Metabolites

15 pages, 1178 KiB

Open AccessReview

Microbial and Host Metabolites at the Backstage of Fever: Current Knowledge about the Co-Ordinate Action of Receptors and Molecules Underlying Pathophysiology and Clinical Implications

by Luigi Santacroce, Marica Colella, Ioannis Alexandros Charitos, Marina Di Domenico, Raffaele Palmirotta and Emilio Jirillo

Metabolites 2023, 13(3), 461; https://doi.org/10.3390/metabo13030461 - 22 Mar 2023

Cited by 8 | Viewed by 3073

Abstract

Fever represents an elevation of body temperature, that exerts a protective effect against pathogens. Innate immune cells and neurons are implicated in the regulation of body temperature. Pathogen-associated molecular patterns, i.e., lipopolysaccharides from Gram-negative bacteria and peptidoglycan and lipoteichoic acid from Gram-positive bacteria [...] Read more.

Fever represents an elevation of body temperature, that exerts a protective effect against pathogens. Innate immune cells and neurons are implicated in the regulation of body temperature. Pathogen-associated molecular patterns, i.e., lipopolysaccharides from Gram-negative bacteria and peptidoglycan and lipoteichoic acid from Gram-positive bacteria are exogenous pyrogens, that bind to Toll-like receptors on immune and non-immune cells. The subsequent release of pro-inflammatory cytokines [interleukin-1 (IL-1), IL-6 and Tumor necrosis factor-alpha] and their passage through the brain trigger the febrile response. In fact, neurons of the pre-optic area produce prostaglandin E2 (PGE2), that, in turn, bind to the PGE2 receptors; thus, generating fever. Apart from classical non-steroidal anti-inflammatory drugs, i.e., aspirin and acetaminophen, various botanicals are currently used as antipyretic agents and, therefore, their mechanisms of action will be elucidated. Full article

(This article belongs to the Special Issue Role of Microbial Metabolites in the Regulation of Host Immunity and Metabolism)

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13 pages, 2634 KiB

Open AccessEditor’s ChoiceArticle

A Strategy for Uncovering the Serum Metabolome by Direct-Infusion High-Resolution Mass Spectrometry

by Xiaoshan Sun, Zhen Jia, Yuqing Zhang, Xinjie Zhao, Chunxia Zhao, Xin Lu and Guowang Xu

Metabolites 2023, 13(3), 460; https://doi.org/10.3390/metabo13030460 - 22 Mar 2023

Cited by 3 | Viewed by 1678

Abstract

Direct infusion nanoelectrospray high-resolution mass spectrometry (DI-nESI-HRMS) is a promising tool for high-throughput metabolomics analysis. However, metabolite assignment is limited by the inadequate mass accuracy and chemical space of the metabolome database. Here, a serum metabolome characterization method was proposed to make full [...] Read more.

Direct infusion nanoelectrospray high-resolution mass spectrometry (DI-nESI-HRMS) is a promising tool for high-throughput metabolomics analysis. However, metabolite assignment is limited by the inadequate mass accuracy and chemical space of the metabolome database. Here, a serum metabolome characterization method was proposed to make full use of the potential of DI-nESI-HRMS. Different from the widely used database search approach, unambiguous formula assignments were achieved by a reaction network combined with mass accuracy and isotopic patterns filter. To provide enough initial known nodes, an initial network was directly constructed by known metabolite formulas. Then experimental formula candidates were screened by the predefined reaction with the network. The effects of sources and scales of networks on assignment performance were investigated. Further, a scoring rule for filtering unambiguous formula candidates was proposed. The developed approach was validated by a pooled serum sample spiked with reference standards. The coverage and accuracy rates for the spiked standards were 98.9% and 93.6%, respectively. A total of 1958 monoisotopic features were assigned with unique formula candidates for the pooled serum, which is twice more than the database search. Finally, a case study of serum metabolomics in diabetes was carried out using the developed method. Full article

(This article belongs to the Special Issue State-of-the-Art Metabolomics and Lipidomics in Life Sciences: Methods and Applications)

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16 pages, 1317 KiB

Open AccessArticle

Changes in a Protein Profile Can Account for the Altered Phenotype of the Yeast Saccharomyces cerevisiae Mutant Lacking the Copper-Zinc Superoxide Dismutase

by Magdalena Kwolek-Mirek, Aleksandra Dubicka-Lisowska, Sabina Bednarska, Renata Zadrag-Tecza and Pawel Kaszycki

Metabolites 2023, 13(3), 459; https://doi.org/10.3390/metabo13030459 - 22 Mar 2023

Cited by 3 | Viewed by 1763

Abstract

Copper-zinc superoxide dismutase (SOD1) is an antioxidant enzyme that catalyzes the disproportionation of superoxide anion to hydrogen peroxide and molecular oxygen (dioxygen). The yeast Saccharomyces cerevisiae lacking SOD1 (Δsod1) is hypersensitive to the superoxide anion and displays a number of oxidative [...] Read more.

Copper-zinc superoxide dismutase (SOD1) is an antioxidant enzyme that catalyzes the disproportionation of superoxide anion to hydrogen peroxide and molecular oxygen (dioxygen). The yeast Saccharomyces cerevisiae lacking SOD1 (Δsod1) is hypersensitive to the superoxide anion and displays a number of oxidative stress-related alterations in its phenotype. We compared proteomes of the wild-type strain and the Δsod1 mutant employing two-dimensional gel electrophoresis and detected eighteen spots representing differentially expressed proteins, of which fourteen were downregulated and four upregulated. Mass spectrometry-based identification enabled the division of these proteins into functional classes related to carbon metabolism, amino acid and protein biosynthesis, nucleotide biosynthesis, and metabolism, as well as antioxidant processes. Detailed analysis of the proteomic data made it possible to account for several important morphological, biochemical, and physiological changes earlier observed for the SOD1 mutation. An example may be the proposed additional explanation for methionine auxotrophy. It is concluded that protein comparative profiling of the Δsod1 yeast may serve as an efficient tool in the elucidation of the mutation-based systemic alterations in the resultant S. cerevisiae phenotype. Full article

(This article belongs to the Special Issue Advances in Functional Proteomics and Metabolomics)

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12 pages, 1832 KiB

Open AccessArticle

DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate

by Ali A. Alshamrani, Samiyah Alshehri, Sana S. Alqarni, Sheikh F. Ahmad, Hanan Alghibiwi, Naif O. Al-Harbi, Saleh A. Alqarni, Laila Y. Al-Ayadhi, Sabry M. Attia, Ali S. Alfardan, Saleh A. Bakheet and Ahmed Nadeem

Metabolites 2023, 13(3), 458; https://doi.org/10.3390/metabo13030458 - 22 Mar 2023

Cited by 3 | Viewed by 1881

Abstract

Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to regulate genetic expression through [...] Read more.

Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to regulate genetic expression through various mechanisms. One such mechanism is DNA methylation, which is regulated by DNA methyltransferases (DNMTs). DNMT transfers methyl groups onto the fifth carbon atom of the cytosine nucleotide, thus converting it into 5-methylcytosine (5mC) in the promoter region of the DNA. Disruptions in methylation patterns of DNA are usually associated with modulation of genetic expression. Environmental pollutants such as the plasticizer Di(2-ethylhexyl) phthalate (DEHP) have been reported to affect epigenetic mechanisms; however, whether DEHP modulates DNMT1 expression, DNA methylation, and inflammatory mediators in the neutrophils of ASD subjects has not previously been investigated. Hence, this investigation focused on the role of DNMT1 and overall DNA methylation in relation to inflammatory mediators (CCR2, MCP-1) in the neutrophils of children with ASD and typically developing healthy children (TDC). Further, the effect of DEHP on overall DNA methylation, DNMT1, CCR2, and MCP-1 in the neutrophils was explored. Our results show that the neutrophils of ASD subjects have diminished DNMT1 expression, which is associated with hypomethylation of DNA and increased inflammatory mediators such as CCR2 and MCP-1. DEHP further causes downregulation of DNMT1 expression in the neutrophils of ASD subjects, probably through oxidative inflammation, as antioxidant treatment led to reversal of a DEHP-induced reduction in DNMT1. These data highlight the importance of the environmental pollutant DEHP in the modification of epigenetic machinery such as DNA methylation in the neutrophils of ASD subjects. Full article

(This article belongs to the Special Issue Metabolism of Immune System in Inflammatory and Infectious Diseases)

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17 pages, 1174 KiB

Open AccessReview

Atherosclerosis Calcification: Focus on Lipoproteins

by Jaap G. Neels, Georges Leftheriotis and Giulia Chinetti

Metabolites 2023, 13(3), 457; https://doi.org/10.3390/metabo13030457 - 21 Mar 2023

Cited by 9 | Viewed by 5405

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and [...] Read more.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolism in Cardiometabolic Diseases Vol.2)

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14 pages, 3086 KiB

Open AccessArticle

The Dynamic Changes in the Main Substances in Codonopsis pilosula Root Provide Insights into the Carbon Flux between Primary and Secondary Metabolism during Different Growth Stages

by Sheng-Song Wang, Tong Zhang, Long Wang, Shuai Dong, Dong-Hao Wang, Bin Li and Xiao-Yan Cao

Metabolites 2023, 13(3), 456; https://doi.org/10.3390/metabo13030456 - 21 Mar 2023

Cited by 3 | Viewed by 1690

Abstract

The dried root of Codonopsis pilosula (Franch.) Nannf., referred to as Dangshen in Chinese, is a famous traditional Chinese medicine. Polysaccharides, lobetyolin, and atractylenolide III are the major bioactive components contributing to its medicinal properties. Here, we investigated the dynamic changes of the [...] Read more.

The dried root of Codonopsis pilosula (Franch.) Nannf., referred to as Dangshen in Chinese, is a famous traditional Chinese medicine. Polysaccharides, lobetyolin, and atractylenolide III are the major bioactive components contributing to its medicinal properties. Here, we investigated the dynamic changes of the main substances in annual Dangshen harvested at 12 time points from 20 May to 20 November 2020 (from early summer to early winter). Although the root biomass increased continuously, the crude polysaccharides content increased and then declined as the temperature fell, and so did the content of soluble proteins. However, the content of total phenolics and flavonoids showed an opposite trend, indicating that the carbon flux was changed between primary metabolism and secondary metabolism as the temperature and growth stages changed. The changes in the contents of lobetyolin and atractylenolide III indicated that autumn might be a suitable harvest time for Dangshen. The antioxidant capacity in Dangshen might be correlated with vitamin C. Furthermore, we analyzed the expression profiles of a few enzyme genes involved in the polysaccharide biosynthesis pathways at different growth stages, showing that CpUGpase and CPPs exhibited a highly positive correlation. These results might lay a foundation for choosing cultivars using gene expression levels as markers. Full article

(This article belongs to the Special Issue Identification and Therapeutic Properties of Secondary Metabolites of Medicinal Plants)

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34 pages, 1476 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Maternal Diet-Induced Obesity Affecting the Offspring Brain and Development of Affective Disorders

by Daniel E. Radford-Smith and Daniel C. Anthony

Metabolites 2023, 13(3), 455; https://doi.org/10.3390/metabo13030455 - 20 Mar 2023

Cited by 11 | Viewed by 3778

Abstract

Depression and metabolic disease are common disorders that share a bidirectional relationship and continue to increase in prevalence. Maternal diet and maternal behaviour both profoundly influence the developmental trajectory of offspring during the perinatal period. At an epidemiological level, both maternal depression and [...] Read more.

Depression and metabolic disease are common disorders that share a bidirectional relationship and continue to increase in prevalence. Maternal diet and maternal behaviour both profoundly influence the developmental trajectory of offspring during the perinatal period. At an epidemiological level, both maternal depression and obesity during pregnancy have been shown to increase the risk of neuropsychiatric disease in the subsequent generation. Considerable progress has been made to understand the mechanisms by which maternal obesity disrupts the developing offspring gut–brain axis, priming offspring for the development of affective disorders. This review outlines such mechanisms in detail, including altered maternal care, the maternal microbiome, inflammation, breast milk composition, and maternal and placental metabolites. Subsequently, offspring may be prone to developing gut–brain interaction disorders with concomitant changes to brain energy metabolism, neurotransmission, and behaviour, alongside gut dysbiosis. The gut microbiome may act as a key modifiable, and therefore treatable, feature of the relationship between maternal obesity and the offspring brain function. Further studies examining the relationship between maternal nutrition, the maternal microbiome and metabolites, and offspring neurodevelopment are warranted to identify novel therapeutic targets. Full article

(This article belongs to the Special Issue Obesity and Associated Comorbidities: Implications for Neural and Immune Regulation of Energy Metabolism)

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19 pages, 387 KiB

Open AccessReview

Data Science and Plant Metabolomics

by Anna Kisiel, Adrianna Krzemińska, Danuta Cembrowska-Lech and Tymoteusz Miller

Metabolites 2023, 13(3), 454; https://doi.org/10.3390/metabo13030454 - 20 Mar 2023

Cited by 5 | Viewed by 2352

Abstract

The study of plant metabolism is one of the most complex tasks, mainly due to the huge amount and structural diversity of metabolites, as well as the fact that they react to changes in the environment and ultimately influence each other. Metabolic profiling [...] Read more.

The study of plant metabolism is one of the most complex tasks, mainly due to the huge amount and structural diversity of metabolites, as well as the fact that they react to changes in the environment and ultimately influence each other. Metabolic profiling is most often carried out using tools that include mass spectrometry (MS), which is one of the most powerful analytical methods. All this means that even when analyzing a single sample, we can obtain thousands of data. Data science has the potential to revolutionize our understanding of plant metabolism. This review demonstrates that machine learning, network analysis, and statistical modeling are some techniques being used to analyze large quantities of complex data that provide insights into plant development, growth, and how they interact with their environment. These findings could be key to improving crop yields, developing new forms of plant biotechnology, and understanding the relationship between plants and microbes. It is also necessary to consider the constraints that come with data science such as quality and availability of data, model complexity, and the need for deep knowledge of the subject in order to achieve reliable outcomes. Full article

(This article belongs to the Section Plant Metabolism)

16 pages, 5741 KiB

Open AccessArticle

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain

by Haein Lee, Jina Park and Seyun Kim

Metabolites 2023, 13(3), 453; https://doi.org/10.3390/metabo13030453 - 20 Mar 2023

Cited by 1 | Viewed by 2255

Abstract

Acute stress response triggers various physiological responses such as energy mobilization to meet metabolic demands. However, the underlying molecular changes in the brain remain largely obscure. Here, we used a brief water avoidance stress (WAS) to elicit an acute stress response in mice. [...] Read more.

Acute stress response triggers various physiological responses such as energy mobilization to meet metabolic demands. However, the underlying molecular changes in the brain remain largely obscure. Here, we used a brief water avoidance stress (WAS) to elicit an acute stress response in mice. By employing RNA-sequencing and metabolomics profiling, we investigated the acute stress-induced molecular changes in the mouse whole brain. The aberrant expression of 60 genes was detected in the brain tissues of WAS-exposed mice. Functional analyses showed that the aberrantly expressed genes were enriched in various processes such as superoxide metabolism. In our global metabolomic profiling, a total of 43 brain metabolites were significantly altered by acute WAS. Metabolic pathways upregulated from WAS-exposed brain tissues relative to control samples included lipolysis, eicosanoid biosynthesis, and endocannabinoid synthesis. Acute WAS also elevated the levels of branched-chain amino acids, 5-aminovalerates, 4-hydroxy-nonenal-glutathione as well as mannose, suggesting complex metabolic changes in the brain. The observed molecular events in the present study provide a valuable resource that can help us better understand how acute psychological stress impacts neural functions. Full article

(This article belongs to the Section Advances in Metabolomics)

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12 pages, 746 KiB

Open AccessArticle

Oxylipins as Biomarkers for Aromatase Inhibitor-Induced Arthralgia (AIA) in Breast Cancer Patients

by Jessica A. Martinez, Betsy C. Wertheim, Denise J. Roe, Mihra S. Taljanovic, H-H. Sherry Chow, Wade Chew, Sima Ehsani, Sao Jiralerspong, Jennifer Segar and Pavani Chalasani

Metabolites 2023, 13(3), 452; https://doi.org/10.3390/metabo13030452 - 20 Mar 2023

Cited by 1 | Viewed by 1894

Abstract

Aromatase inhibitor-induced arthralgia (AIA) presents a major problem for patients with breast cancer but is poorly understood. This prospective study explored the inflammatory metabolomic changes in the development of AIA. This single-arm, prospective clinical trial enrolled 28 postmenopausal women with early-stage (0–3) ER+ [...] Read more.

Aromatase inhibitor-induced arthralgia (AIA) presents a major problem for patients with breast cancer but is poorly understood. This prospective study explored the inflammatory metabolomic changes in the development of AIA. This single-arm, prospective clinical trial enrolled 28 postmenopausal women with early-stage (0–3) ER+ breast cancer starting adjuvant anastrozole. Patients completed the Breast Cancer Prevention Trial (BCPT) Symptom Checklist and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) at 0, 3, and 6 months. The plasma levels of four polyunsaturated fatty acids (PUFAs) and 48 oxylipins were quantified at each timepoint. The subscores for WOMAC-pain and stiffness as well as BCPT-total, hot flash, and musculoskeletal pain significantly increased from baseline to 6 months (all p < 0.05). PUFA and oxylipin levels were stable over time. The baseline levels of 8-HETE were positively associated with worsening BCPT-total, BCPT-hot flash, BCPT-musculoskeletal pain, WOMAC-pain, and WOMAC- stiffness at 6 months (all p < 0.05). Both 9-HOTrE and 13(S)-HOTrE were related to worsening hot flash, and 5-HETE was related to worsening stiffness (all p < 0.05). This is the first study to prospectively characterize oxylipin and PUFA levels in patients with breast cancer starting adjuvant anastrozole. The oxylipin 8-HETE should be investigated further as a potential biomarker for AIA. Full article

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13 pages, 3129 KiB

Open AccessArticle

2 Hydroxybutyric Acid-Producing Bacteria in Gut Microbiome and Fusobacterium nucleatum Regulates 2 Hydroxybutyric Acid Level In Vivo

by Fujian Qin, Jiankang Li, Tianxiao Mao, Shuo Feng, Jing Li and Maode Lai

Metabolites 2023, 13(3), 451; https://doi.org/10.3390/metabo13030451 - 20 Mar 2023

Cited by 4 | Viewed by 3524

Abstract

2-hydroxybutyric acid (2HB) serves as an important regulatory factor in a variety of diseases. The circulating level of 2HB in serum is significantly higher in multiple diseases, such as cancer and type 2 diabetes (T2D). However, there is currently no systematic study on [...] Read more.

2-hydroxybutyric acid (2HB) serves as an important regulatory factor in a variety of diseases. The circulating level of 2HB in serum is significantly higher in multiple diseases, such as cancer and type 2 diabetes (T2D). However, there is currently no systematic study on 2HB-producing bacteria that demonstrates whether gut bacteria contribute to the circulating 2HB pool. To address this question, we used BLASTP to reveal the taxonomic profiling of 2HB-producing bacteria in the human microbiome, which are mainly distributed in the phylum Proteobacteria and Firmicutes. In vitro experiments showed that most gut bacteria (21/32) have at least one path to produce 2HB, which includes Aspartic acid, methionine, threonine, and 2-aminobutyric acid. Particularly, Fusobacterium nucleatum has the strongest ability to synthesize 2HB, which is sufficient to alter colon 2HB concentration in mice. Nevertheless, neither antibiotic (ABX) nor Fusobacterium nucleatum gavage significantly affected mouse serum 2HB levels during the time course of this study. Taken together, our study presents the profiles of 2HB-producing bacteria and demonstrates that gut microbiota was a major contributor to 2HB concentration in the intestinal lumen but a relatively minor contributor to serum 2HB concentration. Full article

(This article belongs to the Special Issue The Role of Gut Microbes in Metabolism Regulation)

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18 pages, 2062 KiB

Open AccessArticle

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease

by Marcin Sochal, Marta Ditmer, Agata Binienda, Agata Gabryelska, Piotr Białasiewicz, Renata Talar-Wojnarowska, Jakub Fichna and Ewa Małecka-Wojciesko

Metabolites 2023, 13(3), 450; https://doi.org/10.3390/metabo13030450 - 19 Mar 2023

Cited by 3 | Viewed by 1867

Abstract

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD [...] Read more.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain–gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn’s disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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17 pages, 5913 KiB

Open AccessArticle

In Silico Prediction of Metabolic Reaction Catalyzed by Human Aldehyde Oxidase

by Mengting Huang, Keyun Zhu, Yimeng Wang, Chaofeng Lou, Huimin Sun, Weihua Li, Yun Tang and Guixia Liu

Metabolites 2023, 13(3), 449; https://doi.org/10.3390/metabo13030449 - 19 Mar 2023

Viewed by 2040

Abstract

Aldehyde oxidase (AOX) plays an important role in drug metabolism. Human AOX (hAOX) is widely distributed in the body, and there are some differences between species. Currently, animal models cannot accurately predict the metabolism of hAOX. Therefore, more and more in silico models [...] Read more.

Aldehyde oxidase (AOX) plays an important role in drug metabolism. Human AOX (hAOX) is widely distributed in the body, and there are some differences between species. Currently, animal models cannot accurately predict the metabolism of hAOX. Therefore, more and more in silico models have been constructed for the prediction of the hAOX metabolism. These models are based on molecular docking and quantum chemistry theory, which are time-consuming and difficult to automate. Therefore, in this study, we compared traditional machine learning methods, graph convolutional neural network methods, and sequence-based methods with limited data, and proposed a ligand-based model for the metabolism prediction catalyzed by hAOX. Compared with the published models, our model achieved better performance (ACC = 0.91, F1 = 0.77). What’s more, we built a web server to predict the sites of metabolism (SOMs) for hAOX. In summary, this study provides a convenient and automatable model and builds a web server named Meta-hAOX for accelerating the drug design and optimization stage. Full article

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22 pages, 821 KiB

Open AccessReview

Participation of Krüppel-like Factors in Atherogenesis

by Stanislav Kotlyarov and Anna Kotlyarova

Metabolites 2023, 13(3), 448; https://doi.org/10.3390/metabo13030448 - 19 Mar 2023

Cited by 7 | Viewed by 2161

Abstract

Atherosclerosis is an important problem in modern medicine, the keys to understanding many aspects of which are still not available to clinicians. Atherosclerosis develops as a result of a complex chain of events in which many cells of the vascular wall and peripheral [...] Read more.

Atherosclerosis is an important problem in modern medicine, the keys to understanding many aspects of which are still not available to clinicians. Atherosclerosis develops as a result of a complex chain of events in which many cells of the vascular wall and peripheral blood flow are involved. Endothelial cells, which line the vascular wall in a monolayer, play an important role in vascular biology. A growing body of evidence strengthens the understanding of the multifaceted functions of endothelial cells, which not only organize the barrier between blood flow and tissues but also act as regulators of hemodynamics and play an important role in regulating the function of other cells in the vascular wall. Krüppel-like factors (KLFs) perform several biological functions in various cells of the vascular wall. The large family of KLFs in humans includes 18 members, among which KLF2 and KLF4 are at the crossroads between endothelial cell mechanobiology and immunometabolism, which play important roles in both the normal vascular wall and atherosclerosis. Full article

(This article belongs to the Special Issue Manipulation of Metabolic Pathways by Transcription Factors)

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14 pages, 279 KiB

Open AccessEditor’s ChoiceReview

Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives

by Marcello Cossu, Roberta Pintus, Marco Zaffanello, Michele Mussap, Fabiola Serra, Maria Antonietta Marcialis and Vassilios Fanos

Metabolites 2023, 13(3), 447; https://doi.org/10.3390/metabo13030447 - 18 Mar 2023

Cited by 6 | Viewed by 2850

Abstract

The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are [...] Read more.

The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are not covered in newborn screening and the diagnostic profiling in the metabolic laboratory is indispensable to reach a correct diagnosis. In recent years, Metabolomics helped to obtain a better understanding of pathogenesis and pathophysiology of IEMs, by validating diagnostic biomarkers, discovering new specific metabolic patterns and new IEMs itself. The expansion of Metabolomics in clinical biochemistry and laboratory medicine has brought these approaches in clinical practice as part of newborn screenings, as an exam for differential diagnosis between IEMs, and evaluation of metabolites in follow up as markers of severity or therapies efficacy. Lastly, several research groups are trying to profile metabolomics data in platforms to have a holistic vision of the metabolic, proteomic and genomic pathways of every single patient. In 2018 this team has made a review of literature to understand the value of Metabolomics in IEMs. Our review offers an update on use and perspectives of metabolomics in IEMs, with an overview of the studies available from 2018 to 2022. Full article

(This article belongs to the Special Issue Metabolic Profiles and Biomarkers in Pregnancy)

15 pages, 4471 KiB

Open AccessArticle

Probing Serum Albumins and Cyclodextrins as Binders of the Mycotoxin Metabolites Alternariol-3-Glucoside, Alternariol-9-Monomethylether-3-Glucoside, and Zearalenone-14-Glucuronide

by Miklós Poór, Beáta Lemli, Péter Vilmányi, Ágnes Dombi, Zoltán Nagymihály, Eszter Borbála Both, Nándor Lambert, Tamás Czömpöly and Lajos Szente

Metabolites 2023, 13(3), 446; https://doi.org/10.3390/metabo13030446 - 18 Mar 2023

Cited by 2 | Viewed by 1603

Abstract

Mycotoxins are toxic metabolites of molds. Chronic exposure to alternariol, zearalenone, and their metabolites may cause the development of endocrine-disrupting and carcinogenic effects. Alternariol-3-glucoside (AG) and alternariol-9-monomethylether-3-glucoside (AMG) are masked derivatives of alternariol. Furthermore, in mammals, zearalenone-14-glucuronide (Z14Glr) is one of the most [...] Read more.

Mycotoxins are toxic metabolites of molds. Chronic exposure to alternariol, zearalenone, and their metabolites may cause the development of endocrine-disrupting and carcinogenic effects. Alternariol-3-glucoside (AG) and alternariol-9-monomethylether-3-glucoside (AMG) are masked derivatives of alternariol. Furthermore, in mammals, zearalenone-14-glucuronide (Z14Glr) is one of the most dominant metabolites of zearalenone. In this study, we examined serum albumins and cyclodextrins (CDs) as potential binders of AG, AMG, and Z14Glr. The most important results/conclusions were as follows: AG and AMG formed moderately strong complexes with human, bovine, porcine, and rat albumins. Rat albumin bound Z14Glr approximately 4.5-fold stronger than human albumin. AG–albumin and Z14Glr–albumin interactions were barely influenced by the environmental pH, while the formation of AMG–albumin complexes was strongly favored by alkaline conditions. Among the mycotoxin–CD complexes examined, AMG–sugammadex interaction proved to be the most stable. CD bead polymers decreased the mycotoxin content of aqueous solutions, with moderate removal of AG and AMG, while weak extraction of Z14Glr was observed. In conclusion, rat albumin is a relatively strong binder of Z14Glr, and albumin can form highly stable complexes with AMG at pH 8.5. Therefore, albumins can be considered as affinity proteins with regard to the latter mycotoxin metabolites. Full article

(This article belongs to the Special Issue Bioactive Metabolites from Natural Sources)

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13 pages, 3959 KiB

Open AccessArticle

NMR-Based Metabolomics Demonstrates a Metabolic Change during Early Developmental Stages from Healthy Infants to Young Children

by Liana Bastos Freitas-Fernandes, Gabriela Pereira Fontes, Aline dos Santos Letieri, Ana Paula Valente, Ivete Pomarico Ribeiro de Souza and Tatiana Kelly da Silva Fidalgo

Metabolites 2023, 13(3), 445; https://doi.org/10.3390/metabo13030445 - 18 Mar 2023

Cited by 2 | Viewed by 1546

Abstract

The present study aims to identify the salivary metabolic profile of healthy infants and young children, and to correlate this with age, salivary gland maturation, and dentition. Forty-eight children were selected after clinical evaluation in which all intraoral structures were examined. Total unstimulated [...] Read more.

The present study aims to identify the salivary metabolic profile of healthy infants and young children, and to correlate this with age, salivary gland maturation, and dentition. Forty-eight children were selected after clinical evaluation in which all intraoral structures were examined. Total unstimulated saliva was collected, and salivary metabolites were analyzed by 1H Nuclear Magnetic Resonance (NMR) at 25 °C. Partial least squares discriminant analysis (PLS-DA), orthogonal PLS-DA (O-PLS-DA), and univariate analysis were used, adopting a 95% confidence interval. The study showed a distinct salivary metabolomic profile related to age and developmental phase. The saliva of children in the pre-eruption teeth period showed a different metabolite profile than that of children after the eruption. However, more evident changes were observed in the saliva profile of children older than 30 months. Alanine, choline, ethanol, lactate, and sugar region were found in higher levels in the saliva of patients before 30 months old. Acetate, N-acetyl sugar, butyrate, caproate, creatinine, leucine, phenylalanine, propionate, valine, succinate, and valerate were found to be more abundant in the saliva of children after 30 months old. The saliva profile is a result of changes in age and dental eruption, and these findings can be useful for monitoring the physiological changes that occur in infancy. Full article

(This article belongs to the Special Issue Salivary Fingerprint in Metabolomics Era: Potential and Challenges)

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13 pages, 653 KiB

Open AccessArticle

Baseline Tyrosine Level Is Associated with Dynamic Changes in FAST Score in NAFLD Patients under Lifestyle Modification

by Hwi Young Kim, Da Jung Kim, Hye Ah Lee, Joo-Youn Cho and Won Kim

Metabolites 2023, 13(3), 444; https://doi.org/10.3390/metabo13030444 - 17 Mar 2023

Cited by 1 | Viewed by 1996

Abstract

Noninvasive risk stratification is a challenging issue in the management of patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to identify multiomics-based predictors of NAFLD progression, as assessed by changes in serial FibroScan-aspartate aminotransferase (FAST) scores during lifestyle modification. A total [...] Read more.

Noninvasive risk stratification is a challenging issue in the management of patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to identify multiomics-based predictors of NAFLD progression, as assessed by changes in serial FibroScan-aspartate aminotransferase (FAST) scores during lifestyle modification. A total of 266 patients with available metabolomics and genotyping data were included. The follow-up sub-cohort included patients with paired laboratory and transient elastography results (n = 160). The baseline median FAST score was 0.37. The PNPLA3 rs738409 genotype was significantly associated with a FAST score > 0.35. Circulating metabolomics significantly associated with a FAST score > 0.35 included SM C24:0 (odds ratio [OR] = 0.642; 95% confidence interval [CI], 0.463–0.891), PC ae C40:6 (OR = 0.477; 95% CI, 0.340–0.669), lysoPC a C18:2 (OR = 0.570; 95% CI, 0.417–0.779), and tyrosine (OR = 2.743; 95% CI, 1.875–4.014). A combination of these metabolites and PNPLA3 genotype yielded a c-index = 0.948 for predicting a FAST score > 0.35. In the follow-up sub-cohort (median follow-up = 23.7 months), 47/76 patients (61.8%) with a baseline FAST score > 0.35 had a follow-up FAST score ≤ 0.35. An improved FAST score at follow-up was significantly associated with age, serum alanine aminotransferase, and tyrosine. In conclusion, baseline risk stratification in NAFLD patients may be assisted using a multiomics-based model. Particularly, patients with increased tyrosine may benefit from an earlier switch to pharmacologic approaches. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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16 pages, 3317 KiB

Open AccessArticle

Phytochemicals Identification and Bioactive Compounds Estimation of Artemisia Species Grown in Saudia Arabia

by Abdalrhaman M. Salih, Ahmed A. Qahtan and Fahad Al-Qurainy

Metabolites 2023, 13(3), 443; https://doi.org/10.3390/metabo13030443 - 17 Mar 2023

Cited by 7 | Viewed by 2493

Abstract

Artemisia species are very important medicinal plants, particularly in the Middle East and in developing countries. Their products have been used in traditional and medicine contemporary for the treating of infectious ulcers, gangrenous ulcers, inflammations, and malaria. Artemisinin derived from Artemisia species has [...] Read more.

Artemisia species are very important medicinal plants, particularly in the Middle East and in developing countries. Their products have been used in traditional and medicine contemporary for the treating of infectious ulcers, gangrenous ulcers, inflammations, and malaria. Artemisinin derived from Artemisia species has been used as a drug in many countries for malaria disease treatment. Hence, this study aimed to identify and evaluate the bioactive compounds of three species of Artemisia (Artemisia judaica, Artemisia monosperma, and Artemisia sieberi) growing in Saudi Arabia. Therefore, several analytical techniques, such as gas chromatography–mass spectrometry (GC-MS), UV-Visible spectrophotometry (UV-Vis), and high-performance liquid chromatography (HPLC), with reference standards, were used. The GC-MS analysis of the artemisia species revealed many bioactive constituents associated with plant secondary metabolites; some of these identified phytochemical components have biological activity. A. Judaica showed the highest number of bioactive compounds, followed by A. sieberi and A. monosperma. Further, the total phenol, total flavonoid, total tannin, terpenoids, and TCA were estimated. Furthermore, biomolecules such gallic acid, tannin acid, quercetin, and artemisinin in different artemisia species were quantified using HPLC with the reference standard. The amount of artemisinin in the leaf extract of these species (A. sieberi, A. Judaica, and A. monosperma) was found to be about 3.01, 2.5, and 1.9 mg/g DW, respectively. Moreover, the antioxidant activity of the samples was estimated. The obtained results have shown that these species possessed high antioxidant activity, and the scavenging of the DPPH radical and hydrogen peroxide were found to be raised with the increase in the plant extract concentration. This reflects the number of bioactive compounds in these species. The findings of this research support and justify the utilization of Artemisia species in folk medicine in the Middle East. Full article

(This article belongs to the Special Issue Extraction, Characterization, Chemical Composition and Biological Activity of Natural Metabolites)

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19 pages, 4533 KiB

Open AccessReview

Biosynthesis of Phytocannabinoids and Structural Insights: A Review

by Rasiravathanahalli Kaveriyappan Govindarajan, Awdhesh Kumar Mishra, Kiu-Hyung Cho, Ki-Hyun Kim, Kyoung Mi Yoon and Kwang-Hyun Baek

Metabolites 2023, 13(3), 442; https://doi.org/10.3390/metabo13030442 - 17 Mar 2023

Cited by 7 | Viewed by 3300

Abstract

Cannabis belongs to the family Cannabaceae, and phytocannabinoids are produced by the Cannabis sativa L. plant. A long-standing debate regarding the plant is whether it contains one or more species. Phytocannabinoids are bioactive natural products found in flowers, seeds, and fruits. They can [...] Read more.

Cannabis belongs to the family Cannabaceae, and phytocannabinoids are produced by the Cannabis sativa L. plant. A long-standing debate regarding the plant is whether it contains one or more species. Phytocannabinoids are bioactive natural products found in flowers, seeds, and fruits. They can be beneficial for treating human diseases (such as multiple sclerosis, neurodegenerative diseases, epilepsy, and pain), the cellular metabolic process, and regulating biological function systems. In addition, several phytocannabinoids are used in various therapeutic and pharmaceutical applications. This study provides an overview of the different sources of phytocannabinoids; further, the biosynthesis of bioactive compounds involving various pathways is elucidated. The structural classification of phytocannabinoids is based on their decorated resorcinol core and the bioactivities of naturally occurring cannabinoids. Furthermore, phytocannabinoids have been studied in terms of their role in animal models and antimicrobial activity against bacteria and fungi; further, they show potential for therapeutic applications and are used in treating various human diseases. Overall, this review can help deepen the current understanding of the role of biotechnological approaches and the importance of phytocannabinoids in different industrial applications. Full article

(This article belongs to the Section Plant Metabolism)

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13 pages, 1383 KiB

Open AccessArticle

A Pilot Study on Biochemical Profile of Follicular Fluid in Breast Cancer Patients

by Maria A. Castiglione Morelli, Assunta Iuliano, Ilenia Matera, Licia Viggiani, Sergio C. A. Schettini, Paola Colucci and Angela Ostuni

Metabolites 2023, 13(3), 441; https://doi.org/10.3390/metabo13030441 - 17 Mar 2023

Cited by 2 | Viewed by 1694

Abstract

Breast cancer (BC) is the most common type of cancer among women in almost all countries worldwide and is one of the oncological pathologies for which is indicated fertility preservation, a type of procedure used to help keep a person’s ability to have [...] Read more.

Breast cancer (BC) is the most common type of cancer among women in almost all countries worldwide and is one of the oncological pathologies for which is indicated fertility preservation, a type of procedure used to help keep a person’s ability to have children. Follicular fluid (FF) is a major component of oocyte microenvironment, which is involved in oocyte growth, follicular maturation, and in communication between germ and somatic cells; furthermore, it accumulates all metabolites during oocytes growth. To obtain information about changes on fertility due to cancer, we aimed at investigating potential biomarkers to discriminate between FF samples obtained from 16 BC patients and 10 healthy women undergoing in vitro fertilization treatments. An NMR-based metabolomics approach was performed to investigate the FF metabolic profiles; ELISA and western blotting assays were used to investigate protein markers of oxidative and inflammatory stress, which are processes closely related to cancer. Our results seem to suggest that FFs of BC women display some significant metabolic alterations in comparison to healthy controls, and these variations are also related with tumor staging. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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18 pages, 1756 KiB

Open AccessEditor’s ChoiceReview

Detecting and Profiling of Milk Thistle Metabolites in Food Supplements: A Safety-Oriented Approach by Advanced Analytics

by Ancuța Cristina Raclariu-Manolică and Carmen Socaciu

Metabolites 2023, 13(3), 440; https://doi.org/10.3390/metabo13030440 - 17 Mar 2023

Cited by 5 | Viewed by 2865

Abstract

Milk thistle (Silybum marianum (L.) Gaertn.) is among the top-selling botanicals used as a supportive treatment for liver diseases. Silymarin, a mixture of unique flavonolignan metabolites, is the main bioactive component of milk thistle. The biological activities of silymarin have been well [...] Read more.

Milk thistle (Silybum marianum (L.) Gaertn.) is among the top-selling botanicals used as a supportive treatment for liver diseases. Silymarin, a mixture of unique flavonolignan metabolites, is the main bioactive component of milk thistle. The biological activities of silymarin have been well described in the literature, and its use is considered safe and well-tolerated in appropriate doses. However, commercial preparations do not always contain the recommended concentrations of silymarin, failing to provide the expected therapeutic effect. While the poor quality of raw material may explain the low concentrations of silymarin, its deliberate removal is suspected to be an adulteration. Toxic contaminants and foreign matters were also detected in milk thistle preparations, raising serious health concerns. Standard methods for determination of silymarin components include thin-layer chromatography (TLC), high-performance thin-layer chromatography (HPTLC), and high-performance liquid chromatography (HPLC) with various detectors, but nuclear magnetic resonance (NMR) and ultra-high-performance liquid chromatography (UHPLC) have also been applied. This review surveys the extraction techniques of main milk thistle metabolites and the quality, efficacy, and safety of the derived food supplements. Advanced analytical authentication approaches are discussed with a focus on DNA barcoding and metabarcoding to complement orthogonal chemical characterization and fingerprinting of herbal products. Full article

(This article belongs to the Special Issue Plant, Food and Nutritional Metabolomics)

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19 pages, 1704 KiB

Open AccessReview

Biological Characteristics and Energy Metabolism of Migrating Insects

by Xiaokang Li, Yan Zhou and Kongming Wu

Metabolites 2023, 13(3), 439; https://doi.org/10.3390/metabo13030439 - 17 Mar 2023

Cited by 4 | Viewed by 2711

Abstract

Through long-distance migration, insects not only find suitable breeding locations and increase the survival space and opportunities for the population but also facilitate large-scale material, energy, and information flow between regions, which is important in maintaining the stability of agricultural ecosystems and wider [...] Read more.

Through long-distance migration, insects not only find suitable breeding locations and increase the survival space and opportunities for the population but also facilitate large-scale material, energy, and information flow between regions, which is important in maintaining the stability of agricultural ecosystems and wider natural ecosystems. In this study, we summarize the changes in biological characteristics such as morphology, ovarian development, reproduction, and flight capability during the seasonal migration of the insect. In consideration of global research work, the interaction between flight and reproduction, the influence and regulation of the insulin-like and juvenile hormone on the flight and reproductive activities of migrating insects, and the types of energy substances, metabolic processes, and hormone regulation processes during insect flight are elaborated. This systematic review of the latest advances in the studies on insect migration biology and energy metabolism will help readers to better understand the biological behavior and regulation mechanism of the energy metabolism of insect migration. Full article

(This article belongs to the Special Issue Endocrine and Metabolic Regulation in Insects)

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34 pages, 1279 KiB

Open AccessReview

The Role of Dietary Antioxidants and Their Potential Mechanisms in Alzheimer’s Disease Treatment

by Emily Knight, Thangiah Geetha, Tom L. Broderick and Jeganathan Ramesh Babu

Metabolites 2023, 13(3), 438; https://doi.org/10.3390/metabo13030438 - 17 Mar 2023

Cited by 5 | Viewed by 2689

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and characterized by amyloid-β plaques and neurofibrillary tau tangles. Although AD’s exact pathophysiology remains unclear, oxidative stress is known to play a role in the neurodegenerative process. Since no curative treatment [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and characterized by amyloid-β plaques and neurofibrillary tau tangles. Although AD’s exact pathophysiology remains unclear, oxidative stress is known to play a role in the neurodegenerative process. Since no curative treatment exists, antioxidants represent a potential treatment for AD due to their ability to modulate oxidative stress. Therefore, this review aims to examine the impact of antioxidant supplementation and its potential mechanisms on cognitive function. The review primarily discusses research articles published between 2012 and 2022 reporting the results of clinical trials involving antioxidant supplementation on cognitive function in individuals with AD. Antioxidant supplementation included probiotics, selenium, melatonin, resveratrol, rosmarinic acid, carotenoids, curcumin, vitamin E, and coenzyme Q. While the studies included in this review did not provide much evidence for the beneficial role of antioxidant supplements on cognitive function in AD, the results varied from antioxidant to antioxidant and among trials examining the same antioxidant. Furthermore, many of the studies’ findings face several limitations, including short trial durations, small sample sizes, and a lack of diversity among study participants. As a result, more research is required to examine the impact of antioxidant supplementation on cognitive function in AD. Full article

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24 pages, 4077 KiB

Open AccessArticle

Overexpression of Bacterial Beta-Ketothiolase Improves Flax (Linum usitatissimum L.) Retting and Changes the Fibre Properties

by Justyna Mierziak, Wioleta Wojtasik, Anna Kulma, Magdalena Żuk, Magdalena Grajzer, Aleksandra Boba, Lucyna Dymińska, Jerzy Hanuza, Jakub Szperlik and Jan Szopa

Metabolites 2023, 13(3), 437; https://doi.org/10.3390/metabo13030437 - 17 Mar 2023

Viewed by 1524

Abstract

Beta-ketothiolases are involved in the beta-oxidation of fatty acids and the metabolism of hormones, benzenoids, and hydroxybutyrate. The expression of bacterial beta-ketothiolase in flax (Linum usitatissimum L.) results in an increase in endogenous beta-ketothiolase mRNA levels and beta-hydroxybutyrate content. In the present [...] Read more.

Beta-ketothiolases are involved in the beta-oxidation of fatty acids and the metabolism of hormones, benzenoids, and hydroxybutyrate. The expression of bacterial beta-ketothiolase in flax (Linum usitatissimum L.) results in an increase in endogenous beta-ketothiolase mRNA levels and beta-hydroxybutyrate content. In the present work, the effect of overexpression of beta-ketothiolase on retting and stem and fibre composition of flax plants is presented. The content of the components was evaluated by high-performance liquid chromatography, gas chromatography–mass spectrometry, Fourier-transform infrared spectroscopy, and biochemical methods. Changes in the stem cell walls, especially in the lower lignin and pectin content, resulted in more efficient retting. The overexpression of beta-ketothiolase reduced the fatty acid and carotenoid contents in flax and affected the distribution of phenolic compounds between free and cell wall-bound components. The obtained fibres were characterized by a slightly lower content of phenolic compounds and changes in the composition of the cell wall. Based on the IR analysis, we concluded that the production of hydroxybutyrate reduced the cellulose crystallinity and led to the formation of shorter but more flexible cellulose chains, while not changing the content of the cell wall components. We speculate that the changes in chemical composition of the stems and fibres are the result of the regulatory properties of hydroxybutyrate. This provides us with a novel way to influence metabolic composition in agriculturally important crops. Full article

(This article belongs to the Section Plant Metabolism)

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15 pages, 1510 KiB

Open AccessArticle

Oral Administration of Chaetoceros gracilis—A Marine Microalga—Alleviates Hepatic Lipid Accumulation in Rats Fed a High-Sucrose and Cholesterol-Containing Diet

by Bungo Shirouchi, Yuri Kawahara, Yuka Kutsuna, Mina Higuchi, Mai Okumura, Sarasa Mitsuta, Norio Nagao and Kazunari Tanaka

Metabolites 2023, 13(3), 436; https://doi.org/10.3390/metabo13030436 - 16 Mar 2023

Cited by 2 | Viewed by 2046

Abstract

Microalgae are attracting attention as a next-generation alternative source of protein and essential fatty acids that do not consume large amounts of water or land. Chaetoceros gracilis (C. gracilis)—a marine microalga—is rich in proteins, fucoxanthin, and eicosapentaenoic acid (EPA). Growing [...] Read more.

Microalgae are attracting attention as a next-generation alternative source of protein and essential fatty acids that do not consume large amounts of water or land. Chaetoceros gracilis (C. gracilis)—a marine microalga—is rich in proteins, fucoxanthin, and eicosapentaenoic acid (EPA). Growing evidence indicates that dietary fucoxanthin and EPA have beneficial effects in humans. However, none of these studies have shown that dietary C. gracilis has beneficial effects in mammals. In this study, we investigated the effects of dietary C. gracilis on lipid abnormalities in Sprague-Dawley rats fed a high-sucrose cholesterol-containing diet. Dried C. gracilis was added to the control diet at a final dose of 2 or 5% (w/w). After four weeks, the soleus muscle weights were found to be dose-responsive to C. gracilis and showed a tendency to increase. The hepatic triglyceride and total cholesterol levels were significantly reduced by C. gracilis feeding compared to those in the control group. The activities of FAS and G6PDH, which are related to fatty acid de novo synthesis, were found to be dose-responsive to C. gracilis and tended to decrease. The hepatic glycerol content was also significantly decreased by C. gracilis feeding, and the serum HDL cholesterol levels were significantly increased, whereas the serum levels of cholesterol absorption markers (i.e., campesterol and β-sitosterol) and the hepatic mRNA levels of Scarb1 were significantly decreased. Water-soluble metabolite analysis showed that the muscular contents of several amino acids, including leucine, were significantly increased by C. gracilis feeding. The tendency toward an increase in the weight of the soleus muscle as a result of C. gracilis feeding may be due to the enhancement of muscle protein synthesis centered on leucine. Collectively, these results show that the oral administration of C. gracilis alleviates hepatic lipid accumulation in rats fed a high-sucrose and cholesterol-containing diet, indicating the potential use of C. gracilis as a food resource. Full article

(This article belongs to the Special Issue Metabolic Syndrome: Causes and Effects)

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17 pages, 5390 KiB

Open AccessArticle

Neogrisphenol A, a Potential Ovarian Cancer Inhibitor from a New Record Fungus Neohelicosporium griseum

by Li-Juan Zhang, Ming-Fei Yang, Jian Ma, Xing-Juan Xiao, Xiao-Yan Ma, De-Ge Zheng, Mei-Yan Han, Ming-Lei Xia, Ruvishika S. Jayawardena, Ausana Mapook, Yuan-Pin Xiao, Ji-Chuan Kang and Yong-Zhong Lu

Metabolites 2023, 13(3), 435; https://doi.org/10.3390/metabo13030435 - 16 Mar 2023

Cited by 7 | Viewed by 2175

Abstract

From the rice fermentation product of a new record fungus, Neohelicosporium griseum, two new polyketides, neogrisphenol A (1) and neogrisphenol B (2), one new isochroman-1-one, (S)-6-hydroxy-7-methoxy-3,5-dimethylisochroman-1-one (3), and four known compounds (4– [...] Read more.

From the rice fermentation product of a new record fungus, Neohelicosporium griseum, two new polyketides, neogrisphenol A (1) and neogrisphenol B (2), one new isochroman-1-one, (S)-6-hydroxy-7-methoxy-3,5-dimethylisochroman-1-one (3), and four known compounds (4–7) were isolated. Their structures were determined using 1D- and 2D-NMR, mass spectrometry, and chemical calculations. The C-3~C-2′ polymerization mode between the two α-naphthalenone derivative moieties is uncommon in compounds 1 and 2. Meanwhile, compounds 1–2 and 5 exhibited antibacterial activity against Bacillus subtilis, Clostridium perfringens, Staphylococcus aureus, and Staphylococcus aureus, with MIC values ranging between 16 and 31 µg/mL. In addition, compound 5 showed antifungal activity against Sclerotinia sclerotiorum and Phytophthora nicotianae var. nicotianae, with respective IC₅₀ values of 88.14 ± 2.21 µg/mL and 52.36 ± 1.38 µg/mL. Compound 1 showed significant cytotoxicity against A2780, PC-3, and MBA-MD-231 cell lines with respective IC₅₀ values of 3.20, 10.68, and 16.30 µM, and the cytotoxicity against A2780 cells was even higher than that of cisplatin (CDDP). With an IC₅₀ value of 10.13 µM, compound 2 also exhibited cytotoxicity against A2780. The in vitro results showed that compound 1 inhibited A2780 cell proliferation, induced apoptosis, and arrested the cell cycle at the S-phase in a concentration-dependent manner. Full article

(This article belongs to the Section Microbiology and Ecological Metabolomics)

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12 pages, 2111 KiB

Open AccessBrief Report

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

by Naseer A. Kutchy, Amelia Palermo, Rong Ma, Zhong Li, Alexandria Ulanov, Shannon Callen, Gary Siuzdak, Sabita Roy, Shilpa Buch and Guoku Hu

Metabolites 2023, 13(3), 434; https://doi.org/10.3390/metabo13030434 - 16 Mar 2023

Cited by 2 | Viewed by 2225

Abstract

Morphine administration causes system-level metabolic changes. Here, we show that morphine-tolerant mice exhibited distinct plasma metabolic signatures upon acute and chronic administration. We utilized a mouse model of morphine tolerance by exposing mice to increasing doses of the drug over 4 days. We [...] Read more.

Morphine administration causes system-level metabolic changes. Here, we show that morphine-tolerant mice exhibited distinct plasma metabolic signatures upon acute and chronic administration. We utilized a mouse model of morphine tolerance by exposing mice to increasing doses of the drug over 4 days. We collected plasma samples from mice undergoing acute or chronic morphine or saline injections and analyzed them using targeted GC–MS-based metabolomics to profile approximately 80 metabolites involved in the central carbon, amino acid, nucleotide, and lipid metabolism. Our findings reveal distinct alterations in plasma metabolite concentrations in response to acute or chronic morphine intake, and these changes were linked to the development of tolerance to morphine’s analgesic effects. We identified several metabolites that had been differentially affected by acute versus chronic morphine use, suggesting that metabolic changes may be mitigated by prolonged exposure to the drug. Morphine-tolerant mice showed a restoration of amino acid and glycolytic metabolites. Additionally, we conducted reconstructed metabolic network analysis on the first 30 VIP-ranked metabolites from the PLSDA of the saline, acute, and morphine-tolerant mice groups, which uncovered four interaction networks involving the amino acid metabolism, the TCA cycle, the glutamine-phenylalanine-tyrosine pathway, and glycolysis. These pathways were responsible for the metabolic differences observed following distinct morphine administration regimens. Overall, this study provides a valuable resource for future investigations into the role of metabolites in morphine-induced analgesia and associated effects following acute or chronic use in mice. Full article

(This article belongs to the Special Issue Biofluid-Based Metabolomics for Biomarker Discovery)

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25 pages, 2717 KiB

Open AccessArticle

A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations

by Stephanann M. Costello, Alexandra M. Cheney, Annie Waldum, Brian Tripet, Maria Cotrina-Vidal, Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Frances Lefcort and Valérie Copié

Metabolites 2023, 13(3), 433; https://doi.org/10.3390/metabo13030433 - 16 Mar 2023

Cited by 4 | Viewed by 2751

Abstract

Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental [...] Read more.

Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut–brain axis of FD. Here, ¹H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut–brain–metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients. Full article

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14 pages, 1400 KiB

Open AccessArticle

Characterization of 3-Hydroxyeticyclidine (3-HO-PCE) Metabolism in Human Liver Microsomes and Biological Samples Using High-Resolution Mass Spectrometry

by Islam Amine Larabi, Delphine Joseph, Camille Lesueur and Jean-Claude Alvarez

Metabolites 2023, 13(3), 432; https://doi.org/10.3390/metabo13030432 - 16 Mar 2023

Cited by 6 | Viewed by 2004

Abstract

3-Hydroxyeticyclidine (3-HO-PCE) is a ketamine derivative that produces dissociative, hallucinogenic, and euphoric effects when consumed, but little is known about its pharmacological properties, metabolism, and toxicity compared to other designer ketamine analogs. To address this gap in knowledge, this study explored for the [...] Read more.

3-Hydroxyeticyclidine (3-HO-PCE) is a ketamine derivative that produces dissociative, hallucinogenic, and euphoric effects when consumed, but little is known about its pharmacological properties, metabolism, and toxicity compared to other designer ketamine analogs. To address this gap in knowledge, this study explored for the first time the metabolism of 3-HO-PCE. Based on this investigation, it is hypothesized that combining the use of Human Liver Microsomes (HLM) as an In vitro model with urine and hair samples from drug users may enable the identification of key analytes that can extend the detection window of 3-HO-PCE, particularly in cases of overdose. The analysis identified 15 putative metabolites, 12 of which are produced through phase I metabolism involving N-dealkylation, deamination, and oxidation, and 3 through phase II O-glucuronidation. The metabolism of 3-HO-PCE is similar to that of O-PCE, another designer ketamine of the eticyclidine family. The study identified M2a and hydroxy-PCA as reliable biomarkers for untargeted screening of the eticyclidine family in urine and hair, respectively. For targeted screening of 3-HO-PCE, M10 is recommended as the target analyte in urine, and M5 shows promise for long-term monitoring of 3-HO-PCE using hair analysis. Full article

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