Metabolites doi: 10.3390/metabo14030172
Authors: Elif Inan-Eroglu Olga Kuxhaus Franziska Jannasch Daniela V. Nickel Matthias B. Schulze
Our knowledge about the connection between protein intake and diabetes-related complications comes largely from studies among those already diagnosed with type 2 diabetes (T2D). However, there is a lack of information on whether changing protein intake after diabetes diagnosis affects complications risk. We aimed to explore the association between protein intake (total, animal, and plant) and vascular complications in incident T2D patients considering pre-diagnosis intake and changes in intake after diagnosis. This prospective cohort study included 1064 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort who developed T2D during follow-up (physician-verified). Dietary protein intake was measured with a food frequency questionnaire at baseline and follow-up. We included physician-reported incident diabetes complications (myocardial infarction, stroke, nephropathy, and neuropathy). A total of 388 participants developed complications, 82 macrovascular complications, and 343 microvascular complications. Substituting carbohydrates with protein showed a trend towards lower complications risk, although this association was not statistically significant (hazard ratio (HR) for 5% energy (E) substitution: 0.83; 95% confidence intervals (CI): 0.60–1.14). Increasing protein intake at the expense of carbohydrates after diabetes diagnosis was not associated with total and microvascular complications (HR for 5% E change substitution: 0.98; 95% CI: 0.89–1.08 and HR for 5% E change substitution: 1.02; 95% CI: 0.92–1.14, respectively). Replacing carbohydrates with protein did not elevate the risk of diabetes complications in incident T2D cases.
]]>Metabolites doi: 10.3390/metabo14030171
Authors: Siyang Wu Yijun Qi Weiwei Yang
Metabolic reprogramming has emerged as a prominent hallmark of cancer, characterized by substantial alterations in nutrient uptake and intracellular metabolic pathways. Consequently, intracellular metabolite concentrations undergo significant changes which can contribute to tumorigenesis through diverse mechanisms. Beyond their classical roles in regulating metabolic pathway flux, metabolites exhibit noncanonical functions that play a crucial role in tumor progression. In this review, we delve into the nonclassical functions of metabolites in the context of tumor progression, with a particular focus on their capacity to modulate gene expression and cell signaling. Furthermore, we discuss the potential exploitation of these nonclassical functions in the enhancement of cancer therapy.
]]>Metabolites doi: 10.3390/metabo14030170
Authors: Kento Morozumi Yoshihide Kawasaki Tomonori Sato Masamitsu Maekawa Shinya Takasaki Shuichi Shimada Takanari Sakai Shinichi Yamashita Nariyasu Mano Akihiro Ito
Tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of advanced renal cell carcinoma (RCC). However, there is a lack of useful biomarkers for assessing treatment efficacy. Through urinary metabolite analysis, we identified the metabolites and pathways involved in TKI resistance and elucidated the mechanism of TKI resistance. To verify the involvement of the identified metabolites obtained from urine metabolite analysis, we established sunitinib-resistant RCC cells and elucidated the antitumor effects of controlling the identified metabolic pathways in sunitinib-resistant RCC cells. Through the analysis of VEGFR signaling, we aimed to explore the mechanisms underlying the antitumor effects of metabolic control. Glutamine metabolism has emerged as a significant pathway in urinary metabolite analyses. In vitro and in vivo studies have revealed the antitumor effects of sunitinib-resistant RCC cells via knockdown of glutamine transporters. Furthermore, this antitumor effect is mediated by the control of VEGFR signaling via PTEN. Our findings highlight the involvement of glutamine metabolism in the prognosis and sunitinib resistance in patients with advanced RCC. Additionally, the regulating glutamine metabolism resulted in antitumor effects through sunitinib re-sensitivity in sunitinib-resistant RCC. Our results are expected to contribute to the more effective utilization of TKIs with further improvements in prognosis through current drug therapies.
]]>Metabolites doi: 10.3390/metabo14030169
Authors: Rihwa Choi Sang Gon Lee Eun Hee Lee
Traditional lipid parameters—including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C (calculated as TC minus HDL-C)—have long been used as indicators of cardiovascular disease (CVD) risk. The laboratory records of 9604 Korean adults who underwent traditional lipid panel tests (TC, TG, and HDL), as well as ApoB testing, were analyzed to evaluate the prevalence of dyslipidemia and high CVD risk (utilizing the NCEP ATP III criteria for traditional lipid panels and various ApoB test cutoffs recommended by international guidelines (145 mg/dL, 130 mg/dL, and 100 mg/dL)). The overall prevalence of dyslipidemia, as determined by traditional lipid panel criteria, was 27.4%. Utilizing the ApoB cutoffs of 145 mg/dL, 130 mg/dL, and 100 mg/dL resulted in prevalence figures of 5.3%, 11.0%, and 36.3%, respectively. The concordance in dyslipidemia classification between traditional lipid tests and ApoB at cutoffs of 145 mg/dL, 130 mg/dL, and 100 mg/dL was 78.4%, 81.3%, and 74.7%, respectively. Up to 17.5% of participants, based on an ApoB cutoff of ≥100 mg/dL, exhibited isolated high ApoB in the absence of traditional lipid test anomalies. Incorporating ApoB testing could enhance the identification of Koreans at high CVD risk.
]]>Metabolites doi: 10.3390/metabo14030168
Authors: Petr G. Lokhov Elena E. Balashova Oxana P. Trifonova Dmitry L. Maslov Ekaterina A. Shestakova Marina V. Shestakova Ivan I. Dedov
The clinical blood metabogram (CBM) was developed to match a tailored analysis of the blood metabolome to the time, cost, and reproducibility constraints of clinical laboratory testing. By analyzing the main blood metabolite groups, CBM offers clinically relevant information about the intake of low-molecular substances into the organism, humoral regulation, liver function, amino acid level, and the lipid and carbohydrate metabolism. The purpose of this work was to investigate the relevance of using the CBM in patients with diabetes mellitus. For this, a CBM was obtained for 18 healthy individuals, 12 individuals with prediabetes, and 64 individuals with type 2 diabetes mellitus, separated into groups according to fasting blood glucose and oral glucose tolerance tests. The results showed that the CBM reveals diabetes-associated metabolic alterations in the blood, including changes in the levels of carbohydrates, ketone bodies, eicosanoids, phospholipids, and amino acids, which are consistent with the scientific data available to date. The CBM enabled the separation of diabetic patients according to their metabolic metabotypes, providing both a general overview of their metabolic alterations and detailing their individual metabolic characteristics. It was concluded that the CBM is a precise and clinically applicable test for assessing an individual’s metabolic status in diabetes mellitus for diagnostic and treatment purposes.
]]>Metabolites doi: 10.3390/metabo14030167
Authors: Mahmoud M. A. Abulmeaty Ali Almajwal Mervat Elsayed Heba Hassan Thamer Alsager Zaid Aldossari
Active athletes frequently develop low energy (LEA) and protein availabilities (LPA) with consequent changes in the vital metabolic processes, especially resting metabolic rate (RMR) and substrate utilization. This study investigated the association of energy and protein intakes with RMR and substrate utilization in male and female athletes and those with LEA and LPA. Sixty athletes (35% female, 26.83 ± 7.12 y) were enrolled in this study. Anthropometric measurements and body composition analysis were reported to estimate fat-free mass (eFFM). Dietary intakes were recorded by two-day multiple-pass 24 h recall records and three-day food records and then analyzed by food processor software to calculate protein intake (PI) and energy intake (EI). Indirect calorimetry was used to measure RMR and percentages of substrate utilization. Activity–energy expenditure (AEE) was assessed by using an Actighrphy sensor for three days. Energy availability was calculated using the following formula (EA = EI − AEE/eFFM). The correlation of EI and PI with RMR and substrate utilization was tested with Pearson correlation. In the LEA group, both EI and PI correlated positively with RMR (r = 0.308, 0.355, respectively, p < 0.05). In addition, EI showed a positive correlation with the percentage of fat utilization. In the male and sufficient-PA groups, PI correlated positively with the RMR and negatively with the percentage of protein utilization. In conclusion, the percentage of LEA is markedly prevalent in our sample, with a higher prevalence among males. Athletes with LEA had lower fat utilization and lower RMR, while those with sufficient PA showed lower protein utilization with excessive PI. These findings may explain the metabolic responses in the cases of LEA and LPA.
]]>Metabolites doi: 10.3390/metabo14030166
Authors: Saad Salhi Abdellatif Rahim Mouad Chentouf Hasnaa Harrak Jean Loup Bister Naima Hamidallah Bouchra El Amiri
Infertility represents a significant global health challenge affecting both men and women. Despite regular unprotected sexual intercourse, approximately 15% of couples of reproductive age struggle to conceive within 12 months, with 10% of infertility cases attributed to unknown causes worldwide. As a result, numerous studies have turned their attention to exploring the use of natural products for the prevention and treatment of infertility. Among these natural remedies is date palm pollen (DPP), a male reproductive powder derived from the blossoms of the Phoenix dactylifera L. palm tree, which has a long history of use as a dietary supplement, particularly as an aphrodisiac and fertility enhancer for both men and women. This review critically examines the diverse components of DPP, including metabolites, proteins, amino acids, fatty acids, to elucidate its potential impact on human reproduction. The analysis thoroughly assesses the composition of DPP in relation to its effects on enhancing reproductive processes and delves into its traditional uses and therapeutic benefits in male fertility, such as the enhancement of sexual desire, semen quality, and hormonal equilibrium. Similarly, it explores the influence of DPP on female fertility, emphasizing its potential to improve factors such as lubrication, desire, ovulation, and hormonal balance. Overall, this review underscores the potential of DPP as a natural remedy for addressing reproductive disorders.
]]>Metabolites doi: 10.3390/metabo14030165
Authors: Yu Wei Lingfeng Xue Deying Ma Yuxiao Weng Mingkang Liu Luyang Li Ziyi Dai Ziyun Zhao Haifeng Wang Xiao Xu
Protein hydrolysate from black soldier fly larvae (BSFP) has garnered great attention with its lower allergenicity, high amount of essential amino acids, and small bioactive peptides. Schizochytrium is a promising alternative source of n-3 FUFA because it has enriched docosahexaenoic acid (DHA, C22: 6). The aim of this study was to assess palatability, the presence of diarrhea, plasma biochemistry panels, anti-oxidative and anti-inflammatory effects, and immune function in beagle dogs when supplementing a mixture of protein hydrolysate from black soldier fly larvae and schizochytrium (BSFPs) into their diets. Experiment I: 24 young beagle dogs (16 males and 8 females; 4–5 months; BW: 6.40 ± 0.15 kg) were randomly divided into four groups: (1) control (CON), (2) 5% BSFPs, (3) 10% BSFPs, (4) 15% BSFPs. Their body weights and fecal scores were recorded, and blood samples were collected for analysis. Experiment II: three diets containing 5%, 10%, and 15% BSFPs were evaluated by comparing them with a basal diet (CON) to evaluate palatability. These results suggested that a lower presence of diarrhea existed in the BSFP diet than the CON diet (p < 0.05). Three treatment groups remarkably increased their total protein (TP) and albumin (ALB) contents and decreased their concentrations of triglyceride (TG) and total cholesterol (TC) in plasma (p < 0.05). Moreover, the 5% and 15% BSFPs groups had a higher calcium (CA) content in plasma, and the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and contents of creatinine (CREA) and urea nitrogen (BUN) were significantly reduced by supplementing BSFP in their diets (p < 0.05). Their anti-oxidative enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were dramatically enhanced, and their malondialdehyde (MDA) concentrations were remarkably reduced (p < 0.05). Immunoglobulin A and G (IgA and IgG) concentrations in the plasma in the 10% and 15% BSFPs groups were significantly increased (p < 0.05). Furthermore, lower interleukin-8 (IL-8) contents were shown in the BSFP diets than the CON diet (p < 0.05). Similarly, the diets supplemented with BSFPs exhibited a positive effect on palatability (p < 0.05). To sum up, the diets supplemented with BSFPs significantly enhanced palatability, immune function, and anti-oxidative and anti-inflammatory capacity to alleviate diarrhea and improve the general health of the beagle dogs.
]]>Metabolites doi: 10.3390/metabo14030164
Authors: Lanfranco D’Elia Maria Masulli Pietro Cirillo Agostino Virdis Edoardo Casiglia Valerie Tikhonoff Fabio Angeli Carlo Maria Barbagallo Michele Bombelli Federica Cappelli Rosario Cianci Michele Ciccarelli Arrigo F. G. Cicero Massimo Cirillo Raffaella Dell’Oro Giovambattista Desideri Claudio Ferri Loreto Gesualdo Cristina Giannattasio Guido Grassi Guido Iaccarino Luciano Lippa Francesca Mallamaci Alessandro Maloberti Stefano Masi Alberto Mazza Alessandro Mengozzi Maria Lorenza Muiesan Pietro Nazzaro Paolo Palatini Gianfranco Parati Roberto Pontremoli Fosca Quarti-Trevano Marcello Rattazzi Gianpaolo Reboldi Giulia Rivasi Elisa Russo Massimo Salvetti Giuliano Tocci Andrea Ungar Paolo Verdecchia Francesca Viazzi Massimo Volpe Claudio Borghi Ferruccio Galletti
Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan–Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.
]]>Metabolites doi: 10.3390/metabo14030163
Authors: Pfariso Maumela Mahloro Hope Serepa-Dlamini
Resistance to anticancer therapeutics is a major global concern. Thus, new anticancer agents should be aimed against novel protein targets to effectively mitigate the increased resistance. This study evaluated the potential of secondary metabolites from a bacterial endophyte, as new anticancer agents, against a novel protein target, fibroblast growth factor. In silico genomic characterization of the Bacillus sp. strain MHSD_37 was used to identify potential genes involved in encoding secondary metabolites with biological activity. The strain was also exposed to stress and liquid chromatography–mass spectrometry used for the identification and annotation of secondary metabolites of oligopeptide class with anticancer activity. Selected metabolites were evaluated for their anticancer activity through molecular docking and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties analysis. Phylogenetic analysis revealed that strain MHSD_37 shared close evolutionary relationships with Bacillus at the species level, with no identified relationships at the sub-species level. Both in silico genomic characterization and spectrometry analysis identified secondary metabolites with potential anticancer activity. Molecular docking analysis illustrated that the metabolites formed complexes with the target protein, fibroblast growth factor, which were stabilized by hydrogen bonds. Moreover, the ADMET analysis showed that the metabolites passed the toxicity test for use as a potential drug. Thereby, Bacillus sp. strain MHSD_37 is a potential novel strain with oligopeptide metabolites that can be used as new anticancer agents against novel protein targets.
]]>Metabolites doi: 10.3390/metabo14030162
Authors: Jan P. Kleinjan Justin Blom André P. van Beek Hjalmar R. Bouma Peter R. van Dijk
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of drugs that have been proven beneficial in the management of diabetes, chronic kidney disease, and heart failure and in the mitigation of cardiovascular risk. The benefits of SGLT2i therapy have led to the rapid adoption of these drugs in clinical guidelines. Since the introduction of these drugs, concerns have arisen, as diabetic ketoacidosis (DKA) unexpectedly occurred in patients treated with SGLT2i. DKA is an infrequent but serious complication of SGLT2i therapy, and is potentially preventable. The risk factors for the development of SGLT2i-associated DKA are inappropriate dose reductions of insulin, the dietary restriction of carbohydrates, and factors that may increase insulin demand such as excessive alcohol intake and major surgery. Moreover, the risk of SGLT2i-associated DKA is higher in persons with type 1 diabetes. It is crucial that both patients and healthcare providers are aware of the risks of SGLT2i-associated DKA. In an effort to encourage safe prescribing of this effective class of drugs, we present two cases that illustrate the risks of SGLT2i therapy with regard to the development of DKA.
]]>Metabolites doi: 10.3390/metabo14030161
Authors: Luisa O. Schmitt Antonella Blanco Sheila V. Lima Gianni Mancini Natalia F. Mendes Alexandra Latini Joana M. Gaspar
Consumption of high-fat diets (HFD) is associated with brain alterations, including changes in feeding behavior, cognitive decline, and dementia. Astrocytes play a role in HFD-induced neuroinflammation and brain dysfunction; however, this process is not entirely understood. We hypothesized that exposure to saturated fatty acids can compromise astrocyte viability and mitochondrial function. The C6 (astrocytes) cell line was treated with palmitate or stearate (200 µM and 400 µM) for 6 h. Cell viability, morphology, inflammatory markers, and oxidative stress were evaluated. To assess mitochondrial function, various parameters were measured (membrane potential, mass, respiration, and complex activities). We observed that 6 h of treatment with 400 µM palmitate decreased cell viability, and treatment with 200 µM palmitate changed the astrocyte morphology. Palmitate increased inflammatory markers (TNF-α and IL6) but did not induce oxidative stress. Palmitate significantly decreased the mitochondrial membrane potential and mitochondrial mass. Complex I activity also decreased in palmitate-treated cells; however, no changes were observed in mitochondrial respiration. In conclusion, palmitate, a saturated fatty acid, induces inflammation and impairs mitochondrial function, leading to reduced astrocytic cell viability and changes in cellular morphology. Our study provides valuable insights into the potential mechanisms underlying the relationship between saturated fatty acids, astrocytes, and mitochondrial function in obesity-related brain dysfunction.
]]>Metabolites doi: 10.3390/metabo14030160
Authors: Jiedong Li Ruolun Wei Yifan Meng Richard N. Zare
Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging (IDESI-MSI) has proven to be a robust and reliable tool for chemically imaging biological samples such as fungi, animal tissues, and plants, but the choice of the imprint substrate is crucial. It must effectively transfer maximum amounts of species from the sample while preserving the original spatial distribution of detected molecules. In this study, we explored the potential of utilizing an oil-absorbing film, known for its soft nature and excellent lipophilicity, as an imprint substrate for IDESI-MSI on biological samples. To assess the transfer efficiency of the amounts of molecules and molecular patterns, we conducted experiments using mouse brain tissue. The result shows that more than 90% of the analytes can be transferred to the oil-absorbing film from the original tissue. A comparison of IDESI-MSI results between the oil-absorbing film and the original tissue demonstrates the material’s capability to transfer most molecules from the original tissue and retain images of different analytes with high spatial fidelity. We extended our investigation to plant imaging, where we applied IDESI-MSI to a cross-section of okra. The oil-absorbing film exhibited promise in this context as well. These findings suggest that IDESI-MSI utilizing the oil-absorbing film holds potential across various research fields, including biological metabolism, chemistry, and clinical research, making this technique widely applicable.
]]>Metabolites doi: 10.3390/metabo14030159
Authors: Peining Tao Stacey Conarello Thomas P. Wyche Nanyan Rena Zhang Keefe Chng John Kang Theodore R. Sana
Type 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal’s disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease.
]]>Metabolites doi: 10.3390/metabo14030158
Authors: Shen Huang Li Zhu Ke Wang Xinlong Zhang Duobin Mao Aamir Rasool
Sensory attributes strongly influence consumers’ preferences for products. The inoculation of the Klebsiella variicola H8 strain in a reconstituted tobacco leaf concentrate (RTLC) solution increased neutral aroma-enhancing compound (NAEC) production by 45%, decreased the nicotine level by 25%, decreased the water-soluble total sugar content by ~36%, and improved the sensory quality by 5.71%. The production of NAECs such as dihydrokiwi lactone (DHKL: 192.86%), 1,2,3,4-tetrahydro-1,1,6-trimethylnaphthalene (THTMN: 177.77%), 2,4-di-tert-butylphenol (DTBP: 25%), 4-oxoisofolkone (OIFK: 116.66%,) 1,9-heptadecadiene-4,6-diyn-3-ol (HDD: 116.67%), β-damastrone (BDS: 116.67), and megastigmatrienone A (MSTA: 116.67%) was increased. A metagenomics analysis of the microbial community in the fermented RTLC (FRTLC) was performed to elucidate the mechanism by which NAECs were produced. As a result, 24 groups of functional genes were identified, and among them, five families of carbohydrate-active enzymes, (i) glycoside hydrolase (GH), (ii) glycosyltransferase (GT), (iii) polysaccharide lyase (PL), (iv) carbohydrate esterase (CE), and (v) auxiliary active enzyme (AA), were found to be positively correlated with the production of NAECs. However, among the GHs, the GHs annotated from the H8 strain chromosome displayed the highest relative abundance and a positive correlation with the production of NAECs. Specifically, the GH13-14, GH13-20, GH13-38, GH13-25, GH13-10, GH42, and GH28 genes of the H8 strain were relatively more abundant and were key contributors to the production of NAECs. The correlation analyses revealed that the H8 strain plays a leading role among all the microorganisms in FRTLC in the production of NAECs. Our findings support the application of Klebsiella variicola in NAEC production and a reduction in nicotine content in tobacco products.
]]>Metabolites doi: 10.3390/metabo14030157
Authors: Angelica Dessì Roberta Pintus Vassilios Fanos Alice Bosco
The skin is a complex ecosystem colonized by millions of microorganisms, the skin microbiota, which are crucial in regulating not only the physiological functions of the skin but also the metabolic changes underlying the onset of skin diseases. The high microbial colonization together with a low diversity at the phylum level and a high diversity at the species level of the skin is very similar to that of the gastrointestinal tract. Moreover, there is an important communication pathway along the gut–brain–skin axis, especially associated with the modulation of neurotransmitters by the microbiota. Therefore, it is evident that the high complexity of the skin system, due not only to the genetics of the host but also to the interaction of the host with resident microbes and between microbe and microbe, requires a multi-omics approach to be deeply understood. Therefore, an integrated analysis, with high-throughput technologies, of the consequences of microbial interaction with the host through the study of gene expression (genomics and metagenomics), transcription (transcriptomics and meta-transcriptomics), and protein production (proteomics and meta-proteomics) and metabolite formation (metabolomics and lipidomics) would be useful. Although to date very few studies have integrated skin metabolomics data with at least one other ‘omics’ technology, in the future, this approach will be able to provide simple and fast tests that can be routinely applied in both clinical and cosmetic settings for the identification of numerous skin diseases and conditions. It will also be possible to create large archives of multi-omics data that can predict individual responses to pharmacological treatments and the efficacy of different cosmetic products on individual subjects by means of specific allotypes, with a view to increasingly tailor-made medicine. In this review, after analyzing the complexity of the skin ecosystem, we have highlighted the usefulness of this emerging integrated omics approach for the analysis of skin problems, starting with one of the latest ‘omics’ sciences, metabolomics, which can photograph the expression of the genome during its interaction with the environment.
]]>Metabolites doi: 10.3390/metabo14030156
Authors: Rachel L. Gibbs James A. Wilson Rebecca M. Swanson Joslyn K. Beard Zena M. Hicks Haley N. Beer Eileen S. Marks-Nelson Ty B. Schmidt Jessica L. Petersen Dustin T. Yates
Stress-induced fetal programming diminishes β2 adrenergic tone, which coincides with intrauterine growth restriction (IUGR) and lifelong metabolic dysfunction. We determined if stimulating β2 adrenergic activity in IUGR-born lambs would improve metabolic outcomes. IUGR lambs that received daily injections of saline or the β2 agonist clenbuterol from birth to 60 days were compared with controls from pair-fed thermoneutral pregnancies. As juveniles, IUGR lambs exhibited systemic inflammation and robust metabolic dysfunction, including greater (p < 0.05) circulating TNFα, IL-6, and non-esterified fatty acids, increased (p < 0.05) intramuscular glycogen, reduced (p < 0.05) circulating IGF-1, hindlimb blood flow, glucose-stimulated insulin secretion, and muscle glucose oxidation. Daily clenbuterol fully recovered (p < 0.05) circulating TNFα, IL-6, and non-esterified fatty acids, hindlimb blood flow, muscle glucose oxidation, and intramuscular glycogen. Glucose-stimulated insulin secretion was partially recovered (p < 0.05) in clenbuterol-treated IUGR lambs, but circulating IGF-1 was not improved. Circulating triglycerides and HDL cholesterol were elevated (p < 0.05) in clenbuterol-treated IUGR lambs, despite being normal in untreated IUGR lambs. We conclude that deficient β2 adrenergic regulation is a primary mechanism for several components of metabolic dysfunction in IUGR-born offspring and thus represents a potential therapeutic target for improving metabolic outcomes. Moreover, benefits from the β2 agonist were likely complemented by its suppression of IUGR-associated inflammation.
]]>Metabolites doi: 10.3390/metabo14030154
Authors: Luis F. Salas-Nuñez Alvaro Barrera-Ocampo Paola A. Caicedo Natalie Cortes Edison H. Osorio Maria F. Villegas-Torres Andres F. González Barrios
Enzyme–substrate interactions play a fundamental role in elucidating synthesis pathways and synthetic biology, as they allow for the understanding of important aspects of a reaction. Establishing the interaction experimentally is a slow and costly process, which is why this problem has been addressed using computational methods such as molecular dynamics, molecular docking, and Monte Carlo simulations. Nevertheless, this type of method tends to be computationally slow when dealing with a large search space. Therefore, in recent years, methods based on artificial intelligence, such as support vector machines, neural networks, or decision trees, have been implemented, significantly reducing the computing time and covering vast search spaces. These methods significantly reduce the computation time and cover broad search spaces, rapidly reducing the number of interacting candidates, as they allow repetitive processes to be automated and patterns to be extracted, are adaptable, and have the capacity to handle large amounts of data. This article analyzes these artificial intelligence-based approaches, presenting their common structure, advantages, disadvantages, limitations, challenges, and future perspectives.
]]>Metabolites doi: 10.3390/metabo14030155
Authors: Asghar Ali Khalid I. AlHussaini
A vast range of pesticides have been routinely employed for plant protection throughout the last few decades. Pesticides can enter non-target organisms in various ways, posing health hazards. Exposure to different environmental pollutants, including pesticides, can affect the human gut flora. Metabolites generated from the gut microbiota play an essential role in the host’s health by regulating metabolic homeostasis. A disruption in this equilibrium can lead to the emergence of numerous illnesses and their etiology. Pesticides have been shown in a few recent studies to harm the host’s gut microbiome. As a result, there is an urgent need to investigate the impact of pesticides on gut microbiota-mediated immunity. Metabolic alterations in the host may give a better understanding of pesticide-induced harm. This review highlights the potential consequences of pesticide exposure on gut microbiota composition and function, mainly focusing on how it might alter the production of secondary metabolites with potential downstream implications for host health.
]]>Metabolites doi: 10.3390/metabo14030153
Authors: Saira Rafaqat Sanja Gluscevic Filiz Mercantepe Sana Rafaqat Aleksandra Klisic
Inflammatory cytokines have been implicated as crucial contributors to the onset and progression of non-alcoholic fatty liver disease (NAFLD). The exact mechanisms by which interleukins (ILs) contribute to NAFLD may vary, and ongoing research is aimed at understanding the specific roles of different ILs in the pathogenesis of this condition. In addition, variations in environmental factors and genetics in each individual can influence the onset and/or progression of NAFLD. The lack of clinical studies related to the potential therapeutic properties of IL-1 inhibitors currently does not allow us to conclude their validity as a therapeutic option, although preclinical studies show promising results. Further studies are needed to elucidate their beneficial properties in NAFLD treatment.
]]>Metabolites doi: 10.3390/metabo14030152
Authors: Rulan Shaath Aljazi Al-Maraghi Haytham Ali Jehan AlRayahi Adam D. Kennedy Karen L. DeBalsi Sura Hussein Najwa Elbashir Sujitha S. Padmajeya Sasirekha Palaniswamy Sarah H. Elsea Ammira A. Akil Noha A. Yousri Khalid A. Fakhro
Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy–Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms.
]]>Metabolites doi: 10.3390/metabo14030151
Authors: Jéssica Taday Fernanda Telles Fróes Marina Seady Carlos Alberto Gonçalves Marina Concli Leite
Astrocytes play fundamental roles in the maintenance of brain homeostasis. The dysfunction of these cells is widely associated with brain disorders, which are often characterized by variations in the astrocyte protein markers GFAP and S100B, in addition to alterations in some of its metabolic functions. To understand the role of astrocytes in neurodegeneration mechanisms, we induced some of these metabolic alterations, such as energy metabolism, using methylglyoxal (MG) or fluorocitrate (FC); and neuroinflammation, using lipopolysaccharide (LPS) and streptozotocin (STZ), which is used for inducing Alzheimer’s disease (AD) in animal models. We showed that MG, LPS, STZ and FC similarly caused astrocyte dysfunction by increasing GFAP and reducing S100B secretion. In the context of AD, STZ caused an amyloid metabolism impairment verified by increases in Aβ1-40 peptide content and decreases in the amyloid degradation enzymes, IDE and NEP. Our data contribute to the understanding of the role of astrocytes in brain injury mechanisms and suggest that STZ is suitable for use in vitro models for studying the role of astrocytes in AD.
]]>Metabolites doi: 10.3390/metabo14030150
Authors: Yuanjie Zhang Rongrong Li Xue’er Du Zhijie Cui Xingwei Jiang Lamei Wang Junhu Yao Shimin Liu Jianguo Wang Chuanjiang Cai Yangchun Cao
To investigate the difference between rumen-protected niacin (RPN) and rumen-protected nicotinamide (RPM) in the transcriptome of genes relating to the lipid metabolism of the liver of periparturient dairy cows, 10 healthy Chinese Holstein cows were randomly divided into two groups and fed diets supplemented with 18.4 g/d RPN or 18.7 g/d RPM, respectively. The experiment lasted from 14 days before to 21 days after parturition. Liver biopsies were taken 21 days postpartum for transcriptomic sequencing. In addition, human LO2 cells were cultured in a medium containing 1.6 mmol/L of non-esterified fatty acids and 1 mmol/L niacin (NA) or 2 mmol/L nicotinamide (NAM) to verify the expression of the 10 genes selected from the transcriptomic analysis of the liver biopsies. The expression of a total of 9837 genes was detected in the liver biopsies, among which 1210 differentially expressed genes (DEGs) were identified, with 579 upregulated and 631 downregulated genes. These DEGs were associated mainly with lipid metabolism, oxidative stress, and some inflammatory pathways. Gene ontology (GO) enrichment analysis showed that 355 DEGs were enriched in 38 GO terms. The differences in the expression of these DEGs between RPN and RPM were predominantly related to the processes of steroid catabolism, steroid hydroxylase, monooxygenase activity, oxidoreductase activity, hemoglobin binding, and ferric iron binding, which are involved mainly in lipid anabolism and redox processes. The expressions of FADS2, SLC27A6, ARHGAP24, and THRSP in LO2 cells were significantly higher (p < 0.05) while the expressions of BCO2, MARS1, GARS1, S100A12, AGMO, and OSBPL11 were significantly lower (p < 0.05) on the NA treatment compared to the NAM treatment, indicating that NA played a role in liver metabolism by directly regulating fatty acid anabolism and transport, inflammatory factor expression, and oxidative stress; and NAM functioned more as a precursor of nicotinamide adenine dinucleotide (NAD, coenzyme I) and nicotinamide adenine dinucleotide phosphate (NADP, coenzyme II) to participate indirectly in biological processes such as ether lipid metabolism, cholesterol metabolism, energy metabolism, and other processes.
]]>Metabolites doi: 10.3390/metabo14030149
Authors: David Bernal-Casas Joan Serrano-Marín Juan Sánchez-Navés Josep M. Oller Rafael Franco
This paper aimed at devising an intelligence-based method to select compounds that can distinguish between open-angle glaucoma patients, type 2 diabetes patients, and healthy controls. Taking the concentration of 188 compounds measured in the aqueous humour (AH) of patients and controls, linear discriminant analysis (LDA) was used to identify the right combination of compounds that could lead to accurate diagnosis. All possibilities, using the leave-one-out approach, were considered through ad hoc programming and in silico massive data production and statistical analysis. Our proof of concept led to the selection of four molecules: acetyl-ornithine (Ac-Orn), C3 acyl-carnitine (C3), diacyl C42:6 phosphatidylcholine (PC aa C42:6), and C3-DC (C4-OH) acyl-carnitine (C3-DC (C4-OH)) that, taken in combination, would lead to a 95% discriminative success. 100% success was obtained with a non-linear combination of the concentration of three of these four compounds. By discarding younger controls to adjust by age, results were similar although one control was misclassified as a diabetes patient. Methods based on the consideration of individual clinical chemical parameters have limitations in the ability to make a reliable diagnosis, stratify patients, and assess disease progression. Leveraging human AH metabolomic data, we developed a procedure that selects a minimal number of metabolites (3–5) and designs algorithms that maximize the overall accuracy evaluating both positive predictive (PPV) and negative predictive (NPV) values. Our approach of simultaneously considering the levels of a few metabolites can be extended to any other body fluid and has potential to advance precision medicine. Artificial intelligence is expected to use algorithms that use the concentration of three to five molecules to correctly diagnose diseases, also allowing stratification of patients and evaluation of disease progression. In addition, this significant advance shifts focus from a single-molecule biomarker approach to that of an appropriate combination of metabolites.
]]>Metabolites doi: 10.3390/metabo14030148
Authors: Paulo D’Amora Ismael D. C. G. Silva Steven S. Evans Adam J. Nagourney Katharine A. Kirby Brett Herrmann Daniela Cavalheiro Federico R. Francisco Paula J. Bernard Robert A. Nagourney
With 64,050 new diagnoses and 50,550 deaths in the US in 2023, pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all human malignancies. Early detection and improved prognostication remain critical unmet needs. We applied next-generation metabolomics, using quantitative tandem mass spectrometry on plasma, to develop biochemical signatures that identify PDAC. We first compared plasma from 10 PDAC patients to 169 samples from healthy controls. Using metabolomic algorithms and machine learning, we identified ratios that incorporate amino acids, biogenic amines, lysophosphatidylcholines, phosphatidylcholines and acylcarnitines that distinguished PDAC from normal controls. A confirmatory analysis then applied the algorithms to 30 PDACs compared with 60 age- and sex-matched controls. Metabolic signatures were then analyzed to compare survival, measured in months, from date of diagnosis to date of death that identified metabolite ratios that stratified PDACs into distinct survival groups. The results suggest that metabolic signatures could provide PDAC diagnoses earlier than tumor markers or radiographic measures and offer insights into disease severity that could allow more judicious use of therapy by stratifying patients into metabolic-risk subgroups.
]]>Metabolites doi: 10.3390/metabo14030147
Authors: Alberto Muñoz-Prieto Eva Llamas-Amor María Dolores Contreras-Aguilar Ignacio Ayala María Martín Cuervo José Joaquín Cerón Sanni Hansen
Ammonia (NH3) and bicarbonate (HCO3) have been related to gastric ulcers in humans. Ammonia is considered a possible cause of gastric ulcers, whereas bicarbonate has a protective function. The presence of ulcers in the stomach of horses is defined as Equine Gastric Ulcer Syndrome (EGUS), which is a frequent disease in this species, and it has been associated with changes in saliva composition, such as in analytes related to inflammation, immune system and oxidative stress. The objectives of this study were (1) to perform an analytical validation of two automated spectrophotometric assays, one for ammonia and one for bicarbonate, in the horses’ saliva and (2) to evaluate their possible variations with EGUS. Analytical validation of the automated assays for ammonia and bicarbonate in the saliva of horses showed that both assays were precise and accurate. In addition, significantly higher values of ammonia and lower values of bicarbonate were found in the saliva of horses with EGUS compared to healthy horses. It can be concluded that ammonia and bicarbonate can be measured in the saliva of horses and that ammonia increases and bicarbonate decreases in this sample type could be related to the presence of EGUS in this species.
]]>Metabolites doi: 10.3390/metabo14030146
Authors: Eleni Mavrogonatou Dimitris Kletsas
Chronic low back pain, a major cause of disability with a great global socioeconomic impact, has been inextricably associated with intervertebral disc degeneration. On the other hand, an enhanced number of senescent cells has been identified in aged and degenerated intervertebral discs and their senescence-associated secretory phenotype (SASP) has been connected with qualitative/quantitative alterations in the extracellular matrix and ultimately with the disturbance of tissue homeostasis. Given that selective elimination of senescent cells (by the so-called senolytics) or amendment of their secretome towards a less catabolic/inflammatory phenotype (by molecules known as senomorphics) has been reported to alleviate symptoms of several age-associated diseases and to improve tissue quality during aging, here we will review the emerging role of senolytic and senomorphic agents derived from plants and natural products against intervertebral disc degeneration. The mode of action of these senotherapeutics, as well as the challenges in their practical application, will also be explicitly discussed in an attempt to direct their more targeted and effective use in exclusive or combinatorial therapeutic schemes for the prevention and/or treatment of disc degenerative disorders.
]]>Metabolites doi: 10.3390/metabo14030145
Authors: Jamie N. Petersson Elani A. Bykowski Chelsea Ekstrand Sean P. Dukelow Chester Ho Chantel T. Debert Tony Montina Gerlinde A. S. Metz
The neuropathological sequelae of stroke and subsequent recovery are incompletely understood. Here, we investigated the metabolic dynamics following stroke to advance the understanding of the pathophysiological mechanisms orchestrating stroke recovery. Using a nuclear magnetic resonance (NMR)-driven metabolomic profiling approach for urine samples obtained from a clinical group, the objective of this research was to (1) identify novel biomarkers indicative of severity and recovery following stroke, and (2) uncover the biochemical pathways underlying repair and functional recovery after stroke. Urine samples and clinical stroke assessments were collected during the acute (2–11 days) and chronic phases (6 months) of stroke. Using a 700 MHz 1H NMR spectrometer, metabolomic profiles were acquired followed by a combination of univariate and multivariate statistical analyses, along with biological pathway analysis and clinical correlations. The results revealed changes in phenylalanine, tyrosine, tryptophan, purine, and glycerophospholipid biosynthesis and metabolism during stroke recovery. Pseudouridine was associated with a change in post-stroke motor recovery. Thus, NMR-based metabolomics is able to provide novel insights into post-stroke cellular functions and establish a foundational framework for future investigations to develop targeted therapeutic interventions, advance stroke diagnosis and management, and enhance overall quality of life for individuals with stroke.
]]>Metabolites doi: 10.3390/metabo14030144
Authors: Tancredo Souza Damiana Justino Araujo Carlos Alberto Lins Cassimiro Diego Silva Batista
Many biogeochemical processes are modulated by dissolved organic matter (DOM), but the drivers influencing the chemodiversity of DOM compounds in Amazonian soils are poorly understood. It has also been theorized whether deforestation controls the decline of DOM. In this study, we collected soil samples from thirty sites across different regions of Brazil’s Legal Amazon, and we investigated the trade-offs among soil physical–chemical properties and DOM chemodiversity. We employed optical spectroscopy, Fourier transform ion cyclotron resonance, and multivariate analysis. Our results indicated that, despite variations in land use and soil physical–chemical properties, factors such as the deforested site, geometric mean diameter, weighted average diameter, and soil organic carbon were the main influencers of DOM chemodiversity variation. These findings highlight the importance of considering DOM chemodiversity as closely related to land use and its potential use in developing deforestation models for predicting soil quality decline in Brazil’s Legal Amazon.
]]>Metabolites doi: 10.3390/metabo14030143
Authors: Na An Min Zhang Quan-Fei Zhu Yao-Yu Chen Yan-Ling Deng Xiao-Ying Liu Qiang Zeng Yu-Qi Feng
In vitro fertilization (IVF) is a highly effective treatment for infertility; however, it poses challenges for women with decreased ovarian reserve (DOR). Despite the importance of understanding the impact of DOR on IVF outcomes, limited research has explored this relationship, particularly using omics approaches. Hence, we conducted a study to investigate the association between DOR and IVF outcomes, employing a metabolomic approach. We analyzed serum samples from 207 women undergoing IVF treatment, including 89 with DOR and 118 with normal ovarian reserve (NOR). Our findings revealed that DOR was significantly associated with unfavorable IVF outcomes, characterized by a reduced oocyte count, lower embryo quality, and decreased rates of pregnancy and live births. Furthermore, we identified 82 metabolites that displayed significant alterations in DOR patients, impacting diverse metabolic pathways. Notably, a distinct panel of metabolites, including palmitic acid, stearic acid, LysoPC(9:0(CHO)/0:0), PC(18:0/9:0(CHO)), and PC(16:0/9:0(CHO)), exhibited discriminatory power between the DOR and NOR groups, showcasing a strong correlation with IVF outcomes. These findings emphasize the crucial role of metabolomic disruptions in influencing IVF outcomes among women with DOR.
]]>Metabolites doi: 10.3390/metabo14030142
Authors: Yaxin Wang Chaolu Tan Yinghao Li Fengyan Meng Youwei Du Shuyu Zhang Wenxin Jiang Naijie Feng Liming Zhao Dianfeng Zheng
A large number of dead seedlings can occur in saline soils, which seriously affects the large-scale cultivation of rice. This study investigated the effects of plant growth regulators (PGRs) and nitrogen application on seedling growth and salt tolerance (Oryza sativa L.), which is of great significance for agricultural production practices. A conventional rice variety, “Huang Huazhan”, was selected for this study. Non-salt stress treatments included 0% NaCl (CK treatment), CK + 0.05 g N/pot (N treatment), CK + 40 mg·L−1 5-aminolevulinic acid (5-ALA) (A treatment), and CK + 30 mg·L−1 diethylaminoethyl acetate (DTA-6) (D treatment). Salt stress treatments included 0.3% NaCl (S treatment), N + 0.3% NaCl (NS treatment), A + 0.3% NaCl (AS treatment), and D + 0.3% NaCl (DS treatment). When 3 leaves and 1 heart emerged from the soil, plants were sprayed with DTA-6 and 5-ALA, followed by the application of 0.3% NaCl (w/w) to the soil after 24 h. Seedling morphology and photosynthetic indices, as well as carbohydrate metabolism and key enzyme activities, were determined for each treatment. Our results showed that N, A, and D treatments promoted seedling growth, photosynthesis, carbohydrate levels, and the activities of key enzymes involved in carbon metabolism when compared to the CK treatment. The A treatment had the most significant effect, with increases in aboveground dry weight and net photosynthetic rates (Pn) ranging from 17.74% to 41.02% and 3.61% to 32.60%, respectively. Stomatal limiting values (Ls) significantly decreased from 19.17% to 43.02%. Salt stress significantly inhibited seedling growth. NS, AS, and DS treatments alleviated the morphological and physiological damage of salt stress on seedlings when compared to the S treatment. The AS treatment was the most effective in improving seedling morphology, promoting photosynthesis, increasing carbohydrate levels, and key enzyme activities. After AS treatment, increases in aboveground dry weight, net photosynthetic rate, soluble sugar content, total sucrose synthase, and amylase activities were 17.50% to 50.79%, 11.39% to 98.10%, 20.20% to 80.85%, 21.21% to 33.53%, and 22.17% to 34.19%, respectively, when compared to the S treatment. In summary, foliar sprays of 5-ALA, DTA-6, and additional nitrogen fertilizer enhanced rice seedling growth, increased photosynthesis, lowered Ls values, and improved seedling salt tolerance. Spraying two regulators, 5-ALA and DTA-6, quantitatively increased the effect of nitrogen fertilizer, with comparable effects on NaCl stress regulation. This study provides the basis for efficient agricultural production.
]]>Metabolites doi: 10.3390/metabo14030141
Authors: Thomas Piper Gregor Fußhöller Mario Thevis
Adrenosterone (Androst-4-ene-3,11,17-trione, 11OXO) is forbidden in sports according to the Prohibited List of the World Anti-Doping Agency. The administration of 11OXO may be detected by monitoring the urinary concentrations of its main human metabolites 11β-hydroxy-androsterone and 11β-hydroxy-etiocholanolone. Preliminary urinary concentration and concentration ratio thresholds have been established for sports drug testing purposes, but adaptations are desirable as the suggested limits would result in numerous suspicious findings due to naturally elevated concentrations and ratios. Recently, the metabolism of 11-oxo-testosterone (KT) was investigated in the context of anti-doping research, resulting in a preliminary urinary concentration threshold and a confirmation procedure based on the determination of carbon isotope ratios (CIRs). Gas chromatography coupled to isotope ratio mass spectrometry was employed to investigate the CIRs of selected steroids. As KT is also a metabolite of 11OXO, the developed protocols for KT have been tested to elucidate their potential to detect the administration of 11OXO after a single oral dose of 100 mg. In order to further improve the analytical approach, the threshold for urinary concentrations of KT was re-investigated by employing a reference population of n = 5232 routine doping control samples. Quantification of urinary steroids was conducted by employing gas chromatography coupled to triple quadrupole mass spectrometry. Derived from these, a subset of n = 106 samples showing elevated concentrations of KT was investigated regarding their CIRs. By means of this, potentially positive samples due to the illicit administration of 11OXO or KT could be excluded, and the calculation of reference population-derived thresholds for the concentrations and CIR of KT was possible. Based on the results, the urinary concentration threshold for KT is suggested to be established at 130 ng/mL.
]]>Metabolites doi: 10.3390/metabo14030140
Authors: Vladimir Ossipov Firdaus Khazieva Dmitry Baleev Juha-Pekka Salminen Nikolay Sidelnikov
Calendula officinalis L. is a well-known plant widely used in traditional medicine due to the presence of various biologically active compounds. The main raw material for the production of medicinal preparations is the inflorescence, which consists of ligulate and tubular flowers. However, the characteristics of the metabolome of these flowers are not fully understood. This study identified and compared the levels of major metabolites in the ligulate and tubular flowers of two C. officinalis cultivars, ‘Golden Sea’ (GS) and ‘Paradise Garden’ (PG). The metabolome was analysed using ultra-performance liquid chromatography with photodiode array detection and a Q Exactive Orbitrap high-resolution mass spectrometer. It was found that the tubular flowers of both PG and GS cultivars had higher levels of lipids, phenolamides and caffeoylquinic acids and lower levels of triterpenoid glycosides than the ligulate flowers. It was also shown that the inflorescences of the GS, which had a 35% higher proportion of tubular flowers, contained 30% more phenolic compounds and 50% more lipids than the PG. Thus, the results obtained extend our understanding of the features in the metabolomes of ligulate and tubular flowers and suggest that the quality of inflorescences of C. officinalis cultivars, as a source of medicinal preparations, is strongly influenced by the proportion of ligulate and tubular flowers.
]]>Metabolites doi: 10.3390/metabo14030139
Authors: Zhongwen Chen Huiwen Gu Ruiqi Zhou Shuqun Cheng
Herein, we explored the overall association between metal mixtures and lung functions in populations of varying ages and the relationship among the associated components. The 2007–2012 National Health and Nutrition Examination Survey data of 4382 American participants was analyzed, and generalized linear, elastic net, quantile g–computation, and Bayesian kernel machine regression models were used to evaluate the relationship between exposure to the metal mixture and lung function at various ages. The results of barium exposure at distinct stages revealed that children and adolescents exhibited greater lung function changes than those in adults and the elderly. Additionally, compared with children and adolescents, cadmium– and arsenic–containing metabolites contributed to nonconductive lung function changes in adults and the elderly exposed to metal mixtures. The results showed that the effects of exposure to metal mixtures on lung function in children and adolescents were predominantly caused by lead and barium. Altogether, children and adolescents were found to be more susceptible to metal–exposure–mediated lung function changes than adults and the elderly.
]]>Metabolites doi: 10.3390/metabo14030138
Authors: Mingxuan Zhao Jian Zhang Fuzhou Liu Lv Luo Mingbang Wei Yourong Ye Chamba Yangzom Peng Shang
To study the effects of different feed additives on the weaning stress of Tibetan piglets, we selected 28 healthy, 30-day-old Tibetan weaned piglets and divided them into four groups, namely, the control group (basal feed without any antibiotic additions) (Nor), the group with the addition of the antibiotic lincomycin (Ant), the group with the addition of fifteen-flavor black pills of Tibetan medicine (Tib), and the group with the addition of fecal bacterial supernatant (Fec). We measured growth performance, blood physiological indexes, and metabolomics. The results showed that the Ant, Tib, and Fec groups significantly reduced the ratio of diarrhea to feed/weight (F/G) and increased the average daily gain (ADG) compared with the Nor group (p < 0.01). The Nor group had significantly lower leukocyte counts, hemoglobin levels, and erythrocyte counts compared with the other three groups at 21 d (p < 0.05). These physiological indexes tended to stabilize at 42 d. We found that there were beneficial metabolites and metabolic pathways for gastrointestinal function. Specifically, the porphyrin metabolic pathway was elevated in the Ant group, and the tryptophan metabolic pathway was significantly elevated in the Tib and Fec groups compared with the Nor group (p < 0.05). In conclusion, adding fecal bacterial supernatant and fifteen-flavor black pills of Tibetan medicine to the feed reduced the rate of diarrhea and improved the growth performance of the piglets. Moreover, it had an effect on the microorganisms and their metabolites and pathways in the gastrointestinal tract of the animals, which might be the main reason for influencing the diarrhea rate of weaned Tibetan piglets and the growth and development of the piglets. This study provides a new approach for anti-stress applications in weaned Tibetan piglets and the development of substitute anti-products.
]]>Metabolites doi: 10.3390/metabo14030137
Authors: Chuandi Jin Guoping Zhao
Epidemiological studies have linked obesity to the onset of puberty, while its causality and the potential metabolite mediators remain unclear. We employed a two-sample Mendelian randomization (MR) design to evaluate the causal effects of obesity on puberty onset and its associated diseases including type 2 diabetes (T2D) and cardiovascular diseases (CVDs). The potential mediators in this pathway were further explored using a two-step MR design. The robustness of our findings was evaluated using sensitivity analyses. Our MR results revealed that childhood obesity/BMI were causally associated with an increased Tanner stage in girls, younger age at menarche, and increased risk of adulthood T2D and CVD. However, neither childhood BMI nor obesity had a causal effect on the Tanner stage in boys. Mediation analysis further indicated that increased creatine served as a mediator for the causal pathway from childhood obesity/BMI to the Tanner stage of girls, while early puberty onset in girls played a mediating role in the pathway linking childhood obesity to increased risk of adulthood T2D and CVD. This study indicated that the risk of early puberty onset in girls and its associated health issues can be potentially reduced by preventing childhood obesity. The involvement of creatine in this process needs to be further validated and explored.
]]>Metabolites doi: 10.3390/metabo14030136
Authors: Mario Lovrić David Horner Liang Chen Nicklas Brustad Ann-Marie Malby Schoos Jessica Lasky-Su Bo Chawes Morten Arendt Rasmussen
Vertical transmission of metabolic constituents from mother to child contributes to the manifestation of disease phenotypes in early life. This study probes the vertical transmission of metabolites from mothers to offspring by utilizing machine learning techniques to differentiate between true mother–child dyads and randomly paired non-dyads. Employing random forests (RF), light gradient boosting machine (LGBM), and logistic regression (Elasticnet) models, we analyzed metabolite concentration discrepancies in mother–child pairs, with maternal plasma sampled at 24 weeks of gestation and children’s plasma at 6 months. The propensity of vertical transfer was quantified, reflecting the likelihood of accurate mother–child matching. Our findings were substantiated against an external test set and further verified through statistical tests, while the models were explained using permutation importance and SHapley Additive exPlanations (SHAP). The best model was achieved using RF, while xenobiotics were shown to be highly relevant in transfer. The study reaffirms the transmission of certain metabolites, such as perfluorooctanoic acid (PFOA), but also reveals additional insights into the maternal influence on the child’s metabolome. We also discuss the multifaceted nature of vertical transfer. These machine learning-driven insights complement conventional epidemiological findings and offer a novel perspective on using machine learning as a methodology for understanding metabolic interactions.
]]>Metabolites doi: 10.3390/metabo14030135
Authors: Dandan Jia Huijie Zhang Tiemin Liu Ru Wang
Adipose tissue undergoes changes with aging, leading to increased adiposity, inflammatory cell infiltration, reduced angiogenesis, heightened oxidative stress, and alterations in its metabolic function. Regular exercise has been recognized as a powerful intervention that can positively influence adipose tissue health and mitigate the effects of aging. However, the molecular mechanisms underlying the benefits of regular exercise on aging adipose tissue function remain poorly understood. Adipokines released through regular exercise play a potential role in mitigating adipose tissue aging, enhancing the metabolism of glucose and lipids, reducing inflammation and fibrosis, and promoting fat browning and thermogenesis. This review comprehensively summarizes the benefits of regular exercise in addressing the age-related decline in adipose tissue function. Utilizing relevant examples of this approach, we address the possibility of designing therapeutic interventions based on these molecular mechanisms.
]]>Metabolites doi: 10.3390/metabo14030134
Authors: Zhepei Zhang Fengcheng Song Linjuan Wang Zhengrong Yuan
Hibernating mammals confront seasonal and harsh environmental shifts, prompting a cycle of pre-hibernation feeding and subsequent winter fasting. These adaptive practices induce diverse physiological adjustments within the animal’s body. With the gut microbiota’s metabolic activity being heavily reliant on the host’s diet, this cycle’s primary impact is on this microbial community. When the structure and composition of the gut microbiota changes, corresponding alterations in the interactions occur between these microorganisms and their host. These successive adaptations significantly contribute to the host’s capacity to sustain relatively stable metabolic and immune functions in severe environmental conditions. A thorough investigation into the reciprocal interplay between the host and gut microbiota during hibernation-induced adaptive changes holds promise for unveiling new insights. Understanding the underlying mechanisms driving these interactions may potentially unlock innovative approaches to address extreme pathological conditions in humans.
]]>Metabolites doi: 10.3390/metabo14030133
Authors: Alexis N. Pulliam Alyssa F. Pybus David A. Gaul Samuel G. Moore Levi B. Wood Facundo M. Fernández Michelle C. LaPlaca
Traumatic brain injury (TBI) is a significant source of disability in the United States and around the world and may lead to long-lasting cognitive deficits and a decreased quality of life for patients across injury severities. Following the primary injury phase, TBI is characterized by complex secondary cascades that involve altered homeostasis and metabolism, faulty signaling, neuroinflammation, and lipid dysfunction. The objectives of the present study were to (1) assess potential correlations between lipidome and cytokine changes after closed-head mild TBI (mTBI), and (2) examine the reproducibility of our acute lipidomic profiles following TBI. Cortices from 54 Sprague Dawley male and female rats were analyzed by ultra-high-performance liquid chromatography mass spectrometry (LC-MS) in both positive and negative ionization modes and multiplex cytokine analysis after single (smTBI) or repetitive (rmTBI) closed-head impacts, or sham conditions. Tissue age was a variable, given that two cohorts (n = 26 and n = 28) were initially run a year-and-a-half apart, creating inter-batch variations. We annotated the lipidome datasets using an in-house data dictionary based on exact masses of precursor and fragment ions and removed features with statistically significant differences between sham control batches. Our results indicate that lipids with high-fold change between injury groups moderately correlate with the cytokines eotaxin, IP-10, and TNF-α. Additionally, we show a significant decrease in the pro-inflammatory markers IL-1β and IP-10, TNF-α, and RANTES in the rmTBI samples relative to the sham control. We discuss the major challenges in correlating high dimensional lipidomic data with functional cytokine profiles and the implications for understanding the biological significance of two related but disparate analysis modes in the study of TBI, an inherently heterogeneous neurological disorder.
]]>Metabolites doi: 10.3390/metabo14030132
Authors: Gholamreza Bidkhori Saeed Shoaie
Understanding microbial metabolism is crucial for evaluating shifts in human host–microbiome interactions during periods of health and disease. However, the primary hurdle in the realm of constraint-based modeling and genome-scale metabolic models (GEMs) pertaining to host–microbiome interactions lays in the efficient utilization of metagenomic data for constructing GEMs that encompass unexplored and uncharacterized genomes. Challenges persist in effectively employing metagenomic data to address individualized microbial metabolisms to investigate host–microbiome interactions. To tackle this issue, we have created a computational framework designed for personalized microbiome metabolisms. This framework takes into account factors such as microbiome composition, metagenomic species profiles and microbial gene catalogues. Subsequently, it generates GEMs at the microbial level and individualized microbiome metabolisms, including reaction richness, reaction abundance, reactobiome, individualized reaction set enrichment (iRSE), and community models. Using the toolbox, our findings revealed a significant reduction in both reaction richness and GEM richness in individuals with liver cirrhosis. The study highlighted a potential link between the gut microbiota and liver cirrhosis, i.e., increased level of LPS, ammonia production and tyrosine metabolism on liver cirrhosis, emphasizing the importance of microbiome-related factors in liver health.
]]>Metabolites doi: 10.3390/metabo14030131
Authors: Xue Xiao Xiaokang Guan Zhouyi Xu Qiao Lu
With its high resolving power and sensitivity, mass spectrometry is considered the most informative technique for metabolite qualitation and quantification in the plant sciences. However, the spatial location information, which is crucial for the exploration of plant physiological mechanisms, is lost. Mass spectrometry imaging (MSI) is able to visualize the spatial distribution of a large number of metabolites from the complex sample surface in a single experiment. In this paper, a flexible and low-cost laser desorption–dielectric barrier discharge ionization-MSI (LD-DBDI-MSI) platform was constructed by combining an LD system with an in-line DBDI source, a high-precision sample translation stage, and an ambient mass spectrometer. It can be operated at a spatial resolution of 20 μm in an atmospheric environment and requires minimal sample preparation. This study presents images of in-situ metabolic profiling of two kinds of plants from different origins, a wild and a farmed Rheum palmatum L. From the screen of these two root sections, the wild one presented five more endogenous molecules than the farmed one, which provides information about the differences in metabolomics.
]]>Metabolites doi: 10.3390/metabo14020130
Authors: Jieun Kim Kyoungsik Jeong Sueun Lim Siwoo Lee Younghwa Baek
Dietary protein sources and protein adequacy are crucial modulators of muscle quality and body composition. We investigated the association between dietary protein sources (and their adequacy) and body composition and the risk of sarcopenic obesity (SO) in South Korean populations. The participants (n = 1967) were classified into SO, obese, sarcopenia, and normal groups. A cross-sectional survey was conducted using the KS-15 questionnaire, short-form food frequency questionnaire, and anthropometric measurements. The percentage of body fat (male: 35.36 ± 0.51%; female: 44.14 ± 0.36%) was significantly high, while appendicular skeletal muscle (ASM; male: 36.39 ± 0.30%, female: 30.32 ± 0.19%) was low in the SO group. Beef and pork consumption was negatively associated with ASM (%) but positively associated with body fat (%) in the normal group and positively associated with ASM (kg/m2: beta = 0.002, p = 0.02) and BFM (kg: beta = 0.012, p = 0.03) in the SO group, respectively. The highest quintile (Q5: 173.6 g/day) showed a decreased risk of SO prevalence (AORs: 0.46, CI: 0.22–0.94) compared with that in the lowest quintile (Q1: 21.6 g/day) among the people with inadequacy protein intake. Daily poultry and egg intake was positively linked with body composition in the participants with SO, while red meat showed a negative effect on imbalanced body composition in participants in the normal and SO groups. Furthermore, a lower intake of poultry and eggs was strongly associated with SO prevalence in people who consumed inadequate amounts of daily dietary protein.
]]>Metabolites doi: 10.3390/metabo14020129
Authors: Pei-Yi Chu Ying-Chun Yu Yi-Cheng Pan Yun-Hao Dai Juan-Cheng Yang Kuo-Chin Huang Yang-Chang Wu
This study aimed to evaluate the efficacy of Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) in improving body weight, obesity-related outcomes, and lipid profiles of overweight people. Thirty-six overweight participants were randomly assigned to either a probiotic or a placebo group. A placebo powder or L. bulgaricus powder (containing 1 × 108 colony-forming unit (CFU) of the probiotic) was administered daily for 12 weeks. Body composition was determined, and blood tests were performed before and after the intervention. L. bulgaricus supplementation under the present condition did not affect the body weight, fat percentage, or body mass index (BMI) of the participants, while it resulted in a notable decrease in blood triglyceride (TG) levels, which corresponded to a lowering of the TG proportion in the composition of large VLDL (L–XXL sized fractions) and HDL (M and L fractions) in the probiotic-treated group. These results suggest that L. bulgaricus supplementation under the current conditions may not be helpful for losing weight, but it has the potential to decrease blood TG levels by modulating TG accumulation in or transport by VLDL/HDL in obese patients. L. bulgaricus supplements may have health-promoting properties in preventing TG-related diseases in overweight people.
]]>Metabolites doi: 10.3390/metabo14020128
Authors: Ji-Woo Yu Min-Ho Song Ji-Ho Lee Jun-Hwan Song Won-Ho Hahn Young-Soo Keum Nam Mi Kang
Human breastmilk is an invaluable nutritional and pharmacological resource with a highly diverse metabolite profile, which can directly affect the metabolism of infants. Application of metabolomics can discriminate the complex relationship between such nutrients and infant health. As the most common biological fluid in metabolomic study, infant urinary metabolomics may provide the physiological impacts of different nutritional resources, namely human breastmilk and formulated milk. In this study, we aimed to identify possible differences in the urine metabolome of 30 infants (1–14 days after birth) fed with breast milk (n = 15) or formulated milk (n = 15). From metabolomic analysis with gas chromatography-mass spectrometry, 163 metabolites from single mass spectrometry (GC-MS), and 383 metabolites from tandem mass spectrometry (GC-MS/MS) were confirmed in urinary samples. Various multivariate statistical analysis were performed to discriminate the differences originating from physiological/nutritional variables, including human breastmilk/formulate milk feeding, sex, and duration of feeding. Both unsupervised and supervised discriminant analyses indicated that feeding resources (human breastmilk/formulated milk) gave marginal but significant differences in urinary metabolomes, while other factors (sex, duration of feeding) did not show notable discrimination between groups. According to the biomarker analyses, several organic acid and amino acids showed statistically significant differences between different feeding resources, such as 2-hydroxyhippurate.
]]>Metabolites doi: 10.3390/metabo14020127
Authors: Bushra Ejaz Abdul Mujib Rukaya Syeed Jyoti Mamgain Moien Qadir Malik Kanchan Birat Yaser Hassan Dewir Katalin Magyar-Tábori
In this study, a Gas chromatography–mass spectrometry (GC–MS) investigation of embryogenic callus and somatic embryo regenerated shoots of Carthamus tinctorius revealed the presence of a variety of sugars, sugar acids, sugar alcohols, fatty acids, organic acids, and amino acids of broad therapeutic value. The in vitro developed inflorescence contained a wide range of active compounds. In embryogenic calluses, important flavonoids like naringenin, myricetin, kaempferol, epicatechin gallate, rutin, pelargonidin, peonidin, and delphinidin were identified. To augment the synthesis of active compounds, the effect of cadmium chloride (CdCl2) elicitation was tested for various treatments (T1–T4) along with a control (T0). Varying concentrations of CdCl2 [0.05 mM (T1), 0.10 mM (T2), 0.15 mM (T3), and 0.20 mM (T4)] were added to the MS medium, and flavonoid accumulation was quantified through ultra-high-pressure liquid chromatography–tandem mass spectroscopy (UHPLC–MS/MS). The flavonoids naringenin, kaempferol, epicatechin gallate, pelargonidin, cyanidin, and delphinidin increased by 6.7-, 1.9-, 3.3-, 2.1-, 1.9-, and 4.4-fold, respectively, at T3, whereas quercetin, myricetin, rutin, and peonidin showed a linear increase with the increase in CdCl2 levels. The impacts of stress markers, i.e., ascorbate peroxidase (APX), catalase (CAT), and superoxide dismutase (SOD), on defense responses in triggering synthesis were also evaluated. The maximum APX and SOD activity was observed at T3, while CAT activity was at its maximum at T2. The impact of elicitor on biochemical attributes like protein, proline, sugar, and malondialdehyde (MDA) content was investigated. The maximum protein, proline, and sugar accumulation was noted at high elicitor dose T4, while the maximum MDA content was noted at T3. These elevated levels of biochemical parameters indicated stress in culture, and the amendment of CdCl2 in media thus could be a realistic approach for enhancing secondary metabolite synthesis in safflower.
]]>Metabolites doi: 10.3390/metabo14020126
Authors: Tracy K. Her Jin Li Hao Lin Dong Liu Kate M. Root Jean F. Regal Emilyn U. Alejandro Ruifeng Cao
Circadian rhythm disruption is associated with impaired glucose homeostasis and type 2 diabetes. For example, night shift work is associated with an increased risk of gestational diabetes. However, the effects of chronic circadian disruption since early life on adult metabolic health trajectory remain unknown. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was used to disrupt mouse circadian rhythms across the lifespan, we investigated glucose homeostasis in adult mice. Adult SD mice were fully entrained into the 8 h/8 h LD cycle, and control mice were entrained into the 12 h/12 h LD cycle. Under a normal chow diet, female and male SD mice displayed a normal body weight trajectory. However, female but not male SD mice under a normal chow diet displayed glucose intolerance and insulin resistance, which are associated with impaired insulin signaling/AKT in the skeletal muscle and liver. Under high-fat diet (HFD) challenges, male but not female SD mice demonstrated increased body weight gain compared to controls. Both male and female SD mice developed glucose intolerance under HFD. Taken together, these results demonstrate that environmental disruption of circadian rhythms contributes to obesity in a sexually dimorphic manner but increases the risk of glucose intolerance and insulin resistance in both males and females.
]]>Metabolites doi: 10.3390/metabo14020125
Authors: Hani Habra Jennifer L. Meijer Tong Shen Oliver Fiehn David A. Gaul Facundo M. Fernández Kaitlin R. Rempfert Thomas O. Metz Karen E. Peterson Charles R. Evans Alla Karnovsky
Liquid chromatography–high-resolution mass spectrometry (LC-HRMS), as applied to untargeted metabolomics, enables the simultaneous detection of thousands of small molecules, generating complex datasets. Alignment is a crucial step in data processing pipelines, whereby LC-MS features derived from common ions are assembled into a unified matrix amenable to further analysis. Variability in the analytical factors that influence liquid chromatography separations complicates data alignment. This is prominent when aligning data acquired in different laboratories, generated using non-identical instruments, or between batches from large-scale studies. Previously, we developed metabCombiner for aligning disparately acquired LC-MS metabolomics datasets. Here, we report significant upgrades to metabCombiner that enable the stepwise alignment of multiple untargeted LC-MS metabolomics datasets, facilitating inter-laboratory reproducibility studies. To accomplish this, a “primary” feature list is used as a template for matching compounds in “target” feature lists. We demonstrate this workflow by aligning four lipidomics datasets from core laboratories generated using each institution’s in-house LC-MS instrumentation and methods. We also introduce batchCombine, an application of the metabCombiner framework for aligning experiments composed of multiple batches. metabCombiner is available as an R package on Github and Bioconductor, along with a new online version implemented as an R Shiny App.
]]>Metabolites doi: 10.3390/metabo14020124
Authors: He Li Fenglin Li Chaoyi Zhou Jifan Bu Hao Yang Liangchen Zhong Weilong Xing Liangzhong Li
Widespread exposure to organophosphorus flame retardants (OPFRs) has been observed in the general population. Emerging studies have revealed OPFRs possess endocrine-disturbing properties. The present study aims to assess the association between urinary metabolites of OPFRs, BMI, and serum lipid profiles. Data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 were obtained, with 1334 adults enrolled in the current study. Urinary concentrations of bis (1-chloro-2-propyl) phosphate (BCIPP), bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), dibutyl phosphate (DBUP), and diphenyl phosphate (DPHP) were quantified to assess OPFR exposure. Covariate-adjusted linear and logistic regression models were conducted to explore the associations between log2-transformed concentrations of OPFR metabolites, BMI, obesity, and serum lipid profiles. Stratified analyses were performed to assess the heterogeneity of associations by age, gender, race, etc. Positive associations were found between OPFR exposure and the risk of obesity. The multivariate linear analysis indicated that a one-unit increase in log2-transformed urinary concentrations of BCEP and BDCPP was associated with 0.27 (95% CI: 0.02–0.52, p = 0.0338) and 0.56 (95% CI: 0.25–0.87, p = 0.0004) higher BMI value, respectively. One log2-unit increase in urinary BCEP and BDCPP concentrations was associated with 1.1-fold (95% CI: 1.02–1.18, p = 0.0096) and 1.19-fold (95% CI: 1.09–1.30, p = 0.0001) risk for developing obesity. Furthermore, the non-linear relationship between exposure to OPFRs and obesity was identified. Additionally, multivariable linear regression showed that urinary DPHP concentrations were inversely correlated with serum triglyceride (TG) levels (β = −7.41, 95% CI: −12.13 to −2.68, p = 0.0022). However, no other OPFR metabolites were found to be significantly statistically associated with serum lipid levels after adjusting for potential confounders. In conclusion, environmental exposure to OPFRs might contribute to obesity and dysregulated TG concentrations in adults. Future prospective research is warranted to confirm the causal relationship between metabolites of OPFRs and obesity.
]]>Metabolites doi: 10.3390/metabo14020123
Authors: Dimitris Kounatidis Natalia G. Vallianou Aikaterini Poulaki Angelos Evangelopoulos Fotis Panagopoulos Theodora Stratigou Eleni Geladari Irene Karampela Maria Dalamaga
ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.
]]>Metabolites doi: 10.3390/metabo14020122
Authors: Junyi Li Jian Yang Yun Xia Junyi Wang Yuan Xia
Long-term exposure to noise can cause irreversible hearing loss. Considering that there is no effective drug treatment, it is important to seek preventive treatment for noise-induced hearing loss (NIHL). Although astragaloside IV (AS-IV) protects against NIHL by reducing serum inflammatory factors, there is scarce information on the regulation of inflammatory factors by AS-IV to prevent NIHL. We investigated the hearing thresholds and relationship between the serum levels of inflammatory cytokines and intestinal microbiota of c57bl/6j mice exposed to noise (103 dB SPL 4 h·d−1) for 7 days, treated with or without AS-IV. Our results revealed a lower hearing threshold and lower serum levels of TNF-α, TNF-γ, IL-6, IL-1β, and IFN-γ in the mice treated with AS-IV. Additionally, AS-IV increased the abundance levels of the phylum Firmicutes, class Bacillus, order Lactobacillus, and family Lactobacillus (p < 0.05), and decreased those of the phylum Bacteroidetes and order Bacteroidales (p < 0.05). Lactobacillus and Bacilli negatively correlated with TNF-α, TNF-γ, and IL-1β; Erysipelotrichaceae negatively correlated with INF-γ; and Clostridiales positively correlated with IL-1β. In conclusion, AS-IV reduces the elevation of hearing thresholds in mice, preventing hearing loss in mice exposed to noise, and under the intervention of AS-IV, changes in the levels of inflammatory factors correlate with intestinal flora. We suggest that AS-IV improves intestinal flora and reduces inflammation levels in c57bl/6j mice exposed to noise.
]]>Metabolites doi: 10.3390/metabo14020121
Authors: Verónica Riggen-Bueno Susana Del Toro-Arreola Tonatiuh Abimael Baltazar-Díaz Alejandra N. Vega-Magaña Marcela Peña-Rodríguez Paula Alejandra Castaño-Jiménez Laura Verónica Sánchez-Orozco José María Vera-Cruz Miriam Ruth Bueno-Topete
Obesity is a public health problem with a growing prevalence worldwide. In Mexico, it is estimated that one out of three adults suffer from obesity. In these patients, the intestinal microbiota (IM) undergoes pathological changes that are associated with a dysbiotic state; however, the microbiota profile of adult subjects with obesity from western Mexico has not been described. To assess this, fecal samples were obtained from 65 participants (Obese = 38; Control = 27). The microbial composition was characterized by 16S rRNA amplicon sequencing. The IM of the group with obesity revealed a clear decrease in richness and diversity (p < 0.001), as well as a significant increase in proinflammatory bacterial groups, mainly genera belonging to the Negativicutes class, Escherichia/Shigella, and Prevotella. Likewise, an increase in short-chain fatty acid-producing bacteria was found, especially the genus Lachnoclostridium. Additionally, PICRUSt2 analysis showed a depletion of vitamin B9 metabolism and an increase in saccharolytic pathways. The IM of patients with obesity possesses a dysbiotic, proinflammatory environment, possibly contributing to lipogenesis and adiposity. Thus, assessing the IM will allow for a better understanding of the pathophysiology of metabolic diseases of high prevalence, such as obesity. These findings are described for the first time in the adult population of western Mexico.
]]>Metabolites doi: 10.3390/metabo14020120
Authors: Jinyan Zhu Ruizhi Wang Yu Zhang Yanyao Lu Shuo Cai Qiangqiang Xiong
Colored rice is richer in nutrients and contains more nutrients and bioactive substances than ordinary white rice. Moderate consumption of black (purple) rice has a variety of physiological effects, such as antioxidant effects, blood lipid regulation, and blood sugar control. Therefore, we utilized nontargeted metabolomics, quantitative assays for flavonoid and phenolic compounds, and physiological and biochemical data to explore the correlations between metabolites and the development of antioxidant characteristics in pigmented rice seeds. The findings indicated that, among Yangjinnuo 818 (YJN818), Hongnuo (HN), Yangchannuo 1 hao (YCN1H), and Yangzi 6 hao (YZ6H), YZ6H exhibited the highest PAL activity, which was 2.13, 3.08, and 3.25 times greater than those of YJN818, HN, and YCN1H, respectively. YZ6H likewise exhibited the highest flavonoid content, which was 3.8, 7.06, and 35.54 times greater than those of YJN818, HN, and YCN1H, respectively. YZ6H also had the highest total antioxidant capacity, which was 2.42, 3.76, and 3.77 times greater than those of YJN818, HN, and YCN1H, respectively. Thus, purple rice grains have stronger antioxidant properties than other colored rice grains. Receiver operating characteristic (ROC) curve analysis revealed that trans-3,3′,4′,5,5′,7-hexahydroxyflavanone, phorizin, and trilobatin in the YZ6H, HN, and YCN1H comparison groups all had area under the curve (AUC) values of 1. Phlorizin, trans-3,3′,4′,5,5′,7-hexahydroxyflavanone, and trilobatin were recognized as indices of antioxidant capability in colored rice in this research. This research adds to the understanding of antioxidant compounds in pigmented rice, which can increase the nutritional value of rice and promote the overall well-being of individuals. This type of information is of immense importance in maintaining a balanced and healthy diet.
]]>Metabolites doi: 10.3390/metabo14020119
Authors: Ruchi Barthwal Rohit Mahar
Secondary metabolites are essential components for the survival of plants. Secondary metabolites in complex mixtures from plants have been adopted and documented by different traditional medicinal systems worldwide for the treatment of various human diseases. The extraction strategies are the key components for therapeutic development from natural sources. Polarity-dependent solvent-selective extraction, acidic and basic solution-based extraction, and microwave- and ultrasound-assisted extraction are some of the most important strategies for the extraction of natural products from plants. The method needs to be optimized to isolate a specific class of compounds. Therefore, to establish the mechanism of action, the characterization of the secondary metabolites, in a mixture or in their pure forms, is equally important. LC-MS, GC-MS, and extensive NMR spectroscopic strategies are established techniques for the profiling of metabolites in crude extracts. Various protocols for the extraction and characterization of a wide range of classes of compounds have been developed by various research groups and are described in this review. Additionally, the possible means of characterizing the compounds in the mixture and their uniqueness are also discussed. Hyphenated techniques are crucial for profiling because of their ability to analyze a vast range of compounds. In contrast, inherent chemical shifts make NMR an indispensable tool for structure elucidation in complex mixtures.
]]>Metabolites doi: 10.3390/metabo14020117
Authors: Ruoling Xu Peng Deng Yiren Ma Kui Li Fucai Ren Ning Li
Chaenomeles speciosa (Sweet) Nakai (C. speciosa) fruit has medicinal and food applications and exhibits beneficial pharmacological properties. This study aimed to explore the hypouricemic effect of C. speciosa fruit extracts on hyperuricemic rats and uncover potential protective mechanisms. The rats were given hypoxanthine (HX, 100 mg/kg) and potassium oxonate (PO, 300 mg/kg) for 14 days to induce hyperuricemia. Subsequently, the rats were orally administered C. speciosa fruits total extract (CSFTE, 250, 500, and 1000 mg/kg) and allopurinol (AP, 10 mg/kg) one hour after exposure to HX and PO. The results showed that CSFTE had significant xanthine oxidase (XOD) inhibitory activity in vitro (IC50 value of 334.2 μg/mL) and exhibited hypouricemic effects in vivo, reducing uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) levels in serum. CSFTE increased UA excretion through the regulation of URAT1, GLUT9, OAT1, and OAT3 protein expression in the kidneys of hyperuricemic rats. Additionally, CSFTE (500 and 1000 mg/kg) was more effective than AP in improving renal injury and protecting kidney function in hyperuricemic rats. Our study demonstrated that CSFTE effectively reduced UA levels and protected the kidneys by inhibiting XOD expression in vitro and regulating UA, CRE, BUN, URAT1, GLUT9, OAT1, and OAT3 proteins in vivo.
]]>Metabolites doi: 10.3390/metabo14020118
Authors: Mahnoor Zulfiqar Michael R. Crusoe Birgitta König-Ries Christoph Steinbeck Kristian Peters Luiz Gadelha
Scientific workflows facilitate the automation of data analysis tasks by integrating various software and tools executed in a particular order. To enable transparency and reusability in workflows, it is essential to implement the FAIR principles. Here, we describe our experiences implementing the FAIR principles for metabolomics workflows using the Metabolome Annotation Workflow (MAW) as a case study. MAW is specified using the Common Workflow Language (CWL), allowing for the subsequent execution of the workflow on different workflow engines. MAW is registered using a CWL description on WorkflowHub. During the submission process on WorkflowHub, a CWL description is used for packaging MAW using the Workflow RO-Crate profile, which includes metadata in Bioschemas. Researchers can use this narrative discussion as a guideline to commence using FAIR practices for their bioinformatics or cheminformatics workflows while incorporating necessary amendments specific to their research area.
]]>Metabolites doi: 10.3390/metabo14020116
Authors: Mingjing Chen Guanhong Miao Zhiguang Huo Hao Peng Xiaoxiao Wen Stephen Anton Dachuan Zhang Gang Hu Ricky Brock Phillip J. Brantley Jinying Zhao
It is well recognized that patients with severe obesity exhibit remarkable heterogeneity in response to different types of weight-loss interventions. Those who undergo Roux-en-Y gastric bypass (RYGB) usually exhibit more favorable glycemic outcomes than those who receive adjustable gastric banding (BAND) or intensive medical intervention (IMI). The molecular mechanisms behind these observations, however, remain largely unknown. To identify the plasma metabolites associated with differential glycemic outcomes induced by weight-loss intervention, we studied 75 patients with severe obesity (25 each in RYGB, BAND, or IMI). Using untargeted metabolomics, we repeatedly measured 364 metabolites in plasma samples at baseline and 1-year after intervention. Linear regression was used to examine whether baseline metabolites or changes in metabolites are associated with differential glycemic outcomes in response to different types of weight-loss intervention, adjusting for sex, baseline age, and BMI as well as weight loss. Network analyses were performed to identify differential metabolic pathways involved in the observed associations. After correction for multiple testing (q < 0.05), 33 (RYGB vs. IMI) and 28 (RYGB vs. BAND) baseline metabolites were associated with changes in fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c). Longitudinal changes in 38 (RYGB vs. IMI) and 38 metabolites (RYGB vs. BAND) were significantly associated with changes in FPG or HbA1c. The identified metabolites are enriched in pathways involved in the biosynthesis of aminoacyl-tRNA and branched-chain amino acids. Weight-loss intervention evokes extensive changes in plasma metabolites, and the altered metabolome may underlie the differential glycemic outcomes in response to different types of weight-loss intervention, independent of weight loss itself.
]]>Metabolites doi: 10.3390/metabo14020115
Authors: Taillan Martins Oliveira Tathiany Jéssica Ferreira Paula Albuquerque Penna Franca Rudson Ribeiro da Cruz Mauricio Gattás Bara-Filho Fábio Luiz Candido Cahuê Ana Paula Valente Anna Paola Trindade Rocha Pierucci
A competitive volleyball game is a highly metabolic and physically demanding event for professional players. This study aimed to investigate whether a single game at the end of a preseason promotes changes in the biochemical markers of physical exercise responses and the metabolomic profile of professional volleyball players. This cross-sectional study included 13 male Brazilian professional volleyball players. Food intake, body composition, heart rate, physical movement variables, and blood biochemical indicators were evaluated. For non-target metabolomic analysis, serum samples were subjected to 500 MHz Nuclear Magnetic Resonance. Data analysis showed no significant difference in the biochemical indicators after the game (p > 0.05). The level of metabolites present in the groups of the main components (β-hydroxybutyrate, arginine/lysine, isoleucine, leucine, and valine) had decreased after the game. However, formic acid and histidine levels increased. Among the compounds not part of the main components, hypoxanthine and tyrosine increased, whereas low-density lipoprotein and very low-density lipoprotein levels decreased. After the game, the metabolomic profiles of players showed significant negative variations in essential amino acids (leucine, valine, and isoleucine). These decreases might be influenced by athlete diet and reduced glycogen storage due to lower carbohydrate intake, potentially impacting serum-essential amino acid levels via oxidation in skeletal muscle. The study provides insights for developing metabolic compensation strategies in athletes.
]]>Metabolites doi: 10.3390/metabo14020114
Authors: Marco Bucci Eleni Rebelos Vesa Oikonen Juha Rinne Lauri Nummenmaa Patricia Iozzo Pirjo Nuutila
Accurate positron emission tomography (PET) data quantification relies on high-quality input plasma curves, but venous blood sampling may yield poor-quality data, jeopardizing modeling outcomes. In this study, we aimed to recover sub-optimal input functions by using information from the tail (5th–100th min) of curves obtained through the frequent sampling protocol and an input recovery (IR) model trained with reference curves of optimal shape. Initially, we included 170 plasma input curves from eight published studies with clamp [18F]-fluorodeoxyglucose PET exams. Model validation involved 78 brain PET studies for which compartmental model (CM) analysis was feasible (reference (ref) + training sets). Recovered curves were compared with original curves using area under curve (AUC), max peak standardized uptake value (maxSUV). CM parameters (ref + training sets) and fractional uptake rate (FUR) (all sets) were computed. Original and recovered curves from the ref set had comparable AUC (d = 0.02, not significant (NS)), maxSUV (d = 0.05, NS) and comparable brain CM results (NS). Recovered curves from the training set were different from the original according to maxSUV (d = 3) and biologically plausible according to the max theoretical K1 (53//56). Brain CM results were different in the training set (p < 0.05 for all CM parameters and brain regions) but not in the ref set. FUR showed reductions similarly in the recovered curves of the training and test sets compared to the original curves (p < 0.05 for all regions for both sets). The IR method successfully recovered the plasma inputs of poor quality, rescuing cases otherwise excluded from the kinetic modeling results. The validation approach proved useful and can be applied to different tracers and metabolic conditions.
]]>Metabolites doi: 10.3390/metabo14020113
Authors: Dimitar Djilianov Daniela Moyankova Petko Mladenov Tanya Topouzova-Hristova Aneliya Kostadinova Galya Staneva Diana Zasheva Strahil Berkov Lyudmila Simova-Stoilova
Resurrection plant species are a group of higher plants whose vegetative tissues are able to withstand long periods of almost full desiccation and recover quickly upon rewatering. Apart from being a model system for studying desiccation tolerance, resurrection plant species appear to be a valuable source of metabolites, with various areas of application. A significant number of papers have been published in recent years with respect to the extraction and application of bioactive compounds from higher resurrection plant species in various test systems. Promising results have been obtained with respect to antioxidative and antiaging effects in various test systems, particularly regarding valuable anticancer effects in human cell lines. Here, we review the latest advances in the field and propose potential mechanisms of action of myconoside—a predominant secondary compound in the European members of the Gesneriaceae family. In addition, we shed light on the possibilities for the sustainable use of natural products derived from resurrection plants.
]]>Metabolites doi: 10.3390/metabo14020112
Authors: Ian A. Dubery Lerato P. Nephali Fidele Tugizimana Paul A. Steenkamp
Specialized metabolites are produced via discrete metabolic pathways. These small molecules play significant roles in plant growth and development, as well as defense against environmental stresses. These include damping off or seedling blight at a post-emergence stage. Targeted metabolomics was followed to gain insights into metabolome changes characteristic of different developmental stages of sorghum seedlings. Metabolites were extracted from leaves at seven time points post-germination and analyzed using ultra-high performance liquid chromatography coupled to mass spectrometry. Multivariate statistical analysis combined with chemometric tools, such as principal component analysis, hierarchical clustering analysis, and orthogonal partial least squares–discriminant analysis, were applied for data exploration and to reduce data dimensionality as well as for the selection of potential discriminant biomarkers. Changes in metabolome patterns of the seedlings were analyzed in the early, middle, and late stages of growth (7, 14, and 29 days post-germination). The metabolite classes were amino acids, organic acids, lipids, cyanogenic glycosides, hormones, hydroxycinnamic acid derivatives, and flavonoids, with the latter representing the largest class of metabolites. In general, the metabolite content showed an increase with the progression of the plant growth stages. Most of the differential metabolites were derived from tryptophan and phenylalanine, which contribute to innate immune defenses as well as growth. Quantitative analysis identified a correlation of apigenin flavone derivatives with growth stage. Data-driven investigations of these metabolomes provided new insights into the developmental dynamics that occur in seedlings to limit post-germination mortality.
]]>Metabolites doi: 10.3390/metabo14020111
Authors: Yoshitaka Iwazu Kazuhiko Kotani Taro Sugase Daisuke Nagata Toshiyuki Yamada
Nephrotic syndrome and hypothyroidism are respectively reported to influence renal hemodynamics and hypercholesterolemia. However, the relationship of proteinuria-associated thyroid function with renal hemodynamics and cholesterol metabolism has yet to be determined in a simultaneous analysis of thyroid, renal, and cholesterol variables. We investigated the hypothesis that the changes in thyroid hormones by proteinuria may contribute to changes in cholesterol metabolism and renal hemodynamics by proteinuria. Twenty-nine patients (17 men and 12 women) with proteinuric kidney disease (mean age 46 years) were enrolled in a pilot study. Data for serum free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol, and filtration fraction (FF; assessed by para-aminohippuric acid clearance) were used in variable-adjusted correlation analyses. The patients had the following data (mean ± standard deviation): urinary protein 5.18 ± 3.28 g/day, FT3 2.18 ± 0.44 pg/mL, FT4 1.03 ± 0.26 ng/dL, FF 0.27 ± 0.07, and total cholesterol 327 ± 127 mg/dL. There was a significant positive correlation of FT3 with FF (β = 0.58, p = 0.01) and a significant inverse correlation of FT4 with total cholesterol (β = −0.40, p = 0.01). A positive correlation of FT3 with FF and an inverse correlation of FT4 with total cholesterol were demonstrated in patients with proteinuric kidney disease. The proteinuria-associated reduction in serum thyroid hormone levels was correlated with hypercholesterolemia and the reduced glomerular FF. Further studies of these relationships are required.
]]>Metabolites doi: 10.3390/metabo14020110
Authors: Alexander A. Chernonosov Irina A. Mednova Lyudmila A. Levchuk Ekaterina O. Mazurenko Olga V. Roschina German G. Simutkin Nikolay A. Bokhan Vladimir V. Koval Svetlana A. Ivanova
Depressive disorder is a multifactorial disease that is based on dysfunctions in mental and biological processes. The search for biomarkers can improve its diagnosis, personalize therapy, and lead to a deep understanding of the biochemical processes underlying depression. The purpose of this work was a metabolomic analysis of blood serum to classify patients with depressive disorders and healthy individuals using Compound Discoverer software. Using high-resolution mass spectrometry, blood plasma samples from 60 people were analyzed, of which 30 were included in a comparison group (healthy donors), and 30 were patients with a depressive episode (F32.11) and recurrent depressive disorder (F33.11). Differences between patient and control groups were identified using the built-in utilities in Compound Discoverer software. Compounds were identified by their accurate mass and fragment patterns using the mzCloud database and tentatively identified by their exact mass using the ChemSpider search engine and the KEGG, ChEBI, FDA UNII-NLM, Human Metabolome and LipidMAPS databases. We identified 18 metabolites that could divide patients with depressive disorders from healthy donors. Of these, only two compounds were tentatively identified using the mzCloud database (betaine and piperine) based on their fragmentation spectra. For three compounds ((4S,5S,8S,10R)-4,5,8-trihydroxy-10-methyl-3,4,5,8,9,10-hexahydro-2H-oxecin-2-one, (2E,4E)-N-(2-hydroxy-2-methylpropyl)-2,4-tetradecadienamide and 17α-methyl-androstan-3-hydroxyimine-17β-ol), matches were found in the mzCloud database but with low score, which could not serve as reliable evidence of their structure. Another 13 compounds were identified by their exact mass in the ChemSpider database, 9 (g-butyrobetaine, 6-diazonio-5-oxo-L-norleucine, 11-aminoundecanoic acid, methyl N-acetyl-2-diazonionorleucinate, glycyl-glycyl-argininal, dilaurylmethylamine, 12-ketodeoxycholic acid, dicetylamine, 1-linoleoyl-2-hydroxy-sn-glycero-3-PC) had only molecular formulas proposed, and 4 were unidentified. Thus, the use of Compound Discoverer software alone was not sufficient to identify all revealed metabolites. Nevertheless, the combination of the found metabolites made it possible to divide patients with depressive disorders from healthy donors.
]]>Metabolites doi: 10.3390/metabo14020109
Authors: Hicham Benabdelkamel Malak A. Jaber Khalid Akkour Reem H. AlMalki Assim A. Alfadda Afshan Masood Salini Scaria Joy Hani Alhalal Moudi A. Alwehaibi Maria Arafah Eman Alshehri Anas M. Abdel Rahman
Uterine cancer is the most prevalent gynecologic malignancy in women worldwide. Endometrial cancer (EC) has an 81% five-year survival rate, depending on disease stage and time of diagnosis. While endometrial cancer is largely treatable when detected early, no established screening techniques are available in clinical practice. As a result, one of the most significant issues in the medical field is the development of novel ways for early cancer identification, which could boost treatment success rates. Liquid chromatography–high-resolution mass spectrometry (LC-HRMS)-based metabolomics was employed to explore the metabolomic markers and pathways unique to this cancer type and link them to the benign endometrial hyperplasia that may progress to cancer in 5% to 25% of patients. The study involved 59 postmenopausal participants, 20 with EC type 1, 20 with benign hyperplasia, and 19 healthy participants. Metabolite distribution changes were analyzed, and 338 of these features were dysregulated and significant. The first two main components, PC1 and PC2, were responsible for 11.5% and 12.2% of the total metabolites, respectively. Compared with the control group (CO), EC samples had 203 differentially expressed metabolites (180 upregulated and 23 downregulated); in hyperplasia (HP), 157 metabolites were dysregulated (127 upregulated and 30 downregulated) compared to the CO group while 21 metabolites exhibited differential regulation (16 upregulated and 5 downregulated) in EC plasma samples compared to the HP group. Hyperplasia samples exhibited similar metabolic changes to those reported in cancer, except for alterations in triglyceride levels, 7a,12 b-dihydroxy-5b-Cholan-24-oic acid, and Hept-2-enedioyl carnitine levels. The metabolites N-heptanoyl glycine and -(Methylthio)-2,3-isopentyl phosphate and formimino glutamic acid can be specific markers for hyperplasia conditions and dimethyl phosphatidyl ethanolamine and 8-isoprostaglandin E2 can be specific markers for EC conditions. Metabolic activities rely on mitochondrial oxidative phosphorylation for energy generation. The changes in metabolites identified in our study indicate that endometrial cancer cells adopt alternative strategies to increase energy production to meet the energy demand, thereby supporting proliferation.
]]>Metabolites doi: 10.3390/metabo14020108
Authors: Xueqing Li Huixia Niu Zhengliang Huang Man Zhang Mingluan Xing Zhijian Chen Lizhi Wu Peiwei Xu
Emerging pollutants, a category of compounds currently not regulated or inadequately regulated by law, have recently become a focal point of research due to their potential toxic effects on human health. The gut microbiota plays a pivotal role in human health; it is particularly susceptible to disruption and alteration upon exposure to a range of toxic environmental chemicals, including emerging contaminants. The disturbance of the gut microbiome caused by environmental pollutants may represent a mechanism through which environmental chemicals exert their toxic effects, a mechanism that is garnering increasing attention. However, the discussion on the toxic link between emerging pollutants and glucose metabolism remains insufficiently explored. This review aims to establish a connection between emerging pollutants and glucose metabolism through the gut microbiota, delving into the toxic impacts of these pollutants on glucose metabolism and the potential role played by the gut microbiota.
]]>Metabolites doi: 10.3390/metabo14020107
Authors: Alisa K. Pautova
Metabolic profiling is a powerful modern tool in searching for novel biomarkers and indicators of normal or pathological processes in the body [...]
]]>Metabolites doi: 10.3390/metabo14020106
Authors: Jan Milanowski Jarosław Nuszkiewicz Beata Lisewska Paweł Lisewski Karolina Szewczyk-Golec
Parkinson’s disease (PD), a widely recognized neurodegenerative disorder, is characterized by a spectrum of symptoms including motor fluctuations and dyskinesia. Neuroinflammation and dysregulation of adipokines are increasingly implicated in the progression of PD. This preliminary study investigated the levels of inflammatory biomarkers and adipokines, namely interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), C-reactive protein (CRP), visfatin, progranulin, and 25(OH)-vitamin D in 52 PD patients, divided equally between those with and without dyskinesia and 26 healthy controls. Significant differences in the levels of IL-6, TNF-α, visfatin, and progranulin were noted between the groups. Patients with dyskinesia exhibited notably higher IL-6 levels compared to controls, and TNF-α was significantly elevated in both PD patient groups relative to the control group. Additionally, visfatin levels were higher in PD patients without dyskinesia as opposed to those with dyskinesia, and progranulin levels were elevated in the non-dyskinetic PD group compared to controls. The findings highlight the potential role of the examined biomarkers in the pathophysiology of PD. Changes in levels of the tested inflammatory biomarkers and adipokines might be associated with Parkinson’s disease and its symptoms such as dyskinesia.
]]>Metabolites doi: 10.3390/metabo14020105
Authors: Elani A. Bykowski Jamie N. Petersson Sean P. Dukelow Chester Ho Chantel T. Debert Tony Montina Gerlinde A. S. Metz
Metabolomic biomarkers hold promise in aiding the diagnosis and prognostication of traumatic brain injury. In Canada, over 165,000 individuals annually suffer from a traumatic brain injury (TBI), making it one of the most prevalent neurological conditions. In this pilot investigation, we examined blood-derived biomarkers as proxy measures that can provide an objective approach to TBI diagnosis and monitoring. Using a 1H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined whether (1) blood-derived metabolites change during recovery in male participants with mild to severe TBI; (2) biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery; and (3) changes in metabolites correlate to initial injury severity. Eight male participants with mild to severe TBI (with intracranial lesions) provided morning blood samples within 1–4 days and again 6 months post-TBI. Following NMR analysis, the samples were subjected to multivariate statistical and machine learning-based analyses. Statistical modelling displayed metabolic changes during recovery through group separation, and eight significant metabolic pathways were affected by TBI. Metabolic changes were correlated to injury severity. L-alanine (R= −0.63, p < 0.01) displayed a negative relationship with the Glasgow Coma Scale. This study provides pilot data to support the feasibility of using blood-derived metabolites to better understand changes in biochemistry following TBI.
]]>Metabolites doi: 10.3390/metabo14020104
Authors: Bojan Blond Mira Majkić Jovan Spasojević Slavča Hristov Miodrag Radinović Sandra Nikolić Ljiljana Anđušić Aleksandar Čukić Maja Došenović Marinković Biljana Delić Vujanović Nemanja Obradović Marko Cincović
This study aimed to determine whether heat stress affected the values and correlations of metabolic, endocrinological, and inflammatory parameters as well as the rectal and body surface temperature of cows in the early and middle stages of lactation. This experiment was conducted in May (thermoneutral period), June (mild heat stress), and July (moderate to severe heat stress). In each period we included 15 cows in early lactation and 15 in mid-lactation. The increase in rectal and body surface temperatures (°C) in moderate to severe heat stress compared to the thermoneutral period in different regions was significant (p < 0.01) and the results are presented as mean and [95%CI]: rectal + 0.9 [0.81–1.02], eye + 6 [5.74–6.25], ear + 13 [11.9–14.0], nose + 3.5 [3.22–3.71], forehead + 6.6 [6.43–6.75], whole head + 7.5 [7.36–7.68], abdomen + 8.5 [8.25–8.77], udder + 7.5 [7.38–7.65], front limb + 6 [5.89–6.12], hind limb + 3.6 [3.46–3.72], and whole body + 9 [8.80–9.21]. During heat stress (in both mild and moderate to severe stress compared to a thermoneutral period), an increase in the values of extracellular heat shock protein 70 (eHsp70), tumor necrosis factor α (TNFα), cortisol (CORT), insulin (INS), revised quantitative insulin sensitivity check index (RQUICKI), urea, creatinine, total bilirubin, aspartate transpaminase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), and creatin kinase (CK) occurred, as well as a decrease in the values of triiodothyronine (T3), thyroxine (T4), non-esterified fatty acids (NEFA), glucose (GLU), β-Hydroxybutyrate (BHB), calcium, phosphorus, total protein (TPROT), albumin (ALB), triglycerides (TGCs), and cholesterol (CHOL). In cows in early lactation compared to cows in mid-lactation, there was a significantly larger increase (p < 0.01) in the values of eHsp70, TNFα, GLU, RQUICKI, and GGT, while the INS increase was smaller during the three experimental periods. The decrease in the values of Ca, CHOL, and TGC was more pronounced in cows in early lactation compared to cows in mid-lactation during the three experimental periods. Rectal temperature was related to eHsp70 (r = 0.38, p < 0.001) and TNFα (r = 0.36, p < 0.01) and showed non-significant poor correlations with other blood parameters. Blood parameters correlate with body surface temperature, with the following most common results: eHsp70 and TNFα showed a moderately to strongly significant positive correlation (r = 0.79–0.96, p < 0.001); CORT, INS, and Creat showed fairly to moderately significant positive correlations; T3, T4, NEFA and GLU showed fairly to moderately significant negative correlations (r = 0.3–0.79; p < 0.01); RQUICKI, urea, AST, and GGT showed fairly and significantly positive correlations; and TGC, CHOL, TPROT, and ALB showed fairly and significantly negative correlations (r = 0.3–0.59; p < 0.01). Measuring the surface temperature of the whole body or head can be a useful tool in evaluating the metabolic response of cows because it has demonstrated an association with inflammation (TNFα, eHsp70), endocrine response (CORT, T3, T4), the increased use of glucose and decreased use of lipids for energy purposes (INS, NEFA, GLU, and RQUICKI), and protein catabolism (ALB, TPROT, urea, Creat), which underlies thermolysis and thermogenesis in cows under heat stress. In future research, it is necessary to examine the causality between body surface area and metabolic parameters.
]]>Metabolites doi: 10.3390/metabo14020103
Authors: Angeles Carlos-Reyes Susana Romero-Garcia Heriberto Prado-Garcia
Solid tumors frequently present a heterogeneous tumor microenvironment. Because tumors have the potential to proliferate quickly, the consequence is a reduction in the nutrients, a reduction in the pH (<6.8), and a hypoxic environment. Although it is often assumed that tumor clones show a similar growth rate with little variations in nutrient consumption, the present study shows how growth-specific rate (µ), the specific rates of glucose, lactate, and glutamine consumption (qS), and the specific rates of lactate and glutamate production (qP) of 2D-cultured lung tumor cells are affected by changes in their environment. We determined in lung tumor cells (A427, A549, Calu-1, and SKMES-1) the above mentioned kinetic parameters during the exponential phase under different culture conditions, varying the predominant carbon source, pH, and oxygen tension. MCF-7 cells, a breast tumor cell line that can consume lactate, and non-transformed fibroblast cells (MRC-5) were included as controls. We also analyzed how cell-cycle progression and the amino acid transporter CD98 expression were affected. Our results show that: (1) In glucose presence, μ increased, but qS Glucose and qP Lactate decreased when tumor cells were cultured under acidosis as opposed to neutral conditions; (2) most lung cancer cell lines consumed lactate under normoxia or hypoxia; (3) although qS Glutamine diminished under hypoxia or acidosis, it slightly increased in lactate presence, a finding that was associated with CD98 upregulation; and (4) under acidosis, G0/G1 arrest was induced in A427 cancer cells, although this phenomenon was significantly increased when glucose was changed by lactate as the predominant carbon-source. Hence, our results provide an understanding of metabolic responses that tumor cells develop to survive under stressful conditions, providing clues for developing promising opportunities to improve traditional cancer therapies.
]]>Metabolites doi: 10.3390/metabo14020102
Authors: Na-Rae Lee Yangmin X. Kim Yerim Lee Chanwook Lee Yosung Song Hyejin Park Choong Hwan Lee Yejin Lee
Fertilizers are widely used to improve the quality of fruits and vegetables. However, the overuse of fertilizers has become an issue because it causes environmental problems and negatively affects productivity and fruit quality. In this study, we examined the effects of nitrogen, phosphorus, and potassium (NPK) fertilizer levels on the metabolism of cucumber fruit in low- and high-nutrient soils using mass-spectrometry-based metabolomics approaches. Cucumber metabolite content was notably different depending on the initial soil nutrient status. Most amino acids and phenylpropanoids were abundant in the cucumbers raised in low-nutrient soil, whereas organic acids, some amino acids (aspartate, glutamate, and ornithine), and carbohydrates were comparatively higher in fruits from high-nutrient soil. The fertilizer supply resulted in an alteration in the metabolite profile, while no change in fruit yield was observed in either low- or high-nutrient soils. Fertilizer treatment perturbed the metabolite contents in cucumbers from low-nutrient soil. In contrast, treatment with higher concentrations of fertilizer in high-nutrient soil increased phenylpropanoid content in the cucumbers, while most metabolites decreased. In conclusion, fertilization levels should be carefully determined, considering culture conditions such as the original soil status, to increase product yield and fruit quality and avoid environmental problems.
]]>Metabolites doi: 10.3390/metabo14020101
Authors: Charles M. Moreno Jaclyn N. Moreno Matthew C. Valdez Melinda P. Baldwin Ana C. Vallor Paulo B. Carvalho
The synthetic cytokinin forchlorfenuron (FCF), while seemingly presenting relatively low toxicity for mammalian organisms, has been the subject of renewed scrutiny in the past few years due to its increasing use in fruit crops and potential for bioaccumulation. Despite many toxicological properties of FCF being known, little research has been conducted on the toxicological effects of its secondary metabolites. Given this critical gap in the existing literature, understanding the formation of relevant FCF secondary metabolites and their association with mammalian metabolism is essential. To investigate the formation of FCF metabolites in sufficient quantities for toxicological studies, a panel of four fungi were screened for their ability to catalyze the biotransformation of FCF. Of the organisms screened, Cunninghamella elegans (ATCC 9245), a filamentous fungus, was found to convert FCF to 4-hydroxyphenyl-forchlorfenuron, the major FCF secondary metabolite identified in mammals, after 26 days. Following the optimization of biotransformation conditions using a solid support system, media screening, and inoculation with a solid pre-formed fungal mass of C. elegans, this conversion time was significantly reduced to 7 days—representing a 73% reduction in total reaction time as deduced from the biotransformation products and confirmed by LC-MS, NMR spectroscopic data, as well as a comparison with synthetically prepared metabolites. Our study provides the first report of the metabolism of FCF by C. elegans. These findings suggest that C. elegans can produce FCF secondary metabolites consistent with those produced via mammalian metabolism and could be used as a more efficient, cost-effective, and ethical alternative for producing those metabolites in useful quantities for toxicological studies.
]]>Metabolites doi: 10.3390/metabo14020100
Authors: Manjula Senthilkumaran Coen Koch Mauritz Frederick Herselman Larisa Bobrovskaya
Hypoglycaemia-associated autonomic failure (HAAF) is characterised by an impairment in adrenal medullary and neurogenic symptom responses following episodes of recurrent hypoglycaemia. Here, we review the status quo of research related to the regulatory mechanisms of the adrenal medulla in its response to single and recurrent hypoglycaemia in both diabetic and non-diabetic subjects with particular focus given to catecholamine synthesis, enzymatic activity, and the impact of adrenal medullary peptides. Short-term post-transcriptional modifications, particularly phosphorylation at specific residues of tyrosine hydroxylase (TH), play a key role in the regulation of catecholamine synthesis. While the effects of recurrent hypoglycaemia on catecholamine synthetic enzymes remain inconsistent, long-term changes in TH protein expression suggest species-specific responses. Adrenomedullary peptides such as neuropeptide Y (NPY), galanin, and proenkephalin exhibit altered gene and protein expression in response to hypoglycaemia, suggesting a potential role in the modulation of catecholamine secretion. Of note is NPY, since its antagonism has been shown to prevent reductions in TH protein expression. This review highlights the need for further investigation into the molecular mechanisms involved in the adrenal medullary response to hypoglycaemia. Despite advancements in our understanding of HAAF in non-diabetic rodents, a reliable diabetic rodent model of HAAF remains a challenge.
]]>Metabolites doi: 10.3390/metabo14020099
Authors: Yung-Husan Chen Qiaoqiao Zhu Jingyi Li Rong Yang Jingwen Zhang Minxin You Lianzhong Luo Bingye Yang
A novel ceramide compound, named Aspercerebroside A (AcA), was successfully isolated from the ethyl acetate layer of the marine symbiotic fungus Aspergillus sp. AcA exhibited notable anti-inflammatory activity by effectively inhibiting the production of nitric oxide (NO) in RAW 264.7 cells at concentrations of 30 μg/mL and 40 μg/mL, offering a promising avenue for the treatment of inflammatory diseases. To optimize the yield of glycosylceramide (AcA), a series of techniques, including single-factor experiments, orthogonal experiments, and response surface optimization, were systematically employed to fine-tune the composition of the fermentation medium. Initially, the optimal carbon source (sucrose), nitrogen source (yeast extract powder), and the most suitable medium salinity (14 ppt) were identified through single-factor experiments. Subsequently, orthogonal experiments, employing an orthogonal table for planning and analyzing multifactor experiments, were conducted. Finally, a mathematical model, established using a Box–Behnken design, comprehensively analyzed the interactions between the various factors to determine the optimal composition of the fermentation medium. According to the model’s prediction, when the sucrose concentration was set at 37.47 g/L, yeast extract powder concentration at 19.66 g/L, and medium salinity at 13.31 ppt, the predicted concentration of glycosylceramide was 171.084 μg/mL. The experimental results confirmed the model’s accuracy, with the actual average concentration of glycosylceramide under these conditions measured at 171.670 μg/mL, aligning closely with the predicted value.
]]>Metabolites doi: 10.3390/metabo14020098
Authors: Fenna Sillé Thomas Hartung
Metabolomics is emerging as a powerful systems biology approach for improving preclinical drug safety assessment. This review discusses current applications and future trends of metabolomics in toxicology and drug development. Metabolomics can elucidate adverse outcome pathways by detecting endogenous biochemical alterations underlying toxicity mechanisms. Furthermore, metabolomics enables better characterization of human environmental exposures and their influence on disease pathogenesis. Metabolomics approaches are being increasingly incorporated into toxicology studies and safety pharmacology evaluations to gain mechanistic insights and identify early biomarkers of toxicity. However, realizing the full potential of metabolomics in regulatory decision making requires a robust demonstration of reliability through quality assurance practices, reference materials, and interlaboratory studies. Overall, metabolomics shows great promise in strengthening the mechanistic understanding of toxicity, enhancing routine safety screening, and transforming exposure and risk assessment paradigms. Integration of metabolomics with computational, in vitro, and personalized medicine innovations will shape future applications in predictive toxicology.
]]>Metabolites doi: 10.3390/metabo14020097
Authors: Xu Guo Xiang Yan Yuanyuan Wang Zhiyong Shi Jingping Niu Jianping Liang Xiaoyun Jia
Astragali Radix, derived from the roots of Astragalus mongholicus, is a traditional Chinese medicine containing flavonoids and saponins as its key ingredients. With a shortage in the wild sources of the herbal plant, it is especially important to explore a cultivation mode for A. mongholicus for medicinal purposes. Cutting, a physical environmental stress method, was used in this study with the objective of improving the quality of this herbal legume. We found that cutting of the top 1/3 of the aboveground part of A. mongholicus during the fruiting period resulted in a significant increase in the content of flavonoids and saponins, as well as in root growth, including length, diameter, and dry weight. Furthermore, the leaves were sampled and analyzed using a combined transcriptome and metabolome analysis approach at five different time points after the treatment. Sixteen differentially expressed unigenes (DEGs) involved in the biosynthesis of flavonoids were identified; these were found to stimulate the synthesis of flavonoids such as formononetin and calycosin–7–O–β–D–glucoside. Moreover, we identified 10 DEGs that were associated with the biosynthesis of saponins, including astragaloside IV and soyasaponin I, and found that they only regulated the mevalonic acid (MVA) pathway. These findings provide new insights into cultivating high-quality A. mongholicus, which could potentially alleviate the scarcity of this valuable medicinal plant.
]]>Metabolites doi: 10.3390/metabo14020096
Authors: Chen Zeng Wen-Jing Cai Liu-Cheng Jiang Tiantian Ye Yu-Qi Feng
Gibberellins (GAs) play a pivotal role in modulating plant growth and development. Glucose–conjugated gibberellins (Glc–GAs), a prevalent conjugated form of GAs, regulate intracellular GA levels by the coupling and decoupling of glucose groups. However, the diversity of Glc–GAs identified within individual species remains limited, hinting at a multitude of yet undiscovered gibberellin metabolites. This lacuna poses considerable impediments to research efforts dedicated to comprehensively delineating the GA metabolic pathway. In this study, we developed a structure–oriented screening and identification method for Glc–GAs in plant species by employing LC–MS/MS coupled with chemical derivatization. Through the application of chemical derivatization technique, carboxyl groups on Glc–GAs were labeled which effectively enhanced the sensitivity and selectivity of mass spectrometry detection for these compounds. Concurrently, the integration of mass spectrometry fragmentation and chromatographic retention behavior facilitated the efficient screening and identification of potential Glc–GAs. With this strategy, we screened and identified 12 potential Glc–GAs from six plant species. These findings expand the Glc–GA diversity in plants and contribute to understanding GA metabolic pathways.
]]>Metabolites doi: 10.3390/metabo14020095
Authors: Shuji Ueda Yuka Yoshida Biniam Kebede Chiaki Kitamura Ryo Sasaki Masakazu Shinohara Itsuko Fukuda Yasuhito Shirai
Efficient cold-chain delivery is essential for maintaining a sustainable global food supply. This study used metabolomic analysis to examine meat quality changes during the “wet aging” of crossbred Wagyu beef during cold storage. The longissimus thoracic (Loin) and adductor muscles (Round) of hybrid Wagyu beef, a cross between the Japanese Black and Holstein–Friesian breeds, were packaged in vacuum film and refrigerated for up to 40 days. Sensory evaluation indicated an increase in the umami and kokumi taste owing to wet aging. Comprehensive analysis using gas chromatography-mass spectrometry identified metabolite changes during wet aging. In the Loin, 94 metabolites increased, and 24 decreased; in the Round, 91 increased and 18 decreased. Metabolites contributing to the umami taste of the meat showed different profiles during wet aging. Glutamic acid increased in a cold storage-dependent manner, whereas creatinine and inosinic acid degraded rapidly even during cold storage. In terms of lipids, wet aging led to an increase in free fatty acids. In particular, linoleic acid, a polyunsaturated fatty acid, increased significantly among the free fatty acids. These results provide new insight into the effects of wet aging on Wagyu-type beef, emphasizing the role of free amino acids, organic acids, and free fatty acids generated during cold storage.
]]>Metabolites doi: 10.3390/metabo14020094
Authors: Zhi Cao Hongyu Chen Chenli Zhou Ming Gong Yan Li Youran Shao Yingying Wu Dapeng Bao
γ-Aminobutyric (GABA) acid is a nutrient and signaling molecule existing in many plants, participating in the regulation of metabolism and various physiological activities. Two strains of Hypsizygus marmoreus (a white variety and a brown variety) were investigated to study the impact of exogenous GABA on mycelial growth and the response to stress. Mycelial growth, microscopic morphology, antioxidant profile, and gad2 expression in H. marmoreu were investigated under salt, dehydration, or cold stress. The results indicated that 5 mM GABA stimulated mycelial growth under standard cultivation conditions, whereas GABA addition over 10 mM hindered the growth. Under salt, dehydration, or cold stress, treatment with 5 mM GABA significantly enhanced the mycelial growth rate and density of both H. marmoreus strains by promoting front hyphae branching. Meanwhile, the activities of key antioxidant enzymes such as peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) were enhanced by GABA, thereby augmenting the defensive network against abiotic stress. Additionally, gad2 expression and GABA concentration were increased under abiotic stresses as a resistance regulation response. The exogenous addition of GABA strengthened the upregulation of gad2 expression and GABA production. These findings indicated that exogenously adding low concentrations of GABA effectively enhanced the mycelial growth and antioxidant profile of H. marmoreus, thereby improving its resistance against stresses.
]]>Metabolites doi: 10.3390/metabo14020093
Authors: Weiyu Meng Hongxin Pan Yuyang Sha Xiaobing Zhai Abao Xing Sai Sachin Lingampelly Srinivasa R. Sripathi Yuefei Wang Kefeng Li
The interconnectivity of advanced biological systems is essential for their proper functioning. In modern connectomics, biological entities such as proteins, genes, RNA, DNA, and metabolites are often represented as nodes, while the physical, biochemical, or functional interactions between them are represented as edges. Among these entities, metabolites are particularly significant as they exhibit a closer relationship to an organism’s phenotype compared to genes or proteins. Moreover, the metabolome has the ability to amplify small proteomic and transcriptomic changes, even those from minor genomic changes. Metabolic networks, which consist of complex systems comprising hundreds of metabolites and their interactions, play a critical role in biological research by mediating energy conversion and chemical reactions within cells. This review provides an introduction to common metabolic network models and their construction methods. It also explores the diverse applications of metabolic networks in elucidating disease mechanisms, predicting and diagnosing diseases, and facilitating drug development. Additionally, it discusses potential future directions for research in metabolic networks. Ultimately, this review serves as a valuable reference for researchers interested in metabolic network modeling, analysis, and their applications.
]]>Metabolites doi: 10.3390/metabo14020092
Authors: Purum Kang Ka Young Kim Hye Young Shin
Diabetes mellitus and dyslipidemia are well-known risk factors for cardiovascular disease. Unfortunately, the prevalence of dyslipidemia and diabetes mellitus among individuals over 30 years of age in Korea has continuously increased. The current study therefore investigated the association between dyslipidemia and high glycated hemoglobin (Hemoglobin A1c, HbA1c) levels according to age group in adults over 20 years old. We used data from the 7th Korea National Health and Nutrition Examination Survey conducted by the Korea Centers for Disease Control and Prevention from 2016 to 2017. Glycated hemoglobin, a well-established marker for elevated glucose levels, was categorized into three groups, normal (<5.7%), prediabetes (5.7–6.4%), and diabetes (≥6.5%). The presence of dyslipidemia was defined based on a diagnosis of dyslipidemia by a physician. Logistic regression analyses were performed to evaluate the association between the prevalence of dyslipidemia and glycated hemoglobin according to age group. After adjusting for possible confounders, including age, sex, body mass index, marital status, education, occupation, household income, drinking, and smoking, we found a significant increase in the odds ratios (ORs) for dyslipidemia in the prediabetes (OR; 1.915, 95% CI; 1.696 to 2.163) and diabetes (OR; 3.533, 95% CI; 3.019 to 4.134) groups. Among subjects with higher glycated hemoglobin levels, those in their 40s or over had significantly increased odds for dyslipidemia. The current study found an association between high glycated hemoglobin levels and a diagnosis of dyslipidemia among Korean adults. Markers of lipid metabolism in adults with high glycated hemoglobin levels may need to be monitored, especially those in their 40s and older.
]]>Metabolites doi: 10.3390/metabo14020091
Authors: Freyr Jóhannsson James T. Yurkovich Steinn Guðmundsson Ólafur E. Sigurjónsson Óttar Rolfsson
Temperature plays a fundamental role in biology, influencing cellular function, chemical reaction rates, molecular structures, and interactions. While the temperature dependence of many biochemical reactions is well defined in vitro, the effect of temperature on metabolic function at the network level is poorly understood, and it remains an important challenge in optimizing the storage of cells and tissues at lower temperatures. Here, we used time-course metabolomic data and systems biology approaches to characterize the effects of storage temperature on human platelets (PLTs) in a platelet additive solution. We observed that changes to the metabolome with storage time do not simply scale with temperature but instead display complex temperature dependence, with only a small subset of metabolites following an Arrhenius-type relationship. Investigation of PLT energy metabolism through integration with computational modeling revealed that oxidative metabolism is more sensitive to temperature changes than glycolysis. The increased contribution of glycolysis to ATP turnover at lower temperatures indicates a stronger glycolytic phenotype with decreasing storage temperature. More broadly, these results demonstrate that the temperature dependence of the PLT metabolic network is not uniform, suggesting that efforts to improve the health of stored PLTs could be targeted at specific pathways.
]]>Metabolites doi: 10.3390/metabo14020090
Authors: Shuang Hao Liqun Chen Wenhui Du Huiyan Sun
Metastasis is one of the leading causes of cancer-related deaths. A comprehensive comparison of the differences between primary and metastatic cancers within the same organ can aid in understanding the growth mechanisms of cancer cells at metastatic sites, thereby helping to develop more effective targeted treatment strategies. Primary liver cancer is one of the most common types of cancer, and the liver is also one of the main metastatic sites. In this paper, we utilize single-cell RNA-Seq data to compare primary liver cancer and colorectal liver metastases from multiple perspectives, including cell types and proportions, activity of various cell types, cell–cell communication, mRNA expression differences within the same types of cells, key factors associated with cell proliferation, etc. Our analysis results show the following: (i) Compared to primary tissue, metastatic tissue contains more cytotoxic T cells and exhausted T cells, and it retains some specific characteristics of the primary site. (ii) Cells of the same type exhibit functional differences between primary and metastatic cancers, with metastatic cancer cells showing lower metabolism levels and immune cells exhibiting stronger immune activity. (iii) Interactions between monocytes and hepato-associated cells are strong in primary cancer, while depleted T cells frequently communicate with hepatocytes in metastatic cancer. (iv) Proliferation-related genes in primary and metastatic cancers are mainly involved in cell energy supply and basic metabolism activity, respectively.
]]>Metabolites doi: 10.3390/metabo14020089
Authors: Elina Tsopp Kalle Kilk Egon Taalberg Pille Pärn Anni Viljaste-Seera Ants Kavak Ülle Jaakma
This study investigated whether metabolomic fingerprints of bovine embryo growth media improve the prediction of successful embryo implantation. In this prospective cohort study, the metabolome from in vitro-produced day 7 blastocysts with successful implantation (n = 11), blastocysts with failed implantation (n = 10), and plain culture media without embryos (n = 5) were included. Samples were analyzed using an AbsoluteIDQ® p180 Targeted Metabolomics Kit with LC-MS/MS, and a total of 189 metabolites were analyzed from each sample. Blastocysts that resulted in successful embryo implantation had significantly higher levels of methionine sulfoxide (p < 0.001), DOPA (p < 0.05), spermidine (p < 0.001), acetylcarnitine-to-free-carnitine ratio (p < 0.05), C2 + C3-to-free-carnitine ratio (p < 0.05), and lower levels of threonine (nep < 0.001) and phosphatidylcholine PC ae C30:0 (p < 0.001) compared to control media. However, when compared to embryos that failed to implant, only DOPA, spermidine, C2/C0, (C2 + C3)/C0, and PC ae C30:0 levels differentiated significantly. In summary, our study identifies a panel of differential metabolites in the culture media of bovine blastocysts that could act as potential biomarkers for the selection of viable blastocysts before embryo transfer.
]]>Metabolites doi: 10.3390/metabo14020088
Authors: Jie Zhang Yunfang Gao Jiangwei Yan
Prolonged inactivity and disuse conditions, such as those experienced during spaceflight and prolonged bedrest, are frequently accompanied by detrimental effects on the motor system, including skeletal muscle atrophy and bone loss, which greatly increase the risk of osteoporosis and fractures. Moreover, the decrease in glucose and lipid utilization in skeletal muscles, a consequence of muscle atrophy, also contributes to the development of metabolic syndrome. Clarifying the mechanisms involved in disuse-induced musculoskeletal deterioration is important, providing therapeutic targets and a scientific foundation for the treatment of musculoskeletal disorders under disuse conditions. Skeletal muscle, as a powerful endocrine organ, participates in the regulation of physiological and biochemical functions of local or distal tissues and organs, including itself, in endocrine, autocrine, or paracrine manners. As a motor organ adjacent to muscle, bone tissue exhibits a relative lag in degenerative changes compared to skeletal muscle under disuse conditions. Based on this phenomenon, roles and mechanisms involved in the communication between skeletal muscle and bone, especially from muscle to bone, under disuse conditions have attracted widespread attention. In this review, we summarize the roles and regulatory mechanisms of muscle-derived myokines and extracellular vesicles (EVs) in the occurrence of muscle atrophy and bone loss under disuse conditions, as well as discuss future perspectives based on existing research.
]]>Metabolites doi: 10.3390/metabo14020087
Authors: Tae Jin Kim Ye Ji Hwang Young Jin Park Jong Sung Lee Jae Kwang Kim Mi-Hwa Lee
Climate change has increased variable weather patterns that affect plants. To address these issues, we developed a microbial biocontrol agent against drought stress in kimchi cabbage (Brassica rapa L. subsp. pekinensis). We selected three bacterial strains (Leifsonia sp. CS9, Bacillus toyonensis TSJ7, and Lysinibacillus capsici TT41) because they showed a survival rate of up to 50% and good growth rate when treated with 30% PEG 6000. The three strains were treated with kimchi cabbage to confirm their enhanced drought stress resistance under non-watering conditions. Among the three strains, the TT41 treated group showed a significant increase in various plant parameters compared with the negative control on the 7th day. We performed extensive profiling of primary and secondary metabolites from kimchi cabbage and the TT41 strain. Multivariate and pathway analyses revealed that only the TT41 group clustered with the well-watered group and showed almost the same metabolome on the 7th day. When treated with TT41, lactic acid was identified as an indicator metabolite that significantly improved drought stress tolerance. Furthermore, lactic acid treatment effectively induced drought stress tolerance in kimchi cabbage, similar to that achieved with the TT41 strain.
]]>Metabolites doi: 10.3390/metabo14020086
Authors: Augusto Pietro Casani Roberto Albera Cristina Piras Andrea Albera Antonio Noto Nicola Ducci Luigi Atzori Sergio Lucisano Michele Mussap Vassilios Fanos
Benign paroxysmal positional vertigo (BPPV) represents the most frequent cause of peripheral vertigo. In most cases, it is successfully treated using the canalith repositioning procedure, but it is often followed by continuous lightheadedness in the absence of vertigo or nystagmus (residual dizziness, RD). Our aim is to describe the clinical effectiveness and the urine metabolomics profile of treating these patients with polyphenol compound supplementation. We enrolled 30 patients reporting RD after BPPV of the posterior semicircular canal (PSC) successfully treated using the Semont maneuver. Supplementation with a polyphenol compound was administered for 60 days, and patients were evaluated after 30 and 60 days of treatment using self-administered questionnaires (Visual Analog Scales for Dizziness and Nausea, Dizziness Handicap Inventory, DHI) and urine metabolomics analysis performed using 1H-NMR spectroscopy and multivariate followed by univariate analysis. Most patients reported excellent or good efficacy in the treatment of RD with a significant decrease in VAS and DHI values. The metabolomics analysis identified six significant metabolites related to the treatment, namely 1-methylnicotinamide, anserine, hippurate, lysine, methyl succinate and urea, indicating the inflammatory activities and antioxidant properties of the polyphenol compound. These preliminary data suggest that supplementation with a polyphenol compound could induce some metabolic changes that can help in recovery from RD. However, future steps will require confirmation with a more significant cohort of patients and an extension of the metabolomics evaluation to other problems concerning the different clinical aspects of BPPV, such as the high rate of relapse.
]]>Metabolites doi: 10.3390/metabo14020085
Authors: Zihan Zhou Qichen Jiang You Zheng Chen Hao Shuyan Ding Mengya Guo Yunlong Zhao Guoxing Liu Shuyan Miao
Live prey is characterized by balanced rich nutrients and high palatability and is widely used for the seedling cultivation of freshwater dark sleeper (Odontobutis potamophila) larvae. In this study, we evaluated the effects of four groups of paired feeding regimens (group C (Daphnia magna), group L (Limnodrilus hoffmeisteri), group H (Hypophthalmichthys molitrix fry), and group M (mixed groups C, L, and H)) on glycolipid and energy metabolism in O. potamophila larvae. We observed that fatty acid synthase (FAS) and sterol-regulatory-element-binding protein-1 (SREBP-1) mRNA levels were significantly lower in group H when compared to mRNA levels in the other three groups (p < 0.05) and that carnitine palmitoyltransferase 1α (CPT1-α) mRNA levels were significantly lower in group L when compared to group M (p < 0.05). Relative glucokinase (GK) expression levels were significantly lower in group M when compared to the other three groups (p < 0.05). Using proteomics, we analyzed and compared groups H and L and identified 457 differentially expressed proteins (DEPs), of which 151 were significantly up-regulated and 306 were significantly down-regulated. In the comparison of group M with groups C, L, and H, we found significant enrichment in glycolytic processes, the endoplasmic reticulum lumen, NAD binding, intermediate filaments, and nutrient reservoir activity. Our results provide a theoretical guidance for bait selection during larvae cultivation stages in carnivorous fish.
]]>Metabolites doi: 10.3390/metabo14020084
Authors: Adriana S. Beltran
The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders.
]]>Metabolites doi: 10.3390/metabo14020083
Authors: Modesto A. Lebron Jeffrey R. Stout David H. Fukuda
Combat sports athletes seeking a competitive edge often engage in weight management practices to become larger than their opponents, which ultimately includes periods of gradual weight loss, rapid weight loss, and weight regain. This pattern of weight loss and regain is known as weight cycling and often includes periods of low energy availability, making combat sports athletes susceptible to metabolic dysfunction. This narrative review represents an effort to explore the metabolic perturbations associated with weight cycling and outline the short-, medium-, and long-term effects on metabolic flexibility, function, and health. The short-term effects of rapid weight loss, such as a reduced metabolic rate and alterations to insulin and leptin levels, may prelude the more pronounced metabolic disturbances that occur during weight regain, such as insulin resistance. Although definitive support is not currently available, this cycle of weight loss and regain and associated metabolic changes may contribute to metabolic syndrome or other metabolic dysfunctions over time.
]]>Metabolites doi: 10.3390/metabo14020082
Authors: Oseias R. Feitosa-Junior Andrea Lubbe Suzanne M. Kosina Joaquim Martins-Junior Deibs Barbosa Clelia Baccari Paulo A. Zaini Benjamin P. Bowen Trent R. Northen Steven E. Lindow Aline M. da Silva
Microbial competition within plant tissues affects invading pathogens’ fitness. Metabolomics is a great tool for studying their biochemical interactions by identifying accumulated metabolites. Xylella fastidiosa, a Gram-negative bacterium causing Pierce’s disease (PD) in grapevines, secretes various virulence factors including cell wall-degrading enzymes, adhesion proteins, and quorum-sensing molecules. These factors, along with outer membrane vesicles, contribute to its pathogenicity. Previous studies demonstrated that co-inoculating X. fastidiosa with the Paraburkholderia phytofirmans strain PsJN suppressed PD symptoms. Here, we further investigated the interaction between the phytopathogen and the endophyte by analyzing the exometabolome of wild-type X. fastidiosa and a diffusible signaling factor (DSF) mutant lacking quorum sensing, cultivated with 20% P. phytofirmans spent media. Liquid chromatography–mass spectrometry (LC-MS) and the Method for Metabolite Annotation and Gene Integration (MAGI) were used to detect and map metabolites to genomes, revealing a total of 121 metabolites, of which 25 were further investigated. These metabolites potentially relate to host adaptation, virulence, and pathogenicity. Notably, this study presents the first comprehensive profile of X. fastidiosa in the presence of a P. phytofirmans spent media. The results highlight that P. phytofirmans and the absence of functional quorum sensing affect the ratios of glutamine to glutamate (Gln:Glu) in X. fastidiosa. Additionally, two compounds with plant metabolism and growth properties, 2-aminoisobutyric acid and gibberellic acid, were downregulated when X. fastidiosa interacted with P. phytofirmans. These findings suggest that P. phytofirmans-mediated disease suppression involves modulation of the exometabolome of X. fastidiosa, impacting plant immunity.
]]>Metabolites doi: 10.3390/metabo14020081
Authors: Deepika Dugan Rachael J. Bell Robert Brkljača Colin Rix Sylvia Urban
Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930 to 2023 was conducted. This is the first review for this plant genus, and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.
]]>Metabolites doi: 10.3390/metabo14020079
Authors: Ryann M. Fame Ilhan Ali Maria K. Lehtinen Naama Kanarek Boryana Petrova
Thyroid hormones (TH) are required for brain development and function. Cerebrospinal fluid (CSF), which bathes the brain and spinal cord, contains TH as free hormones or as bound to transthyretin (TTR). Tight TH level regulation in the central nervous system is essential for developmental gene expression, which governs neurogenesis, myelination, and synaptogenesis. This integrated function of TH highlights the importance of developing precise and reliable methods for assessing TH levels in CSF. We report an optimized liquid chromatography–mass spectrometry (LC-MS)-based method to measure TH in rodent CSF and serum, applicable to both fresh and frozen samples. Using this new method, we find distinct differences in CSF TH in pregnant dams vs. non-pregnant adults and in embryonic vs. adult CSF. Further, targeted LC-MS metabolic profiling uncovers distinct central carbon metabolism in the CSF of these populations. TH detection and metabolite profiling of related metabolic pathways open new avenues of rigorous research into CSF TH and will inform future studies on metabolic alterations in CSF during normal development.
]]>Metabolites doi: 10.3390/metabo14020080
Authors: Yana Zorkina Valeria Ushakova Aleksandra Ochneva Anna Tsurina Olga Abramova Valeria Savenkova Anna Goncharova Irina Alekseenko Irina Morozova Daria Riabinina Georgy Kostyuk Anna Morozova
Lipids are a crucial component of the human brain, serving important structural and functional roles. They are involved in cell function, myelination of neuronal projections, neurotransmission, neural plasticity, energy metabolism, and neuroinflammation. Despite their significance, the role of lipids in the development of mental disorders has not been well understood. This review focused on the potential use of lipids as blood biomarkers for common mental illnesses, such as major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. This review also discussed the impact of commonly used psychiatric medications, such as neuroleptics and antidepressants, on lipid metabolism. The obtained data suggested that lipid biomarkers could be useful for diagnosing psychiatric diseases, but further research is needed to better understand the associations between blood lipids and mental disorders and to identify specific biomarker combinations for each disease.
]]>Metabolites doi: 10.3390/metabo14010078
Authors: Sandra Cabała Małgorzata Ożgo Agnieszka Herosimczyk
A well-balanced diet is integral for overall health, aiding in managing key risk factors for kidney damage like hypertension while supplying necessary precursors for metabolite production. Dietary choices directly influence the composition and metabolic patterns of the gut microbiota, showing promise as therapeutic tools for addressing various health conditions, including chronic kidney diseases (CKD). CKD pathogenesis involves a decline in the glomerular filtration rate and the retention of nitrogen waste, fostering gut dysbiosis and the excessive production of bacterial metabolites. These metabolites act as uremic toxins, contributing to inflammation, oxidative stress, and tissue remodeling in the kidneys. Dietary interventions hold significance in reducing oxidative stress and inflammation, potentially slowing CKD progression. Functional ingredients, nutrients, and nephroprotective phytoconstituents could modulate inflammatory pathways or impact the gut mucosa. The “gut–kidney axis” underscores the impact of gut microbes and their metabolites on health and disease, with dysbiosis serving as a triggering event in several diseases, including CKD. This review provides a comprehensive overview, focusing on the gut–liver axis, and explores well-established bioactive substances as well as specific, less-known nutraceuticals showing promise in supporting kidney health and positively influencing CKD progression.
]]>Metabolites doi: 10.3390/metabo14010077
Authors: Atsuko Miyake Sei Harada Daisuke Sugiyama Minako Matsumoto Aya Hirata Naoko Miyagawa Ryota Toki Shun Edagawa Kazuyo Kuwabara Tomonori Okamura Asako Sato Kaori Amano Akiyoshi Hirayama Masahiro Sugimoto Tomoyoshi Soga Masaru Tomita Kazuharu Arakawa Toru Takebayashi Miho Iida
Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys—at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.
]]>Metabolites doi: 10.3390/metabo14010076
Authors: Bruna Ruschel Ewald Vega Garcia Edson Naoto Makiyama Geni Rodrigues Sampaio Rosana Aparecida Manólio Soares-Freitas Andrea Bonvini Andressa Godoy Amaral Silvana Bordin Ricardo Ambrósio Fock Marcelo Macedo Rogero
Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions.
]]>Metabolites doi: 10.3390/metabo14010075
Authors: Monika Sijko-Szpańska Lucyna Kozłowska
Nutrients involved in the metabolism of inorganic arsenic (iAs) may play a crucial role in mitigating the adverse health effects associated with such exposure. Consequently, the objective of this study was to analyze the association between the intake levels of nutrients involved in iAs metabolism and alterations in the metabolic profile during arsenic exposure. The study cohort comprised environmentally exposed women: WL (lower total urinary arsenic (As), n = 73) and WH (higher As, n = 73). The analysis included urinary untargeted metabolomics (conducted via liquid chromatography–mass spectrometry) and the assessment of nutrient intake involved in iAs metabolism, specifically methionine, vitamins B2, B6, and B12, folate, and zinc (based on 3-day dietary records of food and beverages). In the WL group, the intake of all analyzed nutrients exhibited a negative correlation with 5 metabolites (argininosuccinic acid, 5-hydroxy-L-tryptophan, 11-trans-LTE4, mevalonic acid, aminoadipic acid), while in the WH group, it correlated with 10 metabolites (5-hydroxy-L-tryptophan, dihyroxy-1H-indole glucuronide I, 11-trans-LTE4, isovalerylglucuronide, 18-oxocortisol, 3-hydroxydecanedioic acid, S-3-oxodecanoyl cysteamine, L-arginine, p-cresol glucuronide, thromboxane B2). Furthermore, nutrient intake demonstrated a positive association with 3 metabolites in the WL group (inosine, deoxyuridine, glutamine) and the WH group (inosine, N-acetyl-L-aspartic acid, tetrahydrodeoxycorticosterone). Altering the intake of nutrients involved in iAs metabolism could be a pivotal factor in reducing the negative impact of arsenic exposure on the human body. This study underscores the significance of maintaining adequate nutrient intake, particularly in populations exposed to arsenic.
]]>Metabolites doi: 10.3390/metabo14010074
Authors: Bijay Gurung Maranda Stricklin Shaohua Wang
Clostridioides difficile (C. difficile) infection (CDI) is the most common hospital-acquired infection. With the combination of a high rate of antibiotic resistance and recurrence, it has proven to be a debilitating public health threat. Current treatments for CDI include antibiotics and fecal microbiota transplantation, which contribute to recurrent CDIs and potential risks. Therefore, there is an ongoing need to develop new preventative treatment strategies for CDI. Notably, gut microbiota dysbiosis is the primary risk factor for CDI and provides a promising target for developing novel CDI therapy approaches. Along with gut microbiota dysbiosis, a reduction in important gut metabolites like secondary bile acids and short-chain fatty acids (SCFAs) were also seen in patients suffering from CDI. In this review study, we investigated the roles and mechanisms of gut microbiota and gut microbiota-derived gut metabolites, especially secondary bile acids and SCFAs in CDI pathogenesis. Moreover, specific signatures of gut microbiota and gut metabolites, as well as different factors that can modulate the gut microbiota, were also discussed, indicating that gut microbiota modulators like probiotics and prebiotics can be a potential therapeutic strategy for CDI as they can help restore gut microbiota and produce gut metabolites necessary for a healthy gut. The understanding of the associations between gut microbiota–gut metabolites and CDI will allow for developing precise and sustainable approaches, distinct from antibiotics and fecal transplant, for mitigating CDI and other gut microbiota dysbiosis-related diseases.
]]>Metabolites doi: 10.3390/metabo14010073
Authors: Nicholas G. Norwitz William C. Cromwell
Recent research has identified a unique population of ‘Lean Mass Hyper-Responders’ (LMHR) who exhibit increases in LDL cholesterol (LDL-C) in response to carbohydrate-restricted diets to levels ≥ 200 mg/dL, in association with HDL cholesterol ≥ 80 mg/dL and triglycerides ≤ 70 mg/dL. This triad of markers occurs primarily in lean metabolically healthy subjects, with the magnitude of increase in LDL-C inversely associated with body mass index. The lipid energy model has been proposed as one explanation for LMHR phenotype and posits that there is increased export and subsequent turnover of VLDL to LDL particles to meet systemic energy needs in the setting of hepatic glycogen depletion and low body fat. This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies, to an LMHR subject on a ketogenic diet would reduce LDL-C levels by a similar, or greater, magnitude than high-intensity statin therapy. The study was designed as follows: after a 2-week run-in period on a standardized ketogenic diet, study arm 1 consisted of supplementation with 12 regular Oreo cookies, providing 100 g/d of additional carbohydrates for 16 days. Throughout this arm, ketosis was monitored and maintained at levels similar to the subject’s standard ketogenic diet using supplemental exogenous d-β-hydroxybutyrate supplementation four times daily. Following the discontinuation of Oreo supplementation, the subject maintained a stable ketogenic diet for 3 months and documented a return to baseline weight and hypercholesterolemic status. During study arm 2, the subject received rosuvastatin 20 mg daily for 6 weeks. Lipid panels were drawn water-only fasted and weekly throughout the study. Baseline LDL-C was 384 mg/dL and reduced to 111 mg/dL (71% reduction) after Oreo supplementation. Following the washout period, LDL-C returned to 421 mg/dL, and was reduced to a nadir of 284 mg/dL with 20 mg rosuvastatin therapy (32.5% reduction). In conclusion, in this case study experiment, short-term Oreo supplementation lowered LDL-C more than 6 weeks of high-intensity statin therapy in an LMHR subject on a ketogenic diet. This dramatic metabolic demonstration, consistent with the lipid energy model, should provoke further research and not be seen as health advice.
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