Metabolites

Open AccessArticle

Metabolically Active Zones Involving Fatty Acid Elongation Delineated by DESI-MSI Correlate with Pathological and Prognostic Features of Colorectal Cancer

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Antonio Caycedo-Marulanda

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Christopher J. B. Nicol

Metabolites 2023, 13(4), 508; https://doi.org/10.3390/metabo13040508 - 31 Mar 2023

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer deaths. Despite recent advances, five-year survival rates remain largely unchanged. Desorption electrospray ionization mass spectrometry imaging (DESI) is an emerging nondestructive metabolomics-based method that retains the spatial orientation of small-molecule profiles on tissue [...] Read more.

Colorectal cancer (CRC) is the second leading cause of cancer deaths. Despite recent advances, five-year survival rates remain largely unchanged. Desorption electrospray ionization mass spectrometry imaging (DESI) is an emerging nondestructive metabolomics-based method that retains the spatial orientation of small-molecule profiles on tissue sections, which may be validated by ‘gold standard’ histopathology. In this study, CRC samples were analyzed by DESI from 10 patients undergoing surgery at Kingston Health Sciences Center. The spatial correlation of the mass spectral profiles was compared with histopathological annotations and prognostic biomarkers. Fresh frozen sections of representative colorectal cross sections and simulated endoscopic biopsy samples containing tumour and non-neoplastic mucosa for each patient were generated and analyzed by DESI in a blinded fashion. Sections were then hematoxylin and eosin (H and E) stained, annotated by two independent pathologists, and analyzed. Using PCA/LDA-based models, DESI profiles of the cross sections and biopsies achieved 97% and 75% accuracies in identifying the presence of adenocarcinoma, using leave-one-patient-out cross validation. Among the m/z ratios exhibiting the greatest differential abundance in adenocarcinoma were a series of eight long-chain or very-long-chain fatty acids, consistent with molecular and targeted metabolomics indicators of de novo lipogenesis in CRC tissue. Sample stratification based on the presence of lympovascular invasion (LVI), a poor CRC prognostic indicator, revealed the abundance of oxidized phospholipids, suggestive of pro-apoptotic mechanisms, was increased in LVI-negative compared to LVI-positive patients. This study provides evidence of the potential clinical utility of spatially-resolved DESI profiles to enhance the information available to clinicians for CRC diagnosis and prognosis. Full article

(This article belongs to the Special Issue Advances in Ambient Ionization Techniques for Mass Spectrometry Volume 2)

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Open AccessArticle

H3 Lysine 4 Methylation Is Required for Full Activation of Genes Involved in α-Ketoglutarate Availability in the Nucleus of Yeast Cells after Diauxic Shift

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Metabolites 2023, 13(4), 507; https://doi.org/10.3390/metabo13040507 - 31 Mar 2023

Abstract

We show that in S. cerevisiae the metabolic diauxic shift is associated with a H3 lysine 4 tri-methylation (H3K4me3) increase which involves a significant fraction of transcriptionally induced genes which are required for the metabolic changes, suggesting a role for histone methylation in [...] Read more.

We show that in S. cerevisiae the metabolic diauxic shift is associated with a H3 lysine 4 tri-methylation (H3K4me3) increase which involves a significant fraction of transcriptionally induced genes which are required for the metabolic changes, suggesting a role for histone methylation in their transcriptional regulation. We show that histone H3K4me3 around the start site correlates with transcriptional induction in some of these genes. Among the methylation-induced genes are IDP2 and ODC1, which regulate the nuclear availability of α-ketoglutarate, which, as a cofactor for Jhd2 demethylase, regulates H3K4 tri-methylation. We propose that this feedback circuit could be used to regulate the nuclear α-ketoglutarate pool concentration. We also show that yeast cells adapt to the absence of Jhd2 by decreasing Set1 methylation activity. Full article

(This article belongs to the Special Issue Metabolic Changes and Epigenetic Alterations)

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Open AccessArticle

Association of Metabolomic Biomarkers with Sleeve Gastrectomy Weight Loss Outcomes

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Metabolites 2023, 13(4), 506; https://doi.org/10.3390/metabo13040506 - 31 Mar 2023

Abstract

This prospective observational study aimed to evaluate the association of metabolomic alterations with weight loss outcomes following sleeve gastrectomy (SG). We evaluated the metabolomic profile of serum and feces prior to SG and three months post-SG, along with weight loss outcomes in 45 [...] Read more.

This prospective observational study aimed to evaluate the association of metabolomic alterations with weight loss outcomes following sleeve gastrectomy (SG). We evaluated the metabolomic profile of serum and feces prior to SG and three months post-SG, along with weight loss outcomes in 45 adults with obesity. The percent total weight loss for the highest versus the lowest weight loss tertiles (T3 vs. T1) was 17.0 ± 1.3% and 11.1 ± 0.8%, p < 0.001. Serum metabolite alterations specific to T3 at three months included a decrease in methionine sulfoxide concentration as well as alterations to tryptophan and methionine metabolism (p < 0.03). Fecal metabolite changes specific to T3 included a decrease in taurine concentration and perturbations to arachidonic acid metabolism, and taurine and hypotaurine metabolism (p < 0.002). Preoperative metabolites were found to be highly predictive of weight loss outcomes in machine learning algorithms, with an average area under the curve of 94.6% for serum and 93.4% for feces. This comprehensive metabolomics analysis of weight loss outcome differences post-SG highlights specific metabolic alterations as well as machine learning algorithms predictive of weight loss. These findings could contribute to the development of novel therapeutic targets to enhance weight loss outcomes after SG. Full article

(This article belongs to the Special Issue Advanced Metabolomics and Lipidomics Approaches in Studying Human Diseases)

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Open AccessArticle

Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort

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Brooke Gleason

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Alan Kuang

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James R. Bain

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Michael J. Muehlbauer

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Olga R. Ilkayeva

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Denise M. Scholtens

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William L. Lowe, Jr.

Metabolites 2023, 13(4), 505; https://doi.org/10.3390/metabo13040505 - 31 Mar 2023

Abstract

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn [...] Read more.

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24–32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity. Full article

(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)

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Open AccessArticle

Effects of Different Storage Conditions on Lipid Stability in Mice Tissue Homogenates

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Metabolites 2023, 13(4), 504; https://doi.org/10.3390/metabo13040504 - 31 Mar 2023

Abstract

Lipids are biomolecules involved in numerous (patho-)physiological processes and their elucidation in tissue samples is of particular interest. However, tissue analysis goes hand in hand with many challenges and the influence of pre-analytical factors can intensively change lipid concentrations ex vivo, compromising the [...] Read more.

Lipids are biomolecules involved in numerous (patho-)physiological processes and their elucidation in tissue samples is of particular interest. However, tissue analysis goes hand in hand with many challenges and the influence of pre-analytical factors can intensively change lipid concentrations ex vivo, compromising the results of the whole research project. Here, we study the influence of pre-analytical factors on lipid profiles during the processing of homogenized tissues. Homogenates from four different mice tissues (liver, kidney, heart, spleen) were stored at room temperature as well as in ice water for up to 120 min and analyzed via ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). Lipid class ratios were calculated since their suitability as indicators for sample stability has been previously illustrated. Only approx. 40% of lipid class ratios were unchanged after 35 min, which was further reduced to 25% after 120 min during storage at room temperature. In contrast, lipids in tissue homogenates were generally stable when samples were kept in ice water, as more than 90% of investigated lipid class ratios remained unchanged after 35 min. Ultimately, swift processing of tissue homogenates under cooled conditions represents a viable option for lipid analysis and pre-analytical factors require more attention to achieve reliable results. Full article

(This article belongs to the Special Issue Application of Mass Spectrometry Analysis in Metabolomics)

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Open AccessArticle

Analysis of Floral Scent and Volatile Profiles of Different Aster Species by E-nose and HS-SPME-GC-MS

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Metabolites 2023, 13(4), 503; https://doi.org/10.3390/metabo13040503 - 31 Mar 2023

Abstract

Plants from the Aster species are known to be a rich source of bioactive chemical compositions and are popularly known for their medicinal properties. To investigate the relationship between the nine species of Aster, the floral fragrance and volatile profile patterns were [...] Read more.

Plants from the Aster species are known to be a rich source of bioactive chemical compositions and are popularly known for their medicinal properties. To investigate the relationship between the nine species of Aster, the floral fragrance and volatile profile patterns were characterized using E-nose and HS-SPME-GC-MS. Initial optimization for fragrance analysis was performed with Aster yomena using E-nose by evaluating the scent patterns in different flowering stages. Aster yomena exhibited varied scent patterns in each flowering stage, with the highest relative aroma intensity (RAI) in the full flowering stage. PCA analysis to compare and analyze the scent characteristics of nine Aster species, showed a species-specific classification. HS-SPME-GC-MS analysis of flowers from nine Aster species revealed 52 volatile compounds including β-myrcene, α-phellandrene, D-limonene, trans-β-ocimene, caryophyllene, and β-cadinene. The terpenoid compounds accounted for the largest proportion. Among the nine Aster species flowers, Aster koraiensis had sesquiterpenes as the major component, and the remaining eight varieties had monoterpenes in abundance. These results could distinguish the species according to the scent patterns and volatile components of the nine Aster species. Additionally, flower extracts from the Aster species’ plants exhibited radical scavenging antioxidant activity. Among them, it was confirmed that Aster pseudoglehnii, Aster maackii, and Aster arenarius had high antioxidant activity. In conclusion, the results of this study provide fundamental data of the volatile compound properties and antioxidant activity of Aster species, offering basic information of valuable natural sources that can be utilized in the pharmaceutical, perfume, and cosmetic industries. Full article

(This article belongs to the Special Issue Plant Metabolites: Therapeutics, Toxicology, and Pharmacology)

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Graphical abstract

Open AccessArticle

An Experimental and Computational Analysis of Plant Compounds from Whole Urtica dioica L. Plant’s Essential Oil for Antioxidant and Antibacterial Activities

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Nehal Ahmed Talaat Nouh

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Jawaher A. Abdulhakim

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Mohamed M. Abdel-Daim

Metabolites 2023, 13(4), 502; https://doi.org/10.3390/metabo13040502 - 30 Mar 2023

Abstract

As the Urtica dioica L whole plant’s essential oil has presented significant multiple activities, it was therefore evaluated using the GC–MS technique. This essential oil was investigated for its antioxidant, phytotoxic, and antibacterial activities in vitro. The GC–MS analysis data assisted in the [...] Read more.

As the Urtica dioica L whole plant’s essential oil has presented significant multiple activities, it was therefore evaluated using the GC–MS technique. This essential oil was investigated for its antioxidant, phytotoxic, and antibacterial activities in vitro. The GC–MS analysis data assisted in the identification of various constituents. The study of the essential oil of U. dioica showed potential antioxidant effects and antibacterial activity against the selected pathogens Escherichia coli -ATCC 9837 (E. coli), Bacillus subtilis-ATCC 6633 (B. subtilis), Staphylococcus aureus-ATCC6538 (S. aureus), Pseudomonas aeruginosa-ATCC 9027 (P. aeruginosa), and Salmonella typhi-ATCC 6539 (S. typhi). The library of 23 phytochemicals was docked by using MOE software, and three top virtual hits with peroxiredoxin protein [PDB ID: 1HD2] and potential target protein [PDB ID: 4TZK] were used; hence, the protein–ligand docking results estimated the best binding conformations and a significant correlation with the experimental analysis, in terms of the docking score and binding interactions with the key residues of the native active binding site. The essential oil in the silico pharmacokinetic profile explained the structure and activity relationships of the selected best hits, and their additional parameters provided insight for further clinical investigations. Therefore, it is concluded that the U. dioica essential oil could be a potent antioxidant and antibacterial agent for aromatherapy through its topical application, if further tested in a laboratory and validated. Full article

(This article belongs to the Special Issue Natural Products: Chemical Profiling, Computational Studies and Bioactivities)

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Graphical abstract

Open AccessArticle

Efficacy Confirmation Test of Black Cumin (Nigella sativa L.) Seeds Extract Using a High-Fat Diet Mouse Model

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Khawaja Muhammad Imran Bashir

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Metabolites 2023, 13(4), 501; https://doi.org/10.3390/metabo13040501 - 30 Mar 2023

Abstract

To deal with the adverse effects associated with the use of currently available treatments for metabolic disorders, such as type 2 diabetes, there is a need to find an alternative drug compound. In the present study, we investigated the therapeutic potential of black [...] Read more.

To deal with the adverse effects associated with the use of currently available treatments for metabolic disorders, such as type 2 diabetes, there is a need to find an alternative drug compound. In the present study, we investigated the therapeutic potential of black cumin (Nigella sativa L.) seeds extract (BCS extract) for type 2 diabetes using a 45% Kcal-fed obese mouse model. The BCS extract at different doses (400–100 mg/kg) showed a dose-dependent improvement tendency in high-fat diet (HFD)-induced obesity, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and diabetic nephropathy compared to the metformin (250 mg/kg). In particular, BCS extract at a dose of 200 mg/kg significantly inhibited the HFD-induced metabolic conditions. The oral administration of BCS extract (200 mg/kg) significantly inhibited the oxidative stress through lipid peroxidation, normalized the activity of sugar metabolism-related enzymes and the expression of genes involved in fat metabolism, and inhibited insulin resistance through glucose and fat metabolism by regulating the 5’-AMP-activated protein kinase (AMPK) expression. Furthermore, BCS extract (200 mg/kg) showed renal damage improvement effects compared to the metformin (250 mg/kg). The results clearly show that BCS aqueous extract at an appropriate concentration could help in the treatment of metabolic disorders, and BCS aqueous extract can be used as a functional food for various diabetic complications, such as obesity, diabetes, and NAFLD. Full article

(This article belongs to the Special Issue Functional Foods and Diabetes)

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Open AccessHypothesis

Kynurenine Pathway Regulation at Its Critical Junctions with Fluctuation of Tryptophan

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Metabolites 2023, 13(4), 500; https://doi.org/10.3390/metabo13040500 - 30 Mar 2023

Abstract

The kynurenine pathway (KP) is the primary route for the catabolism of the essential amino acid tryptophan. The central KP metabolites are neurologically active molecules or biosynthetic precursors to critical molecules, such as NAD⁺. Within this pathway are three enzymes of [...] Read more.

The kynurenine pathway (KP) is the primary route for the catabolism of the essential amino acid tryptophan. The central KP metabolites are neurologically active molecules or biosynthetic precursors to critical molecules, such as NAD⁺. Within this pathway are three enzymes of interest, HAO, ACMSD, and AMSDH, whose substrates and/or products can spontaneously cyclize to form side products such as quinolinic acid (QA or QUIN) and picolinic acid. Due to their unstable nature for spontaneous autocyclization, it might be expected that the levels of these side products would be dependent on tryptophan intake; however, this is not the case in healthy individuals. On top of that, the regulatory mechanisms of the KP remain unknown, even after a deeper understanding of the structure and mechanism of the enzymes that handle these unstable KP metabolic intermediates. Thus, the question arises, how do these enzymes compete with the autocyclization of their substrates, especially amidst increased tryptophan levels? Here, we propose the formation of a transient enzyme complex as a regulatory mechanism for metabolite distribution between enzymatic and non-enzymatic routes during periods of increased metabolic intake. Amid high levels of tryptophan, HAO, ACMSD, and AMSDH may bind together, forming a tunnel to shuttle the metabolites through each enzyme, consequently regulating the autocyclization of their products. Though further research is required to establish the formation of transient complexation as a solution to the regulatory mysteries of the KP, our docking model studies support this new hypothesis. Full article

(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)

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Open AccessCorrection

Correction: Vu et al. Specific Changes in Arabidopsis thaliana Rosette Lipids during Freezing Can Be Associated with Freezing Tolerance. Metabolites 2022, 12, 385

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Metabolites 2023, 13(4), 499; https://doi.org/10.3390/metabo13040499 - 30 Mar 2023

Abstract

There was an error in the original publication [...] Full article

Open AccessReview

Oral Sources of Salivary Metabolites

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Eelis Hyvärinen

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Bina Kashyap

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Arja M. Kullaa

Metabolites 2023, 13(4), 498; https://doi.org/10.3390/metabo13040498 - 29 Mar 2023

Abstract

The oral cavity is very diverse, where saliva plays an important role in maintaining oral health. The metabolism of saliva has been used to investigate oral diseases as well as general diseases, mainly to detect diagnostic biomarkers. There are many sources of salivary [...] Read more.

The oral cavity is very diverse, where saliva plays an important role in maintaining oral health. The metabolism of saliva has been used to investigate oral diseases as well as general diseases, mainly to detect diagnostic biomarkers. There are many sources of salivary metabolites in the mouth. The online English language search and PubMed databases were searched to retrieve relevant studies on oral salivary metabolites. The physiological balance of the mouth is influenced by many factors that are reflected in the salivary metabolite profile. Similarly, the dysbiosis of microbes can alter the salivary metabolite profile, which may express oral inflammation or oral diseases. This narrative review highlights the factors to be considered when examining saliva and its use as a diagnostic biofluid for different diseases. Salivary metabolites, mainly small molecular metabolites may enter the bloodstream and cause illness elsewhere in the body. The importance of salivary metabolites produced in the oral cavity as risk factors for general diseases and their possible relationship to the body’s function are also discussed. Full article

(This article belongs to the Special Issue Salivary Metabolomics for Oral and Systemic Diseases Volume 2)

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Open AccessArticle

The Potency of Goat Milk in Reducing the Induced Neurotoxic Effects of Valproic Acid in Rat Pups as a Rodent Model of Autism Spectrum Disorder

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Alhanouf Mohammed Al-dossari

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Laila Naif Al-Harbi

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Norah M. Al-Otaibi

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Abdullah Almubarak

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Ahmed Tayseer Almnaizel

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Ghedeir M. Alshammari

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Ghalia Shamlan

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Ali A. Alshatwi

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Afaf El-Ansary

Metabolites 2023, 13(4), 497; https://doi.org/10.3390/metabo13040497 - 29 Mar 2023

Abstract

Autism spectrum disorder (ASD) is a progressively prevalent neurodevelopmental disorder with substantial clinical heterogeneity. Despite the considerable interest in dietary interventions, no consensus has been reached regarding the optimal nutritional therapy. The present study aimed to investigate the possible positive effect of goat’s [...] Read more.

Autism spectrum disorder (ASD) is a progressively prevalent neurodevelopmental disorder with substantial clinical heterogeneity. Despite the considerable interest in dietary interventions, no consensus has been reached regarding the optimal nutritional therapy. The present study aimed to investigate the possible positive effect of goat’s milk (GM) compared to cow’s milk (CM) on ASD autistic features in a valproic acid (VPA; 600 mg/kg)-induced white albino rat model of autism. All tests were conducted on rats that were divided into four groups (n = 15/group): control with goat milk (GM) treatment, control with cow milk (CM) treatment, autistic with goat milk (GM) treatment, and autistic with cow milk treatment. The casein levels were also measured in GM and CM. Social behavior was assessed by three-chambered sociability to test social interaction after the intervention. After 15 days of intervention, selected biomarkers, such as glutathione (GSH), thiobarbituric acid reactive substance (TBARS), interleukin-6 (IL-6), neurotransmitter dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and glutamate (GLU), were measured in blood serum and brain homogenates. The results showed a significant positive effect on social interaction in the VPA rat ASD model fed GM. Blood serum and brain samples showed a positive increase in TBARS in the VPA rat model fed GM, but brain and serum serotonin levels were lower in both VPA-GM and VPA-CM groups. Dopamine in serum was also lower in the VPA-CM group than in the VPA-GM group. IL-6 levels were slightly lower in the VPA-GM group than in the VPA-CM group. In comparison with cow’s milk, goat’s milk was effective in ameliorating the neurotoxic effects of VPA. Goat’s milk may be considered a suitable source of dairy for children diagnosed with ASD. Autistic children with allergies to cow’s milk could possibly convert to goat’s milk. Nevertheless, more in-depth studies and clinical trials are recommended. Full article

(This article belongs to the Special Issue Complementary and Alternative Medicine in Autism Spectrum Disorders)

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Open AccessArticle

Expression of STING in Women with Morbid Obesity and Nonalcoholic Fatty Liver Disease

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Laia Bertran

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Laia Adalid

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Mercè Vilaró-Blay

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Andrea Barrientos-Riosalido

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Metabolites 2023, 13(4), 496; https://doi.org/10.3390/metabo13040496 - 29 Mar 2023

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease. Although mostly benign, this disease can evolve into nonalcoholic steatohepatitis (NASH). The stimulator of interferon genes (STING) plays an important role in the immune response against stressed cells, but this protein [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease. Although mostly benign, this disease can evolve into nonalcoholic steatohepatitis (NASH). The stimulator of interferon genes (STING) plays an important role in the immune response against stressed cells, but this protein may also be involved in liver lipogenesis and microbiota composition. In this study, the role of STING in NAFLD was evaluated by RT–qPCR to analyze STING mRNA abundance and by immunohistochemical analysis to evaluate protein expression in liver biopsies from a cohort composed of 69 women with morbid obesity classified according to their liver involvement (normal liver, n = 27; simple steatosis (SS), n = 26; NASH, n = 16). The results showed that STING mRNA expression in the liver increases with the occurrence of NAFLD, specifically in the SS stage in which the degree of steatosis is mild or moderate. Protein analysis corroborated these results. Positive correlations were observed among hepatic STING mRNA abundance and gamma-glutamyl transferase and alkaline phosphatase levels, hepatic Toll-like receptor 9 expression and some circulating microbiota-derived bile acids. In conclusion, STING may be involved in the outcome and progression of NAFLD and may be related to hepatic lipid metabolism. However, further studies are needed to confirm these findings. Full article

(This article belongs to the Special Issue Regulation of Oxidative Stress on Gut Microbial Homeostasis and Metabolism)

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Open AccessArticle

Targeted Metabolomics of Organophosphate Pesticides and Chemical Warfare Nerve Agent Simulants Using High- and Low-Dose Exposure in Human Liver Microsomes

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Metabolites 2023, 13(4), 495; https://doi.org/10.3390/metabo13040495 - 29 Mar 2023

Abstract

Our current understanding of organophosphorus agent (pesticides and chemical warfare nerve agents) metabolism in humans is limited to the general transformation by cytochrome P450 enzymes and, to some extent, by esterases and paraoxonases. The role of compound concentrations on the rate of clearance [...] Read more.

Our current understanding of organophosphorus agent (pesticides and chemical warfare nerve agents) metabolism in humans is limited to the general transformation by cytochrome P450 enzymes and, to some extent, by esterases and paraoxonases. The role of compound concentrations on the rate of clearance is not well established and is further explored in the current study. We discuss the metabolism of 56 diverse organophosphorus compounds (both pesticides and chemical warfare nerve agent simulants), many of which were explored at two variable dose regimens (high and low), determining their clearance rates (Cl_int) in human liver microsomes. For compounds that were soluble at high concentrations, 1D-NMR, 31P, and MRM LC-MS/MS were used to calculate the Cl_int and the identity of certain metabolites. The determined Cl_int rates ranged from 0.001 to 2245.52 µL/min/mg of protein in the lower dose regimen and from 0.002 to 98.57 µL/min/mg of protein in the high dose regimen. Though direct equivalency between the two regimens was absent, we observed (1) both mono- and bi-phasic metabolism of the OPs and simulants in the microsomes. Compounds such as aspon and formothion exhibited biphasic decay at both high and low doses, suggesting either the involvement of multiple enzymes with different K_M or substrate/metabolite effects on the metabolism. (2) A second observation was that while some compounds, such as dibrom and merphos, demonstrated a biphasic decay curve at the lower concentrations, they exhibited only monophasic metabolism at the higher concentration, likely indicative of saturation of some metabolic enzymes. (3) Isomeric differences in metabolism (between Z- and E- isomers) were also observed. (4) Lastly, structural comparisons using examples of the oxon group over the original phosphorothioate OP are also discussed, along with the identification of some metabolites. This study provides initial data for the development of in silico metabolism models for OPs with broad applications. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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Open AccessArticle

A Pilot Study on Across-Generation Impacts of Maternal Heat Stress on Blood Metabolites of Female Holstein Dairy Calves

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Metabolites 2023, 13(4), 494; https://doi.org/10.3390/metabo13040494 - 29 Mar 2023

Abstract

Heat stress (HS) during late gestation implies unfavorable effects on dairy cows and their in-utero heat stressed offspring. The objective of the present study was to elucidate the effect of intrauterine (maternal) HS during the last week of gestation on blood metabolite concentrations [...] Read more.

Heat stress (HS) during late gestation implies unfavorable effects on dairy cows and their in-utero heat stressed offspring. The objective of the present study was to elucidate the effect of intrauterine (maternal) HS during the last week of gestation on blood metabolite concentrations of female dairy calves during their first week of life. We defined the mean temperature humidity index (mTHI) during the last gestation week of ≥60 as threshold for maternal HS. In this regard, we compared differences in metabolite concentrations of maternally heat stressed (MHS_CALVES) (n = 14) and not heat stressed (NMHS_CALVES) (n = 33) calves. We identified 15 metabolites from five different biochemical classes (phosphatidylcholines, cholesteryl esters, sphingomyelins, cresols and hexoses) as potential biomarkers for maternal HS in calves. The plasma concentrations of all significantly affected metabolites were lower in MHS_CALVES when compared to NMHS_CALVES. The effect of maternal HS during the last week of gestation on blood metabolite concentrations of the female offspring during the first week after birth might be due to HS induced intergenerational physiological alterations, impaired colostrum quality or epigenetic modifications of the calf genome. The results of this pilot study should be validated in ongoing fully standardized studies. Full article

(This article belongs to the Special Issue Metabolic and Endocrine Responses to Stress and Disease in Animal Production)

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Open AccessSystematic Review

Effects of Hypolipidemic Drugs on Psoriasis

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Mateusz Matwiejuk

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Hanna Mysliwiec

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Olivia Jakubowicz-Zalewska

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Adrian Chabowski

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Iwona Flisiak

Metabolites 2023, 13(4), 493; https://doi.org/10.3390/metabo13040493 - 29 Mar 2023

Abstract

Psoriasis is a chronic, systematic, inflammatory disease in which multiple metabolic and immunologic disturbances lead to lipid abnormalities, impaired glucose tolerance, metabolic syndrome, diabetes mellitus, atherosclerosis, hypertension, ischemic heart disease, and numerous metabolic disorders. In clinical practice, the most commonly used drugs in [...] Read more.

Psoriasis is a chronic, systematic, inflammatory disease in which multiple metabolic and immunologic disturbances lead to lipid abnormalities, impaired glucose tolerance, metabolic syndrome, diabetes mellitus, atherosclerosis, hypertension, ischemic heart disease, and numerous metabolic disorders. In clinical practice, the most commonly used drugs in the treatment of lipid abnormalities are statins and fibrates. Statins are characterized by pleiotropic effects such as antioxidant, anti-inflammatory, anticoagulant, and antiproliferative. They work by reducing the concentrations of low-density lipoprotein (LDL), total cholesterol, and triglycerides and stabilizing atherosclerotic plaque. Fibrates are medications, which help to lower triglycerides, LDL, very low-density lipoprotein (VLDL) levels and increase lower high-density lipoprotein (HDL). In recent years, many new drugs were found to normalize the lipid profile in patients with psoriasis: glitazones (pioglitazone, troglitazone), and glucagon-like peptide-1 (GLP-1) receptor agonists. Pioglitazone improves the lipid profile, including the decrease of triglycerides, fatty acids, and LDL, as well as the increase of HDL. Glucagon-like peptide 1 (GLP-1) analogs decrease modestly low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides. The purpose of this study is to assess the current state of knowledge on the effect of different hypolipidemic treatments on the course of psoriasis. The study includes literature from medical databases PubMed and Google Scholar. We were browsing PubMed and Google Scholar until the beginning of December. The systematic review includes 41 eligible original articles. Full article

(This article belongs to the Special Issue Lipid Expression and Metabolism Aberrations in Skin Diseases)

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Open AccessArticle

Elimination of Cefquinome Sulfate Residue in Cow’s Milk after Intrauterine Infusion

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Metabolites 2023, 13(4), 492; https://doi.org/10.3390/metabo13040492 - 29 Mar 2023

Abstract

As set in the maximum residue limit regulations of the European Commission, this study aimed to obtain the residual parameters in milk with optimized UPLC-MS/MS conditions and to determine the conclusive drug withdrawal period to ensure food safety. In this research, an ultra-high [...] Read more.

As set in the maximum residue limit regulations of the European Commission, this study aimed to obtain the residual parameters in milk with optimized UPLC-MS/MS conditions and to determine the conclusive drug withdrawal period to ensure food safety. In this research, an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to study cefquinome sulfate’s residue elimination in milk and to calculate cefquinome’s withdrawal period. Twelve healthy cows free of endometritis were selected for the experiment. Before using the drug, the vaginal orifice and perineum of each cow was disinfected. One dose of intrauterine perfusion was used for each cow, followed by an additional dose after 72 h. Before administration and 12 h, 18 h, 24 h, 36 h, 42 h, 48 h, 60 h, 66 h, 72 h, 84 h, 90 h, and 96 h after the last dose, milk (10 mL) was gathered from each cow’s teat and pooled. For the measurement of cefquinome concentrations in milk, UPLC-MS/MS was performed. A calibration curve was generated using linear regression as follows: Y = 250.86X − 102.29, with a correlation coefficient of 0.9996; the limits of detection and the limits of quantitation were 0.1 μg·kg⁻¹ and 0.2 μg·kg⁻¹, respectively. The average recovery of cefquinome was 88.60 ± 16.33% at 0.2 μg·kg⁻¹, 100.95 ± 2.54% at 10 μg·kg⁻¹, and 97.29 ± 1.77% at 50 μg·kg⁻¹. For 5 consecutive days at the three spiking levels, the intra and inter-day relative standard deviations (RSD) were 1.28%–13.73% and 1.81%–18.44%, respectively; the residual amount of cefquinome was less than the maximum residue limit of 20 μg·kg⁻¹, 36 h after administration; and the residual amount was less than the limit of detection (0.1 μg·kg⁻¹) 48 h after administration. The withdrawal time of cefquinome in cow’s milk was 39.8 h, as calculated using WTM1.4 software. In terms of clinical practical use, the withdrawal period of milk was temporarily set at 48 h after the administration of the cefquinome sulfate uterus injection to cows, in accordance with the recommended dose and course. Full article

(This article belongs to the Special Issue Veterinary Drug Residue Detection and Pharmacokinetics)

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Open AccessArticle

Quorum Sensing-Mediated Lipid Oxidation Further Regulating the Environmental Adaptability of Aspergillus ochraceus

by

,

,

and

Metabolites 2023, 13(4), 491; https://doi.org/10.3390/metabo13040491 - 29 Mar 2023

Abstract

Quorum sensing (QS) is a cellular strategy of communication between intra- and inter-specific microorganisms, characterized by the release of quorum sensing molecules (QSMs) that achieve coordination to adaptation to the environment. In Aspergillus, lipids carry population density-mediated stresses, and their oxidative metabolite [...] Read more.

Quorum sensing (QS) is a cellular strategy of communication between intra- and inter-specific microorganisms, characterized by the release of quorum sensing molecules (QSMs) that achieve coordination to adaptation to the environment. In Aspergillus, lipids carry population density-mediated stresses, and their oxidative metabolite oxylipins act as signaling to transmit information inside cells to regulate fungal development in a synchronized way. In this study, we investigated the regulation of density-dependent lipid metabolism in the toxigenic fungi Aspergillus ochraceus by the oxidative lipid metabolomics in conjunction with transcriptomics. In addition to proven hydroxyoctadecadienoic acids (HODEs), prostaglandins (PGs) also appear to have the properties of QSM. As a class of signaling molecule, oxylipins regulate the fungal morphology, secondary metabolism, and host infection through the G protein signaling pathway. The results of combined omics lay a foundation for further verification of oxylipin function, which is expected to elucidate the complex adaptability mechanism in Aspergillus and realize fungal utilization and damage control. Full article

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

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Open AccessArticle

Chronometabolism: The Timing of the Consumption of Meals Has a Greater Influence Than Glycemic Index (GI) on the Postprandial Metabolome

by

Yi Ning Yong

,

Jiangwen Dong

,

Leroy Sivappiragasam Pakkiri

,

Christiani Jeyakumar Henry

,

Sumanto Haldar

and

Chester Lee Drum

Metabolites 2023, 13(4), 490; https://doi.org/10.3390/metabo13040490 - 29 Mar 2023

Abstract

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover [...] Read more.

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover study in 36 healthy older Chinese adults, we have compared postprandial metabolic responses between high (HI) glycemic index (GI) or low-GI (LO) meals, consumed either at breakfast (BR) or at dinner (DI). 29 out of 234 plasma metabolites exhibited significant differences (p < 0.05) in postprandial AUC between BR and DI sessions, whereas only five metabolites were significantly different between HI and LO sessions. There were no significant interactions between intake timing and meal GI. Lower glutamine: glutamate ratio, lower lysine and higher trimethyllysine (TML) levels were found during DI compared with BR, along with greater postprandial reductions (δAUC) in creatine and ornithine levels during DI, indicating a worse metabolic state during the evening DI period. Greater reductions (δAUC) in postprandial creatine and ornithine were also observed during HI compared with LO (both p < 0.05). These metabolomic changes may indicate potential molecular signatures and/or pathways linking metabolic responses with cardiometabolic disease risk between different meal intake timings and/or meals with variable GI. Full article

(This article belongs to the Special Issue Roles of the Circadian Rhythms in Metabolic Disease and Health)

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