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Metabolites, Volume 12, Issue 9 (September 2022) – 110 articles

Cover Story (view full-size image): Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. Here, we analyzed a large multi-omic database of over 8500 markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights. View this paper
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12 pages, 1342 KiB  
Article
Non-Invasive Differential Diagnosis of Cervical Neoplastic Lesions by the Lipid Profile Analysis of Cervical Scrapings
by Alisa Tokareva, Vitaliy Chagovets, Djamilja Attoeva, Natalia Starodubtseva, Niso Nazarova, Kirill Gusakov, Eugenii Kukaev, Vladimir Frankevich and Gennady Sukhikh
Metabolites 2022, 12(9), 883; https://doi.org/10.3390/metabo12090883 - 19 Sep 2022
Cited by 1 | Viewed by 1561
Abstract
Cervical cancer is one of the most common cancers in women with pronounced stages of precancerous lesions. Accurate differential diagnosis of such lesions is one of the primary challenges of medical specialists, which is vital to improving patient survival. The aim of this [...] Read more.
Cervical cancer is one of the most common cancers in women with pronounced stages of precancerous lesions. Accurate differential diagnosis of such lesions is one of the primary challenges of medical specialists, which is vital to improving patient survival. The aim of this study was to develop and test an algorithm for the differential diagnosis of cervical lesions based on lipid levels in scrapings from the cervical epithelium and cervicovaginal canal. The lipid composition of the samples was analyzed by high-performance chromato-mass spectrometry. Lipid markers were selected using the Mann–Whitney test with a cutoff value of 0.05 and by projections to latent structures discriminant analysis, where a projection threshold of one was chosen. The final selection of variables for binomial logistic regressions was carried out using the Akaike information criterion. As a result, a final neoplasia classification method, based on 20 logistic regression sub-models, has an accuracy of 79% for discrimination NILM/cervicitis/LSIL/HSIL/cancer. The model has a sensitivity of 83% and a specificity of 88% for discrimination of several lesions (HSIL and cancer). This allows us to discuss the prospective viability of further validation of the developed non-invasive method of differential diagnosis. Full article
(This article belongs to the Special Issue Personalized Metabolomics)
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24 pages, 3158 KiB  
Article
Impaired Neurovascular Function Underlies Poor Neurocognitive Outcomes and Is Associated with Nitric Oxide Bioavailability in Congenital Heart Disease
by Vanessa J. Schmithorst, Phillip S. Adams, Daryaneh Badaly, Vincent K. Lee, Julia Wallace, Nancy Beluk, Jodie K. Votava-Smith, Jacqueline G. Weinberg, Sue R. Beers, Jon Detterich, John C. Wood, Cecilia W. Lo and Ashok Panigrahy
Metabolites 2022, 12(9), 882; https://doi.org/10.3390/metabo12090882 - 19 Sep 2022
Cited by 2 | Viewed by 2084
Abstract
We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes [...] Read more.
We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes and nitric oxide bioavailability. In a prospective single-center study, resting-state blood-oxygen-level-dependent (BOLD) and arterial spin labeling (ASL) MRI scans were successfully obtained from 24 CHD patients (age = 15.4 ± 4.06 years) and 63 normal referents (age = 14.1 ± 3.49) years. Pnvf was computed on a voxelwise basis as the negative of the ratio of functional connectivity strength (FCS) estimated from the resting-state BOLD acquisition to regional cerebral blood flow (rCBF) as estimated from the ASL acquisition. Pnvf was used to predict end-tidal CO2 (PETCO2) levels and compared to those estimated from the BOLD data. Nitric oxide availability was obtained via nasal measurements (nNO). Pnvf was compared on a voxelwise basis between CHD patients and normal referents and correlated with nitric oxide availability and neurocognitive outcomes as assessed via the NIH Toolbox. Pnvf was shown as highly predictive of PETCO2 using theoretical modeling. Pnvf was found to be significantly reduced in CHD patients in default mode network (DMN, comprising the ventromedial prefrontal cortex and posterior cingulate/precuneus), salience network (SN, comprising the insula and dorsal anterior cingulate), and central executive network (CEN, comprising posterior parietal and dorsolateral prefrontal cortex) regions with similar findings noted in single cardiac ventricle patients. Positive correlations of Pnvf in these brain regions, as well as the hippocampus, were found with neurocognitive outcomes. Similarly, positive correlations between Pnvf and nitric oxide availability were found in frontal DMN and CEN regions, with particularly strong correlations in subcortical regions (putamen). Reduced Pnvf in CHD patients was found to be mediated by nNO. Mediation analyses further supported that reduced Pnvf in these regions underlies worse neurocognitive outcome in CHD patients and is associated with nitric oxide bioavailability. Impaired neuro-vascular function, which may be non-invasively estimated via combined arterial-spin label and BOLD MR imaging, is a nitric oxide bioavailability dependent factor implicated in adverse neurocognitive outcomes in pediatric and young adult CHD. Full article
(This article belongs to the Special Issue Exploring Oxidative Stress Biomarkers in Human Disease)
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16 pages, 2237 KiB  
Article
Association of Metabolic Signatures with Nonalcoholic Fatty Liver Disease in Pediatric Population
by Woori Chae, Kyung Jae Lee, Ki Young Huh, Jin Soo Moon, Jae Sung Ko and Joo-Youn Cho
Metabolites 2022, 12(9), 881; https://doi.org/10.3390/metabo12090881 - 19 Sep 2022
Cited by 4 | Viewed by 2219
Abstract
Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this [...] Read more.
Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this study, we aimed to evaluate the metabolome profile and metabolic pathway changes associated with pediatric NAFLD to elucidate its pathophysiology and to develop machine learning-based NAFLD diagnostic models. We analyzed the metabolic profiles of healthy control, lean NAFLD, overweight control, and overweight NAFLD groups of children and adolescent participants (N = 165) by assessing plasma samples. Additionally, we constructed diagnostic models by applying three machine learning methods (ElasticNet, random forest, and XGBoost) and multiple logistic regression by using NAFLD-specific metabolic features, genetic variants, and clinical data. We identified 18 NAFLD-specific metabolic features and metabolic changes in lipid, glutathione-related amino acid, and branched-chain amino acid metabolism by comparing the control and NAFLD groups in the overweight pediatric population. Additionally, we successfully developed and cross-validated diagnostic models that showed excellent diagnostic performance (ElasticNet and random forest model: area under the receiver operating characteristic curve, 0.95). Metabolome changes in the plasma of pediatric patients with NAFLD are associated with the pathophysiology of the disease and can be utilized as a less-invasive approach to diagnosing the disease. Full article
(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)
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9 pages, 1284 KiB  
Article
A Feasibility Study to Evaluate Changes in Urinary Metabolites after OnabotulinumtoxinA Injection for Refractory Overactive Bladder
by Laura M. Tellechea, Samantha Freeman, Ilir Agalliu, Melissa A. Laudano, Sylvia O. Suadicani and Nitya Abraham
Metabolites 2022, 12(9), 880; https://doi.org/10.3390/metabo12090880 - 19 Sep 2022
Viewed by 1684
Abstract
Metabolomics analysis of urine before and after overactive bladder (OAB) treatment may demonstrate a unique molecular profile, allowing predictions of responses to treatment. This feasibility study aimed to correlate changes in urinary metabolome with changes in OAB symptoms after intravesical onabotulinumtoxinA (BTX-A) injections [...] Read more.
Metabolomics analysis of urine before and after overactive bladder (OAB) treatment may demonstrate a unique molecular profile, allowing predictions of responses to treatment. This feasibility study aimed to correlate changes in urinary metabolome with changes in OAB symptoms after intravesical onabotulinumtoxinA (BTX-A) injections for refractory OAB. Women 18 years or older with non-neurogenic refractory OAB were recruited to complete OAB-V8 questionnaires and submit urine samples before and after 100 units intravesical BTX-A injection. Samples were submitted to CE-TOFMS metabolomics profiling. Data were expressed as percent of change from pre-treatment and were correlated with OAB-V8 score improvement. Urinary metabolite changes in the OAB-V8 groups were compared using the Kruskal–Wallis test, and associations between metabolites and OAB-V8 scores were examined using quantile regression analysis. Of 61 urinary metabolites commonly detected before and after BTX-A, there was a statistically significant decrease in adenosine and an increase in N8-acetylspermidine and guanidinoacetic acid levels associated with OAB score improvement, suggesting that intravesical BTX-A injection modifies the urinary metabolome. These urinary metabolites could provide insight into OAB pathophysiology and help identify patients who would benefit most from chemodenervation. Full article
(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)
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12 pages, 803 KiB  
Review
The Role of Hydrogen Sulfide Targeting Autophagy in the Pathological Processes of the Nervous System
by Huijie Zhao, Yihan Yang, Huiyang Liu and Honggang Wang
Metabolites 2022, 12(9), 879; https://doi.org/10.3390/metabo12090879 - 17 Sep 2022
Cited by 6 | Viewed by 2104
Abstract
Autophagy is an important cellular process, involving the transportation of cytoplasmic contents in the double membrane vesicles to lysosomes for degradation. Autophagy disorder contributes to many diseases, such as immune dysfunction, cancers and nervous system diseases. Hydrogen sulfide (H2S) is a [...] Read more.
Autophagy is an important cellular process, involving the transportation of cytoplasmic contents in the double membrane vesicles to lysosomes for degradation. Autophagy disorder contributes to many diseases, such as immune dysfunction, cancers and nervous system diseases. Hydrogen sulfide (H2S) is a volatile and toxic gas with a rotten egg odor. For a long time, it was considered as an environmental pollution gas. In recent years, H2S is regarded as the third most important gas signal molecule after NO and CO. H2S has a variety of biological functions and can play an important role in a variety of physiological and pathological processes. Increasingly more evidences show that H2S can regulate autophagy to play a protective role in the nervous system, but the mechanism is not fully understood. In this review, we summarize the recent literatures on the role of H2S in the pathological process of the nervous system by regulating autophagy, and analyze the mechanism in detail, hoping to provide the reference for future related research. Full article
(This article belongs to the Section Cell Metabolism)
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18 pages, 5483 KiB  
Article
In Vitro Induction of Apoptosis in Isolated Acute Myeloid Leukemia Cells: The Role of Anastatica hierochuntica Methanolic Extract
by Islam M. El-Garawani, Amira S. Abd El-Gaber, Noura A. Algamdi, Aamer Saeed, Chao Zhao, Omar M. Khattab, Mohamed F. AlAjmi, Zhiming Guo, Shaden A. M. Khalifa and Hesham R. El-Seedi
Metabolites 2022, 12(9), 878; https://doi.org/10.3390/metabo12090878 - 17 Sep 2022
Cited by 3 | Viewed by 1873
Abstract
Anastatica hierochuntica L. (Cruciferae) has been known in Egyptian folk medicine as a remedy for gastrointestinal disorders, diabetes and heart diseases. Despite the wide usage, A. hierochuntica research provides insufficient data to support its traditional practice. The cytotoxicity of A. hierochuntica methanolic extract [...] Read more.
Anastatica hierochuntica L. (Cruciferae) has been known in Egyptian folk medicine as a remedy for gastrointestinal disorders, diabetes and heart diseases. Despite the wide usage, A. hierochuntica research provides insufficient data to support its traditional practice. The cytotoxicity of A. hierochuntica methanolic extract was investigated on acute myeloid leukemia blasts (AML) and normal human peripheral leucocytes (NHPL). The phytochemical identification of bioactive compounds using 1H-NMR and LC-ESI-MS was also performed. A. hierochuntica extract caused non-significant cytotoxicity on NHPL, while the cytotoxicity on AML was significant (IC50: 0.38 ± 0.02 μg/mL). The negative expression of p53, upregulation of Caspase-3 and increase in the BAX/BCL-2 ratio were reported at the protein and mRNA levels. The results suggest that A. hierochuntica extract induced AML cell death via the p53-independent mitochondrial intrinsic pathway and further attention should be paid to this plant as a promising natural anticancer agent. Full article
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7 pages, 1114 KiB  
Communication
Angiopoietin-Like 4 (ANGPTL4) in Patients with Psoriasis, Lichen Planus and Vitiligo—A Pilot Study from the Bialystok+ Polish Longitudinal University Study
by Julia Nowowiejska, Anna Baran, Justyna Magdalena Hermanowicz, Joanna Mikłosz, Karol Adam Kamiński, Marcin Kondraciuk, Marlena Dubatówka, Dariusz Pawlak and Iwona Flisiak
Metabolites 2022, 12(9), 877; https://doi.org/10.3390/metabo12090877 - 17 Sep 2022
Cited by 1 | Viewed by 1491
Abstract
Psoriasis, vitiligo and lichen planus (LP) are autoimmune skin diseases associated with metabolic syndrome. Angiopoietin-like 4 (ANGPTL4) is a member of angiopoietin-like proteins, which play an important role in lipid metabolism, and its serum concentration has been proposed as a biomarker of cardiometabolic [...] Read more.
Psoriasis, vitiligo and lichen planus (LP) are autoimmune skin diseases associated with metabolic syndrome. Angiopoietin-like 4 (ANGPTL4) is a member of angiopoietin-like proteins, which play an important role in lipid metabolism, and its serum concentration has been proposed as a biomarker of cardiometabolic complications, especially coronary artery disease (CAD). The study involved 56 patients with abovementioned dermatoses and 29 sex- and age-matched volunteers without dermatoses. ANGPTL4 serum concentration was measured by ELISA. ANGPTL4 concentration was statistically significantly higher in patients with LP compared to the control group (p < 0.01); moreover, it was significantly higher than in patients with psoriasis and vitiligo (p < 0.001, p < 0.01, respectively). There was no statistically significant difference in ANGPTL4 concentration between patients with psoriasis or vitiligo and controls. There was no correlation between ANGPTL4 concentration and age or BMI in all study groups. There was a positive correlation between ANGPTL4 concentration and fasting glucose (R = 0.43) and AST activity (R = 0.39) in psoriatic patients and ALT activity in patients with vitiligo (R = 0.44). ANGPTL4 could be a potential marker of metabolic complications in patients with LP, especially CAD. Perhaps patients with LP are more prone to CAD compared to the other two dermatoses, which requires further research. Full article
(This article belongs to the Special Issue Psoriasis and Its Related Metabolic Complications)
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23 pages, 1463 KiB  
Review
The Impact of Maternal Folates on Brain Development and Function after Birth
by Sapna Virdi and Nafisa M. Jadavji
Metabolites 2022, 12(9), 876; https://doi.org/10.3390/metabo12090876 - 16 Sep 2022
Cited by 14 | Viewed by 2848
Abstract
Folate is vital for biological processes within the body, including DNA synthesis, DNA repair, and methylation reactions that metabolize homocysteine. The role of folate is particularly important in pregnancy, where there is rapid cellular and tissue growth. Maternal folate deficiencies secondary to inadequate [...] Read more.
Folate is vital for biological processes within the body, including DNA synthesis, DNA repair, and methylation reactions that metabolize homocysteine. The role of folate is particularly important in pregnancy, where there is rapid cellular and tissue growth. Maternal folate deficiencies secondary to inadequate dietary supplementation are known to produce defects in the neural tube and spinal cord, yet the exact mechanism of folate in neurodevelopment is unknown. The consequences of maternal folate deficiency on offspring brain development and function beyond gestation are not well defined. The objective of this review is to investigate the role of folate deficiency in offspring neurodevelopment, and the complications that arise post-gestation. This was accomplished through a comprehensive review of the data presented in both clinical and preclinical studies. Evidence supports that folate deficiency is associated with altered offspring neurodevelopment, including smaller total brain volume, altered cortical thickness and cerebral white matter, altered neurogenesis, and neuronal apoptosis. Some of these changes have been associated with altered brain function in offspring with memory, motor function, language skills, and psychological issues. This review of literature also presents potential mechanisms of folate deficiency in neurodevelopment with altered metabolism, neuroinflammation, epigenetic modification through DNA methylation, and a genetic deficiency in one-carbon metabolism. Full article
(This article belongs to the Special Issue Folate Homeostasis and Metabolism)
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9 pages, 265 KiB  
Article
Type 2 Diabetes Risk and Lipid Metabolism Related to the Pleiotropic Effects of an ABCB1 Variant: A Chinese Family-Based Cohort Study
by Junhui Wu, Xiaowen Wang, Hongbo Chen, Ruotong Yang, Huan Yu, Yiqun Wu and Yonghua Hu
Metabolites 2022, 12(9), 875; https://doi.org/10.3390/metabo12090875 - 16 Sep 2022
Cited by 3 | Viewed by 1557
Abstract
The single nucleotide polymorphism (SNP) rs4148727 in ABCB1 (encoding p-glycoprotein) is associated with lipid levels; however, its association with type 2 diabetes (T2DM) and its the genetic correlation with lipid profiles and T2DM are unclear. We included 2300 participants from 593 families. A [...] Read more.
The single nucleotide polymorphism (SNP) rs4148727 in ABCB1 (encoding p-glycoprotein) is associated with lipid levels; however, its association with type 2 diabetes (T2DM) and its the genetic correlation with lipid profiles and T2DM are unclear. We included 2300 participants from 593 families. A generalized estimating equations (GEE) model and Cox regression models were used to estimate the SNP’s effects on T2DM and lipid profiles. The participation of the SNP in T2DM pathogenesis through lipid-associated pathways was tested using mediation analysis. The G allele of the SNP was related to a 32% (6–64%, p = 0.015) increase in T2DM risk. It was also associated with a 10% (1–20%, p = 0.029), 17% (3–32%, p = 0.015), and 4% (1–7%, p = 0.015) increment in total cholesterol (TC), triglyceride (TG), and apolipoprotein A (Apo-A) concentrations, respectively. According to the mediation analysis, only TG (6.9%) and Apo-B (4.0%) had slight but significant mediation effects on the total impact of the SNP on T2DM. The pleiotropic effects of the ABCB1 variant on T2DM and lipids likely act via different pathways. The biological mechanisms should be verified in a future study. Full article
(This article belongs to the Topic Metabolism and Health)
28 pages, 1666 KiB  
Review
Seleno-Metabolites and Their Precursors: A New Dawn for Several Illnesses?
by Cristina Morán-Serradilla, Eduardo Angulo-Elizari, Andreina Henriquez-Figuereo, Carmen Sanmartín, Arun K. Sharma and Daniel Plano
Metabolites 2022, 12(9), 874; https://doi.org/10.3390/metabo12090874 - 16 Sep 2022
Cited by 9 | Viewed by 2597
Abstract
Selenium (Se) is an essential element for human health as it is involved in different physiological functions. Moreover, a great number of Se compounds can be considered potential agents in the prevention and treatment of some diseases. It is widely recognized that Se [...] Read more.
Selenium (Se) is an essential element for human health as it is involved in different physiological functions. Moreover, a great number of Se compounds can be considered potential agents in the prevention and treatment of some diseases. It is widely recognized that Se activity is related to multiple factors, such as its chemical form, dose, and its metabolism. The understanding of its complex biochemistry is necessary as it has been demonstrated that the metabolites of the Se molecules used to be the ones that exert the biological activity. Therefore, the aim of this review is to summarize the recent information about its most remarkable metabolites of acknowledged biological effects: hydrogen selenide (HSe/H2Se) and methylselenol (CH3SeH). In addition, special attention is paid to the main seleno-containing precursors of these derivatives and their role in different pathologies. Full article
(This article belongs to the Section Advances in Metabolomics)
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10 pages, 1383 KiB  
Brief Report
Are the Bacteria and Their Metabolites Contributing for Gut Inflammation on GSD-Ia Patients?
by Karina Colonetti, Evelise Leis de Carvalho, Darlene Lopes Rangel, Paulo Marcos Pinto, Luiz Fernando Wurdig Roesch, Franciele Cabral Pinheiro and Ida Vanessa Doederlein Schwartz
Metabolites 2022, 12(9), 873; https://doi.org/10.3390/metabo12090873 - 16 Sep 2022
Cited by 3 | Viewed by 1757
Abstract
Recently, patients with glycogen storage disease (GSD) have been described as having gut dysbiosis, lower fecal pH, and an imbalance in SCFAs due to an increase in acetate and propionate levels. Here, we report the fecal measurement of bacterial-related metabolites formic, acetic, lactic, [...] Read more.
Recently, patients with glycogen storage disease (GSD) have been described as having gut dysbiosis, lower fecal pH, and an imbalance in SCFAs due to an increase in acetate and propionate levels. Here, we report the fecal measurement of bacterial-related metabolites formic, acetic, lactic, propionic, and succinic acid, a key metabolite of both host and microbiota, on a previously described cohort of 24 patients (GSD Ia = 15, GSD Ib = 5, 1 GSD III = 1 and GSD IX = 3) and 16 healthy controls, with similar sex and age, using the high-performance liquid chromatography technique. The succinic acid levels were higher in the GSD patients than in the controls (patients = 38.02; controls = 27.53; p = 0.045), without differences between the groups for other metabolites. Fecal pH present inverse correlation with lactic acid (R = −0.54; p = 0.0085), while OTUs were inversely correlated with both lactic (R = −0.46; p = 0.026) and formic (R = −0.54; p = 0.026) acids. Using two distinct metrics of diversity, borderline significance was obtained for propionic acid, affecting the microbial structure on Euclidean basis in 8% (r2 = 0.081; p = 0.079), and for lactic acid, affecting 6% of microbial structure using Bray–Curtis distance (r2 = 0.065; p = 0.060). No correlation was found between SCFAs and total carbohydrate consumption among the participants or uncooked cornstarch consumption among the patients. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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11 pages, 2846 KiB  
Article
Non-Invasive Metabolic and Structural Retinal Markers in Patients with Giant Cell Arteritis and Polymyalgia Rheumatica: A Cross-Sectional Study
by Simon J. Lowater, Torkell J. Ellingsen, Jens K. Pedersen, Jimmi Wied, Jakob Grauslund and Keld-Erik Byg
Metabolites 2022, 12(9), 872; https://doi.org/10.3390/metabo12090872 - 16 Sep 2022
Viewed by 1195
Abstract
Giant cell arteritis (GCA) is a potential sight-threatening disease. Although it is associated with polymyalgia rheumatica (PMR), visual loss is not common in PMR. A retinal oximeter can be used to conduct a direct, non-invasive, in vivo assessment of the vascular system. In [...] Read more.
Giant cell arteritis (GCA) is a potential sight-threatening disease. Although it is associated with polymyalgia rheumatica (PMR), visual loss is not common in PMR. A retinal oximeter can be used to conduct a direct, non-invasive, in vivo assessment of the vascular system. In a cross-sectional study, we measured the retinal oxygen saturation and retinal vessel calibers in GCA patients, PMR patients, and control participants. Twenty GCA patients (38 eyes), 19 PMR patients (33 eyes), and 12 controls (20 eyes) were investigated. Images were analyzed using Oxymap Analyzer software 2.5.0 (Oxymap ehf., Reykjavik, Iceland). Groups were compared using an age- and sex-adjusted linear mixed model regression. The median (IQR) age for GCA patients was 69.0 (66.5–76.5) years, for PMR 69.0 (67.0–72.0) years, and for the controls 75.5 (71.5–81.0) years, respectively. As compared to the controls (115.3 µm), the retinal arterioles were significantly wider in patients with GCA (124.4 µm; p = 0.023) and PMR (124.8 µm; p = 0.049). No difference was found in the retinal venular caliber or vascular oxygen saturation. These results indicate that GCA and PMR patients differ similarly in the retinal arteriolar diameter compared to controls. Further studies are needed in order to clarify the underlying inflammatory mechanisms in retinal arteriolar vessels and if these parameters can be used to predict clinical outcomes. Full article
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14 pages, 1963 KiB  
Review
Regulation Mechanism of Plant Pigments Biosynthesis: Anthocyanins, Carotenoids, and Betalains
by Xuecheng Zhao, Yueran Zhang, Tuan Long, Shouchuang Wang and Jun Yang
Metabolites 2022, 12(9), 871; https://doi.org/10.3390/metabo12090871 - 16 Sep 2022
Cited by 25 | Viewed by 4454
Abstract
Anthocyanins, carotenoids, and betalains are known as the three major pigments in the plant kingdom. Anthocyanins are flavonoids derived from the phenylpropanoid pathway. They undergo acylation and glycosylation in the cytoplasm to produce anthocyanin derivatives and deposits in the cytoplasm. Anthocyanin biosynthesis is [...] Read more.
Anthocyanins, carotenoids, and betalains are known as the three major pigments in the plant kingdom. Anthocyanins are flavonoids derived from the phenylpropanoid pathway. They undergo acylation and glycosylation in the cytoplasm to produce anthocyanin derivatives and deposits in the cytoplasm. Anthocyanin biosynthesis is regulated by the MBW (comprised by R2R3-MYB, basic helix-loop-helix (bHLH) and WD40) complex. Carotenoids are fat-soluble terpenoids whose synthetic genes also are regulated by the MBW complex. As precursors for the synthesis of hormones and nutrients, carotenoids are not only synthesized in plants, but also synthesized in some fungi and bacteria, and play an important role in photosynthesis. Betalains are special water-soluble pigments that exist only in Caryophyllaceae plants. Compared to anthocyanins and carotenoids, the synthesis and regulation mechanism of betalains is simpler, starting from tyrosine, and is only regulated by MYB (myeloblastosis). Recently, a considerable amount of novel information has been gathered on the regulation of plant pigment biosynthesis, specifically with respect to aspects. In this review, we summarize the knowledge and current gaps in our understanding with a view of highlighting opportunities for the development of pigment-rich plants. Full article
(This article belongs to the Section Plant Metabolism)
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14 pages, 2765 KiB  
Article
Sulfation and Its Effect on the Bioactivity of Magnolol, the Main Active Ingredient of Magnolia Officinalis
by Cong Xie, Wanyu Hu, Lili Gan, Bingxuan Fu, Xiaojie Zhao, Dafu Tang, Rongxin Liao and Ling Ye
Metabolites 2022, 12(9), 870; https://doi.org/10.3390/metabo12090870 - 15 Sep 2022
Cited by 1 | Viewed by 1567
Abstract
Magnolol, the main active ingredient of Magnolia officinalis, has been reported to display anti-inflammatory activity. Sulfation plays an important role in the metabolism of magnolol. The magnolol sulfated metabolite was identified by the ultra-performance liquid chromatography to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) [...] Read more.
Magnolol, the main active ingredient of Magnolia officinalis, has been reported to display anti-inflammatory activity. Sulfation plays an important role in the metabolism of magnolol. The magnolol sulfated metabolite was identified by the ultra-performance liquid chromatography to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and a proton nuclear magnetic resonance (1H-NMR). The magnolol sulfation activity of seven major recombinant sulfotransferases (SULTs) isoforms (SULT1A1*1, SULT1A1*2, SULT1A2, SULT1A3, SULT1B1, SULT1E1, and SULT2A1) was analyzed. The metabolic profile of magnolol was investigated in liver S9 fractions from human (HLS9), rat (RLS9), and mouse (MLS9). The anti-inflammatory effects of magnolol and its sulfated metabolite were evaluated in RAW264.7 cells stimulated by lipopolysaccharide (LPS). Magnolol was metabolized into a mono-sulfated metabolite by SULTs. Of the seven recombinant SULT isoforms examined, SULT1B1 exhibited the highest magnolol sulfation activity. In liver S9 fractions from different species, the CLint value of magnolol sulfation in HLS9 (0.96 µL/min/mg) was similar to that in RLS9 (0.99 µL/min/mg) but significantly higher than that in MLS9 (0.30 µL/min/mg). Magnolol and its sulfated metabolite both significantly downregulated the production of inflammatory mediators (IL-1β, IL-6 and TNF-α) stimulated by LPS (p < 0.001). These results indicated that SULT1B1 was the major enzyme responsible for the sulfation of magnolol and that the magnolol sulfated metabolite exhibited potential anti-inflammatory effects. Full article
(This article belongs to the Special Issue Drug Discovery Metabolism and Biotransformation)
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16 pages, 7441 KiB  
Article
Sleep Disorder and Cocaine Abuse Impact Purine and Pyrimidine Nucleotide Metabolic Signatures
by Mayur Doke, Jay P. McLaughlin, Hamid Baniasadi and Thangavel Samikkannu
Metabolites 2022, 12(9), 869; https://doi.org/10.3390/metabo12090869 - 15 Sep 2022
Cited by 2 | Viewed by 1760
Abstract
Disturbances in the circadian rhythm alter the normal sleep-wake cycle, which increases vulnerability to drug abuse. Drug abuse can disrupt several homeostatic processes regulated by the circadian rhythm and influence addiction paradigms, including cravings for cocaine. The relationship between circadian rhythm and cocaine [...] Read more.
Disturbances in the circadian rhythm alter the normal sleep-wake cycle, which increases vulnerability to drug abuse. Drug abuse can disrupt several homeostatic processes regulated by the circadian rhythm and influence addiction paradigms, including cravings for cocaine. The relationship between circadian rhythm and cocaine abuse is complex and bidirectional, and disruption impacts both brain function and metabolic profiles. Therefore, elucidating the impact of circadian rhythm changes and cocaine abuse on the human metabolome may provide new insights into identifying potential biomarkers. We examine the effect of cocaine administration with and without circadian rhythm sleep disruption (CRSD) on metabolite levels and compare these to healthy controls in an in vivo study. A metabolomics analysis is performed on the control, CRSD, cocaine, and CRSD with cocaine groups. Plasma metabolite concentrations are analyzed using a liquid chromatography electrochemical array platform. We identify 242 known metabolites compared to the control; 26 in the CRSD with cocaine group, 4 in the CRSD group, and 22 in the cocaine group are significantly differentially expressed. Intriguingly, in the CRSD with cocaine treatment group, the expression levels of uridine monophosphate (p < 0.008), adenosine 5′-diphosphate (p < 0.044), and inosine (p < 0.019) are significantly altered compared with those in the cocaine group. In summary, alterations in purine and pyrimidine metabolism provide clues regarding changes in the energy profile and metabolic pathways associated with chronic exposure to cocaine and CRSD. Full article
(This article belongs to the Section Integrative Metabolomics)
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26 pages, 1870 KiB  
Systematic Review
Mixed Treatments Comparison of Oral Nutrition Interventions for Blood Immune Cell Parameters in Cancer Patients: Systematic Review and Network Meta-Analysis
by Yufei Fang, Yining Xu, Yuting Zhang, Feng Ren and Julien S. Baker
Metabolites 2022, 12(9), 868; https://doi.org/10.3390/metabo12090868 - 15 Sep 2022
Cited by 1 | Viewed by 1943
Abstract
Oral nutrition interventions are commonly applied as an assistant therapeutic approach, which could affect the balance of the immunological response but with mixed evidence. The objective of this study is to identify the potential of different oral nutrition interventions for blood immune cell [...] Read more.
Oral nutrition interventions are commonly applied as an assistant therapeutic approach, which could affect the balance of the immunological response but with mixed evidence. The objective of this study is to identify the potential of different oral nutrition interventions for blood immune cell parameters in cancer patients. Randomized controlled trials, which were published in peer-reviewed journals in the language of English, and which identified the effects of different oral nutrition interventions on cancer patients, were screened and included in the databases of PubMed, Medline, Embase, and Web of Science. White blood cell count (WBC), lymphocyte count, CD4/CD8, and neutrophil count were selected as outcome measures. For the result, 11 trials were included. The agreement between authors reached a kappa value of 0.78. Beta-carotene supplementation has a high potential in inducing a positive effect on blood immune cell parameters for cancer patients (first positive for WBC and CD4/CD8, second positive for lymphocyte count), as well as a combination of physical exercise and hypocaloric healthy eating intervention (first positive for lymphocyte and neutrophil count, second positive for WBC). Oral nutrition supplementations with a single substance have less potential to provide a positive effect on blood immune cell parameters for cancer patients (glutamine: 0.30 and 0.28 to be the last selection for WBCs and lymphocytes; Omega 3: 0.37 to be the last selection for WBCs; Protein: 0.44 to be the last selection for lymphocytes; Zinc: 0.60 to be the last selection for neutrophils). In conclusion, the programs of immunonutrition therapy for different cancer patients might be different. The past perception that mixed oral nutritional supplementations are superior to oral nutritional supplements with a single substance might be wrong and the selection of oral nutritional supplementation need cautiousness. A combination of physical exercise might have a positive effect but also needs a higher level of evidence. Registration Number: CRD42021286396. Full article
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18 pages, 4287 KiB  
Article
Galacto-Oligosaccharide Alleviates Alcohol-Induced Liver Injury by Inhibiting Oxidative Stress and Inflammation
by Shipeng Zhou, Qiuhua Tan, Bingjian Wen, Yan Bai, Qishi Che, Hua Cao, Jiao Guo and Zhengquan Su
Metabolites 2022, 12(9), 867; https://doi.org/10.3390/metabo12090867 - 15 Sep 2022
Cited by 2 | Viewed by 2031
Abstract
Alcoholic liver disease (ALD) is a primary cause of mortality and morbidity worldwide. Oxidative stress and inflammation are important pathogenic factors contributing to ALD. We investigated the protective mechanism of galacto-oligosaccharide (GOS) against ALD through their antioxidant and anti-inflammatory activities by performing in [...] Read more.
Alcoholic liver disease (ALD) is a primary cause of mortality and morbidity worldwide. Oxidative stress and inflammation are important pathogenic factors contributing to ALD. We investigated the protective mechanism of galacto-oligosaccharide (GOS) against ALD through their antioxidant and anti-inflammatory activities by performing in vivo and in vitro experiments. Western blot and RT‒PCR results indicated that the expression of cytochrome P450 protein 2E1 (CYP2E1) in liver tissues and L02 cells was reduced in the GOS-treated mice compared with the model group. In addition, GOS prominently reduced the expression of Kelch-like ECH-associated protein 1 (Keap1), increased the expression of the nuclear factor erythroid-2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1) proteins, and enhanced the antioxidant capacity. In addition, GOS decreased inflammation by reducing inflammatory factor levels and inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. Based on these results, GOS may be a prospective functional food for the prevention and treatment of ALD. Full article
(This article belongs to the Special Issue Dietary Antioxidants and Metabolic Diseases)
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10 pages, 1506 KiB  
Article
Orthogonality in Principal Component Analysis Allows the Discovery of Lipids in the Jejunum That Are Independent of Ad Libitum Feeding
by David Balgoma, Fredrik Kullenberg, Karsten Peters, David Dahlgren, Femke Heindryckx, Hans Lennernäs and Mikael Hedeland
Metabolites 2022, 12(9), 866; https://doi.org/10.3390/metabo12090866 - 14 Sep 2022
Cited by 2 | Viewed by 1985
Abstract
Ad libitum feeding of experimental animals is preferred because of medical relevance together with technical and practical considerations. In addition, ethical committees may require ad libitum feeding. However, feeding affects the metabolism so ad libitum feeding may mask the effects of drugs on [...] Read more.
Ad libitum feeding of experimental animals is preferred because of medical relevance together with technical and practical considerations. In addition, ethical committees may require ad libitum feeding. However, feeding affects the metabolism so ad libitum feeding may mask the effects of drugs on tissues directly involved in the digestion process (e.g., jejunum and liver). Despite this effect, principal component analysis has the potential of identifying metabolic traits that are statistically independent (orthogonal) to ad libitum feeding. Consequently, we used principal component analysis to discover the metabolic effects of doxorubicin independent of ad libitum feeding. First, we analyzed the lipidome of the jejunum and the liver of rats treated with vehicle or doxorubicin. Subsequently, we performed principal component analysis. We could identify a principal component associated to the hydrolysis of lipids during digestion and a group of lipids that were orthogonal. These lipids in the jejunum increased with the treatment time and presented a polyunsaturated fatty acid as common structural trait. This characteristic suggests that doxorubicin increases polyunsaturated fatty acids. This behavior agrees with our previous in vitro results and suggests that doxorubicin sensitized the jejunum to ferroptosis, which may partially explain the toxicity of doxorubicin in the intestines. Full article
(This article belongs to the Special Issue Application of Metabolomics in Toxicology Research)
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12 pages, 660 KiB  
Review
Intravenous Ascorbic Acid and Lung Function in Severely Ill COVID-19 Patients
by Sara Sokary, Asma Ouagueni and Vijay Ganji
Metabolites 2022, 12(9), 865; https://doi.org/10.3390/metabo12090865 - 14 Sep 2022
Cited by 2 | Viewed by 1874
Abstract
Current evidence suggests that ascorbic acid improves the host’s immune system and, therefore, may play a role in reducing the severity of infectious diseases. Coronavirus disease 2019 (COVID-19) is a potentially life-threatening viral infection that mainly infects the lungs. The objective of this [...] Read more.
Current evidence suggests that ascorbic acid improves the host’s immune system and, therefore, may play a role in reducing the severity of infectious diseases. Coronavirus disease 2019 (COVID-19) is a potentially life-threatening viral infection that mainly infects the lungs. The objective of this review was to synthesize the existing findings from studies related to the effect of intravenous ascorbic acid on lung function in COVID-19 patients. For this review, PubMed, Cochrane, SCOPUS, EMBASE, Clinical Trial Registry, and Google Scholar databases were searched from December 2019 to May 2022. There was a total of six studies that investigated the large dose of ascorbic acid infusion intravenously on lung function in severely ill subjects with COVID-19. Out of six, three studies found that high-dose intravenous ascorbic acid improved lung function markers, and three studies found null results. Infusions of 12 g/d and 24 g/d of intravenous ascorbic acid had shown a significant improvement in lung function markers in two clinical trials. Studies that administered 8 g/d, 2 g/d, and 50 mg/kg/d of intravenous ascorbic acid found no influence on mechanical ventilation need and other lung function markers in critically ill subjects with COVID-19. Overall, the effect of intravenous ascorbic acid on the lung function of subjects with COVID yielded equivocal findings. More double-blinded, randomized, clinical studies with a larger sample size are required to confirm the effect of ascorbic acid in ameliorating the lung pathologies associated with COVID infection. Full article
(This article belongs to the Section Nutrition and Metabolism)
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20 pages, 1341 KiB  
Review
Metabolomics as a Crucial Tool to Develop New Therapeutic Strategies for Neurodegenerative Diseases
by Débora Lanznaster, Giulia Dingeo, Rayhanatou Altine Samey, Patrick Emond and Hélène Blasco
Metabolites 2022, 12(9), 864; https://doi.org/10.3390/metabo12090864 - 14 Sep 2022
Cited by 2 | Viewed by 2790
Abstract
Neurodegenerative diseases (NDs), such as Alzheimer’s (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS), share common pathological mechanisms, including metabolism alterations. However, their specific neuronal cell types affected and molecular biomarkers suggest that there are both common and specific alterations regarding metabolite levels. [...] Read more.
Neurodegenerative diseases (NDs), such as Alzheimer’s (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS), share common pathological mechanisms, including metabolism alterations. However, their specific neuronal cell types affected and molecular biomarkers suggest that there are both common and specific alterations regarding metabolite levels. In this review, we were interested in identifying metabolite alterations that have been reported in preclinical models of NDs and that have also been documented as altered in NDs patients. Such alterations could represent interesting targets for the development of targeted therapy. Importantly, the translation of such findings from preclinical to clinical studies is primordial for the study of possible therapeutic agents. We found that N-acetyl-aspartate (NAA), myo-inositol, and glutamate are commonly altered in the three NDs investigated here. We also found other metabolites commonly altered in both AD and PD. In this review, we discuss the studies reporting such alterations and the possible pathological mechanism underlying them. Finally, we discuss clinical trials that have attempted to develop treatments targeting such alterations. We conclude that the treatment combination of both common and differential alterations would increase the chances of patients having access to efficient treatments for each ND. Full article
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8 pages, 778 KiB  
Review
Identification of Plant-Derived Bioactive Compounds Using Affinity Mass Spectrometry and Molecular Networking
by Thabo Ramatapa, Anathi Msobo, Pfano W. Maphari, Efficient N. Ncube, Noluyolo Nogemane and Msizi I. Mhlongo
Metabolites 2022, 12(9), 863; https://doi.org/10.3390/metabo12090863 - 14 Sep 2022
Cited by 4 | Viewed by 2032
Abstract
Affinity selection-mass spectrometry (AS-MS) is a label-free binding assay system that uses UHPLC-MS size-based separation methods to separate target-compound complexes from unbound compounds, identify bound compounds, classify compound binding sites, quantify the dissociation rate constant of compounds, and characterize affinity-extracted ligands. This label-free [...] Read more.
Affinity selection-mass spectrometry (AS-MS) is a label-free binding assay system that uses UHPLC-MS size-based separation methods to separate target-compound complexes from unbound compounds, identify bound compounds, classify compound binding sites, quantify the dissociation rate constant of compounds, and characterize affinity-extracted ligands. This label-free binding assay, in contrast to conventional biochemical (i.e., high-throughput screening (HTS)) approaches, is applicable to any drug target, and is also concise, accurate, and adaptable. Although AS-MS is an innovative approach for identifying lead compounds, the possibilities of finding bioactive compounds are limited by competitive binding, which occurs during the equilibration of extracts with the target protein(s). Here, we discuss the potential for metabolite profiling complemented with molecular networking to be used alongside AS-MS to improve the identification of bioactive compounds in plant extracts. AS-MS has gained significant prominence in HTS labs and shows potential to emerge as the driving force behind novel drug development in the future. Full article
(This article belongs to the Special Issue Metabolomics in Natural Products)
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11 pages, 1525 KiB  
Article
Sugarcane Metabolome Compositional Stability in Pretreatment Processes for NMR Measurements
by Yasuhiro Date, Chiaki Ishikawa, Makoto Umeda, Yusuke Tarumoto, Megumi Okubo, Yasuaki Tamura and Hiroshi Ono
Metabolites 2022, 12(9), 862; https://doi.org/10.3390/metabo12090862 - 14 Sep 2022
Cited by 1 | Viewed by 1568
Abstract
Sugarcane is essential for global sugar production and its compressed juice is a key raw material for industrial products. Sugarcane juice includes various metabolites with abundances and compositional balances influencing product qualities and functionalities. Therefore, understanding the characteristic features of the sugarcane metabolome [...] Read more.
Sugarcane is essential for global sugar production and its compressed juice is a key raw material for industrial products. Sugarcane juice includes various metabolites with abundances and compositional balances influencing product qualities and functionalities. Therefore, understanding the characteristic features of the sugarcane metabolome is important. However, sugarcane compositional variability and stability, even in pretreatment processes for nuclear magnetic resonance (NMR)-based metabolomic studies, remains elusive. The objective of this study is to evaluate sugarcane juice metabolomic variability affected by centrifugation, filtration, and thermal pretreatments, as well as the time-course changes for determining optimal conditions for NMR-based metabolomic approach. The pretreatment processes left the metabolomic compositions unchanged, indicating that these pretreatments are compatible with one another and the studied metabolomes are comparable. The thermal processing provided stability to the metabolome for more than 32 h at room temperature. Based on the determined analytical conditions, we conducted an NMR-based metabolomic study to discriminate the differences in the harvest period and allowed for successfully identifying the characteristic metabolome. Our findings denote that NMR-based sugarcane metabolomics enable us to provide an opportunity to collect a massive amount of data upon collaboration between multiple researchers, resulting in the rapid construction of useful databases for both research purposes and industrial use. Full article
(This article belongs to the Special Issue Proteomics and Metabolomics Studies of Food Plants)
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13 pages, 2461 KiB  
Article
Relationship between Cardiometabolic Factors and the Response of Blood Pressure to a One-Year Primary Care Lifestyle Intervention in Metabolic Syndrome Patients
by Elisa Marin-Couture, Marie-Josée Filion, Ryma Boukari, Khursheed Jeejeebhoy, Rupinder Dhaliwal, Paula Brauer, Dawna Royall, David M. Mutch, Doug Klein, Angelo Tremblay and Caroline Rhéaume
Metabolites 2022, 12(9), 861; https://doi.org/10.3390/metabo12090861 - 14 Sep 2022
Cited by 2 | Viewed by 1979
Abstract
Systemic hypertension has been recognized as a modifiable traditional cardiovascular risk factor and influenced by many factors such as eating habits, physical activity, diabetes, and obesity. The objective of this cross-sectional study was to identify factors that predict changes in blood pressure induced [...] Read more.
Systemic hypertension has been recognized as a modifiable traditional cardiovascular risk factor and influenced by many factors such as eating habits, physical activity, diabetes, and obesity. The objective of this cross-sectional study was to identify factors that predict changes in blood pressure induced by a one-year lifestyle intervention in primary care settings involving a collaboration between family physicians, dietitians, and exercise specialists. Patients with metabolic syndrome diagnosis were recruited by family physicians participating in primary care lifestyle intervention among several family care clinics across Canada. Participants for whom all cardiometabolic data at the beginning (T0) and the end (T12) of the one-year intervention were available were included in the present analysis (n = 101). Patients visited the dietitian and the exercise specialist weekly for the first three months and monthly for the last nine months. Diet quality, exercise capacity, anthropometric indicators, and cardiometabolic variables were evaluated at T0 and at T12. The intervention induced a statistically significant decrease in waist circumference (WC), systolic (SBP) and diastolic (DBP) blood pressure, and plasma triglycerides, and an increase in cardiorespiratory fitness (estimated VO2max). Body weight (p < 0.001), body mass index (BMI) (p < 0.001), and fasting blood glucose (p = 0.006) reduction, and VO2max increase (p = 0.048) were all related to changes in SBP. WC was the only variable for which changes were significantly correlated with those in both SBP (p < 0.0001) and DBP (p = 0.0004). Variations in DBP were not associated with changes in other cardiometabolic variables to a statistically significant extent. Twelve participants were identified as adverse responders (AR) in both SBP and DBP and displayed less favorable changes in WC. The beneficial effects of the primary care lifestyle intervention on blood pressure were significantly associated with cardiometabolic variables, especially WC. These findings suggest that a structured lifestyle intervention in primary care can help improve cardiometabolic risk factors in patients with metabolic syndrome and that WC should be systematically measured to better stratify the patient’s hypertension risk. Full article
(This article belongs to the Special Issue Metabolomics Meets Lifestyle Medicine)
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17 pages, 1181 KiB  
Systematic Review
The Exploration of Fetal Growth Restriction Based on Metabolomics: A Systematic Review
by Mengxin Yao, Zhuoqiao Yang, Xin Rong, Xuan Hu, Na Yao, Manting Zhu, Xinnan Wang, Xiaoyan Zhu and Jieyun Yin
Metabolites 2022, 12(9), 860; https://doi.org/10.3390/metabo12090860 - 13 Sep 2022
Cited by 5 | Viewed by 2277
Abstract
Fetal growth restriction (FGR) is a common complication of pregnancy and a significant cause of neonatal morbidity and mortality. The adverse effects of FGR can last throughout the entire lifespan and increase the risks of various diseases in adulthood. However, the etiology and [...] Read more.
Fetal growth restriction (FGR) is a common complication of pregnancy and a significant cause of neonatal morbidity and mortality. The adverse effects of FGR can last throughout the entire lifespan and increase the risks of various diseases in adulthood. However, the etiology and pathogenesis of FGR remain unclear. This study comprehensively reviewed metabolomics studies related with FGR in pregnancy to identify potential metabolic biomarkers and pathways. Relevant articles were searched through two online databases (PubMed and Web of Science) from January 2000 to July 2022. The reported metabolites were systematically compared. Pathway analysis was conducted through the online MetaboAnalyst 5.0 software. For humans, a total of 10 neonatal and 14 maternal studies were included in this review. Several amino acids, such as alanine, valine, and isoleucine, were high frequency metabolites in both neonatal and maternal studies. Meanwhile, several pathways were suggested to be involved in the development of FGR, such as arginine biosynthesis, arginine, and proline metabolism, glyoxylate and dicarboxylate metabolism, and alanine, aspartate, and glutamate metabolism. In addition, we also included 8 animal model studies, in which three frequently reported metabolites (glutamine, phenylalanine, and proline) were also present in human studies. In general, this study summarized several metabolites and metabolic pathways which may help us to better understand the underlying metabolic mechanisms of FGR. Full article
(This article belongs to the Special Issue Metabolic Profiles and Biomarkers in Pregnancy)
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16 pages, 1475 KiB  
Article
Determination of Lipoxygenase, CYP450, and Non-Enzymatic Metabolites of Arachidonic Acid in Essential Hypertension and Type 2 Diabetes
by Guillaume Feugray, Tony Pereira, Michèle Iacob, Lucile Moreau-Grangé, Gaëtan Prévost, Valéry Brunel, Robinson Joannidès, Jérémy Bellien and Thomas Duflot
Metabolites 2022, 12(9), 859; https://doi.org/10.3390/metabo12090859 - 13 Sep 2022
Cited by 4 | Viewed by 1912
Abstract
Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) [...] Read more.
Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) metabolites, which are known regulators of vascular homeostasis, are affected by HTN and T2D. For this objective, 17 plasma level derivatives of ARA were quantitated by chromatography coupled with mass spectrometry in 44 patients (12 healthy, 8 HTN, 7 T2D, and 17 HTN + T2D). Effects of hyperglycemic and hyperinsulinemic clamps on ARA metabolite levels were assessed in seven healthy subjects. No significant differences in the plasma levels of ARA metabolites were observed for T2D patients compared with healthy volunteers. HTN was associated with an alteration of ARA metabolite correlation patterns with increased 20-, 19-, 15-, and 8-hydroxyeicosatrienoic acid (HETE). A decrease of 20-HETE was also observed during both hyperglycemic and hyperinsulinemic clamps. Additional experiments are needed to assess whether the modulation of HETE metabolites in HTN may be of interest. Furthermore, although not affected by T2D, it remains to investigate whether the decrease of 20-HETE observed during clamps may be related to the regulation of glucose tolerance and insulin signaling. Full article
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23 pages, 693 KiB  
Systematic Review
Are Dental Caries Associated with Oxidative Stress in Saliva in Children and Adolescents? A Systematic Review
by Yago Gecy de Sousa Né, Deborah Ribeiro Frazão, Leonardo Oliveira Bittencourt, Nathalia Carolina Fernandes Fagundes, Guido Marañón-Vásquez, Maria Elena Crespo-Lopez, Lucianne Cople Maia and Rafael Rodrigues Lima
Metabolites 2022, 12(9), 858; https://doi.org/10.3390/metabo12090858 - 13 Sep 2022
Cited by 8 | Viewed by 1935
Abstract
This systematic review aimed to assess whether dental caries is associated with oxidative salivary stress. The searches were carried out in electronic databases, including PubMed, Scopus, Web of Science, the Cochrane Library, LILACS, OpenGrey, and Google Scholar, without restrictions on the date of [...] Read more.
This systematic review aimed to assess whether dental caries is associated with oxidative salivary stress. The searches were carried out in electronic databases, including PubMed, Scopus, Web of Science, the Cochrane Library, LILACS, OpenGrey, and Google Scholar, without restrictions on the date of publication and language. The acronym PECO was used, in which the participants (P) were children and adolescents exposed (E) to dental caries compared (C) to those without dental caries, with the outcome (O) of modulation of oxidative biochemical parameters. After the search retrieval, the duplicates were removed, and the articles were evaluated by title and abstract, following the inclusion and exclusion criteria. Then, the papers were read and thoroughly assessed. After selection, the risk of bias assessment and qualitative synthesis were performed using the Newcastle-Ottawa Scale (NOS) for observational studies. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to assess the level of evidence. A total of 5790 studies were found, and 30 articles were considered eligible and were included for the qualitative synthesis and the level of evidence assessment. The studies showed an imbalance of the antioxidant and pro-oxidant parameters in individuals with dental caries, with primarily increases in both total antioxidant capacity and lipid peroxidation. Most articles showed a low risk of bias, having comparability as the main issue. When exploring through GRADE, a very low level of evidence was found. It was possible to observe an association between oxidative stress and dental caries, showing a disbalance of antioxidants and pro-oxidants, but the evidence level was still very low. Full article
(This article belongs to the Special Issue Salivary Fingerprint in Metabolomics Era: Potential and Challenges)
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9 pages, 287 KiB  
Opinion
Should We Void Lactate in the Pathophysiology of Delayed Onset Muscle Soreness? Not So Fast! Let’s See a Neurocentric View!
by Balázs Sonkodi
Metabolites 2022, 12(9), 857; https://doi.org/10.3390/metabo12090857 - 13 Sep 2022
Cited by 13 | Viewed by 2879
Abstract
The pathophysiology of delayed onset muscle soreness is not entirely known. It seems to be a simple, exercise-induced delayed pain condition, but has remained a mystery for over 120 years. The buildup of lactic acid used to be blamed for muscle fatigue and [...] Read more.
The pathophysiology of delayed onset muscle soreness is not entirely known. It seems to be a simple, exercise-induced delayed pain condition, but has remained a mystery for over 120 years. The buildup of lactic acid used to be blamed for muscle fatigue and delayed onset muscle soreness; however, studies in the 1980s largely refuted the role of lactate in delayed onset muscle soreness. Regardless, this belief is widely held even today, not only in the general public, but within the medical and scientific community as well. Current opinion is highlighting lactate’s role in delayed onset muscle soreness, if neural dimension and neuro-energetics are not overlooked. By doing so, lactate seems to have an essential role in the initiation of the primary damage phase of delayed onset muscle soreness within the intrafusal space. Unaccustomed or strenuous eccentric contractions are suggested to facilitate lactate nourishment of proprioceptive sensory neurons in the muscle spindle under hyperexcitation. However, excessive acidosis and lactate could eventually contribute to impaired proprioception and increased nociception under pathological condition. Furthermore, lactate could also contribute to the secondary damage phase of delayed onset muscle soreness in the extrafusal space, primarily by potentiating the role of bradykinin. After all, neural interpretation may help us to dispel a 40-year-old controversy about lactate’s role in the pathophysiology of delayed onset muscle soreness. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
10 pages, 1866 KiB  
Article
Stimulation of GLUT4 Glucose Uptake by Anthocyanin-Rich Extract from Black Rice (Oryza sativa L.) via PI3K/Akt and AMPK/p38 MAPK Signaling in C2C12 Cells
by Shui-Yuan Feng, Shu-Jing Wu, Yun-Ching Chang, Lean-Teik Ng and Sue-Joan Chang
Metabolites 2022, 12(9), 856; https://doi.org/10.3390/metabo12090856 - 12 Sep 2022
Cited by 7 | Viewed by 4570
Abstract
Anthocyanin from black rice was reported to have beneficial effects on diabetes, but the molecular mechanisms are still largely unknown. Black rice cultivated from different regions in Taiwan (Hualien and Changhua) were included in this study. Concentrations of anthocyanin were significantly higher using [...] Read more.
Anthocyanin from black rice was reported to have beneficial effects on diabetes, but the molecular mechanisms are still largely unknown. Black rice cultivated from different regions in Taiwan (Hualien and Changhua) were included in this study. Concentrations of anthocyanin were significantly higher using the ethanol extraction method than those using water; therefore, ethanol extracts from Hualien and Changhua black rice (HBRE and CBRE) were used for further investigation. 2-NBDG glucose uptake analysis revealed that both HBRE and CBRE promote glucose uptake in C2C12 myotubes. The membrane expression levels of GLUT4 and phosphorylation of IRS-1 also had been markedly increased by both HBRE and CBRE, which was in accordance with the glucose uptake results. CBRE did not affect the downstream of IRS-1 but significantly enhanced protein levels of p-AMPK/AMPK. In contrast, HBRE was shown to target various signaling participated in GLUT4 glucose uptake, including PI3K/Akt and the p38 MAPK/ERK. Overall, we demonstrated that anthocyanin-rich extracts from black rice stimulate GLUT4 glucose uptake via upregulation of PI3K/Akt and AMPK/p38 MAPK signaling in C2C12 myotubes. Our findings revealed that anthocyanin-rich black rice might be a promising functional food for the prevention and treatment of insulin resistance and diabetic hyperglycemia. Full article
(This article belongs to the Special Issue Functional Foods and Diabetes)
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12 pages, 2518 KiB  
Article
Skeletal Muscle Mitochondrial and Perilipin Content in a Cohort of Obese Subjects Undergoing Moderate and High Intensity Training
by Giuseppe Sirago, Filippo Vaccari, Stefano Lazzer, Andrea D’Amuri, Juana M. Sanz, Marco V. Narici, Carlo Reggiani, Angelina Passaro and Luana Toniolo
Metabolites 2022, 12(9), 855; https://doi.org/10.3390/metabo12090855 - 11 Sep 2022
Viewed by 1873
Abstract
Obesity is a complex condition characterized by abnormal and excessive fat accumulation, resulting in an increased risk for severe health problems. Skeletal muscles play a major role in movement and fat catabolism, but the insulin resistance that comes with obesity makes it difficult [...] Read more.
Obesity is a complex condition characterized by abnormal and excessive fat accumulation, resulting in an increased risk for severe health problems. Skeletal muscles play a major role in movement and fat catabolism, but the insulin resistance that comes with obesity makes it difficult to fulfill these tasks. In this study, we analyse two types of training protocols, moderate intensity continuous training (MICT) versus high intensity interval training (HIIT), in a cohort of obese subjects to establish which muscle adaptations favour fat consumption in response to exercise. Mitochondria play a role in fat oxidation. We found protein upregulation of mitochondrial biomarkers, TOMM20 and Cox-4, in HIIT but not in MICT, without detecting any shifts in fibre composition phenotype of the vastus lateralis in both training groups. Interestingly, both MICT and HIIT protocols showed increased protein levels of perilipin PLIN2, which is involved in the delivery and consumption of fats. HIIT also augmented perilipin PLIN5. Perilipins are involved in fat storage in skeletal muscles and their upregulation, along with the analysis of circulatory lipid profiles reported in the present study, suggest important adaptations induced by the two types of training protocols that favour fat consumption and weight loss in obese subjects. Full article
(This article belongs to the Special Issue Skeletal Muscle Metabolic Signatures in Health and Disease)
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12 pages, 1688 KiB  
Article
Optimization of Elicitation Conditions to Enhance the Production of Potent Metabolite Withanolide from Withania somnifera (L.)
by Manali Singh, Sanjeev Agrawal, Obaid Afzal, Abdulmalik S. A. Altamimi, Alya Redhwan, Nawaf Alshammari, Mitesh Patel, Mohd Adnan, Abdelbaset Mohamed Elasbali and Shahanavaj Khan
Metabolites 2022, 12(9), 854; https://doi.org/10.3390/metabo12090854 - 11 Sep 2022
Cited by 1 | Viewed by 1697
Abstract
This study aimed at optimizing conditions for increased withanolide production in Withania somnifera. The elicitors used for the foliar spray on the aerial parts of the plant were salicylic acid, jasmonic acid, and chitosan for the enhancement of withanolides in Withania somnifera [...] Read more.
This study aimed at optimizing conditions for increased withanolide production in Withania somnifera. The elicitors used for the foliar spray on the aerial parts of the plant were salicylic acid, jasmonic acid, and chitosan for the enhancement of withanolides in Withania somnifera under different environmental regimes. Three different elicitors, i.e., chitosan, jasmonic acid and salicylic acid, were applied on the plants through foliar route every 15th day for 6 months, and later plants were used for sample preparation. Further, the elicitors were used in different concentration, i.e., jasmonic acid (50, 200 and 400 ppm), chitosan (10, 50 and 100 ppm) and salicylic acid (0.5, 1 and 2 ppm). The elicitors were sprayed on the foliar parts of the plant between 10:00–11:00 a.m. on application days. For elicitor spray, a calibrated sprayer was used. The withanolide A/withaferin A was quantified through HPLC. It was found that in an open environment, maximum withaferin A content, i.e., 0.570 mg/g (DW), was recorded with jasmonic acid (50 ppm) treatment in comparison to control (0.067 mg/g DW). Thus, there was an 8.5-fold increase in the withaferin A content. Maximum withanolide A content of 0.352 mg/g (DW) was recorded when chitosan (50 ppm) was sprayed, while in the control, withanolide A content was recorded to be 0.031 mg/g (DW); thus, chitosan application increased the production of withanolide A by 11.3-fold. Under controlled conditions, maximum withaferin A content of 1.659 mg/g (DW) was recorded when plants were sprayed with chitosan (100 ppm), which was 8.1 times greater than the control content of 0.203 mg/g (DW). Maximum withanolide A content of 0.460 mg/g (DW) was recorded when chitosan (100 ppm) was applied, whereas in the control, withanolide A content was found to be 0.061 mg/g (DW). Thus, foliar spraying of elicitors in very low concentrations can serve as a low-cost, eco-friendly, labor-intensive and elegant alternative approach that can be practiced by farmers for the enhancement, consistent production and improved yield of withanolide A/withaferin A. This can be a suitable way to enhance plant productivity, thus increasing the availability of withanolide A and withaferin A for the health and pharma industry. Full article
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