Metabolites Potentially Derived from Gut Microbiota Associated with Podocyte, Proximal Tubule, and Renal and Cerebrovascular Endothelial Damage in Early Diabetic Kidney Disease in T2DM Patients
Assessing Repeated Urinary Proline Betaine Measures as a Biomarker of Usual Citrus Intake during Pregnancy: Sources of Within-Person Variation and Correlation with Reported Intake
Vitamin D Deficiency in Obese Children Is Associated with Some Metabolic Syndrome Components, but Not with Metabolic Syndrome Itself
Multi-Modality, Multi-Dimensional Characterization of Pediatric Non-Alcoholic Fatty Liver Disease
Evolution of Status of Trace Elements and Metallothioneins in Patients with COVID-19: Relationship with Clinical, Biochemical, and Inflammatory Parameters

Journal Description

Metabolites

Metabolites is an international, peer-reviewed, open access journal of metabolism and metabolomics, published monthly online by MDPI.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q2 (Biochemistry & Molecular Biology) / CiteScore - Q2 (Endocrinology, Diabetes and Metabolism)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 12.9 days after submission; acceptance to publication is undertaken in 2.7 days (median values for papers published in this journal in the first half of 2023).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.

Impact Factor: 4.1 (2022); 5-Year Impact Factor: 4.5 (2022)

Imprint Information Journal Flyer Open Access ISSN: 2218-1989

Latest Articles

21 pages, 389 KiB

Open AccessReview

Bridging the Gap from Enterotypes to Personalized Dietary Recommendations: A Metabolomics Perspective on Microbiome Research

Madeline Bartsch

Andreas Hahn

and

Shoma Berkemeyer

Metabolites 2023, 13(12), 1182; https://doi.org/10.3390/metabo13121182 (registering DOI) - 02 Dec 2023

Abstract

Advances in high-throughput DNA sequencing have propelled research into the human microbiome and its link to metabolic health. We explore microbiome analysis methods, specifically emphasizing metabolomics, how dietary choices impact the production of microbial metabolites, providing an overview of studies examining the connection between enterotypes and diet, and thus, improvement of personalized dietary recommendations. Acetate, propionate, and butyrate constitute more than 95% of the collective pool of short-chain fatty acids. Conflicting data on acetate’s effects may result from its dynamic signaling, which can vary depending on physiological conditions and metabolic phenotypes. Human studies suggest that propionate has overall anti-obesity effects due to its well-documented chemistry, cellular signaling mechanisms, and various clinical benefits. Butyrate, similar to propionate, has the ability to reduce obesity by stimulating the release of appetite-suppressing hormones and promoting the synthesis of leptin. Tryptophan affects systemic hormone secretion, with indole stimulating the release of GLP-1, which impacts insulin secretion, appetite suppression, and gastric emptying. Bile acids, synthesized from cholesterol in the liver and subsequently modified by gut bacteria, play an essential role in the digestion and absorption of dietary fats and fat-soluble vitamins, but they also interact directly with intestinal microbiota and their metabolites. One study using statistical methods identified primarily two groupings of enterotypes Bacteroides and Ruminococcus. The Prevotella-dominated enterotype, P-type, in humans correlates with vegetarians, high-fiber and carbohydrate-rich diets, and traditional diets. Conversely, individuals who consume diets rich in animal fats and proteins, typical in Western-style diets, often exhibit the Bacteroides-dominated, B-type, enterotype. The P-type showcases efficient hydrolytic enzymes for plant fiber degradation but has limited lipid and protein fermentation capacity. Conversely, the B-type features specialized enzymes tailored for the degradation of animal-derived carbohydrates and proteins, showcasing an enhanced saccharolytic and proteolytic potential. Generally, models excel at predictions but often struggle to fully elucidate why certain substances yield varied responses. These studies provide valuable insights into the potential for personalized dietary recommendations based on enterotypes. Full article

(This article belongs to the Special Issue Metabolomics of Human Nutrition: The Dot of Human Nutrition and the Circle of Soil, Plants, Animals and Microbes in Relation to It)

16 pages, 3087 KiB

Open AccessArticle

Technical Report: A Comprehensive Comparison between Different Quantification Versions of Nightingale Health’s ¹H-NMR Metabolomics Platform

Daniele Bizzarri

Marcel J. T. Reinders

Marian Beekman

P. Eline Slagboom

Erik B. van den Akker

and on behalf of the BbmriNl

Metabolites 2023, 13(12), 1181; https://doi.org/10.3390/metabo13121181 - 30 Nov 2023

Abstract

¹H-NMR metabolomics data is increasingly used to track health and disease. Nightingale Health, a major supplier of ¹H-NMR metabolomics, has recently updated the quantification strategy to further align with clinical standards. Such updates, however, might influence backward replicability, particularly affecting studies with repeated measures. Using data from BBMRI-NL consortium (~28,000 samples from 28 cohorts), we compared Nightingale data, originally released in 2014 and 2016, with a re-quantified version released in 2020, of which both versions were based on the same NMR spectra. Apart from two discontinued and twenty-three new analytes, we generally observe a high concordance between quantification versions with 73 out of 222 (33%) analytes showing a mean

ρ

> 0.9 across all cohorts. Conversely, five analytes consistently showed lower Spearman’s correlations (

ρ

< 0.7) between versions, namely acetoacetate, LDL-L, saturated fatty acids, S-HDL-C, and sphingomyelins. Furthermore, previously trained multi-analyte scores, such as MetaboAge or MetaboHealth, might be particularly sensitive to platform changes. Whereas MetaboHealth replicated well, the MetaboAge score had to be retrained due to use of discontinued analytes. Notably, both scores in the re-quantified data recapitulated mortality associations observed previously. Concluding, we urge caution in utilizing different platform versions to avoid mixing analytes, having different units, or simply being discontinued. Full article

(This article belongs to the Topic Biomarker Development and Application)

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23 pages, 3953 KiB

Open AccessArticle

Impact of Different Treatment Regimens and Timeframes in the Plasmatic Metabolic Profiling of Patients with Lung Adenocarcinoma

Daniela Madama

David F. Carrageta

Bárbara Guerra-Carvalho

and

Metabolites 2023, 13(12), 1180; https://doi.org/10.3390/metabo13121180 - 30 Nov 2023

Abstract

In recent years, the treatment of advanced non-small cell lung cancer (NSCLC) has suffered a variety of alterations. Chemotherapy (CTX), immunotherapy (IT) and tyrosine kinase inhibitors (TKI) have shown remarkable results. However, not all patients with NSCLC respond to these drug treatments or receive durable benefits. In this framework, metabolomics has been applied to improve the diagnosis, treatment, and prognosis of lung cancer and particularly lung adenocarcinoma (AdC). In our study, metabolomics was used to analyze plasma samples from 18 patients with AdC treated with CTX or IT via ¹H-NMR spectroscopy. Relevant clinical information was gathered, and several biochemical parameters were also evaluated throughout the treatments. During the follow-up of patients undergoing CTX or IT, imaging control is recommended in order to assess the effectiveness of the therapy. This evaluation is usually performed every three treatments. Based on this procedure, all the samples were collected before the beginning of the treatment and after three and six treatments. The identified and quantified metabolites in the analyzed plasma samples were the following: isoleucine, valine, alanine, acetate, lactate, glucose, tyrosine, and formate. Multivariate/univariate statistical analyses were performed. Our data are in accordance with previous published results, suggesting that the plasma glucose levels of patients under CTX become higher throughout the course of treatment, which we hypothesize could be related to the tumor response to the therapy. It was also found that alanine levels become lower during treatment with CTX regimens, a fact that could be associated with frailty. NMR spectra of long responders’ profiles also showed similar results. Based on the results of the study, metabolomics can represent a potential option for future studies, in order to facilitate patient selection and the monitoring of therapy efficacy in treated patients with AdC. Further studies are needed to improve the prospective identification of predictive markers, particularly glucose and alanine levels, as well as confer guidance to NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies. Full article

(This article belongs to the Section Advances in Metabolomics)

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18 pages, 3765 KiB

Open AccessArticle

Solanaceae Glycoalkaloids Disturb Lipid Metabolism in the Tenebrio molitor Beetle

Magdalena Joanna Winkiel

and

Metabolites 2023, 13(12), 1179; https://doi.org/10.3390/metabo13121179 - 30 Nov 2023

Abstract

Glycoalkaloids (GAs) are produced naturally by plants and affect insect survivability and fertility. These compounds can be considered potential bioinsecticides; however, the mechanisms and effects of their action remain undiscovered. As lipids are essential molecules for the proper functioning of an insect organism, this research aimed to determine the effects of GAs on the lipid metabolism of the Tenebrio molitor beetle. Solanine, chaconine, tomatine, and tomato leaf extract were applied to larvae by injection at two concentrations, 10⁻⁸ and 10⁻⁵ M. Then, the tissue was isolated after 2 and 24 h to determine the levels of free fatty acids, sterols and esters using the GC–MS technique. Moreover, the triacylglyceride level and the activity of the key β-oxidation enzyme, 3-hydroxyacyl-CoA dehydrogenase (HADH), were measured. The results indicate that GAs affect the content and composition of lipid compounds in the beetles’ haemolymph and fat body. The effects depend on the GA concentrations, incubation time, and kind of tissue. Moreover, the tested compounds decrease HADH activity, especially in the fat body, which may affect energy production. To our knowledge, this is the first study concerning lipid metabolism in T. molitor after GA application. Our results provide some insights into that topic. Full article

(This article belongs to the Special Issue Insect Metabolism and Physiology)

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21 pages, 1203 KiB

Open AccessReview

Metabolomics to Understand Alterations Induced by Physical Activity during Pregnancy

Ana Carolina Rosa da Silva

Shannon A. Bainbridge

Cory Harris

and

Kristi B. Adamo

Metabolites 2023, 13(12), 1178; https://doi.org/10.3390/metabo13121178 - 29 Nov 2023

Abstract

Physical activity (PA) and exercise have been associated with a reduced risk of cancer, obesity, and diabetes. In the context of pregnancy, maintaining an active lifestyle has been shown to decrease gestational weight gain (GWG) and lower the risk of gestational diabetes mellitus (GDM), hypertension, and macrosomia in offspring. The main pathways activated by PA include BCAAs, lipids, and bile acid metabolism, thereby improving insulin resistance in pregnant individuals. Despite these known benefits, the underlying metabolites and biological mechanisms affected by PA remain poorly understood, highlighting the need for further investigation. Metabolomics, a comprehensive study of metabolite classes, offers valuable insights into the widespread metabolic changes induced by PA. This narrative review focuses on PA metabolomics research using different analytical platforms to analyze pregnant individuals. Existing studies support the hypothesis that exercise behaviour can influence the metabolism of different populations, including pregnant individuals and their offspring. While PA has shown considerable promise in maintaining metabolic health in non-pregnant populations, our comprehension of metabolic changes in the context of a healthy pregnancy remains limited. As a result, further investigation is necessary to clarify the metabolic impact of PA within this unique group, often excluded from physiological research. Full article

(This article belongs to the Special Issue Metabolomic Advances in Promoting Exercise-Induced Metabolic Changes)

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21 pages, 7960 KiB

Open AccessArticle

In Vitro Anti-Oxidant, In Vivo Anti-Hyperglycemic, and Untargeted Metabolomics-Aided-In Silico Screening of Macroalgae Lipophilic Extracts for Anti-Diabetes Mellitus and Anti-COVID-19 Potential Metabolites

Anggit Listyacahyani Sunarwidhi

Wahyu Rahmaniar

Eka Sunarwidhi Prasedya

Hasriaton Padmi

Sri Widyastuti

Kukuh Waseso Jati Pangestu

Bq Tri Khairina Ilhami

Ervina Handayani

Ni Wayan Putri Utami

Farreh Alan Maulana

Muhammad Syach Maulad Ichfa

and

Ari Hernawan

Metabolites 2023, 13(12), 1177; https://doi.org/10.3390/metabo13121177 - 27 Nov 2023

Abstract

COVID-19 patients with comorbid DM face more severe outcomes, indicating that hyperglycemic conditions exacerbate SARS-CoV-2 infection. Negative side effects from existing hyperglycemia treatments have urged the need for safer compounds. Therefore, sourcing potential compounds from marine resources becomes a new potential approach. Algal lipids are known to possess beneficial activities for human health. However, due to limitations in analyzing large amounts of potential anti-hyperglycemic and anti-COVID-19-related marine metabolites, there is an increasing need for new approaches to reduce risks and costs. Therefore, the main aim of this study was to identify potential compounds in macroalgae Sargassum cristaefolium, Tricleocarpa cylindrica, and Ulva lactuca lipophilic extracts for treating DM and COVID-19 by an integrated approach utilizing in vitro anti-oxidant, in vivo anti-hyperglycemic, and metabolomic-integrated in silico approaches. Among them, S. cristaefolium and T. cylindrica showed potential anti-hyperglycemic activity, with S. cristaefolium showing the highest anti-oxidant activity. A GC-MS-based untargeted metabolomic analysis was used to profile the lipophilic compounds in the extracts followed by an in silico molecular docking analysis to examine the binding affinity of the compounds to anti-DM and anti-COVID-19 targets, e.g., α-amylase, α-glucosidase, ACE2, and TMPRSS2. Notably, this study reveals for the first time that steroid-derived compounds in the macroalgae T. cylindrica had higher binding activity than known ligands for all the targets mentioned. Studies on drug likeliness indicate that these compounds possess favorable drug properties. These findings suggest the potential for these compounds to be further developed to treat COVID-19 patients with comorbid DM. The information in this study would be a basis for further in vitro and in vivo analysis. It would also be useful for the development of these candidate compounds into drug formulations. Full article

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

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60 pages, 18089 KiB

Open AccessReview

Porokeratoses—A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants

Monika Bowszyc-Dmochowska

Anna Pogorzelska-Antkowiak

and

Cristian Navarrete-Dechent

Metabolites 2023, 13(12), 1176; https://doi.org/10.3390/metabo13121176 - 26 Nov 2023

Abstract

Porokeratosis is a heterogeneous group of keratinising disorders characterised by the presence of particular microscopic structural changes, namely the presence of the cornoid lamella. This structure develops as a consequence of a defective isoprenoid pathway, critical for cholesterol synthesis. Commonly recognised variants include disseminated superficial actinic porokeratosis, disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar porokeratosis (including porokeratosis palmaris et plantaris disseminata and punctate porokeratosis), linear porokeratosis, verrucous porokeratosis (also known as genitogluteal porokeratosis), follicular porokeratosis and porokeratoma. Apart from the clinical presentation and epidemiology of each variant listed, this review aims at providing up-to-date information on the precise genetic background, introduces imaging methods facilitating the diagnosis (conventional and ultraviolet-induced fluorescence dermatoscopy, reflectance confocal microscopy and pathology), discusses their oncogenic potential and reviews the literature data on the efficacy of the treatment used, including the drugs directly targeting the isoprenoid–mevalonate pathway. Full article

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

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12 pages, 2256 KiB

Open AccessArticle

Sex-Specific Relationships between HDL-Cholesterol Levels and 10-Year Mortality in Individuals with Atherosclerotic Cardiovascular Disease: A Nationwide Cohort Study of South Koreans

and

Metabolites 2023, 13(12), 1175; https://doi.org/10.3390/metabo13121175 - 26 Nov 2023

Abstract

Large epidemiological studies show U-shaped relationships between high-density lipoprotein cholesterol (HDL-C) levels and all-cause mortality in individuals without atherosclerotic cardiovascular diseases (ASCVD). Association in those with ASCVD by sex is unclear. We examined the association between HDL-C levels and 10-year all-cause mortality in subjects (≥40 years of age) with ASCVD using the 2010 National Health Insurance Service and the National Death Registry of Korea. We categorized HDL-C levels into three groups (low: <40 mg/dL for males, <50 mg/dL for females; high: 40–90 mg/dL for males, 50–90 mg/dL for females; extremely high: >90 mg/dL) and 10 mg/dL intervals. We conducted a sex-stratified and adjusted Cox proportional hazards analysis. Out of 1,711,548 individuals (54% female, mean age 61.4 years), 10-year mortality was observed in 218,252 (12.8%). Males had a higher mortality rate than females (16.2% vs. 9.8%; p < 0.001). When adjusting for age, body mass index, LDL-cholesterol, triglycerides, hypertension, diabetes, smoking, and alcohol consumption, the low and extremely high HDL-C groups had significantly higher hazard ratios for 10-year mortality compared to the high HDL-C group in males [1.183 (1.166–1.199), 1.359 (1.288–1.434)] and in females [1.153 (1.138–1.169), 1.095 (1.029–1.167)]. The frequency distribution bars for the 10-year mortality rate showed sex-specific nadirs of 50–59 mg/dL in males and 70–79 mg/dL in females. In this ASCVD cohort, the extremely high HDL-C (>90 mg/dL) group had 35.9% and 9.5% higher 10-year mortality risks than the high HDL-C group for males and females, respectively. There was a slightly U-shaped relationship between baseline HDL-C levels and a 10-year mortality rate, with earlier inflection in males than in females. Full article

(This article belongs to the Special Issue Lipid Biomarkers and Cardiometabolic Diseases)

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14 pages, 2321 KiB

Open AccessArticle

Lifestyle and Quality of Life of Women Diagnosed with Hypothyroidism in the Context of Non-Alcoholic Fatty Liver

and

Metabolites 2023, 13(12), 1174; https://doi.org/10.3390/metabo13121174 - 26 Nov 2023

Abstract

Interconnections between hypothyroidism and metabolic disturbances manifesting in the liver and body composition have not yet been comprehensively analyzed in the context of lifestyle. This study aimed to assess the selected lifestyle factors and quality of life in the context of the development of NAFL (non-alcoholic fatty liver) in women diagnosed with hypothyroidism. This study included 134 women categorized into three groups: with hypothyroidism and NAFL, with only hypothyroidism, and with only NAFL. We compared the groups concerning the KomPAN and WHOQOL-BREF questionnaires, anthropometric measurements, body composition parameters, and the stage of liver steatosis. The individuals with NAFL most frequently consumed lard, fried dishes, processed meats, red meat, sweets, and sweetened beverages. The individuals with hypothyroidism without coexisting NAFL exhibited the highest satisfaction with health. The NAFL group had the highest average body fat percentage. Selected lifestyle aspects influenced the development of NAFL in women diagnosed with hypothyroidism. Women’s overall quality of life did not vary depending on the coexisting medical conditions. Preventive programs should promote the following: the regular consumption of meals, the appropriate energy supply, physical activity, mental health support, and striving for proper body composition parameters. Full article

(This article belongs to the Special Issue Hormones and Metabolic Syndrome: Importance of Hormones in the Epidemiology, Physiopathology and Treatment of Metabolic Disorders)

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13 pages, 1318 KiB

Open AccessArticle

Baicalin Exhibits a Protective Effect against Cisplatin-Induced Cytotoxic Damage in Canine Renal Tubular Epithelial Cells

and

Metabolites 2023, 13(12), 1173; https://doi.org/10.3390/metabo13121173 - 24 Nov 2023

Abstract

Renal failure is a common chronic disease in dogs that substantially affects both their quality of life and longevity. The objective of this study was to assess the protective mechanisms of baicalin in cisplatin-induced Madin–Darby canine kidney (MDCK) epithelial cells’ apoptosis model and explore the impacts of baicalin at varying doses on various indexes, such as cisplatin-induced MDCK cell apoptosis, oxidation and antioxidation, and inflammatory factors. (Methods) MDCK cells in the logarithmic growth phase were randomly divided into a control group, a model group (20 μmol/L cisplatin), and a baicalin-protection group (20 μmol/L cisplatin + 50, 25 μmol/L baicalin) and received the corresponding treatments for 24 h. The effects of cisplatin on MDCK cell apoptosis, oxidation and antioxidation, inflammatory factors, and other indicators were studied, and the relieving effect of baicalin on cisplatin-induced MDCK cell damage was explored. Calcein/PI staining and Annexin V-FITC/PI staining showed that cisplatin induced the apoptosis of MDCK cells, while baicalin effectively reduced the damage caused by cisplatin. The ELISA results demonstrated a significant elevation in the nitric oxide (NO) and malondialdehyde (MDA) levels within the MDCK cells following treatment with cisplatin (p < 0.01). In addition, superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT) activities remarkably declined (p < 0.01), while tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) expression within the MDCK cells were apparently elevated (p < 0.01). However, baicalin treatment resulted in opposite changes in these factors. The findings suggested that baicalin exhibits potential in mitigating cisplatin-induced oxidative stress and inflammation in MDCK cells. As revealed with the Western blot results, cisplatin promoted P62, P53, and BAX protein levels, increased mTOR phosphorylation, inhibited AMPK phosphorylation, and reduced Beclin1 and BCL-2 protein levels. However, a contrasting trend was observed following baicalin treatment. Cisplatin can inhibit the activity of MDCK cells, lead to abnormalities in oxidation and antioxidation functions and cell inflammatory factors, and accelerate cell apoptosis. Moreover, baicalin can significantly alleviate the damage of cisplatin to MDCK cells. Full article

(This article belongs to the Special Issue Nutrient Metabolism Studies in Companion Animals)

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17 pages, 4923 KiB

Open AccessArticle

Aldose Reductase (AR) Mediates and Perivascular Adipose Tissue (PVAT) Modulates Endothelial Dysfunction of Short-Term High-Fat Diet Feeding in Mice

and

Metabolites 2023, 13(12), 1172; https://doi.org/10.3390/metabo13121172 - 24 Nov 2023

Abstract

Increased adiposity of both visceral and perivascular adipose tissue (PVAT) depots is associated with an increased risk of diabetes and cardiovascular disease (CVD). Under healthy conditions, PVAT modulates vascular tone via the release of PVAT-derived relaxing factors, including adiponectin and leptin. However, when PVAT expands with high-fat diet (HFD) feeding, it appears to contribute to the development of endothelial dysfunction (ED). Yet, the mechanisms by which PVAT alters vascular health are unclear. Aldose reductase (AR) catalyzes glucose reduction in the first step of the polyol pathway and has been long implicated in diabetic complications including neuropathy, retinopathy, nephropathy, and vascular diseases. To better understand the roles of both PVAT and AR in HFD-induced ED, we studied structural and functional changes in aortic PVAT induced by short-term HFD (60% kcal fat) feeding in wild type (WT) and aldose reductase-null (AR-null) mice. Although 4 weeks of HFD feeding significantly increased body fat and PVAT mass in both WT and AR-null mice, HFD feeding induced ED in the aortas of WT mice but not of AR-null mice. Moreover, HFD feeding augmented endothelial-dependent relaxation in aortas with intact PVAT only in WT and not in AR-null mice. These data indicate that AR mediates ED associated with short-term HFD feeding and that ED appears to provoke ‘compensatory changes’ in PVAT induced by HFD. As these data support that the ED of HFD feeding is AR-dependent, vascular-localized AR remains a potential target of temporally selective intervention. Full article

(This article belongs to the Special Issue Metabolic Regulation of Aldo-Keto Reductases)

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14 pages, 3775 KiB

Open AccessArticle

Correlation of Elemental Transfer, Bioactive Compounds and Antioxidant Activity on Lactuca sativa L. Grown in Soil with Functionalized CNT and HMs

and

Metabolites 2023, 13(12), 1171; https://doi.org/10.3390/metabo13121171 - 24 Nov 2023

Abstract

While heavy metals (HM) have been considered in recent decades to be the most common and problematic pollutants, the expansion of the list of pollutants due to the active use of carbon nanotubes (CNT) raises new questions about the benefit and harm of HM released to nature individually or fixed on CNT walls. A pot experiment was conducted to compare the effect of two classes of potential pollutants—metal salts of Pb, Mn, Cu, Zn, Cd, and Ni; and functionalized CNTs with COOH, MnO₂, Fe₃O₄, and MnO₂-Fe₃O₄—applied in soil, on the elemental transfer, the bioactive compounds accumulation, and the antioxidant activity in lettuce. While CNTs mainly increased the elemental transfer from soil to leaves, HM salts strongly obstructed it. In the presence of CNTs, the antioxidant activity in lettuce leaves correlated with the transfer of elements from soil to root and from root to leaves. The excess of HMs in soil induced a greater variation of the polyphenols quantity and antioxidant activity than the excess of CNTs. It might be assumed that lettuce perceived HMs as a more aggressive stressor than CNTs and more strongly activated the defense mechanism, showing the reduction of the element transfer and enhancing of total polyphenol production and antioxidant activity. Full article

(This article belongs to the Special Issue Effects of Biotic/Abiotic Stress on Plant Metabolism)

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19 pages, 1550 KiB

Open AccessReview

Lipid Metabolism and Improvement in Oilseed Crops: Recent Advances in Multi-Omics Studies

and

Metabolites 2023, 13(12), 1170; https://doi.org/10.3390/metabo13121170 - 23 Nov 2023

Abstract

Oilseed crops are rich in plant lipids that not only provide essential fatty acids for the human diet but also play important roles as major sources of biofuels and indispensable raw materials for the chemical industry. The regulation of lipid metabolism genes is a major factor affecting oil production. In this review, we systematically summarize the metabolic pathways related to lipid production and storage in plants and highlight key research advances in characterizing the genes and regulatory factors influencing lipid anabolic metabolism. In addition, we integrate the latest results from multi-omics studies on lipid metabolism to provide a reference to better understand the molecular mechanisms underlying oil anabolism in oilseed crops. Full article

(This article belongs to the Section Plant Metabolism)

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13 pages, 2498 KiB

Open AccessArticle

Evidence of 11-Hydroxy-hexahydrocannabinol and 11-Nor-9-carboxy-hexahydrocannabinol as Novel Human Metabolites of Δ⁹-Tetrahydrocannabinol

Christian Falck Jørgensen

Brian Schou Rasmussen

Kristian Linnet

and

Ragnar Thomsen

Metabolites 2023, 13(12), 1169; https://doi.org/10.3390/metabo13121169 - 23 Nov 2023

Abstract

(−)-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is the primary psychoactive compound in the Cannabis sativa plant. Δ⁹-THC undergoes extensive metabolism, with the main human phase I metabolites being 11-hydroxy-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH). Early animal studies have indicated that the 9-10 double bond may be reduced in vivo to yield 11-hydroxy-hexahydrocannabinol (11-OH-HHC) and 11-nor-9-carboxy-hexahydrocannabinol (HHC-COOH). These metabolites have not been confirmed in humans. In this study, we aimed to investigate whether this metabolic transformation occurs in humans. A range of cannabinoids and metabolites, including 11-OH-HHC and HHC-COOH, were measured in whole blood from 308 authentic forensic traffic cases, of which 222 were positive for Δ⁹-THC. HHC-COOH and 11-OH-HHC were detected in 84% and 15% of the Δ⁹-THC positive cases, respectively, and the estimated median concentration of HHC-COOH was 7%, relative to that of THC-COOH. To corroborate the in vivo findings, Δ⁹-THC and its metabolites 11-OH-THC and THC-COOH were incubated with pooled human liver microsomes. HHC-COOH was detected in both the Δ⁹-THC and 11-OH-THC incubations, while 11-OH-HHC was only detectable in the 11-OH-THC incubation. Hexahydrocannabinol was not detected in any of the incubations, indicating that it is 11-OH-THC or the corresponding aldehyde that undergoes double bond reduction with subsequent oxidation of the aliphatic alcohol to HHC-COOH. In summary, the presented data provide the first evidence of HHC-COOH and 11-OH-HHC being human phase I metabolites of Δ⁹-THC. These findings have implications for interpretation of analytical results from subjects exposed to Δ⁹-THC or HHC. Full article

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

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13 pages, 2795 KiB

Open AccessFeature PaperArticle

A Metabolomic Analysis to Assess the Responses of the Male Gonads of Mytilus galloprovincialis after Heavy Metal Exposure

and

Metabolites 2023, 13(12), 1168; https://doi.org/10.3390/metabo13121168 - 22 Nov 2023

Abstract

In recent years, metabolomics has become a valuable new resource in environmental monitoring programs based on the use of bio-indicators such as Mytilus galloprovincialis. The reproductive system is extremely susceptible to the effects of environmental pollutants, and in a previous paper, we showed metabolomic alterations in mussel spermatozoa exposed to metal chlorides of copper, nickel, and cadmium, and the mixture with these metals. In order to obtain a better overview, in the present work, we evaluated the metabolic changes in the male gonad under the same experimental conditions used in the previous work, using a metabolomic approach based on GC-MS analysis. A total of 248 endogenous metabolites were identified in the male gonads of mussels. Statistical analyses of the data, including partial least squares discriminant analysis, enabled the identification of key metabolites through the use of variable importance in projection scores. Furthermore, a metabolite enrichment analysis revealed complex and significant interactions within different metabolic pathways and between different metabolites. Particularly significant were the results on pyruvate metabolism, glycolysis, and gluconeogenesis, and glyoxylate and dicarboxylate metabolism, which highlighted the complex and interconnected nature of these biochemical processes in mussel gonads. Overall, these results add new information to the understanding of how certain pollutants may affect specific physiological functions of mussel gonads. Full article

(This article belongs to the Special Issue Trace Metal Element Metabolism in Biological Systems)

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14 pages, 1550 KiB

Open AccessFeature PaperArticle

A Metabolites Merging Strategy (MMS): Harmonization to Enable Studies’ Intercomparison

and

Metabolites 2023, 13(12), 1167; https://doi.org/10.3390/metabo13121167 - 21 Nov 2023

Abstract

Metabolomics encounters challenges in cross-study comparisons due to diverse metabolite nomenclature and reporting practices. To bridge this gap, we introduce the Metabolites Merging Strategy (MMS), offering a systematic framework to harmonize multiple metabolite datasets for enhanced interstudy comparability. MMS has three steps. Step 1: Translation and merging of the different datasets by employing InChIKeys for data integration, encompassing the translation of metabolite names (if needed). Followed by Step 2: Attributes’ retrieval from the InChIkey, including descriptors of name (title name from PubChem and RefMet name from Metabolomics Workbench), and chemical properties (molecular weight and molecular formula), both systematic (InChI, InChIKey, SMILES) and non-systematic identifiers (PubChem, CheBI, HMDB, KEGG, LipidMaps, DrugBank, Bin ID and CAS number), and their ontology. Finally, a meticulous three-step curation process is used to rectify disparities for conjugated base/acid compounds (optional step), missing attributes, and synonym checking (duplicated information). The MMS procedure is exemplified through a case study of urinary asthma metabolites, where MMS facilitated the identification of significant pathways hidden when no dataset merging strategy was followed. This study highlights the need for standardized and unified metabolite datasets to enhance the reproducibility and comparability of metabolomics studies. Full article

(This article belongs to the Section Advances in Metabolomics)

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18 pages, 1346 KiB

Open AccessReview

Tryptophan Metabolism and Gut Microbiota: A Novel Regulatory Axis Integrating the Microbiome, Immunity, and Cancer

Yingjian Hou

Jing Li

and

Shuhuan Ying

Metabolites 2023, 13(11), 1166; https://doi.org/10.3390/metabo13111166 - 20 Nov 2023

Abstract

Tryptophan metabolism and gut microbiota form an integrated regulatory axis that impacts immunity, metabolism, and cancer. This review consolidated current knowledge on the bidirectional interactions between microbial tryptophan processing and the host. We focused on how the gut microbiome controls tryptophan breakdown via the indole, kynurenine, and serotonin pathways. Dysbiosis of the gut microbiota induces disruptions in tryptophan catabolism which contribute to disorders like inflammatory conditions, neuropsychiatric diseases, metabolic syndromes, and cancer. These disruptions affect immune homeostasis, neurotransmission, and gut-brain communication. Elucidating the mechanisms of microbial tryptophan modulation could enable novel therapeutic approaches like psychobiotics and microbiome-targeted dietary interventions. Overall, further research on the microbiota-tryptophan axis has the potential to revolutionize personalized diagnostics and treatments for improving human health. Full article

(This article belongs to the Special Issue Natural Metabolites on Gut Microbiome Modulation)

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14 pages, 2213 KiB

Open AccessArticle

Metabolomics Assessment of Volume Overload-Induced Heart Failure and Oxidative Stress in the Kidney

and

Metabolites 2023, 13(11), 1165; https://doi.org/10.3390/metabo13111165 - 20 Nov 2023

Abstract

The incidence of heart failure (HF) is increasing and is associated with a poor prognosis. Moreover, HF often coexists with renal dysfunction and is associated with a worsened outcome. In many experimental studies on cardiac dysfunction, the function of other organs was either not addressed or did not show any decline. Until now, the exact mechanisms for initiating and sustaining this interaction are still unknown. The objective of this study is to use volume overload to induce cardiac hypertrophy and HF in aortocaval fistula (ACF) rat models, and to elucidate how volume overload affects metabolic changes in the kidney, even with normal renal function, in HF. The results showed the metabolic changes between control and ACF rats, including taurine metabolism; purine metabolism; glycine, serine, and threonine metabolism; glycerophospholipid metabolism; and histidine metabolism. Increasing the downstream purine metabolism from inosine to uric acid in the kidneys of ACF rats induced oxidative stress through xanthine oxidase. This result was consistent with HK-2 cells treated with xanthine and xanthine oxidase. Under oxidative stress, taurine accumulation was observed in ACF rats, indicating increased activity of the hypotaurine–taurine pathway as a defense mechanism against oxidative stress in the kidney. Another antioxidant, ascorbic acid 2-sulfate, showed lower levels in ACF rats, indicating that the kidneys experience elevated oxidative stress due to volume overload and HF. In summary, metabolic profiles are more sensitive than clinical parameters in reacting to damage to the kidney in HF. Full article

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

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16 pages, 3324 KiB

Open AccessArticle

Metabolomic Insights into the Mechanisms of Ganoderic Acid: Protection against α-Amanitin-Induced Liver Injury

and

Metabolites 2023, 13(11), 1164; https://doi.org/10.3390/metabo13111164 - 20 Nov 2023

Abstract

α-Amanitin is a representative toxin found in the Amanita genus of mushrooms, and the consumption of mushrooms containing α-Amanitin can lead to severe liver damage. In this study, we conduct toxicological experiments to validate the protective effects of Ganoderic acid A against α-amanitin-induced liver damage. By establishing animal models with different durations of Ganoderic acid A treatment and conducting a metabolomic analysis of the serum samples, we further confirmed the differences in serum metabolites between the AMA+GA and AMA groups. The analysis of differential serum metabolites after the Ganoderic acid A intervention suggests that Ganoderic acid A may intervene in α-amanitin-induced liver damage by participating in the regulation of retinol metabolism, tyrosine and tryptophan biosynthesis, fatty acid biosynthesis, sphingosine biosynthesis, spermidine and spermine biosynthesis, and branched-chain amino acid metabolism. This provides initial insights into the protective intervention mechanisms of GA against α-amanitin-induced liver damage and offers new avenues for the development of therapeutic drugs for α-Amanitin poisoning. Full article

(This article belongs to the Special Issue Association between Natural Products and the Metabolism in Humans)

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14 pages, 901 KiB

Open AccessArticle

Associations between Smoking and Smoking Cessation during Pregnancy and Newborn Metabolite Concentrations: Findings from PRAMS and INSPIRE Birth Cohorts

and

Metabolites 2023, 13(11), 1163; https://doi.org/10.3390/metabo13111163 - 19 Nov 2023

Abstract

Newborn metabolite perturbations may identify potential biomarkers or mechanisms underlying adverse, smoking-related childhood health outcomes. We assessed associations between third-trimester smoking and newborn metabolite concentrations using the Tennessee Pregnancy Risk Assessment Monitoring System (PRAMS, 2009–2019) as the discovery cohort and INSPIRE (2012–2014) as the replication cohort. Children were linked to newborn screening metabolic data (33 metabolites). Third-trimester smoking was ascertained from birth certificates (PRAMS) and questionnaires (INSPIRE). Among 8600 and 1918 mother–child dyads in PRAMS and INSPIRE cohorts, 14% and 13% of women reported third-trimester smoking, respectively. Third-trimester smoking was associated with higher median concentrations of free carnitine (C0), glycine (GLY), and leucine (LEU) at birth (PRAMS: C0: adjusted fold change 1.11 [95% confidence interval (CI) 1.08, 1.14], GLY: 1.03 [95% CI 1.01, 1.04], LEU: 1.04 [95% CI 1.03, 1.06]; INSPIRE: C0: 1.08 [95% CI 1.02, 1.14], GLY: 1.05 [95% CI 1.01, 1.09], LEU: 1.05 [95% CI 1.01, 1.09]). Smoking cessation (vs. continued smoking) during pregnancy was associated with lower median metabolite concentrations, approaching levels observed in infants of non-smoking women. Findings suggest potential pathways underlying fetal metabolic programming due to in utero smoke exposure and a potential reversible relationship of cessation. Full article

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

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