Metabolites

15 pages, 8732 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning-Based Plasma Metabolomics in Liraglutide-Treated Type 2 Diabetes Mellitus Patients and Diet-Induced Obese Mice

by Seokjae Park and Eun-Kyoung Kim

Metabolites 2024, 14(9), 483; https://doi.org/10.3390/metabo14090483 - 2 Sep 2024

Viewed by 954

Abstract

Liraglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Despite its benefits, including improved glycemic control and weight loss, the common metabolic changes induced by liraglutide and correlations between those in rodents and [...] Read more.

Liraglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Despite its benefits, including improved glycemic control and weight loss, the common metabolic changes induced by liraglutide and correlations between those in rodents and humans remain unknown. Here, we used advanced machine learning techniques to analyze the plasma metabolomic data in diet-induced obese (DIO) mice and patients with T2DM treated with liraglutide. Among the machine learning models, Support Vector Machine was the most suitable for DIO mice, and Gradient Boosting was the most suitable for patients with T2DM. Through the cross-evaluation of machine learning models, we found that liraglutide promotes metabolic shifts and interspecies correlations in these shifts between DIO mice and patients with T2DM. Our comparative analysis helped identify metabolic correlations influenced by liraglutide between humans and rodents and may guide future therapeutic strategies for T2DM and obesity. Full article

(This article belongs to the Special Issue Nutrition and Metabolism in Human Diseases 2nd Edition)

► Show Figures

Figure 1

25 pages, 5241 KiB

Open AccessEditor’s ChoiceArticle

Impact of Phenylketonuria on the Serum Metabolome and Plasma Lipidome: A Study in Early-Treated Patients

by Jorine C. van der Weerd, Annemiek M. J. van Wegberg, Theo S. Boer, Udo F. H. Engelke, Karlien L. M. Coene, Ron A. Wevers, Stephan J. L. Bakker, Pim de Blaauw, Joost Groen, Francjan J. van Spronsen and M. Rebecca Heiner-Fokkema

Metabolites 2024, 14(9), 479; https://doi.org/10.3390/metabo14090479 - 30 Aug 2024

Viewed by 986

Abstract

Background: Data suggest that metabolites, other than blood phenylalanine (Phe), better and independently predict clinical outcomes in patients with phenylketonuria (PKU). Methods: To find new biomarkers, we compared the results of untargeted lipidomics and metabolomics in treated adult PKU patients to those of [...] Read more.

Background: Data suggest that metabolites, other than blood phenylalanine (Phe), better and independently predict clinical outcomes in patients with phenylketonuria (PKU). Methods: To find new biomarkers, we compared the results of untargeted lipidomics and metabolomics in treated adult PKU patients to those of matched controls. Samples (lipidomics in EDTA-plasma (22 PKU and 22 controls) and metabolomics in serum (35 PKU and 20 controls)) were analyzed using ultra-high-performance liquid chromatography and high-resolution mass spectrometry. Data were subjected to multivariate (PCA, OPLS-DA) and univariate (Mann–Whitney U test, p < 0.05) analyses. Results: Levels of 33 (of 20,443) lipid features and 56 (of 5885) metabolite features differed statistically between PKU patients and controls. For lipidomics, findings include higher glycerolipids, glycerophospholipids, and sphingolipids species. Significantly lower values were found for sterols and glycerophospholipids species. Seven features had unknown identities. Total triglyceride content was higher. Higher Phe and Phe catabolites, tryptophan derivatives, pantothenic acid, and dipeptides were observed for metabolomics. Ornithine levels were lower. Twenty-six metabolite features were not annotated. Conclusions: This study provides insight into the metabolic phenotype of PKU patients. Additional studies are required to establish whether the observed changes result from PKU itself, diet, and/or an unknown reason. Full article

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

► Show Figures

Figure 1

16 pages, 4642 KiB

Open AccessEditor’s ChoiceArticle

Sitting Interruption Modalities during Prolonged Sitting Acutely Improve Postprandial Metabolome in a Crossover Pilot Trial among Postmenopausal Women

by Jeffrey S. Patterson, Brinda K. Rana, Haiwei Gu and Dorothy D. Sears

Metabolites 2024, 14(9), 478; https://doi.org/10.3390/metabo14090478 - 30 Aug 2024

Viewed by 1066

Abstract

Older adults sit during most hours of the day; more than 30% are considered physically inactive. The accumulation of prolonged sitting time is an exercise-independent risk factor for aging-related conditions such as cardiometabolic disease and cancer. Archival plasma samples from a randomized controlled, [...] Read more.

Older adults sit during most hours of the day; more than 30% are considered physically inactive. The accumulation of prolonged sitting time is an exercise-independent risk factor for aging-related conditions such as cardiometabolic disease and cancer. Archival plasma samples from a randomized controlled, four-condition crossover study conducted in 10 postmenopausal women with overweight or obesity were analyzed. During 5-hour conditions completed on separate days, the trial tested three interruption modalities: two-minute stands each 20 min (STS), hourly ten-minute standing breaks (Stand), hourly two-minute walks (Walk), and a controlled sit. Fasting baseline and 5-hour end point (2 h postprandial) samples were used for targeted metabolomic profiling. Condition-associated metabolome changes were compared using paired t-tests. STS eliminated the postprandial elevation of amino acid metabolites that was observed in the control. A norvaline derivative shown to have anti-hypertensive and -hyperglycemic effects was significantly increased during Stand and STS. Post-hoc testing identified 19 significantly different metabolites across the interventions. Tight metabolite clustering by condition was driven by amino acid, vasoactive, and sugar metabolites, as demonstrated by partial least squares-discriminant analyses. This exploratory study suggests that brief, low-intensity modalities of interrupting prolonged sitting can acutely elucidate beneficial cardiometabolic changes in postmenopausal women with cardiometabolic risk. Full article

(This article belongs to the Special Issue The Emerging Role of Metabolomics in Epidemiological Studies of Atherosclerosis and Cardiovascular Disease)

► Show Figures

Figure 1

24 pages, 377 KiB

Open AccessEditor’s ChoiceReview

An Overview of Pre-Analytical Factors Impacting Metabolomics Analyses of Blood Samples

by Amy Thachil, Li Wang, Rupasri Mandal, David Wishart and Tom Blydt-Hansen

Metabolites 2024, 14(9), 474; https://doi.org/10.3390/metabo14090474 - 28 Aug 2024

Cited by 1 | Viewed by 1428

Abstract

Discrepant sample processing remains a significant challenge within blood metabolomics research, introducing non-biological variation into the measured metabolome and biasing downstream results. Inconsistency during the pre-analytical phase can influence experimental processes, producing metabolome measurements that are non-representative of in vivo composition. To minimize [...] Read more.

Discrepant sample processing remains a significant challenge within blood metabolomics research, introducing non-biological variation into the measured metabolome and biasing downstream results. Inconsistency during the pre-analytical phase can influence experimental processes, producing metabolome measurements that are non-representative of in vivo composition. To minimize variation, there is a need to create and adhere to standardized pre-analytical protocols for blood samples intended for use in metabolomics analyses. This will allow for reliable and reproducible findings within blood metabolomics research. In this review article, we provide an overview of the existing literature pertaining to pre-analytical factors that influence blood metabolite measurements. Pre-analytical factors including blood tube selection, pre- and post-processing time and temperature conditions, centrifugation conditions, freeze–thaw cycles, and long-term storage conditions are specifically discussed, with recommendations provided for best practices at each stage. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

24 pages, 1235 KiB

Open AccessEditor’s ChoiceSystematic Review

Peripheral Lipid Signatures, Metabolic Dysfunction, and Pathophysiology in Schizophrenia Spectrum Disorders

by Sally Wu, Kristoffer J. Panganiban, Jiwon Lee, Dan Li, Emily C.C. Smith, Kateryna Maksyutynska, Bailey Humber, Tariq Ahmed, Sri Mahavir Agarwal, Kristen Ward and Margaret Hahn

Metabolites 2024, 14(9), 475; https://doi.org/10.3390/metabo14090475 - 28 Aug 2024

Viewed by 908

Abstract

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and [...] Read more.

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways. Full article

(This article belongs to the Special Issue Metabolomics in Disease Mechanisms and Drug Targets)

► Show Figures

Figure 1

17 pages, 1998 KiB

Open AccessEditor’s ChoiceArticle

Disposition of Oral Nalbuphine and Its Metabolites in Healthy Subjects and Subjects with Hepatic Impairment: Preliminary Modeling Results Using a Continuous Intestinal Absorption Model with Enterohepatic Recirculation

by Swati Nagar, Amale Hawi, Thomas Sciascia and Ken Korzekwa

Metabolites 2024, 14(9), 471; https://doi.org/10.3390/metabo14090471 - 27 Aug 2024

Viewed by 735

Abstract

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe [...] Read more.

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child–Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver–gallbladder–compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition. Full article

(This article belongs to the Special Issue The Role of Metabolites in Translational and Clinical Pharmacology)

► Show Figures

Figure 1

16 pages, 3813 KiB

Open AccessEditor’s ChoiceArticle

Combining the Vaginal Microbiome and Serum Metabolome to Screen for Potential Biomarkers of Early Pregnancy in Cows

by Yan Luo, Zhen Wang, Xin Zhao, Jiankang Xing, Zhiliang Chen, Wenxue Zhao, Xiaoqing Long, Yanbing Zhang and Yongbin Shao

Metabolites 2024, 14(9), 469; https://doi.org/10.3390/metabo14090469 - 26 Aug 2024

Viewed by 954

Abstract

Early pregnancy diagnostic techniques are of significant importance in livestock farming, particularly in dairy farming. This study aimed to screen artificially inseminated cows for potential biomarkers at day 21 of pregnancy using microbiota–metabolomics analysis. The microbiome analysis revealed significant changes (p < [...] Read more.

Early pregnancy diagnostic techniques are of significant importance in livestock farming, particularly in dairy farming. This study aimed to screen artificially inseminated cows for potential biomarkers at day 21 of pregnancy using microbiota–metabolomics analysis. The microbiome analysis revealed significant changes (p < 0.05) in the composition and abundance of the vaginal microbiota in cows after pregnancy. Notably, there was an increase in the abundance of [Eubacterium]_hallii_group (p < 0.05) associated with the production of short-chain fatty acids in the pregnant group compared with the non-pregnant group. Furthermore, significant alterations were observed in the serum metabolome, with notable changes in the concentrations of prolyl-hydroxyproline (Pro-Hyp) (p < 0.01) and bonactin (p < 0.01). The majority of differential metabolites clustered within the pathways of amino acid metabolism and lipid metabolism, with lipid metabolism exhibiting a higher proportion and playing a pivotal role in early pregnancy. An enzyme-linked immunosorbent assay was employed to quantify three key metabolites of the arachidonic acid pathway. The results demonstrated significant decreases in serum concentrations of leukotriene B4 (LTB4) (p < 0.05) and prostaglandin F2α (PGF2α) (p < 0.01) and no significant changes in arachidonic acid (AA) (NS) concentrations after 21 days of gestation in cows. Spearman’s correlation analysis was utilized to investigate the interrelationship between the vaginal microbiota and serum metabolites. In conclusion, the present study demonstrated that biomaterials such as bonactin, Pro-hyp, LTB4, PGF2α in serum metabolites and [Eubacterium]_hallii_group in the vaginal flora of cows could be utilized as potential biomarkers for 21 days of gestation in cows. Full article

(This article belongs to the Section Animal Metabolism)

► Show Figures

Figure 1

14 pages, 2082 KiB

Open AccessEditor’s ChoiceArticle

Untargeted Blood Lipidomics Analysis in Critically Ill Pediatric Patients with Ventilator-Associated Pneumonia: A Pilot Study

by Christina Virgiliou, Olga Begou, Argyro Ftergioti, Maria Simitsopoulou, Maria Sdougka, Emmanuel Roilides, Georgios Theodoridis, Helen Gika and Elias Iosifidis

Metabolites 2024, 14(9), 466; https://doi.org/10.3390/metabo14090466 - 23 Aug 2024

Viewed by 855

Abstract

This study aims to explore the diagnostic potential of blood lipid profiles in suspected ventilator-associated pneumonia (VAP). Early detection of VAP remains challenging for clinicians due to subjective clinical criteria and the limited effectiveness of current diagnostic tests. Blood samples from 20 patients, [...] Read more.

This study aims to explore the diagnostic potential of blood lipid profiles in suspected ventilator-associated pneumonia (VAP). Early detection of VAP remains challenging for clinicians due to subjective clinical criteria and the limited effectiveness of current diagnostic tests. Blood samples from 20 patients, with ages between 6 months and 15 years, were collected at days 1, 3, 6, and 12, and an untargeted lipidomics analysis was performed using a Ultra high Pressure Liquid Chromatography hyphenated with High Resolution Mass Spectrometry UPLC-HRMS (TIMS-TOF/MS) platform. Patients were stratified based on modified pediatric clinical pulmonary index score (mCPIS) into high (mCPIS ≥ 6, n = 12) and low (mCPIS < 6, n = 8) VAP suspicion groups. With the untargeted lipid profiling, we were able to identify 144 lipid species from different lipid groups such as glycerophospholipids, glycerolipids, and sphingolipids, in the blood of children with VAP. Multivariate and univariate statistical analyses revealed a distinct distribution of blood lipid profiles between the studied groups, indicating the potential utility of lipid biomarkers in discriminating VAP presence. Additionally, specific lipids were associated with pharyngeal culture results, notably the presence of Klebsiella pneumoniae and Staphylococcus aureus, underscoring the importance of lipid profiling in identifying the microbial etiology of VAP. Full article

(This article belongs to the Special Issue Metabolomics: An Emerging Potential Approach to Study Critical Illnesses, 2nd Edition)

► Show Figures

Figure 1

18 pages, 2528 KiB

Open AccessEditor’s ChoiceArticle

The Effects of Maternal Nutrient Restriction during Mid to Late Gestation with Realimentation on Fetal Metabolic Profiles in the Liver, Skeletal Muscle, and Blood in Sheep

by Brandon I. Smith, Manuel A. Vásquez-Hidalgo, Xiaomeng Li, Kimberly A. Vonnahme, Anna T. Grazul-Bilska, Kendall C. Swanson, Timothy E. Moore, Sarah A. Reed and Kristen E. Govoni

Metabolites 2024, 14(9), 465; https://doi.org/10.3390/metabo14090465 - 23 Aug 2024

Viewed by 1012

Abstract

Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with [...] Read more.

Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with singletons were fed 100% (CON) or 60% (RES) of requirements until day 90 of gestation, when a subset of ewes (n = 7/treatment) were euthanized, and fetal samples were collected. The remaining ewes were maintained on a current diet (CON-CON, n = 6; RES-RES, n = 7) or switched to an alternative diet (CON-RES, RES-CON; n = 7/treatment). On day 130 of gestation, the remaining ewes were euthanized, and fetal samples were collected. Fetal liver, longissimus dorsi (LD), and blood metabolites were analyzed using LC-MS/MS, and pathway enrichment analysis was conducted using MetaboAnalyst. Then, 600, 518, and 524 metabolites were identified in the liver, LD, and blood, respectively, including 345 metabolites that were present in all three. Nutrient restriction was associated with changes in amino acid, carbohydrate, lipid, and transulfuration/methionine metabolic pathways, some of which were alleviated by realimentation. Fetal age also affected metabolite abundance. The differential abundance of metabolites involved in amino acid, methionine, betaine, and bile acid metabolism could impact fetal epigenetic regulation, protein synthesis, lipid metabolism, and signaling associated with glucose and lipid metabolism. Full article

(This article belongs to the Special Issue Unlocking the Mysteries of Muscle Metabolism in the Animal Sciences)

► Show Figures

Figure 1

20 pages, 590 KiB

Open AccessEditor’s ChoiceArticle

Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women’s Health Initiative

by Sandi L. Navarro, Brian D. Williamson, Ying Huang, G. A. Nagana Gowda, Daniel Raftery, Lesley F. Tinker, Cheng Zheng, Shirley A. A. Beresford, Hayley Purcell, Danijel Djukovic, Haiwei Gu, Howard D. Strickler, Fred K. Tabung, Ross L. Prentice, Marian L. Neuhouser and Johanna W. Lampe

Metabolites 2024, 14(8), 463; https://doi.org/10.3390/metabo14080463 - 20 Aug 2024

Viewed by 1358

Abstract

Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = [...] Read more.

Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = 758 controls with available specimens (collected mean 7.2 years prior to diagnosis) in the Women’s Health Initiative Bone Mineral Density subcohort. Fasting samples were analyzed by LC-MS/MS and lipidomics in serum, plus GC-MS and NMR in 24 h urine. For feature selection, we applied LASSO regression and Super Learner algorithms. Prediction models were subsequently derived using logistic regression and Super Learner procedures, with performance assessed using cross-validation (CV). For BC, metabolites did not increase predictive performance over established risk factors (CV-AUCs~0.57). For CRC, prediction increased with the addition of metabolites (median CV-AUC across platforms increased from ~0.54 to ~0.60). Metabolites related to energy metabolism: adenosine, 2-hydroxyglutarate, N-acetyl-glycine, taurine, threonine, LPC (FA20:3), acetate, and glycerate; protein metabolism: histidine, leucic acid, isoleucine, N-acetyl-glutamate, allantoin, N-acetyl-neuraminate, hydroxyproline, and uracil; and dietary/microbial metabolites: myo-inositol, trimethylamine-N-oxide, and 7-methylguanine, consistently contributed to CRC prediction. Energy metabolism may play a key role in the development of CRC and may be evident prior to disease development. Full article

(This article belongs to the Special Issue Metabolomics-Based Biomarkers for Nutrition and Health)

► Show Figures

Graphical abstract

15 pages, 985 KiB

Open AccessEditor’s ChoiceArticle

Local and Systemic Micro-Rheological Changes during Intestinal Anastomosis Operation: A Metabolic Dependence in an Experimental Model

by Adam Varga, Adam Attila Matrai, Barbara Bedocs-Barath, Laszlo Adam Fazekas, Felipe Salignac Brasil, Aashna Mehta, Erzsebet Vanyolos, Adam Deak, Tamas Lesznyak, Katalin Peto and Norbert Nemeth

Metabolites 2024, 14(8), 458; https://doi.org/10.3390/metabo14080458 - 18 Aug 2024

Viewed by 908

Abstract

Hemorheological factors may show arterio-venous differences. Alterations in acid-base and metabolic parameters may also influence these factors. However, little is known about changes in micro-rheological parameters during abdominal surgery, influencing splanchnic circulation. In anesthetized pigs, the external jugular vein, femoral artery and vein [...] Read more.

Hemorheological factors may show arterio-venous differences. Alterations in acid-base and metabolic parameters may also influence these factors. However, little is known about changes in micro-rheological parameters during abdominal surgery, influencing splanchnic circulation. In anesthetized pigs, the external jugular vein, femoral artery and vein were cannulated unilaterally, and paramedian laparotomy was performed. In the anastomosis group, after resecting a bowel segment, end-to-end jejuno-jejunostomy was completed. Blood samples (from cannulas and by puncturing the portal vein) were taken before and after the intervention. Hematological, acid-base and blood gas parameters, metabolites, red blood cell (RBC) deformability and aggregation were determined. The highest hematocrit was found in portal blood, increasing further by the end of operation. A significant pH decrease was seen, and portal blood showed the highest lactate and creatinine concentration. The highest RBC aggregation values were found in arterial, the lowest in renal venous blood. The RBC aggregation increased with higher lactate concentration and lower pH. Osmotic gradient deformability declined, with the lowest values in portal and renal venous samples. In conclusion, micro-rheological parameters showed arterio-venous and porto-renal venous differences, influenced by oxygenation level, pH and lactate concentration. The intestinal anastomosis operation caused an immediate micro-rheological deterioration with portal venous dominancy in this experiment. Full article

(This article belongs to the Special Issue Metabolic Biomarkers and Nutrition in Degenerative Conditions and Gastrointestinal Cancer Surgery)

► Show Figures

Figure 1

12 pages, 1894 KiB

Open AccessEditor’s ChoiceArticle

Alterations in Choline Metabolism in Non-Obese Individuals with Insulin Resistance and Type 2 Diabetes Mellitus

by Haya Al-Sulaiti, Najeha Anwardeen, Sara S. Bashraheel, Khaled Naja and Mohamed A. Elrayess

Metabolites 2024, 14(8), 457; https://doi.org/10.3390/metabo14080457 - 18 Aug 2024

Cited by 1 | Viewed by 1004

Abstract

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The [...] Read more.

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The study cohort included non-obese individuals from the Qatar Biobank categorized into three groups: insulin sensitive, insulin resistant, and patients with T2D. Each group comprised 236 participants, totaling 708 individuals. Metabolomic profiling was conducted using high-resolution mass spectrometry, and statistical analyses were performed to identify metabolites associated with the progression from IS to IR and T2D. The study observed significant alterations in specific phospholipid metabolites across the IS, IR, and T2D groups. Choline phosphate, glycerophosphoethanolamine, choline, glycerophosphorylcholine (GPC), and trimethylamine N-oxide showed significant changes correlated with disease progression. A distinct metabolic signature in non-obese individuals with IR and T2D was characterized by shifts in choline metabolism, including decreased levels of choline and trimethylamine N-oxide and increased levels of phosphatidylcholines, phosphatidylethanolamines, and their degradation products. These findings suggest that alterations in choline metabolism may play a critical role in the development of glucose intolerance and insulin resistance. Targeting choline metabolism could offer potential therapeutic strategies for treating T2D. Further research is needed to validate these biomarkers and understand their functional significance in the pathogenesis of IR and T2D in non-obese populations. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics in Health and Disease: Targeted Analysis)

► Show Figures

Figure 1

16 pages, 3811 KiB

Open AccessEditor’s ChoiceArticle

Comparison of Growth and Metabolomic Profiles of Two Afforestation Cypress Species Cupressus chengiana and Platycladus orientalis Grown at Minjiang Valley in Southwest China

by Zhengqiao Liao, Lijun Zhu, Lei Liu, Jürgen Kreuzwieser, Christiane Werner and Baoguo Du

Metabolites 2024, 14(8), 453; https://doi.org/10.3390/metabo14080453 - 17 Aug 2024

Cited by 1 | Viewed by 666

Abstract

In recent years, afforestation has been conducted in China’s hot and dry valleys. However, there is still a paucity of knowledge regarding the performance of tree species in these semi-arid regions, particularly with regard to interspecies differences. The present study compares the growth [...] Read more.

In recent years, afforestation has been conducted in China’s hot and dry valleys. However, there is still a paucity of knowledge regarding the performance of tree species in these semi-arid regions, particularly with regard to interspecies differences. The present study compares the growth and metabolome characteristics of two widely used cypress species, namely Cupressus chengiana and Platycladus orientalis, grown at two sites with distinct climate conditions in the hot and dry Minjiang Valley in southwestern China. The findings indicate that C. chengiana trees exhibit superior growth rates compared to P. orientalis trees at both study sites. In comparison to P. orientalis trees, C. chengiana trees demonstrated a greater tendency to close their stomata in order to prevent water loss at the hotter and drier site, Llianghekou (LHK). Additionally, C. chengiana trees exhibited significantly lower hydrogen peroxide levels than P. orientalis trees, either due to lower production and/or higher scavenging of reactive oxygen species. C. chengiana trees accumulated soluble sugars as well as sugar derivatives, particularly those involved in sucrose and galactose metabolisms under stressful conditions. The species-specific differences were also reflected in metabolites involved in the tricarboxylic acid cycle, nitrogen, and secondary metabolisms. The metabolome profiles of the two species appeared to be influenced by the prevailing climatic conditions. It appeared that the trees at the drier and hotter site, LHK, were capable of efficient nitrogen uptake from the soil despite the low soil nitrogen concentration. This study is the first to compare the growth performance and metabolic profiles of two widely used tree species with high resistance to adverse conditions. In addition to the species-specific differences and adaptations to different sites, the present study also provides insights into potential management strategies to alleviate abiotic stress, particularly with regard to nitrogen nutrients, in the context of climate change. Full article

(This article belongs to the Special Issue Metabolic Responses of Plants to Abiotic Stress)

► Show Figures

Figure 1

14 pages, 2236 KiB

Open AccessEditor’s ChoiceArticle

Characterizing Growth-Retarded Japanese Eels (Anguilla japonica): Insights into Metabolic and Appetite Regulation

by Xiangbiao Zeng, Jingwei Liu, Yiwen Chen, Huan Han, Yanhe Liu, Bin Xie, Tianwei Jiang, Chris Kong-Chu Wong, Kang Li and Liping Liu

Metabolites 2024, 14(8), 432; https://doi.org/10.3390/metabo14080432 - 5 Aug 2024

Viewed by 1243

Abstract

During field surveys and culture procedures, large growth disparities in Anguilla japonica have been observed. However, the potential causes are unknown. This study explored differences in digestive ability, metabolic levels, and transcriptomic profiles of appetite-related genes between growth-retarded eel (GRE) and normal-growing eel [...] Read more.

During field surveys and culture procedures, large growth disparities in Anguilla japonica have been observed. However, the potential causes are unknown. This study explored differences in digestive ability, metabolic levels, and transcriptomic profiles of appetite-related genes between growth-retarded eel (GRE) and normal-growing eel (NGE) under the same rearing conditions. The results showed that growth hormone (gh) mRNA expression in GREs was considerably lower than NGEs. The levels of total protein (TP), total cholesterol (T-CHO), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), blood ammonia (BA), blood urea nitrogen (BUN), and alkaline phosphatase (ALP) in GREs were significantly lower than in NGEs. Conversely, levels of glucose (GLU), alanine aminotransferase (ALT), and aspartate transaminase (AST) were higher in GREs. The activities of SOD, CAT, and T-AOC levels were also significantly lower in GREs, as were the activities of glucose-related enzymes including hexokinase (HK), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PASE). Additionally, orexigenic genes (npy and ghrelin) were dramatically downregulated, whereas anorexigenic genes (crh and pyy) were significantly upregulated in GREs. These findings suggested that variances in growth hormone, metabolic activities, and appetite level could be associated with the different growth rates of A. japonica. The present research not only revealed the characteristics of the growth, metabolism, and appetite of GREs but also offered new perspectives into the substantial growth discrepancies in A. japonica, providing novel ideas for enhancing fish growth. Full article

(This article belongs to the Special Issue Nutrition, Metabolism and Physiology in Aquatic Animals)

► Show Figures

Figure 1

25 pages, 7059 KiB

Open AccessEditor’s ChoiceArticle

Propionic Acidemia, Methylmalonic Acidemia, and Cobalamin C Deficiency: Comparison of Untargeted Metabolomic Profiles

by Anna Sidorina, Giulio Catesini, Elisa Sacchetti, Cristiano Rizzo and Carlo Dionisi-Vici

Metabolites 2024, 14(8), 428; https://doi.org/10.3390/metabo14080428 - 2 Aug 2024

Viewed by 1083

Abstract

Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this [...] Read more.

Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this study, we used an untargeted metabolomics approach to investigate the biochemical differences and the possible connections among the pathophysiology of each disease. The significantly changed metabolites in the untargeted urine metabolomic profiles of 21 patients (seven MMA, seven PA, seven cblC) were identified through statistical analysis (p < 0.05; log2FC > |1|) and then used for annotation. Annotated features were associated with different metabolic pathways potentially involved in the disease’s development. Comparative statistics showed markedly different metabolomic profiles between MMA, PA, and cblC, highlighting the characteristic species for each disease. The most affected pathways were related to the metabolism of organic acids (all diseases), amino acids (all diseases), and glycine and its conjugates (in PA); the transsulfuration pathway; oxidative processes; and neurosteroid hormones (in cblC). The untargeted metabolomics study highlighted the presence of significant differences between the three diseases, pointing to the most relevant contrast in the cblC profile compared to MMA and PA. Some new biomarkers were proposed for PA, while novel data regarding the alterations of steroid hormone profiles and biomarkers of oxidative stress were obtained for cblC disease. The elevation of neurosteroids in cblC may indicate a potential connection with the development of ocular and neuronal deterioration. Full article

(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)

► Show Figures

Figure 1

11 pages, 4526 KiB

Open AccessEditor’s ChoiceReview

Metabolic Pathways in Hydrocephalus: Profiling with Proteomics and Advanced Imaging

by Laura May Davis and Misun Hwang

Metabolites 2024, 14(8), 412; https://doi.org/10.3390/metabo14080412 - 27 Jul 2024

Viewed by 881

Abstract

Hemorrhagic hydrocephalus is a common pathology in neonates with high mortality and morbidity. Current imaging approaches fail to capture the mechanisms behind its pathogenesis. Here, we discuss the processes underlying this pathology, the metabolic dysfunction that occurs as a result, and the ways [...] Read more.

Hemorrhagic hydrocephalus is a common pathology in neonates with high mortality and morbidity. Current imaging approaches fail to capture the mechanisms behind its pathogenesis. Here, we discuss the processes underlying this pathology, the metabolic dysfunction that occurs as a result, and the ways in which these metabolic changes inform novel methods of clinical imaging. The imaging advances described allow earlier detection of the cellular and metabolic changes, leading to better outcomes for affected neonates. Full article

(This article belongs to the Special Issue Neurometabolic Monitoring and Imaging in Pediatric Critical Care)

► Show Figures

Figure 1

12 pages, 1732 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment

by Ayenachew Bezawork-Geleta, Diane Moujalled, David P. De Souza, Vinod K. Narayana, James Dimou, Rodney Luwor and Matthew J. Watt

Metabolites 2024, 14(8), 413; https://doi.org/10.3390/metabo14080413 - 27 Jul 2024

Viewed by 1006

Abstract

Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. [...] Read more.

Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood–brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches. Full article

(This article belongs to the Section Lipid Metabolism)

► Show Figures

Figure 1

18 pages, 7899 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Profiling of Adipose Tissue in Type 2 Diabetes: Associations with Obesity and Insulin Resistance

by Argyri Mathioudaki, Giovanni Fanni, Jan W. Eriksson and Maria J. Pereira

Metabolites 2024, 14(8), 411; https://doi.org/10.3390/metabo14080411 - 26 Jul 2024

Viewed by 1161

Abstract

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) [...] Read more.

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions. Full article

(This article belongs to the Special Issue Metabolism in Diabetes Progression and Diabetic Complications)

► Show Figures

Figure 1

19 pages, 4642 KiB

Open AccessEditor’s ChoiceArticle

Photosynthetic Activities, Phytohormones, and Secondary Metabolites Induction in Plants by Prevailing Compost Residue

by Lord Abbey, Samuel Kwaku Asiedu, Sparsha Chada, Raphael Ofoe, Peter Ofori Amoako, Stella Owusu-Nketia, Nivethika Ajeethan, Anagha Pradeep Kumar and Efoo Bawa Nutsukpo

Metabolites 2024, 14(8), 400; https://doi.org/10.3390/metabo14080400 - 24 Jul 2024

Viewed by 841

Abstract

Compost residue enriches soil health with the potential to enhance plant metabolism and hormonal balance, but has not yet been studied. A study was performed to determine how prevailing compost residue induces tomato (Solanum lycopersicum ‘Scotia’) plant morpho-physiology, phytohormones, and secondary metabolites. [...] Read more.

Compost residue enriches soil health with the potential to enhance plant metabolism and hormonal balance, but has not yet been studied. A study was performed to determine how prevailing compost residue induces tomato (Solanum lycopersicum ‘Scotia’) plant morpho-physiology, phytohormones, and secondary metabolites. Plants were grown in soils with a previous history of annual (AN) and biennial (BI) compost amendments. The controls were soil without compost (C) amendment and municipal solid waste compost (MSWC) alone. The MSWC- and AN-plants had similar and significantly (p < 0.05) highest growth and photosynthetic activities compared to the BI- or C-plants. Total phenolics and lipid peroxidase activity were significantly (p < 0.001) high in BI-plants, while hydrogen peroxide and antioxidant capacity were significantly (p < 0.001) high in AN-plants. MSWC-plants recorded the highest cis-abscisic acid, followed by AN-, and then BI- and C-plants. Cis-zeatin, trans-zeatin, and isopentenyladenine ribosides were detected in the MSWC- and AN-plants but not in the BI- or C-plants. Furthermore, gibberellins GA53, GA19, and GA8 were high in the MSWC-plants, but only GA8 was detected in the AN plants and none in the others. Besides, MSWC plants exhibited the highest content of 1-aminocyclopropane-1-carboxylic acid. Conjugated salicylic acid was highest in the BI-plants, while jasmonic acid-isoleucine was highest in MSWC-plants and C plants. In conclusion, prevailing compost chemical residues upregulate plant growth, phytohormones, and metabolic compounds that can potentially increase plant growth and abiotic stress defense. Future work should investigate the flow of these compounds in plants under abiotic stress. Full article

(This article belongs to the Special Issue Plant Biotic and Abiotic Stress Responses and Tolerance: Phytohormonal and Metabolic Insights)

► Show Figures

Figure 1

15 pages, 1353 KiB

Open AccessEditor’s ChoiceArticle

Amino Acid Profile Alterations in Phenylketonuria: Implications for Clinical Practice

by Eliza Matuszewska, Joanna Matysiak, Łukasz Kałużny, Dariusz Walkowiak, Szymon Plewa, Monika Duś-Żuchowska, Natalia Rzetecka, Małgorzata Jamka, Agnieszka Klupczyńska-Gabryszak, Marcin Piorunek, Jan Matysiak and Jarosław Walkowiak

Metabolites 2024, 14(7), 397; https://doi.org/10.3390/metabo14070397 - 21 Jul 2024

Cited by 1 | Viewed by 1332

Abstract

Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and [...] Read more.

Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and compare them with results from 51 healthy subjects. A sample analysis was conducted using liquid chromatography–tandem mass spectrometry. We obtained levels of 28 substances, including amino acids, biogenic amines, carnitine, and acetylcarnitine. Kynurenine (p = 0.000001), tyrosine (p = 0.0002), asparagine (p = 0.001), proline (p = 0.012), and the kynurenine/tryptophan ratio (p < 0.000001) were identified as features that differed between the studied groups, being significantly lower in patients with PKU. Glycine (p = 0.000012), putrescine (p = 0.0055), asymmetric dimethylarginine (p = 0.01), creatinine (p = 0.035) levels, as well as the total level of glucogenic amino acids (p = 0.0018), and the ratios of putrescine/ornithine (p = 0.003) and citrulline/ornithine (p = 0.0043) were significantly higher in the PKU group. In conclusion, the amino acid profiles in patients with PKU differ significantly from those in healthy peers, with potential clinical implications. These findings confirm the importance of metabolic testing in clinical practice and highlight the necessity for adequate dietary monitoring and adjustment. Full article

(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)

► Show Figures

Figure 1

38 pages, 10637 KiB

Open AccessEditor’s ChoiceArticle

A Multiomics, Molecular Atlas of Breast Cancer Survivors

by Brent A. Bauer, Caleb M. Schmidt, Kathryn J. Ruddy, Janet E. Olson, Cem Meydan, Julian C. Schmidt, Sheena Y. Smith, Fergus J. Couch, John C. Earls, Nathan D. Price, Joel T. Dudley, Christopher E. Mason, Bodi Zhang, Stephen M. Phipps and Michael A. Schmidt

Metabolites 2024, 14(7), 396; https://doi.org/10.3390/metabo14070396 - 20 Jul 2024

Viewed by 1522

Abstract

Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched [...] Read more.

Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched healthy control cohort (N = 100) provides deep molecular phenotyping of breast cancer survivors. In this study, the BCS cohort had significantly higher polygenic risk scores for breast cancer than the control group. Carnitine and hexanoyl carnitine were significantly different. Several bile acid and fatty acid metabolites were significantly dissimilar, most notably the Omega-3 Index (O3I) (significantly lower in BCS). Proteomic and metagenomic analyses identified group and pathway differences, which warrant further investigation. The database built from this study contributes a wealth of data on breast cancer survivorship where there has been a paucity, affording the ability to identify patterns and novel insights that can drive new hypotheses and inform future research. Expansion of this database in the treatment-naïve, newly diagnosed, controlling for treatment confounders, and through the disease progression, can be leveraged to profile and contextualize breast cancer and breast cancer survivorship, potentially leading to the development of new strategies to combat this disease and improve the quality of life for its victims. Full article

(This article belongs to the Special Issue Cancer Metabolomics 2024)

► Show Figures

Figure 1

14 pages, 3096 KiB

Open AccessEditor’s ChoiceArticle

Tracking Metabolite Variations during the Degradation of Vegetables in Rice Bran Bed with Intact-State Nuclear Magnetic Resonance Spectroscopy

by Kengo Ito, Ryusei Yamamoto and Yasuyo Sekiyama

Metabolites 2024, 14(7), 391; https://doi.org/10.3390/metabo14070391 - 19 Jul 2024

Viewed by 989

Abstract

Fermentation—a process of compound degradation by microorganisms—is a traditional food processing method utilized worldwide for the long-term preservation of fresh foods. In recent years, fermented foods have gained attention as health foods. Fermentation increases the nutritional value of ingredients, producing complex flavors and [...] Read more.

Fermentation—a process of compound degradation by microorganisms—is a traditional food processing method utilized worldwide for the long-term preservation of fresh foods. In recent years, fermented foods have gained attention as health foods. Fermentation increases the nutritional value of ingredients, producing complex flavors and aromas. To identify unknown components in fermented foods, it is necessary to analyze compounds and conditions nondestructively and comprehensively. We performed intact-state nuclear magnetic resonance (NMR) spectroscopy using intermolecular single quantum coherence (iSQC) to detect the degradation of vegetables directly and nondestructively. We used two types of vegetables and a rice bran bed (nukazuke), which is used for traditional vegetable fermentation in Japan. Major metabolites such as saccharides, organic acids, and amino acids were identified in iSQC-sliced spectra. Comparing NMR signal intensities during degradation revealed the transition of metabolites characteristic of lactic acid fermentation. A pathway-based network analysis showed pathways involved in amino acid metabolism and lactic acid fermentation. Our analytical approach with intact-state NMR spectroscopy using iSQC demonstrated that it may be effective in other experimental systems, allowing for the evaluation of phenomena that have been conventionally overlooked in their true state. Full article

(This article belongs to the Special Issue Emerging Applications of Metabolomics in Fermented Food)

► Show Figures

Graphical abstract

49 pages, 2291 KiB

Open AccessEditor’s ChoiceReview

The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies

by Dimitris Kounatidis, Nikolaos Tentolouris, Natalia G. Vallianou, Iordanis Mourouzis, Irene Karampela, Theodora Stratigou, Eleni Rebelos, Marina Kouveletsou, Vasileios Stamatopoulos, Eleni Tsaroucha and Maria Dalamaga

Metabolites 2024, 14(7), 388; https://doi.org/10.3390/metabo14070388 - 17 Jul 2024

Viewed by 1739

Abstract

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and [...] Read more.

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications Full article

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

► Show Figures

Figure 1

13 pages, 1838 KiB

Open AccessEditor’s ChoiceArticle

Alteration of Fecal Microbiota, Fecal Metabolites, and Serum Metabolites in Dairy Cows with Pre-Retained Placenta

by Tao Zhou, Zhenlong Du, Zhengzhong Luo, Xiaoping Li, Dan Wu, Yixin Huang, Kang Yong, Xueping Yao, Liuhong Shen, Shumin Yu, Zuoting Yan and Suizhong Cao

Metabolites 2024, 14(7), 386; https://doi.org/10.3390/metabo14070386 - 15 Jul 2024

Viewed by 1156

Abstract

Retained placenta (RP) affects lactation and fertility in dairy cows and causes economic losses to the dairy industry. Therefore, screening for early warning of this disease is important. This study used multi omics techniques to reveal the metabolic differences of dairy cows before [...] Read more.

Retained placenta (RP) affects lactation and fertility in dairy cows and causes economic losses to the dairy industry. Therefore, screening for early warning of this disease is important. This study used multi omics techniques to reveal the metabolic differences of dairy cows before RP onset and to find potential warning markers. Fecal samples and serum samples of 90 healthy Holstein cows were collected 7 days pre-calving; 10 healthy and 10 RP cows were enrolled according to normal expulsion of fetal membranes after calving. Fecal samples were subjected to 16S rRNA sequencing and untargeted metabolomics analysis, while plasma was analyzed using targeted metabolomics. Pathogenic bacteria levels increased in the intestines of cows with RP compared to those in healthy cows. Lipid metabolites constituted the largest proportion of differential metabolites between feces and plasma. Six potential warning markers for RP in cows were identified, including two fecal microbiomics markers (Oscillospiraceae UCG-005 and Escherichia-Shigella), one fecal untargeted metabolomics marker (N-acetylmuramic acid), and three plasma targeted metabolomics markers (glycylcholic acid-3 sulfate, 7-ketolithocholic acid, and 12-ketolithocholic acid). These biomarkers can predict RP occurrence in the early perinatal period. These results lay a theoretical foundation for early nutritional intervention and pathogenesis research in dairy cows. Full article

(This article belongs to the Special Issue Metabolites in Ruminant Health)

► Show Figures

Figure 1

14 pages, 7624 KiB

Open AccessEditor’s ChoiceArticle

Non-Alcoholic Fatty Liver Disease Induced by Feeding Medium-Chain Fatty Acids Upregulates Cholesterol and Lipid Homeostatic Genes in Skeletal Muscle of Neonatal Pigs

by Samuel D. Gerrard, Fernando H. Biase, Joseph A. Yonke, Ravi Yadav, Anthony J. Shafron, Nishanth E. Sunny, David E. Gerrard and Samer W. El-Kadi

Metabolites 2024, 14(7), 384; https://doi.org/10.3390/metabo14070384 - 11 Jul 2024

Viewed by 1145

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a range of disorders characterized by lipid accumulation in hepatocytes. Although this spectrum of disorders is associated with adult obesity, recent evidence suggests that this condition could also occur independently of obesity, even in children. Previously, we [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a range of disorders characterized by lipid accumulation in hepatocytes. Although this spectrum of disorders is associated with adult obesity, recent evidence suggests that this condition could also occur independently of obesity, even in children. Previously, we reported that pigs fed a formula containing medium-chain fatty acids (MCFAs) developed hepatic steatosis and weighed less than those fed an isocaloric formula containing long-chain fatty acids (LCFAs). Our objective was to determine the association between NAFLD and the skeletal muscle transcriptome in response to energy and lipid intake. Neonatal pigs were fed one of three formulas: a control formula (CONT, n = 6) or one of two isocaloric high-energy formulas containing either long (LCFA, n = 6) or medium (MCFA, n = 6) chain fatty acids. Pigs were fed for 22 d, and tissues were collected. Body weight at 20 and 22 d was greater for LCFA-fed pigs than their CONT or MCFA counterparts (p < 0.005). Longissimus dorsi weight was greater for LCFA compared with MCFA, while CONT was intermediate (p < 0.05). Lean gain and protein deposition were greater for LCFA than for CONT and MCFA groups (p < 0.01). Transcriptomic analysis revealed 36 differentially expressed genes (DEGs) between MCFA and LCFA, 53 DEGs between MCFA and CONT, and 52 DEGs between LCFA and CONT (FDR < 0.2). Feeding formula high in MCFAs resulted in lower body and muscle weights. Transcriptomics data suggest that the reduction in growth was associated with a disruption in cholesterol metabolism in skeletal muscles. Full article

(This article belongs to the Special Issue Unlocking the Mysteries of Muscle Metabolism in the Animal Sciences)

► Show Figures

Figure 1

39 pages, 1836 KiB

Open AccessEditor’s ChoiceReview

Challenges of Spatially Resolved Metabolism in Cancer Research

by Andrew N. Lane, Richard M. Higashi and Teresa W-M. Fan

Metabolites 2024, 14(7), 383; https://doi.org/10.3390/metabo14070383 - 11 Jul 2024

Viewed by 1264

Abstract

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing [...] Read more.

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies. Full article

(This article belongs to the Special Issue Isotope-Guided Analytical Strategies for Assessing Metabolic Networks in Cancer)

► Show Figures

Figure 1

22 pages, 4088 KiB

Open AccessEditor’s ChoiceArticle

Metabolomics and Multi-Omics Determination of Potential Plasma Biomarkers in PRV-1-Infected Atlantic Salmon

by Lada Ivanova, Oscar D. Rangel-Huerta, Haitham Tartor, Maria K. Dahle, Silvio Uhlig and Christiane Kruse Fæste

Metabolites 2024, 14(7), 375; https://doi.org/10.3390/metabo14070375 - 2 Jul 2024

Viewed by 1831

Abstract

Metabolomic analysis has been explored to search for disease biomarkers in humans for some time. The application to animal species, including fish, however, is still at the beginning. In the present study, we have used targeted and untargeted metabolomics to identify metabolites in [...] Read more.

Metabolomic analysis has been explored to search for disease biomarkers in humans for some time. The application to animal species, including fish, however, is still at the beginning. In the present study, we have used targeted and untargeted metabolomics to identify metabolites in the plasma of Atlantic salmon (Salmo salar) challenged with Piscine orthoreovirus (PRV-1), aiming to find metabolites associated with the progression of PRV-1 infection into heart and skeletal muscle inflammation (HSMI). The metabolomes of control and PRV-1-infected salmon were compared at three time points during disease development by employing different biostatistical approaches. Targeted metabolomics resulted in the determination of affected metabolites and metabolic pathways, revealing a substantial impact of PRV-1 infection on lipid homeostasis, especially on several (lyso)phosphatidylcholines, ceramides, and triglycerides. Untargeted metabolomics showed a clear separation of the treatment groups at later study time points, mainly due to effects on lipid metabolism pathways. In a subsequent multi-omics approach, we combined both metabolomics datasets with previously reported proteomics data generated from the same salmon plasma samples. Data processing with DIABLO software resulted in the identification of significant metabolites and proteins that were representative of the HSMI development in the salmon. Full article

(This article belongs to the Special Issue Proteomic and Metabolomic Analyses of Fisheries and Aquaculture)

► Show Figures

Figure 1

19 pages, 1928 KiB

Open AccessEditor’s ChoiceArticle

Automated Liquid Handling Extraction and Rapid Quantification of Underivatized Amino Acids and Tryptophan Metabolites from Human Serum and Plasma Using Dual-Column U(H)PLC-MRM-MS and Its Application to Prostate Cancer Study

by Tobias Kipura, Madlen Hotze, Alexa Hofer, Anna-Sophia Egger, Lea E. Timpen, Christiane A. Opitz, Paul A. Townsend, Lee A. Gethings, Kathrin Thedieck and Marcel Kwiatkowski

Metabolites 2024, 14(7), 370; https://doi.org/10.3390/metabo14070370 - 30 Jun 2024

Viewed by 1597

Abstract

Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample [...] Read more.

Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample extraction and processing workflows as well as rapid, sensitive absolute quantification are required to identify candidate biomarkers and to improve screening methods. We developed a validated semi-automated robotic liquid extraction and processing workflow and a rapid method for absolute quantification of 20 free, underivatized AAs and six TRP metabolites using dual-column U(H)PLC-MRM-MS. The extraction and sample preparation workflow in a 96-well plate was optimized for robust, reproducible high sample throughput allowing for transfer of samples to the U(H)PLC autosampler directly without additional cleanup steps. The U(H)PLC-MRM-MS method, using a mixed-mode reversed-phase anion exchange column with formic acid and a high-strength silica reversed-phase column with difluoro-acetic acid as mobile phase additive, provided absolute quantification with nanomolar lower limits of quantification within 7.9 min. The semi-automated extraction workflow and dual-column U(H)PLC-MRM-MS method was applied to a human prostate cancer study and was shown to discriminate between treatment regimens and to identify metabolites responsible for discriminating between healthy controls and patients on active surveillance. Full article

(This article belongs to the Special Issue Metabolomics in Human Diseases and Health)

► Show Figures

Figure 1

14 pages, 3930 KiB

Open AccessEditor’s ChoiceArticle

Investigation of Rhizopus oligosporus Metabolites in Fermented Wheat Bran and Its Bio Function in Alleviating Colitis in Mice Model

by Afifah Zahra Agista, Yu-Shan Chien, Takuya Koseki, Hazuki Nagaoka, Takuto Ohnuma, Yusuke Ohsaki, Chiu-Li Yeh, Suh-Ching Yang, Ardiansyah, Slamet Budijanto, Michio Komai and Hitoshi Shirakawa

Metabolites 2024, 14(7), 359; https://doi.org/10.3390/metabo14070359 - 26 Jun 2024

Viewed by 2085

Abstract

Wheat bran (WB) is a low-value by-product of the wheat milling industry. Solid-state fermentation with Rhizopus oligosporus is performed to improve WB’s nutritional quality (RH). Twenty-five mice (11-week-old C57BL/6N male mice) were divided into three groups. The first group was fed a control [...] Read more.

Wheat bran (WB) is a low-value by-product of the wheat milling industry. Solid-state fermentation with Rhizopus oligosporus is performed to improve WB’s nutritional quality (RH). Twenty-five mice (11-week-old C57BL/6N male mice) were divided into three groups. The first group was fed a control diet (n = 8), the second group a 10% WB-supplemented diet (n = 8), and the last group had a 10% RH-supplemented diet (n = 9). The diet treatment was administered for 4 days before dextran sodium sulfate (DSS, 3% in drinking water) was administered for 9 days. RH supplementation prevented bodyweight loss and reduced the disease activity index in mice. An increase in the level of SCFAs in mouse intestines was detected post-RH supplementation, suggesting that SCFAs might have contributed to its anti-colitis effect. Metabolome analysis was conducted to explore other bioactive compounds in RH. R. oligosporus fermentation significantly increased the amounts of ergothioneine, arginine, branched-chain amino acids, and adenosine in wheat bran. All of these compounds are known to have antioxidant and anti-inflammatory capacities. These bioactive compounds might also have contributed to the RH’s ability to ameliorate DSS-induced colitis. Full article

(This article belongs to the Special Issue Emerging Applications of Metabolomics in Fermented Food)

► Show Figures

Figure 1

31 pages, 6428 KiB

Open AccessEditor’s ChoiceArticle

Changes in Plasma Free Amino Acid Profile in Endurance Athletes over a 9-Month Training Cycle

by Krzysztof Kusy, Monika Ciekot-Sołtysiak, Jan Matysiak, Agnieszka Klupczyńska-Gabryszak, Szymon Plewa, Ewa Anna Zarębska, Zenon J. Kokot, Paweł Dereziński and Jacek Zieliński

Metabolites 2024, 14(7), 353; https://doi.org/10.3390/metabo14070353 - 23 Jun 2024

Cited by 1 | Viewed by 1078

Abstract

We aimed to evaluate long-term changes in proteinogenic and non-proteinogenic plasma free amino acids (PFAA). Eleven male endurance triathletes participated in a 9-month study. Blood was collected at rest, immediately after exhaustive exercise, and during 30-min recovery, in four consecutive training phases: transition, [...] Read more.

We aimed to evaluate long-term changes in proteinogenic and non-proteinogenic plasma free amino acids (PFAA). Eleven male endurance triathletes participated in a 9-month study. Blood was collected at rest, immediately after exhaustive exercise, and during 30-min recovery, in four consecutive training phases: transition, general, specific, and competition. Twenty proteinogenic and 22 non-proteinogenic PFAAs were assayed using the LC-ESI-MS/MS technique. The structured training modified the patterns of exercise-induced PFAA response, with the competition phase being the most distinct from the others. Branched-chain amino acids (p = 0.002; η² = 0.216), phenylalanine (p = 0.015; η² = 0.153), methionine (p = 0.002; η² = 0.206), and lysine (p = 0.006; η² = 0.196) declined more rapidly between rest and exhaustion in the competition phase. Glutamine (p = 0.008; η² = 0.255), glutamate (p = 0.006; η² = 0.265), tyrosine (p = 0.001; η² = 0.195), cystine (p = 0.042; η² = 0.183), and serine (p < 0.001; η² = 0.346) levels were reduced in the competition phase. Arginine (p = 0.046; η² = 0.138) and aspartate (p = 0.011; η² = 0.171) levels were highest during exercise in the transition phase. During the competition phase, α-aminoadipic acid (p = 0.023; η² = 0.145), β-aminoisobutyric acid (p = 0.007; η² = 0.167), β-alanine (p < 0.001; η² = 0.473), and sarcosine (p = 0.017; η² = 0.150) levels increased, whereas phosphoethanolamine (p = 0.037; η² = 0.189) and taurine (p = 0.008; η² = 0.251) concentrations decreased. Overtraining indicators were not elevated. The altered PFAA profile suggests adaptations within energy metabolic pathways such as the tricarboxylic acid cycle, oxidative phosphorylation, ammonia neutralization, the purine nucleotide cycle, and buffering of intracellular H⁺ ions. The changes seem to reflect normal adaptations. Full article

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

► Show Figures

Figure 1

17 pages, 3018 KiB

Open AccessEditor’s ChoiceArticle

Disturbances in Muscle Energy Metabolism in Patients with Amyotrophic Lateral Sclerosis

by Petra Parvanovova, Petra Hnilicova, Martin Kolisek, Zuzana Tatarkova, Erika Halasova, Egon Kurca, Simona Holubcikova, Monika Turcanova Koprusakova and Eva Baranovicova

Metabolites 2024, 14(7), 356; https://doi.org/10.3390/metabo14070356 - 23 Jun 2024

Viewed by 1469

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew’s correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model. Full article

(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases)

► Show Figures

Figure 1

33 pages, 2349 KiB

Open AccessEditor’s ChoiceReview

Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies

by Chiara Sanluca, Paolo Spagnolo, Romina Mancinelli, Maria Ilenia De Bartolo, Marina Fava, Mauro Maccarrone, Simone Carotti, Eugenio Gaudio, Alessandro Leuti and Giorgio Vivacqua

Metabolites 2024, 14(7), 352; https://doi.org/10.3390/metabo14070352 - 22 Jun 2024

Viewed by 1441

Abstract

The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and [...] Read more.

The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases. Full article

(This article belongs to the Special Issue Bioactive Lipids in Neuroinflammatory Diseases)

► Show Figures

Figure 1

20 pages, 4907 KiB

Open AccessEditor’s ChoiceArticle

Metabolomics Analysis of Rabbit Plasma after Ocular Exposure to Vapors of Sulfur Mustard

by Jihéne Bouhlel, Fanny Caffin, Fanny Gros-Désormeaux, Thierry Douki, Jean-François Benoist, Florence A. Castelli, Emeline Chu-Van, Christophe Piérard, Christophe Junot and François Fenaille

Metabolites 2024, 14(7), 349; https://doi.org/10.3390/metabo14070349 - 21 Jun 2024

Cited by 1 | Viewed by 1055

Abstract

Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In [...] Read more.

Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies. Full article

(This article belongs to the Special Issue Challenges and Opportunities in Application of Mass Spectrometry for Metabolomics and Lipidomics)

► Show Figures

Graphical abstract

12 pages, 1323 KiB

Open AccessEditor’s ChoiceArticle

Characterization and Metabolism of Drug Products Containing the Cocaine-Like New Psychoactive Substances Indatraline and Troparil

by Sascha K. Manier, Paula Mumber, Josef Zapp, Niels Eckstein and Markus R. Meyer

Metabolites 2024, 14(6), 342; https://doi.org/10.3390/metabo14060342 - 18 Jun 2024

Viewed by 902

Abstract

With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine) and troparil (Methyl (1R,2S,3S,5 [...] Read more.

With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine) and troparil (Methyl (1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate) become popular as well. Both substances share a similar pharmacological profile as cocaine, while their potency is higher, and their duration of action is longer. This study investigated their metabolic fate in rat urine and incubations using pooled human liver S9 fraction (pHLS9). Indatraline formed two phase I and four phase II metabolites, with aromatic hydroxylation and glucuronidation being the main metabolic steps. All metabolites were detected in rat urine, while the parent compound was not detectable. Although low in abundance, indatraline metabolites were well identifiable due to their specific isotopic patterns caused by chlorine. Troparil formed four phase I and three phase II metabolites, with demethylation being the main metabolic step. Hydroxylation of the tropane ring, the phenyl ring, and combinations of these steps, as well as glucuronidation, were found. Phase I metabolites were detectable in rat urine and pHLS9, while phase II metabolites were only detectable in rat urine. Full article

(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)

► Show Figures

Figure 1

21 pages, 3035 KiB

Open AccessEditor’s ChoiceArticle

Phenylpropanoid Metabolism in Phaseolus vulgaris during Growth under Severe Drought

by Luis Eduardo Peña Barrena, Lili Mats, Hugh J. Earl and Gale G. Bozzo

Metabolites 2024, 14(6), 319; https://doi.org/10.3390/metabo14060319 - 31 May 2024

Cited by 1 | Viewed by 1058

Abstract

Drought limits the growth and development of Phaseolus vulgaris L. (known as common bean). Common bean plants contain various phenylpropanoids, but it is not known whether the levels of these metabolites are altered by drought. Here, BT6 and BT44, two white bean recombinant [...] Read more.

Drought limits the growth and development of Phaseolus vulgaris L. (known as common bean). Common bean plants contain various phenylpropanoids, but it is not known whether the levels of these metabolites are altered by drought. Here, BT6 and BT44, two white bean recombinant inbred lines (RILs), were cultivated under severe drought. Their respective growth and phenylpropanoid profiles were compared to those of well-irrigated plants. Both RILs accumulated much less biomass in their vegetative parts with severe drought, which was associated with more phaseollin and phaseollinisoflavan in their roots relative to well-irrigated plants. A sustained accumulation of coumestrol was evident in BT44 roots with drought. Transient alterations in the leaf profiles of various phenolic acids occurred in drought-stressed BT6 and BT44 plants, including the respective accumulation of two separate caftaric acid isomers and coutaric acid (isomer 1) relative to well-irrigated plants. A sustained rise in fertaric acid was observed in BT44 with drought stress, whereas the greater amount relative to well-watered plants was transient in BT6. Apart from kaempferol diglucoside (isomer 2), the concentrations of most leaf flavonol glycosides were not altered with drought. Overall, fine tuning of leaf and root phenylpropanoid profiles occurs in white bean plants subjected to severe drought. Full article

(This article belongs to the Special Issue Metabolic Responses of Plants to Abiotic Stress)

► Show Figures

Figure 1

14 pages, 2026 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning Metabolomics Profiling of Dietary Interventions from a Six-Week Randomised Trial

by Afroditi Kouraki, Ana Nogal, Weronika Nocun, Panayiotis Louca, Amrita Vijay, Kari Wong, Gregory A. Michelotti, Cristina Menni and Ana M. Valdes

Metabolites 2024, 14(6), 311; https://doi.org/10.3390/metabo14060311 - 29 May 2024

Cited by 1 | Viewed by 1196

Abstract

Metabolomics can uncover physiological responses to prebiotic fibre and omega-3 fatty acid supplements with known health benefits and identify response-specific metabolites. We profiled 534 stool and 799 serum metabolites in 64 healthy adults following a 6-week randomised trial comparing daily omega-3 versus inulin [...] Read more.

Metabolomics can uncover physiological responses to prebiotic fibre and omega-3 fatty acid supplements with known health benefits and identify response-specific metabolites. We profiled 534 stool and 799 serum metabolites in 64 healthy adults following a 6-week randomised trial comparing daily omega-3 versus inulin supplementation. Elastic net regressions were used to separately identify the serum and stool metabolites whose change in concentration discriminated between the two types of supplementations. Random forest was used to explore the gut microbiome’s contribution to the levels of the identified metabolites from matching stool samples. Changes in serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate and indoleproprionate levels accurately discriminated between fibre and omega-3 (area under the curve (AUC) = 0.87 [95% confidence interval (CI): 0.63–0.99]), while stool eicosapentaenoate indicated omega-3 supplementation (AUC = 0.86 [95% CI: 0.64–0.98]). Univariate analysis also showed significant increases in indoleproprionate with fibre, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, and eicosapentaenoate with omega-3. Out of these, only the change in indoleproprionate was partly explained by changes in the gut microbiome composition (AUC = 0.61 [95% CI: 0.58–0.64] and Rho = 0.21 [95% CI: 0.08–0.34]) and positively correlated with the increase in the abundance of the genus Coprococcus (p = 0.005). Changes in three metabolites discriminated between fibre and omega-3 supplementation. The increase in indoleproprionate with fibre was partly explained by shifts in the gut microbiome, particularly Coprococcus, previously linked to better health. Full article

(This article belongs to the Collection Advances in Metabolomics)

► Show Figures

Figure 1

27 pages, 3936 KiB

Open AccessEditor’s ChoiceReview

Is Lipid Metabolism of Value in Cancer Research and Treatment? Part II: Role of Specialized Pro-Resolving Mediators in Inflammation, Infections, and Cancer

by Muhammad Usman Babar, Ala F. Nassar, Xinxin Nie, Tianxiang Zhang, Jianwei He, Jacky Yeung, Paul Norris, Hideki Ogura, Anne Muldoon, Lieping Chen and Stephania Libreros

Metabolites 2024, 14(6), 314; https://doi.org/10.3390/metabo14060314 - 29 May 2024

Cited by 2 | Viewed by 2062

Abstract

Acute inflammation is the body’s first defense in response to pathogens or injury that is partially governed by a novel genus of endogenous lipid mediators that orchestrate the resolution of inflammation, coined specialized pro-resolving mediators (SPMs). SPMs, derived from omega-3-polyunstaturated fatty acids (PUFAs), [...] Read more.

Acute inflammation is the body’s first defense in response to pathogens or injury that is partially governed by a novel genus of endogenous lipid mediators that orchestrate the resolution of inflammation, coined specialized pro-resolving mediators (SPMs). SPMs, derived from omega-3-polyunstaturated fatty acids (PUFAs), include the eicosapentaenoic acid-derived and docosahexaenoic acid-derived Resolvins, Protectins, and Maresins. Herein, we review their biosynthesis, structural characteristics, and therapeutic effectiveness in various diseases such as ischemia, viral infections, periodontitis, neuroinflammatory diseases, cystic fibrosis, lung inflammation, herpes virus, and cancer, especially focusing on therapeutic effectiveness in respiratory inflammation and ischemia-related injuries. Resolvins are sub-nanomolar potent agonists that accelerate the resolution of inflammation by reducing excessive neutrophil infiltration, stimulating macrophage functions including phagocytosis, efferocytosis, and tissue repair. In addition to regulating neutrophils and macrophages, Resolvins control dendritic cell migration and T cell responses, and they also reduce the pro-inflammatory cytokines, proliferation, and metastasis of cancer cells. Importantly, several lines of evidence have demonstrated that Resolvins reduce tumor progression in melanoma, oral squamous cell carcinoma, lung cancer, and liver cancer. In addition, Resolvins enhance tumor cell debris clearance by macrophages in the tumor’s microenvironment. Resolvins, with their unique stereochemical structure, receptors, and biosynthetic pathways, provide a novel therapeutical approach to activating resolution mechanisms during cancer progression. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics and Lipidomics for Biomarker Discovery and Drug Development)

► Show Figures

Figure 1

15 pages, 893 KiB

Open AccessEditor’s ChoiceReview

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer

by Eunjin Kook and Do-Hee Kim

Metabolites 2024, 14(6), 309; https://doi.org/10.3390/metabo14060309 - 28 May 2024

Viewed by 1529

Abstract

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might [...] Read more.

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might encourage tumor progression. The reprogramming of lipid metabolism is pivotal in promoting tumorigenesis and cancer progression, with tumors often displaying significant changes in lipid profiles. This review concentrates on the essential factors that drive lipid metabolic reprogramming, which contributes to the advancement and drug resistance in melanoma. Moreover, we discuss recent advances and current therapeutic strategies that employ small-molecule inhibitors to target lipid metabolism in skin cancers, particularly those associated with inflammation and melanoma. Full article

(This article belongs to the Special Issue Advances in Cellular Metabolism and Regulation)

► Show Figures

Figure 1

20 pages, 1202 KiB

Open AccessEditor’s ChoiceArticle

The Metabolomic Profile of Microscopic Colitis Is Affected by Smoking but Not Histopathological Diagnosis, Clinical Course, Symptoms, or Treatment

by Axel Ström, Hans Stenlund and Bodil Ohlsson

Metabolites 2024, 14(6), 303; https://doi.org/10.3390/metabo14060303 - 27 May 2024

Viewed by 1050

Abstract

Microscopic colitis (MC) is classified as collagenous colitis (CC) and lymphocytic colitis (LC). Genetic associations between CC and human leucocyte antigens (HLAs) have been found, with smoking being a predisposing external factor. Smoking has a great impact on metabolomics. The aim of this [...] Read more.

Microscopic colitis (MC) is classified as collagenous colitis (CC) and lymphocytic colitis (LC). Genetic associations between CC and human leucocyte antigens (HLAs) have been found, with smoking being a predisposing external factor. Smoking has a great impact on metabolomics. The aim of this explorative study was to analyze global metabolomics in MC and to examine whether the metabolomic profile differed regarding the type and course of MC, the presence of IBS-like symptoms, treatment, and smoking habits. Of the 240 identified women with MC aged ≤73 years, 131 completed the study questionnaire; the Rome III questionnaire; and the Visual Analog Scale for Irritable Bowel Syndrome (VAS-IBS). Blood samples were analyzed by ultra-high-performance liquid chromatograph mass spectrometry (UHLC-MS/UHPLC-MSMS). The women, 63.1 (58.7–67.2) years old, were categorized based on CC (n = 76) and LC (n = 55); one episode or refractory MC; IBS-like symptoms or not; use of corticosteroids or not; and smoking habits. The only metabolomic differences found in the univariate model after adjustment for false discovery rate (FDR) were between smokers and non-smokers. Serotonin was markedly increased in smokers (p < 0.001). No clear patterns appeared when conducting a principal component analysis (PCA). No differences in the metabolomic profile were found depending on the type or clinical course of the disease, neither in the whole MC group nor in the subgroup analysis of CC. Full article

(This article belongs to the Section Advances in Metabolomics)

► Show Figures

Figure 1

14 pages, 1202 KiB

Open AccessEditor’s ChoiceArticle

Discovery of Delirium Biomarkers through Minimally Invasive Serum Molecular Fingerprinting

by Ana Viegas, Rúben Araújo, Luís Ramalhete, Cristiana Von Rekowski, Tiago A. H. Fonseca, Luís Bento and Cecília R. C. Calado

Metabolites 2024, 14(6), 301; https://doi.org/10.3390/metabo14060301 - 26 May 2024

Viewed by 1232

Abstract

Delirium presents a significant clinical challenge, primarily due to its profound impact on patient outcomes and the limitations of the current diagnostic methods, which are largely subjective. During the COVID-19 pandemic, this challenge was intensified as the frequency of delirium assessments decreased in [...] Read more.

Delirium presents a significant clinical challenge, primarily due to its profound impact on patient outcomes and the limitations of the current diagnostic methods, which are largely subjective. During the COVID-19 pandemic, this challenge was intensified as the frequency of delirium assessments decreased in Intensive Care Units (ICUs), even as the prevalence of delirium among critically ill patients increased. The present study evaluated how the serum molecular fingerprint, as acquired by Fourier-Transform InfraRed (FTIR) spectroscopy, can enable the development of predictive models for delirium. A preliminary univariate analysis of serum FTIR spectra indicated significantly different bands between 26 ICU patients with delirium and 26 patients without, all of whom were admitted with COVID-19. However, these bands resulted in a poorly performing Naïve-Bayes predictive model. Considering the use of a Fast-Correlation-Based Filter for feature selection, it was possible to define a new set of spectral bands with a wider coverage of molecular functional groups. These bands ensured an excellent Naïve-Bayes predictive model, with an AUC, a sensitivity, and a specificity all exceeding 0.92. These spectral bands, acquired through a minimally invasive analysis and obtained rapidly, economically, and in a high-throughput mode, therefore offer significant potential for managing delirium in critically ill patients. Full article

(This article belongs to the Special Issue Novel Approaches for Metabolomics in Drugs and Biomarkers Discovery)

► Show Figures

Figure 1

26 pages, 4637 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic and Physiological Effects of a Cardiorenal Protective Diet Intervention in African American Adults with Chronic Kidney Disease

by Meera J. Patel, Chiamaka Emerenini, Xuan Wang, Teodoro Bottiglieri and Heather Kitzman

Metabolites 2024, 14(6), 300; https://doi.org/10.3390/metabo14060300 - 25 May 2024

Viewed by 1121

Abstract

Chronic kidney disease (CKD) impacts 14% of adults in the United States, and African American (AA) individuals are disproportionately affected, with more than 3 times higher risk of kidney failure as compared to White individuals. This study evaluated the effects of base-producing fruit [...] Read more.

Chronic kidney disease (CKD) impacts 14% of adults in the United States, and African American (AA) individuals are disproportionately affected, with more than 3 times higher risk of kidney failure as compared to White individuals. This study evaluated the effects of base-producing fruit and vegetables (FVs) on cardiorenal outcomes in AA persons with CKD and hypertension (HTN) in a low socioeconomic area. The “Cardiorenal Protective Diet” prospective randomized trial evaluated the effects of a 6-week, community-based FV intervention compared to a waitlist control (WL) in 91 AA adults (age = 58.3 ± 10.1 years, 66% female, 48% income ≤ USD 25K). Biometric and metabolomic variables were collected at baseline and 6 weeks post-intervention. The change in health outcomes for both groups was statistically insignificant (p > 0.05), though small reductions in albumin to creatinine ratio, body mass index, total cholesterol, and systolic blood pressure were observed in the FV group. Metabolomic profiling identified key markers (p < 0.05), including C3, C5, 1-Met-His, kynurenine, PC ae 38:5, and choline, indicating kidney function decline in the WL group. Overall, delivering a directed cardiorenal protective diet intervention improved cardiorenal outcomes in AA adults with CKD and HTN. Additionally, metabolomic profiling may serve as a prognostic technique for the early identification of biomarkers as indicators for worsening CKD and increased CVD risk. Full article

(This article belongs to the Special Issue Nutritional Epidemiology and Metabolic Disorders)

► Show Figures

Figure 1

8 pages, 597 KiB

Open AccessEditor’s ChoiceArticle

Metabolites Associated with Polygenic Risk of Breast Cancer

by Elizabeth Samuels, Jaclyn Parks, Jessica Chu, Treena McDonald, John Spinelli, Rachel A. Murphy and Parveen Bhatti

Metabolites 2024, 14(6), 295; https://doi.org/10.3390/metabo14060295 - 23 May 2024

Viewed by 1107

Abstract

While hundreds of germline genetic variants have been associated with breast cancer risk, the mechanisms underlying the impacts of most of these variants on breast cancer remain uncertain. Metabolomics may offer valuable insights into the mechanisms underlying genetic risks of breast cancer. Among [...] Read more.

While hundreds of germline genetic variants have been associated with breast cancer risk, the mechanisms underlying the impacts of most of these variants on breast cancer remain uncertain. Metabolomics may offer valuable insights into the mechanisms underlying genetic risks of breast cancer. Among 143 cancer-free female participants, we used linear regression analyses to explore associations between the genetic risk of breast cancer, as determined by a previously developed polygenic risk score (PRS) that included 266 single-nucleotide polymorphisms (SNPs), and 223 measures of metabolites obtained from blood samples using nuclear magnetic resonance (NMR). A false discovery rate of 10% was applied to account for multiple comparisons. PRS was statistically significantly associated with 45 metabolite measures. These were primarily measures of very low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs), including triglycerides, cholesterol, and phospholipids. For example, the strongest effect was observed with the percent ratio of medium VLDL triglycerides to total lipids (0.53 unit increase in mean-standardized ln-transformed percent ratio per unit increase in PRS; q = 0.1). While larger-scale studies are needed to confirm these results, this exploratory study presents biologically plausible findings that are consistent with previously reported associations between lipids and breast cancer risk. If confirmed, these lipids could be targeted for lifestyle and pharmaceutical interventions among women at increased genetic risk of breast cancer. Full article

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

► Show Figures

Figure 1

17 pages, 1844 KiB

Open AccessEditor’s ChoiceArticle

Long-Term Consumption of Purified Water Altered Amino Acid, Fatty Acid and Energy Metabolism in Livers of Rats

by Jia Wang, Zhiqun Qiu, Hui Zeng, Yao Tan, Yujing Huang, Jiaohua Luo and Weiqun Shu

Metabolites 2024, 14(5), 289; https://doi.org/10.3390/metabo14050289 - 19 May 2024

Viewed by 1922

Abstract

The consumption of low-mineral water has been increasing worldwide. Drinking low-mineral water is associated with cardiovascular disease, osteopenia, and certain neurodegenerative diseases. However, the specific mechanism remains unclear. The liver metabolic alterations in rats induced by drinking purified water for 3 months were [...] Read more.

The consumption of low-mineral water has been increasing worldwide. Drinking low-mineral water is associated with cardiovascular disease, osteopenia, and certain neurodegenerative diseases. However, the specific mechanism remains unclear. The liver metabolic alterations in rats induced by drinking purified water for 3 months were investigated with a metabolomics-based strategy. Compared with the tap water group, 74 metabolites were significantly changed in the purified water group (6 increased and 68 decreased), including 29 amino acids, 11 carbohydrates, 10 fatty acids, 7 short chain fatty acids (SCFAs), and 17 other biomolecules. Eight metabolic pathways were significantly changed, namely aminoacyl–tRNA biosynthesis; nitrogen metabolism; alanine, aspartate and glutamate metabolism; arginine and proline metabolism; histidine metabolism; biosynthesis of unsaturated fatty acids; butanoate metabolism; and glycine, serine and threonine metabolism. These changes suggested that consumption of purified water induced negative nitrogen balance, reduced expression of some polyunsaturated fatty acids and SCFAs, and disturbed energy metabolism in rats. These metabolic disturbances may contribute to low-mineral-water-associated health risks. The health risk of consuming low-mineral water requires attention. Full article

(This article belongs to the Section Animal Metabolism)

► Show Figures

Figure 1

15 pages, 1576 KiB

Open AccessEditor’s ChoiceArticle

Accurate Prediction of ¹H NMR Chemical Shifts of Small Molecules Using Machine Learning

by Tanvir Sajed, Zinat Sayeeda, Brian L. Lee, Mark Berjanskii, Fei Wang, Vasuk Gautam and David S. Wishart

Metabolites 2024, 14(5), 290; https://doi.org/10.3390/metabo14050290 - 19 May 2024

Cited by 3 | Viewed by 2183

Abstract

NMR is widely considered the gold standard for organic compound structure determination. As such, NMR is routinely used in organic compound identification, drug metabolite characterization, natural product discovery, and the deconvolution of metabolite mixtures in biofluids (metabolomics and exposomics). In many cases, compound [...] Read more.

NMR is widely considered the gold standard for organic compound structure determination. As such, NMR is routinely used in organic compound identification, drug metabolite characterization, natural product discovery, and the deconvolution of metabolite mixtures in biofluids (metabolomics and exposomics). In many cases, compound identification by NMR is achieved by matching measured NMR spectra to experimentally collected NMR spectral reference libraries. Unfortunately, the number of available experimental NMR reference spectra, especially for metabolomics, medical diagnostics, or drug-related studies, is quite small. This experimental gap could be filled by predicting NMR chemical shifts for known compounds using computational methods such as machine learning (ML). Here, we describe how a deep learning algorithm that is trained on a high-quality, “solvent-aware” experimental dataset can be used to predict ¹H chemical shifts more accurately than any other known method. The new program, called PROSPRE (PROton Shift PREdictor) can accurately (mean absolute error of <0.10 ppm) predict ¹H chemical shifts in water (at neutral pH), chloroform, dimethyl sulfoxide, and methanol from a user-submitted chemical structure. PROSPRE (pronounced “prosper”) has also been used to predict ¹H chemical shifts for >600,000 molecules in many popular metabolomic, drug, and natural product databases. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

► Show Figures

Figure 1

15 pages, 5213 KiB

Open AccessEditor’s ChoiceArticle

Desorption Electrospray Ionization Mass Spectrometry Imaging Techniques Depict a Reprogramming of Energy and Purine Metabolism in the Core Brain Regions of Chronic Social Defeat Stress Mice

by Yulong Song, Fan Xiao, Jiye Aa and Guangji Wang

Metabolites 2024, 14(5), 284; https://doi.org/10.3390/metabo14050284 - 15 May 2024

Viewed by 1466

Abstract

Depression is associated with pathological changes and metabolic abnormalities in multiple brain regions. The simultaneous comprehensive and in situ detection of endogenous molecules in all brain regions is essential for a comprehensive understanding of depression pathology, which is described in this paper. A [...] Read more.

Depression is associated with pathological changes and metabolic abnormalities in multiple brain regions. The simultaneous comprehensive and in situ detection of endogenous molecules in all brain regions is essential for a comprehensive understanding of depression pathology, which is described in this paper. A method based on desorption electrospray ionization mass spectrometry imaging (DESI-MSI) technology was developed to classify mouse brain regions using characteristic lipid molecules and to detect the metabolites in mouse brain tissue samples simultaneously. The results showed that characteristic lipid molecules can be used to clearly distinguish each subdivision of the mouse brain, and the accuracy of this method is higher than that of the conventional staining method. The cerebellar cortex, medial prefrontal cortex, hippocampus, striatum, nucleus accumbens-core, and nucleus accumbens-shell exhibited the most significant differences in the chronic social defeat stress model. An analysis of metabolic pathways revealed that 13 kinds of molecules related to energy metabolism and purine metabolism exhibited significant changes. A DESI-MSI method was developed for the detection of pathological brain sections. We found, for the first time, that there are characteristic changes in the energy metabolism in the cortex and purine metabolism in the striatum, which is highly important for obtaining a deeper and more comprehensive understanding of the pathology of depression and discovering regulatory targets. Full article

(This article belongs to the Special Issue Mass Spectrometry Imaging: Theory, Methods and Applications in Biochemical and Pharmaceutical Research)

► Show Figures

Figure 1

18 pages, 5080 KiB

Open AccessEditor’s ChoiceArticle

Olaris Global Panel (OGP): A Highly Accurate and Reproducible Triple Quadrupole Mass Spectrometry-Based Metabolomics Method for Clinical Biomarker Discovery

by Masoumeh Dorrani, Jifang Zhao, Nihel Bekhti, Alessia Trimigno, Sangil Min, Jongwon Ha, Ahram Han, Elizabeth O’Day and Jurre J. Kamphorst

Metabolites 2024, 14(5), 280; https://doi.org/10.3390/metabo14050280 - 11 May 2024

Viewed by 1824

Abstract

Mass spectrometry (MS)-based clinical metabolomics is very promising for the discovery of new biomarkers and diagnostics. However, poor data accuracy and reproducibility limit its true potential, especially when performing data analysis across multiple sample sets. While high-resolution mass spectrometry has gained considerable popularity [...] Read more.

Mass spectrometry (MS)-based clinical metabolomics is very promising for the discovery of new biomarkers and diagnostics. However, poor data accuracy and reproducibility limit its true potential, especially when performing data analysis across multiple sample sets. While high-resolution mass spectrometry has gained considerable popularity for discovery metabolomics, triple quadrupole (QqQ) instruments offer several benefits for the measurement of known metabolites in clinical samples. These benefits include high sensitivity and a wide dynamic range. Here, we present the Olaris Global Panel (OGP), a HILIC LC-QqQ MS method for the comprehensive analysis of ~250 metabolites from all major metabolic pathways in clinical samples. For the development of this method, multiple HILIC columns and mobile phase conditions were compared, the robustness of the leading LC method assessed, and MS acquisition settings optimized for optimal data quality. Next, the effect of U-¹³C metabolite yeast extract spike-ins was assessed based on data accuracy and precision. The use of these U-¹³C-metabolites as internal standards improved the goodness of fit to a linear calibration curve from r² < 0.75 for raw data to >0.90 for most metabolites across the entire clinical concentration range of urine samples. Median within-batch CVs for all metabolite ratios to internal standards were consistently lower than 7% and less than 10% across batches that were acquired over a six-month period. Finally, the robustness of the OGP method, and its ability to identify biomarkers, was confirmed using a large sample set. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

► Show Figures

Figure 1

15 pages, 2491 KiB

Open AccessEditor’s ChoiceArticle

Mass Spectrometric Analysis of Purine Intermediary Metabolism Indicates Cyanide Induces Purine Catabolism in Rabbits

by Jordan Morningstar, Jangwoen Lee, Sari Mahon, Matthew Brenner and Anjali K. Nath

Metabolites 2024, 14(5), 279; https://doi.org/10.3390/metabo14050279 - 10 May 2024

Cited by 1 | Viewed by 1363

Abstract

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are [...] Read more.

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide—a classical histotoxic hypoxia agent—we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development. Full article

(This article belongs to the Special Issue Preclinical and Clinical Application of Metabolomics in Medicine)

► Show Figures

Figure 1

16 pages, 1281 KiB

Open AccessEditor’s ChoiceArticle

A Chemical Structure and Machine Learning Approach to Assess the Potential Bioactivity of Endogenous Metabolites and Their Association with Early Childhood Systemic Inflammation

by Mario Lovrić, Tingting Wang, Mads Rønnow Staffe, Iva Šunić, Kristina Časni, Jessica Lasky-Su, Bo Chawes and Morten Arendt Rasmussen

Metabolites 2024, 14(5), 278; https://doi.org/10.3390/metabo14050278 - 10 May 2024

Viewed by 1800

Abstract

Metabolomics has gained much attention due to its potential to reveal molecular disease mechanisms and present viable biomarkers. This work uses a panel of untargeted serum metabolomes from 602 children from the COPSAC2010 mother–child cohort. The annotated part of the metabolome consists of [...] Read more.

Metabolomics has gained much attention due to its potential to reveal molecular disease mechanisms and present viable biomarkers. This work uses a panel of untargeted serum metabolomes from 602 children from the COPSAC2010 mother–child cohort. The annotated part of the metabolome consists of 517 chemical compounds curated using automated procedures. We created a filtering method for the quantified metabolites using predicted quantitative structure–bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines. The metabolites measured in the children’s serums are predicted to affect specific targeted models, known for their significance in inflammation, immune function, and health outcomes. The targets from Tox21 have been used as targets with quantitative structure–activity relationships (QSARs). They were trained for ~7000 structures, saved as models, and then applied to the annotated metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation. Full article

(This article belongs to the Special Issue Machine Learning Applications in Metabolomics Analysis)

► Show Figures

Graphical abstract

21 pages, 2508 KiB

Open AccessEditor’s ChoiceReview

Salivary Metabolites Produced by Oral Microbes in Oral Diseases and Oral Squamous Cell Carcinoma: A Review

by Bina Kashyap and Arja Kullaa

Metabolites 2024, 14(5), 277; https://doi.org/10.3390/metabo14050277 - 10 May 2024

Cited by 3 | Viewed by 1961

Abstract

In recent years, salivary metabolome studies have provided new biological information and salivary biomarkers to diagnose different diseases at early stages. The saliva in the oral cavity is influenced by many factors that are reflected in the salivary metabolite profile. Oral microbes can [...] Read more.

In recent years, salivary metabolome studies have provided new biological information and salivary biomarkers to diagnose different diseases at early stages. The saliva in the oral cavity is influenced by many factors that are reflected in the salivary metabolite profile. Oral microbes can alter the salivary metabolite profile and may express oral inflammation or oral diseases. The released microbial metabolites in the saliva represent the altered biochemical pathways in the oral cavity. This review highlights the oral microbial profile and microbial metabolites released in saliva and its use as a diagnostic biofluid for different oral diseases. The importance of salivary metabolites produced by oral microbes as risk factors for oral diseases and their possible relationship in oral carcinogenesis is discussed. Full article

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

► Show Figures

Figure 1

18 pages, 1373 KiB

Open AccessEditor’s ChoiceArticle

In Vivo and In Vitro Metabolic Fate and Urinary Detectability of Five Deschloroketamine Derivatives Studied by Means of Hyphenated Mass Spectrometry

by Fabian Frankenfeld, Lea Wagmann, Anush Abelian, Jason Wallach, Adeboye Adejare, Simon D. Brandt and Markus R. Meyer

Metabolites 2024, 14(5), 270; https://doi.org/10.3390/metabo14050270 - 8 May 2024

Viewed by 1175

Abstract

Ketamine derivatives such as deschloroketamine and deschloro-N-ethyl-ketamine show dissociative and psychoactive properties and their abuse as new psychoactive substances (NPSs) has been reported. Though some information is available on the biotransformation of dissociative NPSs, data on deschloro-N-cyclopropyl-ketamine deschloro-N [...] Read more.

Ketamine derivatives such as deschloroketamine and deschloro-N-ethyl-ketamine show dissociative and psychoactive properties and their abuse as new psychoactive substances (NPSs) has been reported. Though some information is available on the biotransformation of dissociative NPSs, data on deschloro-N-cyclopropyl-ketamine deschloro-N-isopropyl-ketamine and deschloro-N-propyl-ketamine concerning their biotransformation and, thus, urinary detectability are not available. The aims of the presented work were to study the in vivo phase I and II metabolism; in vitro phase I metabolism, using pooled human liver microsomes (pHLMs); and detectability, within a standard urine screening approach (SUSA), of five deschloroketamine derivatives. Metabolism studies were conducted by collecting urine samples from male Wistar rats over a period of 24 h after their administration at 2 mg/kg body weight. The samples were analyzed using liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) and gas chromatography–mass spectrometry (GC-MS). The compounds were mainly metabolized by N-dealkylation, hydroxylation, multiple oxidations, and combinations of these metabolic reactions, as well as glucuronidation and N-acetylation. In total, 29 phase I and 10 phase II metabolites were detected. For the LC-HRMS/MS SUSA, compound-specific metabolites were identified, and suitable screening targets could be recommended and confirmed in pHLMs for all derivatives except for deschloro-N-cyclopropyl-ketamine. Using the GC-MS-based SUSA approach, only non-specific acetylated N-dealkylation metabolites could be detected. Full article

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

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI