.

   INTRODUCTION: Metabolic and hormonal disorders resulting from chronic liver diseases culminate in increased proteolysis and decreased protein synthesis, which contributes to the development and progression of malnutrition and, consequently, sarcopenia. Nutritional management of sarcopenia in liver cirrhosis is a continuously evolving field and data on essential amino acid supplementation in chronic liver diseases is scarce.
AREAS COVERED: This review encompasses the current literature on oral amino acids supplementation in patients with chronic liver disease or patients with liver cirrhosis to try to elucidate the possible effects of L-branched-chain amino acids and isolated L-leucine as a therapeutic approach to malnutrition and sarcopenia.
EXPERT COMMENTARY: To ensure an optimal nutritional status and to reduce sarcopenia, it is necessary to assess nutritional status in all patients with liver cirrhosis and to apply nutritional interventions accordingly. The supply of calories, proteins, and essential amino acids are necessary for the maintenance of muscle mass and function. Although supplementation of L-branched-chain amino acids plays an important role in liver disease, L-leucine has been described as the main amino acid involved in protein turnover, reducing proteolysis and stimulating protein synthesis.

Keywords:  L-branched-chain amino acids; L-leucine; food supplementation; liver cirrhosis; sarcopenia

DOI:  https://doi.org/10.1080/17474124.2021.1829470
Sci Rep. 2020 Sep 28. 10(1): 15831

Interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection.

Andrea Fulgione, Marina Papaianni, Paola Cuomo, Debora Paris, Marco Romano, Concetta Tuccillo, Letizia Palomba, Chiara Medaglia, Massimiliano De Seta, Nicolino Esposito, Andrea Motta, Antonio Iannelli, Domenico Iannelli, Rosanna Capparelli.

The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853, TIRAP rs8177374 and IL1RL1 rs11123923. The results show that specific combinations of IL1RL1-TIRAP (AA-CT; P: 2,8 × 10-17) and MyD88-TIRAP-IL1RL1 (AA-CT-AA; P: 1,4 × 10-8) - but not MyD88 alone-act synergistically against Helicobacter pylori. Nuclear magnetic resonance (NMR) clearly discriminates cases from controls by highlighting significantly different expression levels of several metabolites (tyrosine, tryptophan, phenylalanine, branched-chain amino acids, short chain fatty acids, glucose, sucrose, urea, etc.). NMR also identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Furthermore, NMR discriminates between the cases heterozygous at the IL1RL1 locus from those homozygous at the same locus. Heterozygous patients are characterized by high levels of lactate, and IL1RL1-both associated with anti-inflammatory activity-and low levels of the pro-inflammatory molecules IL-1β, TNF-α, COX-2, and IL-6.

DOI: https://doi.org/10.1038/s41598-020-72974-9
Comput Biol Med. 2020 Sep 17. pii: S0010-4825(20)30325-5. [Epub ahead of print]125 103994

Genome-scale metabolic modelling predicts biomarkers and therapeutic targets for neuropsychiatric disorders.

S T R Moolamalla, P K Vinod.

  Distinguishing neuropsychiatric disorders is challenging due to the overlap in symptoms and genetic risk factors. People suffering from these disorders face personal and professional challenges. Understanding the dysregulation of brain metabolism under disease condition can aid in effective diagnosis and in developing treatment strategies based on the metabolism. In this study, we reconstructed the metabolic network of three major neuropsychiatric disorders, schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) using transcriptomic data and constrained based modelling approach. We integrated brain transcriptomic data from six independent studies with a recent comprehensive genome-scale metabolic model Recon3D. The analysis of the reconstructed network revealed the flux-level alterations in the peroxisome-mitochondria-golgi axis in neuropsychiatric disorders. We also extracted reporter metabolites and pathways that distinguish these three neuropsychiatric disorders. We found differences with respect to fatty acid oxidation, aromatic and branched chain amino acid metabolism, bile acid synthesis, glycosaminoglycans synthesis and modifications, and phospholipid metabolism. Further, we predicted network perturbations that transform the disease metabolic state to a healthy metabolic state for each disorder. These analyses provide local and global views of the metabolic changes in SCZ, BD and MDD, which may have clinical implications.

Keywords:  Brain metabolism; Computational modelling; Drug targets; Network biology; Reporter metabolites; Transcriptomics

DOI:  https://doi.org/10.1016/j.compbiomed.2020.103994
ACS Infect Dis. 2020 Sep 28.

Herbicides that target acetohydroxyacid synthase are potent inhibitors of the growth of drug resistant Candida auris.

Kylie A Agnew-Francis, Yu Cheng Tang, Xin Lin, Yu Shang Low, Shun Jie Wun, Andy Kuo, S M A Sayeed Ibn Elias, Thierry G Lonhienne, Nicholas Condon, Bruna Natalia Alves da Silva Pimentel, Carlos Vergani, Maree T Smith, James A Fraser, Craig M Williams, Luke W Guddat.

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6) is the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Ten AHAS inhibiting herbicides have Ki values of < 2 M for this enzyme, with the most potent having Ki values of < 32 nM. Six of these compounds exhibited MIC50 values of < 5 M against C. auris (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC50 of 0.090 M) in defined minimal media. The MIC50 value increase to 0.89 M in media enriched by the addition of branched chain amino acids at the expected concentration in the blood serum. The sessile MIC50 for BSM is 0.6 M. Thus, it is also an excellent inhibitor of the growth of C. auris biofilms. BSM is non-toxic in HEK-293 cells at concentrations >100 M and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections.

DOI: https://doi.org/10.1021/acsinfecdis.0c00229
Front Pharmacol. 2020 ;11 1316

Unveiling the Pharmacological Mechanisms of Eleutheroside E Against Postmenopausal Osteoporosis Through UPLC-Q/TOF-MS-Based Metabolomics.

Yong-Sheng Ma, Zhan-Jiang Hou, You Li, Beng-Beng Zheng, Jia-Ming Wang, Wen-Bo Wang.

  Postmenopausal osteoporosis (PMOP) is a common metabolic bone disease in postmenopausal women in the Worldwide, and seriously affects the quality of life of middle-aged and elderly women. Therefore, there is an urgent need to discover a highly effective drug for PMOP treatment. In this study, ultra-high performance liquid tandem quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to analyze the urine metabolic profiling and potential biomarkers, the relevant metabolic network of PMOP rats, and further to evaluate the intervention effect of Eleutheroside E (EE) against PMOP. Using multivariate statistical analysis combined with UPLC-Q/TOF-MS, a total of 27 biomarkers were identified, which related with 16 metabolic pathways, mainly involving steroidogenesis, beta oxidation of very long chain fatty acids, glutathione metabolism, carnitine synthesis, estrone metabolism, oxidation of branched chain fatty acids, etc. After treatment of EE, these biomarkers were markedly regulated, mainly involving steroid hormone biosynthesis, arachidonic acid metabolism, primary bile acid biosynthesis, indicating that EE had the therapeutic effect on PMOP. This study identified the potential urine metabolic markers and related metabolic pathways of the PMOP, explained the metabolic effect and pharmacological mechanisms of EE against PMOP, and provided a basis for the pharmacological study of EE.

Keywords:  biomarkers; effects; metabolomics; osteoporosis; pharmacological mechanism; ultra-high performance liquid tandem quadrupole time-of-flight mass spectrometry

DOI:  https://doi.org/10.3389/fphar.2020.01316