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Metabolites, Volume 13, Issue 4 (April 2023) – 119 articles

Cover Story (view full-size image): Frailty is a geriatric syndrome that increases the risk of morbidity, disability, and death. Perturbations in amino acid metabolism contribute to muscle loss and functional decline associated with frailty and diabetes. In the cover page study, amino acid profiles of frail older adults with sarcopenia, frail older individuals with type 2 diabetes mellitus, and controls were characterized and analyzed using multivariate statistical analysis. Specific amino acid profiles were found to be associated with distinct types of frailty. Pathways potentially involved in the pathophysiology of different frailty phenotypes were also identified, which included muscle energy and interorgan metabolic regulation, nitric oxide metabolism, and oxidative stress. Amino acid profiling may serve as a valuable tool for frailty biomarker discovery. View this paper
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12 pages, 318 KiB  
Article
Thymoquinone Antifungal Activity against Candida glabrata Oral Isolates from Patients in Intensive Care Units—An In Vitro Study
by Noura Nouri, Shahla Roudbar Mohammadi, Justin Beardsley, Peyman Aslani, Fatemeh Ghaffarifar, Maryam Roudbary and Célia Fortuna Rodrigues
Metabolites 2023, 13(4), 580; https://doi.org/10.3390/metabo13040580 - 21 Apr 2023
Cited by 2 | Viewed by 1716
Abstract
The number of Candida spp. infections and drug resistance are dramatically increasing worldwide, particularly among immunosuppressed patients, and it is urgent to find novel compounds with antifungal activity. In this work, the antifungal and antibiofilm activity of thymoquinone (TQ), a key bioactive constituent [...] Read more.
The number of Candida spp. infections and drug resistance are dramatically increasing worldwide, particularly among immunosuppressed patients, and it is urgent to find novel compounds with antifungal activity. In this work, the antifungal and antibiofilm activity of thymoquinone (TQ), a key bioactive constituent of black cumin seed Nigella sativa L., was evaluated against Candida glabrata, a WHO ‘high-priority’ pathogen. Then, its effect on the expression of C. glabrata EPA6 and EPA7 genes (related to biofilm adhesion and development, respectively) were analyzed. Swab samples were taken from the oral cavity of 90 hospitalized patients in ICU wards, transferred to sterile falcon tubes, and cultured on Sabouraud Dextrose Agar (SDA) and Chromagar Candida for presumptive identification. Next, a 21-plex PCR was carried out for the confirmation of species level. C. glabrata isolates underwent antifungal drug susceptibility testing against fluconazole (FLZ), itraconazole (ITZ), amphotericin B (AMB), and TQ according to the CLSI microdilution method (M27, A3/S4). Biofilm formation was measured by an MTT assay. EPA6 and EPA7 gene expression was assessed by real-time PCR. From the 90 swab samples, 40 isolates were identified as C. glabrata with the 21-plex PCR. Most isolates were resistant to FLZ (n = 29, 72.5%), whereas 12.5% and 5% were ITZ and AMB resistant, respectively. The minimum inhibitory concentration (MIC50) of TQ against C. glabrata was 50 µg/mL. Importantly, TQ significantly inhibited the biofilm formation of C. glabrata isolates, and EPA6 gene expression was reduced significantly at MIC50 concentration of TQ. TQ seems to have some antifungal, antibiofilm (adhesion) effect on C. glabrata isolates, showing that this plant secondary metabolite is a promising agent to overcome Candida infections, especially oral candidiasis. Full article
(This article belongs to the Special Issue The Natural Products in the Treatment and Prevention of Diseases)
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20 pages, 1684 KiB  
Article
Urinary 1H NMR Metabolomic Analysis of Prenatal Maternal Stress Due to a Natural Disaster Reveals Metabolic Risk Factors for Non-Communicable Diseases: The QF2011 Queensland Flood Study
by Joshua P. Heynen, Rebecca R. McHugh, Naveenjyote S. Boora, Gabrielle Simcock, Sue Kildea, Marie-Paule Austin, David P. Laplante, Suzanne King, Tony Montina and Gerlinde A. S. Metz
Metabolites 2023, 13(4), 579; https://doi.org/10.3390/metabo13040579 - 21 Apr 2023
Cited by 1 | Viewed by 1882
Abstract
Prenatal stress alters fetal programming, potentially predisposing the ensuing offspring to long-term adverse health outcomes. To gain insight into environmental influences on fetal development, this QF2011 study evaluated the urinary metabolomes of 4-year-old children (n = 89) who were exposed to the [...] Read more.
Prenatal stress alters fetal programming, potentially predisposing the ensuing offspring to long-term adverse health outcomes. To gain insight into environmental influences on fetal development, this QF2011 study evaluated the urinary metabolomes of 4-year-old children (n = 89) who were exposed to the 2011 Queensland flood in utero. Proton nuclear magnetic resonance spectroscopy was used to analyze urinary metabolic fingerprints based on maternal levels of objective hardship and subjective distress resulting from the natural disaster. In both males and females, differences were observed between high and low levels of maternal objective hardship and maternal subjective distress groups. Greater prenatal stress exposure was associated with alterations in metabolites associated with protein synthesis, energy metabolism, and carbohydrate metabolism. These alterations suggest profound changes in oxidative and antioxidative pathways that may indicate a higher risk for chronic non-communicable diseases such obesity, insulin resistance, and diabetes, as well as mental illnesses, including depression and schizophrenia. Thus, prenatal stress-associated metabolic biomarkers may provide early predictors of lifetime health trajectories, and potentially serve as prognostic markers for therapeutic strategies in mitigating adverse health outcomes. Full article
(This article belongs to the Topic Metabolism and Health)
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16 pages, 2312 KiB  
Review
Influence of Cholesterol on the Regulation of Osteoblast Function
by Alena Akhmetshina, Dagmar Kratky and Elizabeth Rendina-Ruedy
Metabolites 2023, 13(4), 578; https://doi.org/10.3390/metabo13040578 - 21 Apr 2023
Cited by 4 | Viewed by 2216
Abstract
Bone is a dynamic tissue composed of cells, an extracellular matrix, and mineralized portion. Osteoblasts are responsible for proper bone formation and remodeling, and function. These processes are endergonic and require cellular energy in the form of adenosine triphosphate (ATP), which is derived [...] Read more.
Bone is a dynamic tissue composed of cells, an extracellular matrix, and mineralized portion. Osteoblasts are responsible for proper bone formation and remodeling, and function. These processes are endergonic and require cellular energy in the form of adenosine triphosphate (ATP), which is derived from various sources such as glucose, fatty acids, and amino acids. However, other lipids such as cholesterol have also been found to play a critical role in bone homeostasis and can also contribute to the overall bioenergetic capacity of osteoblasts. In addition, several epidemiological studies have found a link between elevated cholesterol, cardiovascular disease, an enhanced risk of osteoporosis, and increased bone metastasis in cancer patients. This review focuses on how cholesterol, its derivatives, and cholesterol-lowering medications (statins) regulate osteoblast function and bone formation. It also highlights the molecular mechanisms underlying the cholesterol–osteoblast crosstalk. Full article
(This article belongs to the Section Cell Metabolism)
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27 pages, 1696 KiB  
Review
Multinuclear Magnetic Resonance Spectroscopy at Ultra-High-Field: Assessing Human Cerebral Metabolism in Healthy and Diseased States
by Pandichelvam Veeraiah and Jacobus F. A. Jansen
Metabolites 2023, 13(4), 577; https://doi.org/10.3390/metabo13040577 - 19 Apr 2023
Cited by 2 | Viewed by 2020
Abstract
The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy [...] Read more.
The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy and a wide variety of intermediate metabolites. Since cerebral metabolic alterations have been repeatedly implicated in several brain disorders, understanding changes in metabolite levels and corresponding cell-specific neurotransmitter fluxes through different substrate utilization may highlight the underlying mechanisms that can be exploited to diagnose or treat various brain disorders. Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure tissue metabolism in vivo. 1H-MRS is widely applied in research at clinical field strengths (≤3T) to measure mostly high abundant metabolites. In addition, X-nuclei MRS including, 13C, 2H, 17O, and 31P, are also very promising. Exploiting the higher sensitivity at ultra-high-field (>4T; UHF) strengths enables obtaining unique insights into different aspects of the substrate metabolism towards measuring cell-specific metabolic fluxes in vivo. This review provides an overview about the potential role of multinuclear MRS (1H, 13C, 2H, 17O, and 31P) at UHF to assess the cerebral metabolism and the metabolic insights obtained by applying these techniques in both healthy and diseased states. Full article
(This article belongs to the Special Issue Brain Substrate Metabolism in Health and Disease)
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16 pages, 3362 KiB  
Article
Study of the Metabolic Profiles of “Indazole-3-Carboxamide” and “Isatin Acyl Hydrazone” (OXIZID) Synthetic Cannabinoids in a Human Liver Microsome Model Using UHPLC-QE Orbitrap MS
by Jiahong Xiang, Di Wen, Junbo Zhao, Ping Xiang, Yan Shi and Chunling Ma
Metabolites 2023, 13(4), 576; https://doi.org/10.3390/metabo13040576 - 18 Apr 2023
Cited by 1 | Viewed by 1386
Abstract
Unregulated core structures, “isatin acyl hydrazones” (OXIZIDs), have quietly appeared on the market since China legislated to ban seven general core scaffolds of synthetic cannabinoids (SCs). The fast evolution of SCs presents clinical and forensic toxicologists with challenges. Due to extensive metabolism, the [...] Read more.
Unregulated core structures, “isatin acyl hydrazones” (OXIZIDs), have quietly appeared on the market since China legislated to ban seven general core scaffolds of synthetic cannabinoids (SCs). The fast evolution of SCs presents clinical and forensic toxicologists with challenges. Due to extensive metabolism, the parent compounds are barely detectable in urine. Therefore, studies on the metabolism of SCs are essential to facilitate their detection in biological matrices. The aim of the present study was to elucidate the metabolism of two cores, “indazole-3-carboxamide” (e.g., ADB-BUTINACA) and “isatin acyl hydrazone” (e.g., BZO-HEXOXIZID). The in vitro phase I and phase II metabolism of these six SCs was investigated by incubating 10 mg/mL pooled human liver microsomes with co-substrates for 3 h at 37 °C, and then analyzing the reaction mixture using ultrahigh-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. In total, 9 to 34 metabolites were detected for each SC, and the major biotransformations were hydroxylation, dihydrodiol formation (MDMB-4en-PINACA and BZO-4en-POXIZID), oxidative defluorination (5-fluoro BZO-POXIZID), hydrogenation, hydrolysis, dehydrogenation, oxidate transformation to ketone and carboxylate, N-dealkylation, and glucuronidation. Comparing our results with previous studies, the parent drugs and SC metabolites formed via hydrogenation, carboxylation, ketone formation, and oxidative defluorination were identified as suitable biomarkers. Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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20 pages, 1181 KiB  
Review
Melatonin and TGF-β-Mediated Release of Extracellular Vesicles
by Klaudia Piekarska, Klaudia Bonowicz, Alina Grzanka, Łukasz M. Jaworski, Russel J. Reiter, Andrzej T. Slominski, Kerstin Steinbrink, Konrad Kleszczyński and Maciej Gagat
Metabolites 2023, 13(4), 575; https://doi.org/10.3390/metabo13040575 - 18 Apr 2023
Cited by 1 | Viewed by 1858
Abstract
The immune system, unlike other systems, must be flexible and able to “adapt” to fully cope with lurking dangers. The transition from intracorporeal balance to homeostasis disruption is associated with activation of inflammatory signaling pathways, which causes modulation of the immunology response. Chemotactic [...] Read more.
The immune system, unlike other systems, must be flexible and able to “adapt” to fully cope with lurking dangers. The transition from intracorporeal balance to homeostasis disruption is associated with activation of inflammatory signaling pathways, which causes modulation of the immunology response. Chemotactic cytokines, signaling molecules, and extracellular vesicles act as critical mediators of inflammation and participate in intercellular communication, conditioning the immune system’s proper response. Among the well-known cytokines allowing for the development and proper functioning of the immune system by mediating cell survival and cell-death-inducing signaling, the tumor necrosis factor α (TNF-α) and transforming growth factor β (TGF-β) are noteworthy. The high bloodstream concentration of those pleiotropic cytokines can be characterized by anti- and pro-inflammatory activity, considering the powerful anti-inflammatory and anti-oxidative stress capabilities of TGF-β known from the literature. Together with the chemokines, the immune system response is also influenced by biologically active chemicals, such as melatonin. The enhanced cellular communication shows the relationship between the TGF-β signaling pathway and the extracellular vesicles (EVs) secreted under the influence of melatonin. This review outlines the findings on melatonin activity on TGF-β-dependent inflammatory response regulation in cell-to-cell communication leading to secretion of the different EV populations. Full article
(This article belongs to the Special Issue Melatonin and Vitamin: Perspectives for Diseases and Health)
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12 pages, 742 KiB  
Article
Hospitalization Burden of Patients with Kidney Stones and Metabolic Comorbidities in Spain during the Period 2017–2020
by Javier Sáenz-Medina, Jesús San Román, María Rodríguez-Monsalve, Manuel Durán, Joaquín Carballido, Dolores Prieto and Ángel Gil Miguel
Metabolites 2023, 13(4), 574; https://doi.org/10.3390/metabo13040574 - 18 Apr 2023
Viewed by 1211
Abstract
Nephrolithiasis has become an increasing worldwide problem during the last decades. Metabolic syndrome, its components, and related dietary factors have been pointed out as responsible for the increasing incidence. The objective of this study was to evaluate the trends in the hospitalization rates [...] Read more.
Nephrolithiasis has become an increasing worldwide problem during the last decades. Metabolic syndrome, its components, and related dietary factors have been pointed out as responsible for the increasing incidence. The objective of this study was to evaluate the trends in the hospitalization rates of patients with nephrolithiasis, hospitalization features, costs, and how metabolic syndrome traits influence both the prevalence and complications of lithiasic patients. An observational retrospective study was conducted by analyzing hospitalization records from the minimum basic data set, including all patient hospitalizations in Spain in which nephrolithiasis has been coded as a main diagnosis or as a comorbidity during the period 2017–2020. A total of 106,407 patients were hospitalized and coded for kidney or ureteral lithiasis in this period. The mean age of the patients was 58.28 years (CI95%: 58.18–58.38); 56.8% were male, and the median length of stay was 5.23 days (CI95%: 5.06–5.39). In 56,884 (53.5%) patients, kidney or ureteral lithiasis were coded as the main diagnosis; the rest of the patients were coded mostly as direct complications of kidney or ureteral stones, such as “non-pecified renal colic”, “acute pyelonephritis”, or “tract urinary infection”. The hospitalization rate was 56.7 (CI95%: 56.3–57.01) patients per 100,000 inhabitants, showing neither a significant increasing nor decreasing trend, although it was influenced by the COVID-19 pandemic. The mortality rate was 1.6% (CI95%: 1.5–1.7), which was higher, if lithiasis was coded as a comorbidity (3.4% CI95%: 3.2–3.6). Metabolic syndrome diagnosis component codes increased the association with kidney lithiasis when age was higher, reaching the highest in the eighth decade of life. Age, diabetes, and hypertension or lithiasis coded as a comorbidity were the most common causes associated with the mortality of lithiasic patients. In Spain, the hospitalization rate of kidney lithiasis has remained stable during the period of study. The mortality rate in lithiasic patients is higher in elderly patients, being associated with urinary tract infections. Comorbidity conditions such as diabetes mellitus and hypertension are mortality predictors. Full article
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16 pages, 771 KiB  
Review
Antioxidants as Protection against Reactive Oxidative Stress in Inflammatory Bowel Disease
by Sara Jarmakiewicz-Czaja, Katarzyna Ferenc and Rafał Filip
Metabolites 2023, 13(4), 573; https://doi.org/10.3390/metabo13040573 - 18 Apr 2023
Cited by 7 | Viewed by 1521
Abstract
Inflammatory bowel disease (IBD) belongs to a group of chronic diseases characterised by periods of exacerbation and remission. Despite many studies and observations, its aetiopathogenesis is still not fully understood. The interactions of genetic, immunological, microbiological, and environmental factors can induce disease development [...] Read more.
Inflammatory bowel disease (IBD) belongs to a group of chronic diseases characterised by periods of exacerbation and remission. Despite many studies and observations, its aetiopathogenesis is still not fully understood. The interactions of genetic, immunological, microbiological, and environmental factors can induce disease development and progression, but there is still a lack of information on these mechanisms. One of the components that can increase the risk of occurrence of IBD, as well as disease progression, is oxidative stress. Oxidative stress occurs when there is an imbalance between reactive oxygen species (ROS) and antioxidants. The endogenous and exogenous components that make up the body’s antioxidant defence can significantly affect IBD prophylaxis and reduce the risk of exacerbation by neutralising and removing ROS, as well as influencing the inflammatory state. Full article
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21 pages, 3132 KiB  
Article
Hepatic Insulin Resistance Model in the Male Wistar Rat Using Exogenous Insulin Glargine Administration
by Victor Enrique Sarmiento-Ortega, Diana Moroni-González, Alfonso Diaz, Miguel Ángel García-González, Eduardo Brambila and Samuel Treviño
Metabolites 2023, 13(4), 572; https://doi.org/10.3390/metabo13040572 - 18 Apr 2023
Viewed by 1481
Abstract
Metabolic diseases are a worldwide health problem. Insulin resistance (IR) is their distinctive hallmark. For their study, animal models that provide reliable information are necessary, permitting the analysis of the cluster of abnormalities that conform to it, its progression, and time-dependent molecular modifications. [...] Read more.
Metabolic diseases are a worldwide health problem. Insulin resistance (IR) is their distinctive hallmark. For their study, animal models that provide reliable information are necessary, permitting the analysis of the cluster of abnormalities that conform to it, its progression, and time-dependent molecular modifications. We aimed to develop an IR model by exogenous insulin administration. The effective dose of insulin glargine to generate hyperinsulinemia but without hypoglycemia was established. Then, two groups (control and insulin) of male Wistar rats of 100 g weight were formed. The selected dose (4 U/kg) was administered for 15, 30, 45, and 60 days. Zoometry, a glucose tolerance test, insulin response, IR, and the serum lipid profile were assessed. We evaluated insulin signaling, glycogenesis and lipogenesis, redox balance, and inflammation in the liver. Results showed an impairment of glucose tolerance, dyslipidemia, hyperinsulinemia, and peripheral and time-dependent selective IR. At the hepatic level, insulin signaling was impaired, resulting in reduced hepatic glycogen levels and triglyceride accumulation, an increase in the ROS level with MAPK-ERK1/2 response, and mild pro-oxidative microenvironmental sustained by MT, GSH, and GR activity. Hepatic IR coincides with additions in MAPK-p38, NF-κB, and zoometric changes. In conclusion, daily insulin glargine administration generated a progressive IR model. At the hepatic level, the IR was combined with oxidative conditions but without inflammation. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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11 pages, 398 KiB  
Article
The Influence of Metabolic Factors in Patients with Chronic Viral Hepatitis C Who Received Oral Antiviral Treatment
by Oana Irina Gavril, Radu Sebastian Gavril, Florin Mitu, Otilia Gavrilescu, Iolanda Valentina Popa, Diana Tatarciuc, Andrei Drugescu, Andrei Catalin Oprescu, Andreea Gherasim, Laura Mihalache and Irina Mihaela Esanu
Metabolites 2023, 13(4), 571; https://doi.org/10.3390/metabo13040571 - 17 Apr 2023
Cited by 1 | Viewed by 1255
Abstract
Hepatic diseases pose a significant public health concern. Regardless of the severity of hepatic fibrosis, treatment is recommended for all chronic hepatitis C virus (HCV) subjects. However, fibrosis and steatosis assessment remains crucial for evaluating the prognosis, progression, and hepatic disease monitoring, particularly [...] Read more.
Hepatic diseases pose a significant public health concern. Regardless of the severity of hepatic fibrosis, treatment is recommended for all chronic hepatitis C virus (HCV) subjects. However, fibrosis and steatosis assessment remains crucial for evaluating the prognosis, progression, and hepatic disease monitoring, particularly following the treatment with direct-acting antivirals (DAAs). The aim of our study was to evaluate the impact of metabolic factors and the extent of hepatic fibrosis and fat accumulation in chronic HCV infection subjects. Additionally, another objective was to investigate modifications regarding fibrosis and steatosis three months after a successful sustained viral response (SVR). A total of 100 patients with compensated cirrhosis and chronic hepatitis C (CHC) were included in our study. These patients received treatment with DAA and underwent Fibromax assessment before and three months post SVR. After DAA treatment, a significant decrease was observed in the degree of hepatic fibrosis and hepatic steatosis. This regression was evident three months following the achievement of SVR. Chronic viral hepatitis C may trigger risk factors for metabolic syndromes, such as obesity and type 2 diabetes mellitus. Conclusions: It is crucial to monitor metabolic factors and take timely measures to prevent or treat metabolic syndrome in patients with chronic viral hepatitis C. Full article
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13 pages, 283 KiB  
Article
Correlations between Cognitive Evaluation and Metabolic Syndrome
by Andrei Cătălin Oprescu, Cristina Grosu and Walther Bild
Metabolites 2023, 13(4), 570; https://doi.org/10.3390/metabo13040570 - 17 Apr 2023
Cited by 1 | Viewed by 1035
Abstract
One of the most common medical diseases is metabolic syndrome (MetS), which encompasses diabetes and obesity. It has a systemic effect, which has long-lasting consequences on the body that are still not fully understood. The objectives of the study were to investigate the [...] Read more.
One of the most common medical diseases is metabolic syndrome (MetS), which encompasses diabetes and obesity. It has a systemic effect, which has long-lasting consequences on the body that are still not fully understood. The objectives of the study were to investigate the association between the severity of metabolic imbalances, insulin resistance, leptin concentration, and the presence of cognitive disorders and to assess the possible protective role of some classes of drugs used in the treatment of type 2 diabetes mellitus (T2D) and dyslipidemia in order to identify a viable target in the near future. The study included 148 diabetic patients. Standardized tests for the evaluation of cognition, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), were applied to all study participants. Serum concentrations of leptin and insulin were determined using the enzyme-linked immunosorbent assay method (ELISA), and insulin resistance was calculated using the homeostatic model assessment for insulin resistance (HOMA-IR). We found that MMSE and MoCA scores were associated with anthropometric parameters, and MoCA was associated with glycemic control parameters and leptin levels. Further research is needed in order to establish the magnitude of the relationship between metabolic syndrome components and cognitive decline in diabetic patients. Full article
13 pages, 1989 KiB  
Article
Cerebrospinal Fluid Metabolomics: Pilot Study of Using Metabolomics to Assess Diet and Metabolic Interventions in Alzheimer’s Disease and Mild Cognitive Impairment
by Angela J. Hanson, William A. Banks, Lisa F. Bettcher, Robert Pepin, Daniel Raftery, Sandi L. Navarro and Suzanne Craft
Metabolites 2023, 13(4), 569; https://doi.org/10.3390/metabo13040569 - 17 Apr 2023
Viewed by 1798
Abstract
Brain glucose hypometabolism is an early sign of Alzheimer’s disease (AD), and interventions which offset this deficit, such as ketogenic diets, show promise as AD therapeutics. Conversely, high-fat feeding may exacerbate AD risk. We analyzed the metabolomic profile of cerebrospinal fluid (CSF) in [...] Read more.
Brain glucose hypometabolism is an early sign of Alzheimer’s disease (AD), and interventions which offset this deficit, such as ketogenic diets, show promise as AD therapeutics. Conversely, high-fat feeding may exacerbate AD risk. We analyzed the metabolomic profile of cerebrospinal fluid (CSF) in a pilot study of older adults who underwent saline and triglyceride (TG) infusions. Older adults (12 cognitively normal (CN), age 65.3 ± 8.1, and 9 with cognitive impairment (CI), age 70.9 ± 8.6) underwent a 5 h TG or saline infusion on different days using a random crossover design; CSF was collected at the end of infusion. Aqueous metabolites were measured using a targeted mass spectroscopy (MS) platform focusing on 215 metabolites from over 35 different metabolic pathways. Data were analyzed using MetaboAnalyst 4.0 and SAS. Of the 215 targeted metabolites, 99 were detectable in CSF. Only one metabolite significantly differed by treatment: the ketone body 3-hydroxybutyrate (HBA). Post hoc analyses showed that HBA levels were associated with age and markers of metabolic syndrome and demonstrated different correlation patterns for the two treatments. When analyzed by cognitive diagnosis group, TG-induced increases in HBA were over 3 times higher for those with cognitive impairment (change score CN +9.8 uM ± 8.3, CI +32.4 ± 7.4, p = 0.0191). Interestingly, individuals with cognitive impairment had higher HBA levels after TG infusion than those with normal cognition. These results suggest that interventions that increase plasma ketones may lead to higher brain ketones in groups at risk for AD and should be confirmed in larger intervention studies. Full article
(This article belongs to the Section Nutrition and Metabolism)
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15 pages, 1942 KiB  
Article
Effect of Grape Seed Proanthocyanidins on Fat Metabolism and Adipocytokines in Obese Rats
by Pengxiang Gao, Luoyun Fang, Yucong Pan and Linshu Jiang
Metabolites 2023, 13(4), 568; https://doi.org/10.3390/metabo13040568 - 17 Apr 2023
Cited by 1 | Viewed by 1321
Abstract
This study aimed to investigate the effect of Grape Seed Proanthocyanidin (GSP) on fat metabolism and adipocytokines in obese rats. Fifty 5-week-old rats were randomly assigned to five groups (n = 10 per group) and given either a basal diet, a high-fat [...] Read more.
This study aimed to investigate the effect of Grape Seed Proanthocyanidin (GSP) on fat metabolism and adipocytokines in obese rats. Fifty 5-week-old rats were randomly assigned to five groups (n = 10 per group) and given either a basal diet, a high-fat diet, or a high-fat diet supplemented with GSP (25, 50, and 100 mg/d) per group. The experiment lasted for five weeks, including a one-week adaptation period and a four-week treatment period. At the end of the experimental period, serum and adipose tissue samples were collected and analyzed. Additionally, we co-cultured 3T3-L1 preadipocytes with varying concentrations of GSP to explore its effect on adipocyte metabolism. The results demonstrated that GSP supplementation reduced weight, daily gain, and abdominal fat weight coefficient (p < 0.05). It also decreased levels of glucose, cholesterol (TC) (p < 0.05), triglycerides (TG) (p < 0.05), low-density lipoprotein (LDL), cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6) in adipose tissue. Furthermore, GSP addition caused adipocyte crumpling in vitro and reduced the mRNA expression of COX-2, LEP, and TNF-α in adipocytes in vitro. These findings provide compelling evidence for exploring the role of GSP in the prevention and treatment of obesity and related diseases. Full article
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21 pages, 21467 KiB  
Article
A Metabolomics-Based Study on the Discriminative Classification Models and Toxicological Mechanism of Estazolam Fatal Intoxication
by Xiaohui Dai, Rui Bai, Bing Xie, Jiahong Xiang, Xingang Miao, Yan Shi, Feng Yu, Bin Cong, Di Wen and Chunling Ma
Metabolites 2023, 13(4), 567; https://doi.org/10.3390/metabo13040567 - 17 Apr 2023
Cited by 1 | Viewed by 1518
Abstract
Fatal intoxication with sedative-hypnotic drugs is increasing yearly. However, the plasma drug concentration data for fatal intoxication involving these substances are not systematic and even overlap with the intoxication group. Therefore, developing a more precise and trustworthy approach to determining the cause of [...] Read more.
Fatal intoxication with sedative-hypnotic drugs is increasing yearly. However, the plasma drug concentration data for fatal intoxication involving these substances are not systematic and even overlap with the intoxication group. Therefore, developing a more precise and trustworthy approach to determining the cause of death is necessary. This study analyzed mice plasma and brainstem samples using the liquid chromatography-high resolution tandem mass spectrometry (LC-HR MS/MS)-based metabolomics method to create discriminative classification models for estazolam fatal intoxication (EFI). The most perturbed metabolic pathway between the EFI and EIND (estazolam intoxication non-death) was examined, Both EIND and EFI groups were administered 500 mg of estazolam per 100 g of body weight. Mice that did not die beyond 8 hours were treated with cervical dislocation and were classified into the EIND groups; the lysine degradation pathway was verified by qPCR (Quantitative Polymerase Chain Reaction), metabolite quantitative and TEM (transmission electron microscopy) analysis. Non-targeted metabolomics analysis with EFI were the experimental group and four hypoxia-related non-drug-related deaths (NDRDs) were the control group. Mass spectrometry data were analyzed with Compound Discoverer (CD) 3.1 software and multivariate statistical analyses were performed using the online software MetaboAnalyst 5.0. After a series of analyses, the results showed the discriminative classification model in plasma was composed of three endogenous metabolites: phenylacetylglycine, creatine and indole-3-lactic acid, and in the brainstem was composed of palmitic acid, creatine, and indole-3-lactic acid. The specificity validation results showed that both classification models distinguished between the other four sedatives–hypnotics, with an area under ROC curve (AUC) of 0.991, and the classification models had an extremely high specificity. When comparing different doses of estazolam, the AUC value of each group was larger than 0.80, and the sensitivity was also high. Moreover, the stability results showed that the AUC value was equal to or very close to 1 in plasma samples stored at 4 °C for 0, 1, 5, 10 and 15 days; the predictive power of the classification model was stable within 15 days. The results of lysine degradation pathway validation revealed that the EFI group had the highest lysine and saccharopine concentrations (mean (ng/mg) = 1.089 and 1.2526, respectively) when compared to the EIND and control group, while the relative expression of SDH (saccharopine dehydrogenase) showed significantly lower in the EFI group (mean = 1.206). Both of these results were statistically significant. Furthermore, TEM analysis showed that the EFI group had the more severely damaged mitochondria. This work gives fresh insights into the toxicological processes of estazolam and a new method for identifying EFI-related causes of mortality. Full article
(This article belongs to the Section Advances in Metabolomics)
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17 pages, 3141 KiB  
Article
Qualitative Analysis of Polyphenols in Glycerol Plant Extracts Using Untargeted Metabolomics
by Joseph Robert Nastasi, Venea Dara Daygon, Vassilis Kontogiorgos and Melissa A. Fitzgerald
Metabolites 2023, 13(4), 566; https://doi.org/10.3390/metabo13040566 - 17 Apr 2023
Cited by 3 | Viewed by 2038
Abstract
Glycerol is a reliable solvent for extracting polyphenols from food and waste products. There has been an increase in the application of glycerol over benchmark alcoholic solvents such as ethanol and methanol for natural product generation because of its non-toxic nature and high [...] Read more.
Glycerol is a reliable solvent for extracting polyphenols from food and waste products. There has been an increase in the application of glycerol over benchmark alcoholic solvents such as ethanol and methanol for natural product generation because of its non-toxic nature and high extraction efficiency. However, plant extracts containing a high glycerol concentration are unsuitable for mass spectrometry-based investigation utilising electrospray ionization, inhibiting the ability to analyse compounds of interest. In this investigation, a solid phase extraction protocol is outlined for removing glycerol from plant extracts containing a high concentration of glycerol and their subsequent analysis of polyphenols using ultra-performance liquid chromatography coupled with quadrupole time of flight tandem mass spectrometry. Using this method, glycerol-based extracts of Queen Garnet Plum (Prunus salicina) were investigated and compared to ethanolic extracts. Anthocyanins and flavonoids in high abundance were found in both glycerol and ethanol extracts. The polyphenol metabolome of Queen Garnet Plum was 53% polyphenol glycoside derivatives and 47% polyphenols in their aglycone forms. Furthermore, 56% of the flavonoid derivates were found to be flavonoid glycosides, and 44% were flavonoid aglycones. In addition, two flavonoid glycosides not previously found in Queen Garnet Plum were putatively identified: Quercetin-3-O-xyloside and Quercetin-3-O-rhamnoside. Full article
(This article belongs to the Section Food Metabolomics)
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16 pages, 1156 KiB  
Article
A Machine-Learning Approach to Target Clinical and Biological Features Associated with Sarcopenia: Findings from Northern and Southern Italian Aging Populations
by Roberta Zupo, Alessia Moroni, Fabio Castellana, Clara Gasparri, Feliciana Catino, Luisa Lampignano, Simone Perna, Maria Lisa Clodoveo, Rodolfo Sardone and Mariangela Rondanelli
Metabolites 2023, 13(4), 565; https://doi.org/10.3390/metabo13040565 - 17 Apr 2023
Cited by 10 | Viewed by 1819
Abstract
Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia [...] Read more.
Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia was carried out across older populations from northern and southern Italy. A dataset of adults >65 years of age (n = 1971) made up of clinical records and fluid markers from either a clinical-based subset from northern Italy (Pavia) and a population-based subset from southern Italy (Apulia) was employed (n = 1312 and n = 659, respectively). Body composition data obtained by dual-energy X-ray absorptiometry (DXA) were used for the diagnosis of sarcopenia, given by the presence of either low muscle mass (i.e., an SMI < 7.0 kg/m2 for males or <5.5 kg/m2 for females) and of low muscle strength (i.e., an HGS < 27 kg for males or <16 kg for females) or low physical performance (i.e., an SPPB ≤ 8), according to the EWGSOP2 panel guidelines. A machine-learning feature-selection approach, the random forest (RF), was used to identify the most predictive features of sarcopenia in the whole dataset, considering every possible interaction among variables and taking into account nonlinear relationships that classical models could not evaluate. Then, a logistic regression was performed for comparative purposes. Leading variables of association to sarcopenia overlapped in the two population subsets and included SMI, HGS, FFM of legs and arms, and sex. Using parametric and nonparametric whole-sample analysis to investigate the clinical variables and biological markers most associated with sarcopenia, we found that albumin, CRP, folate, and age ranked high according to RF selection, while sex, folate, and vitamin D were the most relevant according to logistics. Albumin, CRP, vitamin D, and serum folate should not be neglected in screening for sarcopenia in the aging population. Better preventive medicine settings in geriatrics are urgently needed to lessen the impact of sarcopenia on the general health, quality of life, and medical care delivery of the aging population. Full article
(This article belongs to the Special Issue Epidemiology, Nutrition and Metabolism)
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22 pages, 2768 KiB  
Review
Is the Novel Slot Blot a Useful Method for Quantification of Intracellular Advanced Glycation End-Products?
by Takanobu Takata
Metabolites 2023, 13(4), 564; https://doi.org/10.3390/metabo13040564 - 16 Apr 2023
Cited by 3 | Viewed by 2667
Abstract
Various types of advanced glycation end-products (AGEs) have been identified and studied. I have reported a novel slot blot analysis to quantify two types of AGEs, glyceraldehyde-derived AGEs, also called toxic AGEs (TAGE), and 1,5-anhydro-D-fructose AGEs. The traditional slot blot method has been [...] Read more.
Various types of advanced glycation end-products (AGEs) have been identified and studied. I have reported a novel slot blot analysis to quantify two types of AGEs, glyceraldehyde-derived AGEs, also called toxic AGEs (TAGE), and 1,5-anhydro-D-fructose AGEs. The traditional slot blot method has been used for the detection and quantification of RNA, DNA, and proteins since around 1980 and is one of the more commonly used analog technologies to date. However, the novel slot blot analysis has been used to quantify AGEs from 2017 to 2022. Its characteristics include (i) use of a lysis buffer containing tris-(hydroxymethyl)-aminomethane, urea, thiourea, and 3-[3-(cholamidopropyl)-dimetyl-ammonio]-1-propane sulfonate (a lysis buffer with a composition similar to that used in two-dimensional gel electrophoresis-based proteomics analysis); (ii) probing of AGE-modified bovine serum albumin (e.g., standard AGE aliquots); and (iii) use of polyvinylidene difluoride membranes. In this review, the previously used quantification methods of slot blot, western blot, immunostaining, enzyme-linked immunosorbent assay, gas chromatography–mass spectrometry (MS), matrix-associated laser desorption/ionization–MS, and liquid chromatography–electrospray ionization–MS are described. Lastly, the advantages and disadvantages of the novel slot blot compared to the above methods are discussed. Full article
(This article belongs to the Section Nutrition and Metabolism)
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19 pages, 684 KiB  
Review
Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation
by Evelina Maines, Michele Moretti, Nicola Vitturi, Giorgia Gugelmo, Ilaria Fasan, Livia Lenzini, Giovanni Piccoli, Vincenza Gragnaniello, Arianna Maiorana, Massimo Soffiati, Alberto Burlina and Roberto Franceschi
Metabolites 2023, 13(4), 563; https://doi.org/10.3390/metabo13040563 - 16 Apr 2023
Viewed by 2179
Abstract
The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver [...] Read more.
The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms “propionic acidemia” OR “propionate” AND “cardiomyopathy” OR “Long QT syndrome”. We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation–contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin–angiotensin–aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options. Full article
(This article belongs to the Special Issue Rare Disorders—Challenging and Underdiagnosed)
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14 pages, 2530 KiB  
Article
Physical Performance and Skeletal Muscle Transcriptional Adaptations Are Not Impacted by Exercise Training Frequency in Mice with Lower Extremity Peripheral Artery Disease
by Jessica Lavier, Karima Bouzourène, Grégoire P. Millet, Lucia Mazzolai and Maxime Pellegrin
Metabolites 2023, 13(4), 562; https://doi.org/10.3390/metabo13040562 - 16 Apr 2023
Cited by 2 | Viewed by 2047
Abstract
Exercise training is an important therapeutic strategy for lower extremity peripheral artery disease (PAD). However, the effects of different exercise frequency on physiological adaptations remain unknown. Thus, this study compared the effects of a 7-week moderate-intensity aerobic training performed either three or five [...] Read more.
Exercise training is an important therapeutic strategy for lower extremity peripheral artery disease (PAD). However, the effects of different exercise frequency on physiological adaptations remain unknown. Thus, this study compared the effects of a 7-week moderate-intensity aerobic training performed either three or five times/week on skeletal muscle gene expression and physical performance in mice with PAD. Hypercholesterolemic male ApoE-deficient mice were subjected to unilateral iliac artery ligation and randomly assigned to sedentary or exercise training regimens either three or five times/week. Physical performance was assessed using a treadmill test to exhaustion. Expression of genes related to glucose and lipid metabolism, mitochondrial biogenesis, muscle fiber-type, angiogenesis, and inflammation was analyzed in non-ischemic and ischemic gastrocnemius muscles by real-time polymerase chain reaction. Physical performance was improved to the same extent in both exercise groups. For gene expression patterns, no statistical differences were observed between three or five times/week exercised mice, both in the non-ischemic and ischemic muscles. Our data show that exercising three to five times a week induces similar beneficial effects on performance. Those results are associated with muscular adaptations that remain identical between the two frequencies. Full article
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15 pages, 2344 KiB  
Article
Impact of Maternal Weight Gain on the Newborn Metabolome
by Teresa Guixeres-Esteve, Francisco Ponce-Zanón, José Manuel Morales, Empar Lurbe, Julio Alvarez-Pitti and Daniel Monleón
Metabolites 2023, 13(4), 561; https://doi.org/10.3390/metabo13040561 - 15 Apr 2023
Cited by 2 | Viewed by 1472
Abstract
Pre-pregnancy obesity and excessive gestational weight gain (GWG) appear to affect birth weight and the offspring’s risk of obesity and disease later in life. However, the identification of the mediators of this relationship, could be of clinical interest, taking into account the presence [...] Read more.
Pre-pregnancy obesity and excessive gestational weight gain (GWG) appear to affect birth weight and the offspring’s risk of obesity and disease later in life. However, the identification of the mediators of this relationship, could be of clinical interest, taking into account the presence of other confounding factors, such as genetics and other shared influences. The aim of this study was to evaluate the metabolomic profiles of infants at birth (cord blood) and 6 and 12 months after birth to identify offspring metabolites associated with maternal GWG. Nuclear Magnetic Resonance (NMR) metabolic profiles were measured in 154 plasma samples from newborns (82 cord blood samples) and in 46 and 26 of these samples at 6 months and 12 months of age, respectively. The levels of relative abundance of 73 metabolomic parameters were determined in all the samples. We performed univariate and machine-learning analysis of the association between the metabolic levels and maternal weight gain adjusted for mother‘s age, Body Mass Index (BMI), diabetes, diet adherence and infant sex. Overall, our results showed differences, both at the univariate level and in the machine-learning models, between the offspring, according to the tertiles of maternal weight gain. Some of these differences were resolved at 6 and 12 months of age, whereas some others remained. Lactate and leucine were the metabolites with the strongest and longest association with maternal weight gain during pregnancy. Leucine, as well as other significant metabolites, have been associated in the past with metabolic wellness in both general and obese populations. Our results suggest that the metabolic changes associated to excessive GWG are present in children from early life. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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39 pages, 4479 KiB  
Review
Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence
by Roopak Murali, Vaishnavi Balasubramaniam, Satish Srinivas, Sandhya Sundaram, Ganesh Venkatraman, Sudha Warrier, Arun Dharmarajan and Rajesh Kumar Gandhirajan
Metabolites 2023, 13(4), 560; https://doi.org/10.3390/metabo13040560 - 15 Apr 2023
Cited by 4 | Viewed by 3030
Abstract
Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) [...] Read more.
Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer. Full article
(This article belongs to the Topic Cancer Cell Metabolism)
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21 pages, 4455 KiB  
Article
Comparative LC-ESIMS-Based Metabolite Profiling of Senna italica with Senna alexandrina and Evaluating Their Hepatotoxicity
by Elaheh Zibaee, Maryam Akaberi, Zahra Tayarani-Najaran, Karel Nesměrák, Martin Štícha, Naghmeh Shahraki, Behjat Javadi and Seyed Ahmad Emami
Metabolites 2023, 13(4), 559; https://doi.org/10.3390/metabo13040559 - 13 Apr 2023
Cited by 2 | Viewed by 1820
Abstract
Senna Mill. (Fabaceae) is an important medicinal plant distributed worldwide. Senna alexandrina (S. alexandrina), the officinal species of the genus, is one of the most well-known herbal medicines traditionally used to treat constipation and digestive diseases. Senna italica (S. italica [...] Read more.
Senna Mill. (Fabaceae) is an important medicinal plant distributed worldwide. Senna alexandrina (S. alexandrina), the officinal species of the genus, is one of the most well-known herbal medicines traditionally used to treat constipation and digestive diseases. Senna italica (S. italica), another species of the genus, is native to an area ranging from Africa to the Indian subcontinent, including Iran. In Iran, this plant has been used traditionally as a laxative. However, very little phytochemical information and pharmacological reports investigating its safety of use are available. In the current study, we compared LC-ESIMS metabolite profiles of the methanol extract of S. italica with that of S. alexandrina and measured the content of sennosides A and B as the biomarkers in this genus. By this, we were able to examine the feasibility of using S. italica as a laxative agent like S. alexandrina. In addition, the hepatotoxicity of both species was evaluated against HepG2 cancer cell lines using HPLC-based activity profiling to localize the hepatotoxic components and evaluate their safety of use. Interestingly, the results showed that the phytochemical profiles of the plants were similar but with some differences, particularly in their relative contents. Glycosylated flavonoids, anthraquinones, dianthrones, benzochromenones, and benzophenones constituted the main components in both species. Nevertheless, some differences, particularly in the relative amount of some compounds, were observed. According to the LC-MS results, the amounts of sennoside A in S. alexandrina and S. italica were 1.85 ± 0.095% and 1.00 ± 0.38%, respectively. Moreover, the amounts of sennoside B in S. alexandrina and S. italica were 0.41 ± 0.12 % and 0.32 ± 0.17%, respectively. Furthermore, although both extracts showed significant hepatotoxicity at concentrations of 50 and 100 µg/mL, they were almost non-toxic at lower concentrations. Taken together, according to the results, the metabolite profiles of S. italica and S. alexandrina showed many compounds in common. However, further phytochemical, pharmacological, and clinical studies are necessary to examine the efficacy and safety of S. italica as a laxative agent. Full article
(This article belongs to the Special Issue Metabolomics in Natural Products)
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13 pages, 16006 KiB  
Article
Quality Control of Targeted Plasma Lipids in a Large-Scale Cohort Study Using Liquid Chromatography–Tandem Mass Spectrometry
by Akiyoshi Hirayama, Takamasa Ishikawa, Haruka Takahashi, Sanae Yamanaka, Satsuki Ikeda, Aya Hirata, Sei Harada, Masahiro Sugimoto, Tomoyoshi Soga, Masaru Tomita and Toru Takebayashi
Metabolites 2023, 13(4), 558; https://doi.org/10.3390/metabo13040558 - 13 Apr 2023
Cited by 2 | Viewed by 1134
Abstract
High-throughput metabolomics has enabled the development of large-scale cohort studies. Long-term studies require multiple batch-based measurements, which require sophisticated quality control (QC) to eliminate unexpected bias to obtain biologically meaningful quantified metabolomic profiles. Liquid chromatography–mass spectrometry was used to analyze 10,833 samples in [...] Read more.
High-throughput metabolomics has enabled the development of large-scale cohort studies. Long-term studies require multiple batch-based measurements, which require sophisticated quality control (QC) to eliminate unexpected bias to obtain biologically meaningful quantified metabolomic profiles. Liquid chromatography–mass spectrometry was used to analyze 10,833 samples in 279 batch measurements. The quantified profile included 147 lipids including acylcarnitine, fatty acids, glucosylceramide, lactosylceramide, lysophosphatidic acid, and progesterone. Each batch included 40 samples, and 5 QC samples were measured for 10 samples of each. The quantified data from the QC samples were used to normalize the quantified profiles of the sample data. The intra- and inter-batch median coefficients of variation (CV) among the 147 lipids were 44.3% and 20.8%, respectively. After normalization, the CV values decreased by 42.0% and 14.7%, respectively. The effect of this normalization on the subsequent analyses was also evaluated. The demonstrated analyses will contribute to obtaining unbiased, quantified data for large-scale metabolomics. Full article
(This article belongs to the Special Issue Biofluid-Based Metabolomics for Biomarker Discovery)
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13 pages, 2600 KiB  
Article
Optimization of Ultrasonic-Assisted Extraction of α-Glucosidase Inhibitors from Dryopteris crassirhizoma Using Artificial Neural Network and Response Surface Methodology
by Nguyen Viet Phong, Dan Gao, Jeong Ah Kim and Seo Young Yang
Metabolites 2023, 13(4), 557; https://doi.org/10.3390/metabo13040557 - 13 Apr 2023
Cited by 4 | Viewed by 1376
Abstract
Dryopteris crassirhizoma Nakai is a plant with significant medicinal properties, such as anticancer, antioxidant, and anti-inflammatory activities, making it an attractive research target. Our study describes the isolation of major metabolites from D. crassirhizoma, and their inhibitory activities on α-glucosidase were evaluated [...] Read more.
Dryopteris crassirhizoma Nakai is a plant with significant medicinal properties, such as anticancer, antioxidant, and anti-inflammatory activities, making it an attractive research target. Our study describes the isolation of major metabolites from D. crassirhizoma, and their inhibitory activities on α-glucosidase were evaluated for the first time. The results revealed that nortrisflavaspidic acid ABB (2) is the most potent α-glucosidase inhibitor, with an IC50 of 34.0 ± 0.14 μM. In addition, artificial neural network (ANN) and response surface methodology (RSM) were used in this study to optimize the extraction conditions and evaluate the independent and interactive effects of ultrasonic-assisted extraction parameters. The optimal extraction conditions are extraction time of 103.03 min, sonication power of 342.69 W, and solvent-to-material ratio of 94.00 mL/g. The agreement between the predicted models of ANN and RSM and the experimental values was notably high, with a percentage of 97.51% and 97.15%, respectively, indicating that both models have the potential to be utilized for optimizing the industrial extraction process of active metabolites from D. crassirhizoma. Our results could provide relevant information for producing high-quality extracts from D. crassirhizoma for functional foods, nutraceuticals, and pharmaceutical industries. Full article
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14 pages, 2073 KiB  
Article
Revisiting the Flora of Saudi Arabia: Phytochemical and Biological Investigation of the Endangered Plant Species Euphorbia saudiarabica
by Omer I. Fantoukh, Gadah A. Al-Hamoud, Fahd A. Nasr, Omer M. Almarfadi, Mohammed F. Hawwal, Zulfiqar Ali, Waleed A. Alobaid, Abdulaziz Binawad, Menwer Alrashidi, Fawaz Alasmari, Mohammad Z. Ahmed and Omar M. Noman
Metabolites 2023, 13(4), 556; https://doi.org/10.3390/metabo13040556 - 13 Apr 2023
Cited by 1 | Viewed by 1868
Abstract
Euphorbia plants have a significant place in traditional medicine due to their numerous therapeutic properties, including their anti-tumor effects, which have been observed in several species. In the current study, a phytochemical investigation of Euphorbia saudiarabica methanolic extract led to the isolation and [...] Read more.
Euphorbia plants have a significant place in traditional medicine due to their numerous therapeutic properties, including their anti-tumor effects, which have been observed in several species. In the current study, a phytochemical investigation of Euphorbia saudiarabica methanolic extract led to the isolation and characterization of four secondary metabolites from the chloroform (CHCl3) and ethyl acetate (EtOAc) fractions, which are reported for the first time in this species. One of the constituents, saudiarabicain F (2), is a rare C-19 oxidized ingol-type diterpenoid that has not been previously reported. The structures of these compounds were determined by extensive spectroscopic (HR-ESI-MS, 1D and 2D NMR) analyses. The anticancer properties of the E. saudiarabica crude extract, its fractions and its isolated compounds were examined against several cancer cells. The active fractions were evaluated for their effects on cell-cycle progression and apoptosis induction using flow cytometry. Furthermore, RT-PCR was employed to estimate the gene-expression levels of the apoptosis-related genes. It was demonstrated that the E. saudiarabica CHCl3 and EtOAc fractions suppressed the proliferation of the cancer cells. The MCF-7 cells were the most sensitive to both fractions, with IC50 values of 22.6 and 23.2 µg/mL, respectively. Notably, both fractions caused cell-cycle arrest in the G2/M phase of the treated MCF-7 cells. The inhibition of the MCF-7 cells’ proliferation was also linked with apoptosis induction by flow-cytometry analysis. Additionally, the activation of apoptosis by both fractions was demonstrated by an increase in the ratio of Bax to Bcl-2, with an increase in the expression of caspase-7. Among the isolated compounds, glutinol (1) showed potent activity against the MCF-7 cell line, with an IC50 value of 9.83 µg/mL. Our findings suggest that E. saudiarabica has apoptosis-inducing effects and shows promise as a potential source of new chemotherapeutic drugs. Full article
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13 pages, 17396 KiB  
Article
Multi-Omics Unravels Metabolic Alterations in the Ileal Mucosa of Neonatal Piglets Receiving Total Parenteral Nutrition
by Junkai Yan, Yuling Zhao, Lu Jiang, Ying Wang and Wei Cai
Metabolites 2023, 13(4), 555; https://doi.org/10.3390/metabo13040555 - 13 Apr 2023
Viewed by 1268
Abstract
Total parenteral nutrition (TPN) is life-saving therapy for the pediatric patients with intestinal failure (IF) who cannot tolerate enteral nutrition (EN). However, TPN-induced metabolic alterations are also a critical issue for the maintenance of intestinal homeostasis, and thus the global metabolomic signatures need [...] Read more.
Total parenteral nutrition (TPN) is life-saving therapy for the pediatric patients with intestinal failure (IF) who cannot tolerate enteral nutrition (EN). However, TPN-induced metabolic alterations are also a critical issue for the maintenance of intestinal homeostasis, and thus the global metabolomic signatures need to be addressed. In this study, ileal mucosal biopsies were collected from 12 neonatal Bama piglets receiving either EN or TPN for 14 days, and changes in the intestinal metabolism were examined by multi-omics (HM350 Metabolomics + Tandem Mass Tag (TMT)-based proteomics). As a result, a total of 240 compounds were identified by metabolomics, including 56 down-regulated and 9 up-regulated metabolites. Notably, tissue levels of fatty acyl-carnitines (decreased by 35–85%) and succinate (decreased by 89%) dramatically decreased in the TPN group, suggestive of disrupted processes of fatty acid oxidation (FAO) and the citrate cycle, respectively. Interestingly, however, no differences were found in the production of adenosine 5′-triphosphate (ATP) between groups, suggesting that these dysregulated metabolites may have mainly led to the loss of bioactive compounds rather than energy deficit. Additionally, 4813 proteins were identified by proteomics in total, including 179 down-regulated and 329 up-regulated proteins. The analysis of protein–protein interactions (PPI) indicated that most of the differentially expressed proteins were clustered into “lipid metabolism” and “innate immune responses”. In summary, this work provided new findings in TPN-induced intestinal metabolic alterations, which would be useful to the improvement of nutritional management for IF patients. Full article
(This article belongs to the Special Issue Nutrition and Metabolism in Human Diseases)
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23 pages, 3417 KiB  
Article
Different Diet Energy Levels Alter Body Condition, Glucolipid Metabolism, Fecal Microbiota and Metabolites in Adult Beagle Dogs
by Haoran Sun, Qiaoru Zhang, Chao Xu, Aipeng Mao, Hui Zhao, Miao Chen, Weili Sun, Guangyu Li and Tietao Zhang
Metabolites 2023, 13(4), 554; https://doi.org/10.3390/metabo13040554 - 13 Apr 2023
Cited by 1 | Viewed by 2564
Abstract
Diet energy is a key component of pet food, but it is usually ignored during pet food development and pet owners also have limited knowledge of its importance. This study aimed to explore the effect of diet energy on the body condition, glucolipid [...] Read more.
Diet energy is a key component of pet food, but it is usually ignored during pet food development and pet owners also have limited knowledge of its importance. This study aimed to explore the effect of diet energy on the body condition, glucolipid metabolism, fecal microbiota and metabolites of adult beagles and analyze the relation between diet and host and gut microbiota. Eighteen healthy adult neutered male beagles were selected and randomly divided into three groups. Diets were formulated with three metabolizable energy (ME) levels: the low-energy (Le) group consumed a diet of 13.88 MJ/kg ME; the medium-energy (Me) group consumed a diet of 15.04 MJ/kg ME; and the high-energy (He) group consumed a diet of 17.05 MJ/kg ME. Moreover, the protein content of all these three diets was 29%. The experiment lasted 10 weeks, with a two-week acclimation period and an eight-week test phase. Body weight, body condition score (BCS), muscle condition score (MCS) and body fat index (BFI) decreased in the Le group, and the changes in these factors in the Le group were significantly higher than in the other groups (p < 0.05). The serum glucose and lipid levels of the Le and He groups changed over time (p < 0.05), but those of the Me group were stable (p > 0.05). The fecal pH of the Le and He groups decreased at the end of the trial (p < 0.05) and we found that the profiles of short-chain fatty acids (SCFAs) and bile acids (BAs) changed greatly, especially secondary BAs (p < 0.05). As SCFAs and secondary BAs are metabolites of the gut microbiota, the fecal microbiota was also measured. Fecal 16S rRNA gene sequencing found that the Me group had higher α-diversity indices (p < 0.05). The Me group had notably higher levels of gut probiotics, such as Faecalibacterium prausnitzii, Bacteroides plebeius and Blautia producta (p < 0.05). The diet–host–fecal microbiota interactions were determined by network analysis, and fecal metabolites may help to determine the best physical condition of dogs, assisting pet food development. Overall, feeding dogs low- or high-energy diets was harmful for glucostasis and promoted the relative abundance of pathogenic bacteria in the gut, while a medium-energy diet maintained an ideal body condition. We concluded that dogs that are fed a low-energy diet for an extended period may become lean and lose muscle mass, but diets with low energy levels and 29% protein may not supply enough protein for dogs losing weight. Full article
(This article belongs to the Special Issue Nutrient Metabolism Studies in Companion Animals)
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14 pages, 1971 KiB  
Article
Lipid Differences and Related Metabolism Present on the Hand Skin Surface of Different-Aged Asiatic Females—An Untargeted Metabolomics Study
by Tian Chen, Juan Wang and Zhenxing Mao
Metabolites 2023, 13(4), 553; https://doi.org/10.3390/metabo13040553 - 13 Apr 2023
Viewed by 1278
Abstract
This cross-sectional study aimed to investigate differences in skin surface lipids (SSL) and explore related metabolic pathways among females of different ages in Henan Province. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to determine the lipid composition of the skin [...] Read more.
This cross-sectional study aimed to investigate differences in skin surface lipids (SSL) and explore related metabolic pathways among females of different ages in Henan Province. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to determine the lipid composition of the skin surface of 58 female volunteers who were divided into three age groups. Statistical analysis was performed using Progenesis QI, Ezinfo, and MetaboAnalyst. Multivariate and enrichment analysis were used to identify the different SSL among the groups. A total of 530 lipid entities were identified and classified into eight classes. Among these, 63 lipids were significantly different between the groups. Lower levels of glycerolipids (GLs) and sphingolipids (SPs) were observed in the middle-aged group, while higher levels of GLs were found in the elder group. GLs belonged to the largest and statistically significant enrichment of lipid metabolic pathways, and the lipid individuals enriched to the sphingoid bases metabolism were the most and statistically significant. These findings suggest that there are differences in hand SSL among females of different ages, which may be related to GLs and sphingoid bases metabolism. Full article
(This article belongs to the Special Issue Skin Metabolism and Cutaneous Disorders)
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20 pages, 2552 KiB  
Article
Metabolomic Study of Aging in fa/fa Rats: Multiplatform Urine and Serum Analysis
by Helena Pelantová, Petra Tomášová, Blanka Šedivá, Barbora Neprašová, Lucia Mráziková, Jaroslav Kuneš, Blanka Železná, Lenka Maletínská and Marek Kuzma
Metabolites 2023, 13(4), 552; https://doi.org/10.3390/metabo13040552 - 12 Apr 2023
Cited by 1 | Viewed by 1240
Abstract
Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early [...] Read more.
Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments. Full article
(This article belongs to the Special Issue Treatment of Obesity and Its Metabolic Complications)
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22 pages, 3782 KiB  
Review
Mycotoxin Contamination Status of Cereals in China and Potential Microbial Decontamination Methods
by Jing Zhang, Xi Tang, Yifan Cai and Wen-Wen Zhou
Metabolites 2023, 13(4), 551; https://doi.org/10.3390/metabo13040551 - 12 Apr 2023
Cited by 7 | Viewed by 1719
Abstract
The presence of mycotoxins in cereals can pose a significant health risk to animals and humans. China is one of the countries that is facing cereal contamination by mycotoxins. Treating mycotoxin-contaminated cereals with established physical and chemical methods can lead to negative effects, [...] Read more.
The presence of mycotoxins in cereals can pose a significant health risk to animals and humans. China is one of the countries that is facing cereal contamination by mycotoxins. Treating mycotoxin-contaminated cereals with established physical and chemical methods can lead to negative effects, such as the loss of nutrients, chemical residues, and high energy consumption. Therefore, microbial detoxification techniques are being considered for reducing and treating mycotoxins in cereals. This paper reviews the contamination of aflatoxins, zearalenone, deoxynivalenol, fumonisins, and ochratoxin A in major cereals (rice, wheat, and maize). Our discussion is based on 8700 samples from 30 provincial areas in China between 2005 and 2021. Previous research suggests that the temperature and humidity in the highly contaminated Chinese cereal-growing regions match the growth conditions of potential antagonists. Therefore, this review takes biological detoxification as the starting point and summarizes the methods of microbial detoxification, microbial active substance detoxification, and other microbial inhibition methods for treating contaminated cereals. Furthermore, their respective mechanisms are systematically analyzed, and a series of strategies for combining the above methods with the treatment of contaminated cereals in China are proposed. It is hoped that this review will provide a reference for subsequent solutions to cereal contamination problems and for the development of safer and more efficient methods of biological detoxification. Full article
(This article belongs to the Special Issue Microbial Metabolism and Food Safety)
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