Metabolites

17 pages, 3425 KiB

Open AccessArticle

Utilizing Untargeted Lipidomics Technology to Elucidate Differences in Lipid Compositions Among Sensitive Dry, Sensitive Oily and Healthy Skin Types

by Agui Xie, Xingjiang Zhang, Qing Huang and Jianxin Wu

Metabolites 2025, 15(5), 292; https://doi.org/10.3390/metabo15050292 - 26 Apr 2025

Abstract

Background: Sensitive skin exhibits impaired skin barrier function. The lipid composition of the skin, a pivotal element within the stratum corneum’s “brick-and-mortar” structure, plays a dual role: it is integral to cell differentiation processes and serves as a vital nutrient reservoir for cutaneous [...] Read more.

Background: Sensitive skin exhibits impaired skin barrier function. The lipid composition of the skin, a pivotal element within the stratum corneum’s “brick-and-mortar” structure, plays a dual role: it is integral to cell differentiation processes and serves as a vital nutrient reservoir for cutaneous microbiota, thereby influencing the skin’s microecological balance. There is a notable research gap concerning the comparative analysis of physiological parameters and lipid profiles among individuals with sensitive dry skin (SDS), sensitive oily skin (SOS), and healthy skin (HS). Methods: A total of 95 females (18–25 years) were grouped: SDS (n = 32), SOS (n = 31), and HS (n = 32). Stratum corneum water content, oil content, and TEWL were measured. Lipids from sebaceous glands and stratum corneum (tape-stripping) underwent UPLC-QTOF-MS analysis. Differential lipids were identified via OPLS-DA, volcano plots, and LMSD. Results: In terms of physiological indicators, notable disparities emerged in oil content and stratum corneum water content between the SOS and both the HS and the SDS. Sensitive skin, whether dry or oily, displayed a higher transepidermal water loss (TEWL) value than healthy skin, reflecting a declined state of skin barrier function. Regarding the sebum samples, the relative percentages of sphingolipids (SP) and glycerophospholipids (GP) were significantly higher in SDS. Regarding the stratum corneum samples, the percentages of SP in SDS were significantly higher. Conclusions: This study, for the first time, conducted a comprehensive analysis of the skin’s physiological properties, lipidomics of sebum, and stratum corneum lipids among groups with SDS, SOS, and HS. These observations indicate a profound association between skin barrier dysfunction in SDS individuals and, in particular, sphingolipids (SP). Full article

(This article belongs to the Section Advances in Metabolomics)

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21 pages, 4124 KiB

Open AccessArticle

Xanthoceras sorbifolium Oil Attenuates Hyperlipidemia Through Dual Modulation of Gut Microbiota and Lipid Metabolites: Mechanistic Insights from Lipidomics and 16S rRNA Sequencing

by Yameng Tao, Miaomiao Yao, Qi He, Xiaoyang Kang, Fangkai Shi, Xuan Hu, Zhiyun Meng, Hui Gan, Ruolan Gu, Yunbo Sun, Guifang Dou and Shuchen Liu

Metabolites 2025, 15(5), 291; https://doi.org/10.3390/metabo15050291 - 25 Apr 2025

Abstract

Background/Objectives: Xanthoceras sorbifolium oil (XSO), containing nervonic acid and unsaturated fatty acids (93%), exhibits lipid-lowering potential; yet, its mechanisms involving gut–liver crosstalk remain unclear. This study investigated XSO’s anti-hyperlipidemic effects and gut microbiota interactions. Methods: Forty-eight Sprague Dawley male rats were [...] Read more.

Background/Objectives: Xanthoceras sorbifolium oil (XSO), containing nervonic acid and unsaturated fatty acids (93%), exhibits lipid-lowering potential; yet, its mechanisms involving gut–liver crosstalk remain unclear. This study investigated XSO’s anti-hyperlipidemic effects and gut microbiota interactions. Methods: Forty-eight Sprague Dawley male rats were divided into: normal control (NC), high-fat diet (HFD), XSO prevention (XOP, 1.4 mL/kg pre-HFD), and XSO treatment (XOT, post-HFD). Serum lipids, fecal short-chain fatty acids (SCFAs), gut microbiota (16S rRNA), and lipidomics (UPLC-MS/MS) were analyzed after 12 weeks. Results: XOP significantly reduced serum total cholesterol (TC, 26.8%), triglycerides (TG, 35.9%), and low-density lipoprotein cholesterol (LDL-C, 45.9%) versus HFD (p < 0.05), while increasing high-density lipoprotein cholesterol (HDL-C, 7.98%). XOP showed enhanced hepatoprotection (AST↓ 32.6%, p < 0.01). Although XSO elevated fecal acetate (1.5-fold) and butyrate (1.3-fold), these changes lacked significance (p > 0.05). The analysis of gut microbiota showed that the pro-inflammatory Coriobacteriaceae and Erysipelibacteriaceae were reduced at the family level in the XOP group (p < 0.05). Lipidomics identified 69 differential metabolites: XSO downregulated atherogenic cholesteryl esters and triglycerides, upregulated six phosphatidylethanolamines, and modulated aberrant lysophosphatidylcholines. Conclusions: XSO alleviates hyperlipidemia through direct modulation of lipid metabolism pathways and suppression of pro-inflammatory gut microbiota. While its prebiotic potential warrants further validation, these findings highlight XSO as a functional dietary adjunct for improving lipid homeostasis and mitigating cardiovascular risks. XSO alleviates hyperlipidemia through direct modulation of lipid metabolism pathways and suppression of pro-inflammatory gut microbiota, while its prebiotic potential warrants further validation. These findings support XSO as a dietary adjunct for lipid homeostasis improvement, offering a nutritional strategy for early-stage cardiovascular risk management. Full article

(This article belongs to the Section Lipid Metabolism)

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25 pages, 8600 KiB

Open AccessArticle

Integrated Metabolomics and Lipidomics Analysis Reveals the Mechanism Behind the Action of Chiglitazar on the Protection Against Sepsis-Induced Acute Lung Injury

by Liu-Liu Lu, Yu-Li Cao, Zhen-Chen Lu, Han Wu, Shan-Song Hu, Bing-Qing Ye, Jin-Zhi He, Lei Di, Xu-Lin Chen and Zhi-Cheng Liu

Metabolites 2025, 15(5), 290; https://doi.org/10.3390/metabo15050290 - 25 Apr 2025

Abstract

Background: Sepsis-induced acute lung injury (SALI) is a critical clinical challenge with high mortality. Metabolic dysregulation drives SALI pathogenesis, disrupting lung function and energy metabolism. Despite proven benefits, metabolic restoration is underused in sepsis. This study explores chiglitazar’s role in balancing metabolism to [...] Read more.

Background: Sepsis-induced acute lung injury (SALI) is a critical clinical challenge with high mortality. Metabolic dysregulation drives SALI pathogenesis, disrupting lung function and energy metabolism. Despite proven benefits, metabolic restoration is underused in sepsis. This study explores chiglitazar’s role in balancing metabolism to protect against SALI. Methods: The protective effects of chiglitazar in CLP rats were demonstrated by the survival curve, histological analysis, and immunohistochemical analysis in the lung tissue. Metabolomic and lipidomic analyses of lung tissue samples using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) were performed to evaluate metabolic shifts induced by CLP surgery and chiglitazar pretreatment. The mRNA and protein levels of the underlying targets directing nicotinamide adenine dinucleotide (NAD+) and triglyceride synthesis were analyzed by qPCR and Western blotting. To validate the mechanism by which chiglitazar protected against SALI, the SIRT1 inhibitor EX-527 was applied to human normal lung epithelial (BEAS-2B) cells and another batch of rats to observe its reverse effect against chiglitazar’s action. Results: Chiglitazar pretreatment significantly restored NAD+ and improved dysregulated lipid metabolism by enhancing the synthesis of triglycerides (TGs) and suppressing accumulated fatty acids (FAs). The metabolic modulation mediated by chiglitazar was associated with the upregulations of the SIRT1/PGC-1α/PPARα/GPAT3 axis. Co-treatment with EX-527 in LPS-stimulated BEAS-2B cells and CLP rats inhibited the effects of chiglitazar on the aforementioned signaling pathways and worsened the protective effects of chiglitazar on lung injury, respectively. Conclusions: Chiglitazar alleviates SALI by restoring NAD+ and TG synthesis, highlighting the balancing of metabolism as a promising therapeutic strategy in the management of SALI. Full article

(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)

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18 pages, 954 KiB

Open AccessArticle

Alcohol Exposure May Increase Prenatal Choline Needs Through Redirection of Choline into Lipid Synthesis Rather than Methyl Donation

by Hannah G. Petry, Nipun Saini, Susan M. Smith and Sandra M. Mooney

Metabolites 2025, 15(5), 289; https://doi.org/10.3390/metabo15050289 - 24 Apr 2025

Abstract

Background: Prenatal alcohol exposure (PAE) can reduce fetal growth and cause neurodevelopmental disability. Prenatal choline supplements attenuate PAE-induced behavioral and growth deficits; however, the underlying mechanisms are unknown. Alcohol alters nutrient metabolism and potentially increases nutrient needs. Here, we investigate how alcohol [...] Read more.

Background: Prenatal alcohol exposure (PAE) can reduce fetal growth and cause neurodevelopmental disability. Prenatal choline supplements attenuate PAE-induced behavioral and growth deficits; however, the underlying mechanisms are unknown. Alcohol alters nutrient metabolism and potentially increases nutrient needs. Here, we investigate how alcohol affects choline metabolism in the maternal–fetal dyad and the role of supplemental choline. Methods: Pregnant C57BL/6J mice were assigned to one of four groups: alcohol-exposed (3 g/kg alcohol/day) or control +/− 100 mg/kg choline daily from embryonic day (E)8.5–17.5. We performed an exploratory hypothesis-generating analysis of targeted metabolomics on choline-related metabolites in the maternal liver, plasma, placenta, and fetal brain at E17.5 and Spearman correlation analyses to determine their association with gestational and fetal growth outcomes. Results: Although choline levels were largely unaffected by alcohol or choline, alcohol increased many lipid products in the CDP–choline pathway; this was not normalized by choline. Alcohol increased placental CDP–ethanolamine and reduced the maternal hepatic SAM/SAH ratio as well as dimethylglycine and the serine/glycine ratio across the dyad, suggesting a functional insufficiency in methyl donor pools. These outcomes were rescued by supplemental choline. Correlation analyses among choline metabolites and fetal growth outcomes suggest that maternal plasma methionine, serine, and the serine/glycine ratio may be predictive of maternal–fetal choline status. Conclusions: The increased hepatic lipid synthesis that characterizes chronic alcohol exposure may draw choline into phospholipid biosynthesis at the expense of its use as a methyl donor. We propose that PAE increases choline needs, and that its supplementation is necessary to fulfill these competing demands for lipid and methyl use. Full article

(This article belongs to the Special Issue One-Carbon Metabolism in Pregnant Women, Fetuses, and Infants)

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12 pages, 665 KiB

Open AccessArticle

Probiotic Supplementation Improves Glucose Homeostasis and Modulates Interleukin (IL)-21 and IL-22 Levels in Pediatric Patients with Type 1 Diabetes: A Randomized Placebo-Controlled Trial

by Amira Abdel Moneam Adly, Eman Abdel Rahman Ismail, Mahasen Mohamed Abd-Elgawad and Nouran Yousef Salah

Metabolites 2025, 15(5), 288; https://doi.org/10.3390/metabo15050288 - 24 Apr 2025

Abstract

Background: Probiotics alter gut microbiota and have beneficial effects on immune homeostasis. The role of probiotics in diabetes has been shown in some studies. Interleukin (IL)-21 and IL-22 have been implicated in the pathogenesis of type 1 diabetes mellitus (T1DM). Objectives: This study [...] Read more.

Background: Probiotics alter gut microbiota and have beneficial effects on immune homeostasis. The role of probiotics in diabetes has been shown in some studies. Interleukin (IL)-21 and IL-22 have been implicated in the pathogenesis of type 1 diabetes mellitus (T1DM). Objectives: This study aimed to assess the effect of oral supplementation with probiotics on glycemic control and IL-21 and IL-22 levels in pediatric patients with T1DM. Methods: This randomized controlled trial was registered in ClinicalTrials (NCT04579341) and included 70 children and adolescents with T1DM. They were randomly assigned into two groups to receive either an oral probiotic tablet containing 0.5 mg Lactobacillus acidophilus once daily or a matching placebo. Both groups were followed up for 6 months with assessment of fasting blood glucose (FBG), lipids, hemoglobin A1c (HbA1c), and IL-21 and IL-22 levels. Results: Baseline clinical characteristics and laboratory parameters were similar between both groups (p > 0.05). After six months, probiotic supplementation for the intervention group resulted in significant decreases in FBG, HbA1c, total cholesterol, and IL-21 levels, while IL-22 was increased compared with baseline levels (p < 0.001) and compared with the placebo group (p < 0.001). No adverse reactions were reported. Baseline IL-21 was positively correlated to FBG, HbA1c, and total cholesterol while there were negative correlations between these variables and IL-22 levels. Conclusions: Probiotic supplementation improved glucose homeostasis and glycemic control, possibly through their immunomodulatory effects on cytokines IL-21 and IL-22. Thus, probiotics could be a safe adjuvant therapy to intensive insulin in pediatric patients with T1DM. Full article

(This article belongs to the Special Issue Diet and Nutrition in Relation to Metabolic Health)

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34 pages, 1818 KiB

Open AccessReview

From Childhood Obesity to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Hyperlipidemia Through Oxidative Stress During Childhood

by Siham Accacha, Julia Barillas-Cerritos, Ankita Srivastava, Frances Ross, Wendy Drewes, Shelly Gulkarov, Joshua De Leon and Allison B. Reiss

Metabolites 2025, 15(5), 287; https://doi.org/10.3390/metabo15050287 - 24 Apr 2025

Abstract

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple [...] Read more.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia. Methods: This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers. Results: Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD. Conclusions: Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels. Full article

(This article belongs to the Special Issue Metabolic Dysregulation in Fatty Liver Disease)

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30 pages, 1477 KiB

Open AccessReview

The Influence of the Sympathetic Nervous System on Cardiometabolic Health in Response to Weight Gain or Weight Loss

by Gavin W. Lambert, Mariya Patel and Elisabeth A. Lambert

Metabolites 2025, 15(5), 286; https://doi.org/10.3390/metabo15050286 - 23 Apr 2025

Abstract

Alterations in sympathetic nervous activity are evident in response to changes in body weight. Sympathetic nervous activity and sympathetic responses to weight change are regionalized, with alterations in end organ function dependent on the changes occurring in the brain regulatory pathways invoked and [...] Read more.

Alterations in sympathetic nervous activity are evident in response to changes in body weight. Sympathetic nervous activity and sympathetic responses to weight change are regionalized, with alterations in end organ function dependent on the changes occurring in the brain regulatory pathways invoked and in the effector organs engaged. The obesity-induced activation of the sympathetic nervous system likely contributes to the initiation and worsening of cardiometabolic risk factors, including elevated blood pressure, cardiac dysfunction, dyslipidaemia, increased fasting blood glucose, insulin resistance, and non-alcoholic steatohepatitis. Unintended weight loss, as occurs in cachexia, is driven, at least in part, by the activation of sympathetic nervous-stimulated thermogenesis. The complexity of sympathetic nervous regulation renders the use of global measures of sympathetic activity problematic and the development of targeted therapies difficult, but these are not without promise or precedent. Knowledge of the central and peripheral pathways involved in sympathetic nervous regulation has opened up opportunities for pharmacological, surgical, and device-based approaches to mitigating the burden of disease development and progression. In this narrative review, we elaborate on sympathetic activity in response to changes in body weight, the brain pathways involved, and the cardiovascular and metabolic risks associated with perturbations in regional sympathetic activity. Full article

(This article belongs to the Special Issue Adrenal Neuroendocrine System and Cardiometabolic Health)

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21 pages, 2740 KiB

Open AccessArticle

Metabolic Reprogramming in HIV+ CD4⁺ T-Cells: Implications for Immune Dysfunction and Therapeutic Targets in M. tuberculosis Co-Infection

by Suheena Ayrga and Gerrit Koorsen

Metabolites 2025, 15(5), 285; https://doi.org/10.3390/metabo15050285 - 22 Apr 2025

Abstract

Background/Objectives: HIV and Mycobacterium tuberculosis (M.tb) co-infection presents a major global health burden. The immune response to M.tb is largely orchestrated by cluster of differentiation 4-positive (CD4⁺) T cells, with CD8⁺ T cells playing an auxiliary role. This [...] Read more.

Background/Objectives: HIV and Mycobacterium tuberculosis (M.tb) co-infection presents a major global health burden. The immune response to M.tb is largely orchestrated by cluster of differentiation 4-positive (CD4⁺) T cells, with CD8⁺ T cells playing an auxiliary role. This study aims to investigate the immunometabolic response of CD4⁺ and CD8⁺ T cells to M.tb antigens, analysed using metabolomics, to elucidate metabolic shifts that may influence immune function in an HIV+ environment. Methods: Whole blood samples from newly diagnosed, treatment-naïve HIV+ individuals were stimulated with M.tb antigens early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) using the QuantiFERON^® (QFT) Gold Plus assay. Following incubation, plasma samples were analysed through untargeted nuclear magnetic resonance (1^H-NMR) spectroscopy. Metabolomic data were processed using MetaboAnalyst, with differential metabolites identified through multivariate statistical analyses. Results: Metabolic profiling of PBMCs revealed distinct differences in response to M.tb antigens between CD4⁺ and CD4⁺/CD8⁺ T-cell activation. CD4⁺ T cells exhibited enhanced glycolysis, with elevated levels of metabolites that are linked largely to the Warburg effect. Additionally, vitamin D levels were found to correlate with certain metabolites, suggesting a role in modulating immune responses. Conclusions: These findings suggest a complex interplay between immune cell metabolism and activation in HIV+ individuals. The study demonstrates that HIV and M.tb co-infection significantly influences the broader metabolic profile of peripheral blood mononuclear cells (PBMCs), highlighting the altered metabolic pathways that are critical in immune responses and disease progression. These findings contribute to the understanding of immunometabolism in co-infection and emphasise the need for further research into targeted metabolic interventions. Full article

(This article belongs to the Section Cell Metabolism)

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16 pages, 2448 KiB

Open AccessArticle

Lactobacillus johnsonii N6.2 Phospholipids Induce T Cell Anergy upon Cognate Dendritic Cell Interactions

by Alexandra E. Cuaycal, Monica F. Torrez Lamberti, Graciela L. Lorca and Claudio F. Gonzalez

Metabolites 2025, 15(5), 284; https://doi.org/10.3390/metabo15050284 - 22 Apr 2025

Abstract

Background/Objectives: Lactobacillus johnsonii N6.2 is a gut symbiont with probiotic properties. L. johnsonii N6.2 delayed the progression of type 1 diabetes (T1D) in diabetic-prone rats. The probiotic intake demonstrated immune cell modulation in healthy volunteers, leading to improved wellness and fewer reported [...] Read more.

Background/Objectives: Lactobacillus johnsonii N6.2 is a gut symbiont with probiotic properties. L. johnsonii N6.2 delayed the progression of type 1 diabetes (T1D) in diabetic-prone rats. The probiotic intake demonstrated immune cell modulation in healthy volunteers, leading to improved wellness and fewer reported symptoms like headaches and abdominal pain. These systemic immune-modulating benefits are attributed to L. johnsonii N6.2’s bioactive fractions, including extracellular vesicles (EVs) and purified phospholipids (PLs). We have previously shown that L. johnsonii N6.2 PLs modulate dendritic cell (DC) function towards a regulatory-like phenotype. Here, we further characterize the immune regulatory effects of L. johnsonii N6.2 PLs on adaptive immunity, specifically upon DC and T cell interactions. We hypothesized that PL-stimulated DCs suppress T cell-mediated responses to maintain tolerance in intra- and extra-intestinal sites. Methods: Bone marrow-derived dendritic cells (BMDCs) were generated from Sprague-Dawley rats and stimulated with L. johnsonii N6.2 PLs. Isogenic T cells were isolated from PBMCs obtained via terminal exsanguination. In vitro cellular assays, co-culture experiments, gene expression analysis by qRT-PCR, and flow cytometry assays were conducted to assess the immune regulatory effects of L. johnsonii N6.2 PLs. Results: The PL-stimulated BMDCs upregulated DC regulatory markers and exhibited an immature-like phenotype with reduced surface expression of maturation markers but increased surface migratory molecules (ICAM-1). These BMDCs presented immunosuppressive functions upon cognate T cell interactions and in the presence of TCR stimulation. Specifically, PL-stimulated BMCDs suppressed Th1 effector function and induced the expression of T cell anergy-related genes after co-culturing for 72 h. Conclusions: This study highlights the immune regulatory capacity of L. johnsonii N6.2’s bioactive components on adaptive immunity, specifically that of purified PLs on DC:T cell-mediated responses leading to immunosuppression. Our findings suggest that L. johnsonii N6.2-purified PLs play a role in regulating adaptive immunity, offering potential benefits for managing immune-related diseases like T1D. Full article

(This article belongs to the Special Issue Targeting Microbiota and Metabolites for Prevention and Treatment of Human Diseases)

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15 pages, 1583 KiB

Open AccessArticle

Development and Application of an In-Capillary CE-DAD Method for the Inhibitory Screening of Natural Extracts Towards Acetylcholinesterase Enzyme

by Francesca Rinaldi, Sofia Salerno, Elena Frigoli, Giulia De Soricellis, Gloria Brusotti, Stefano Negri, Matteo Radice, Francesca Merlo, Andrea Speltini, Hellas Cena and Enrica Calleri

Metabolites 2025, 15(4), 283; https://doi.org/10.3390/metabo15040283 - 18 Apr 2025

Abstract

Background: The enzymatic activity of acetylcholinesterase (AChE) has been a focal point in neurodegenerative diseases research, particularly in relation to Alzheimer’s disease. This is attributed to the significantly reduced levels of cholinergic neurons observed in Alzheimer’s patients compared to healthy individuals. The strategy [...] Read more.

Background: The enzymatic activity of acetylcholinesterase (AChE) has been a focal point in neurodegenerative diseases research, particularly in relation to Alzheimer’s disease. This is attributed to the significantly reduced levels of cholinergic neurons observed in Alzheimer’s patients compared to healthy individuals. The strategy to mitigate the onset of these diseases in patients lies in the exploration of new potential AChE inhibitors with a focus also on natural extracts. A rapid and specific capillary electrophoresis method with direct ultraviolet detection (CZE-UV/Vis) was developed to screen natural extracts by assessing their potential to inhibit AChE. Materials and Methods: To enhance the specificity when analysing complex matrixes such as natural extracts, a sequential analysis approach based on the “sandwich model” was implemented using Ellman’s reagent [5,5′-dithiobis-(2-nitrobenzoic acid)] (DTNB) as a colorimetric indicator. Results: A reference inhibitor, neostigmine, was used for system validation through IC₅₀ and K_i values determination by subsequent injections of acetylthiocholine substrate in the presence of neostigmine at increasing concentrations, and the enzyme combined with DTNB in borate-phosphate buffer (30 mM, pH 8.0). The enzymatic product was selectively detected at 412 nm. The validated system was applied to the analysis of seven natural extracts. Conclusions: Results demonstrated promising outcomes for identifying phytotherapeutic agents with potential applications in the prevention of neurodegenerative diseases. This method provides high selectivity and automation, offering a streamlined and effective approach for screening natural matrices containing potential AChE inhibitors. Full article

(This article belongs to the Special Issue Secondary Metabolites and Their Activities: From the Identification to the Biological Investigation)

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27 pages, 788 KiB

Open AccessReview

Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View

by Antonella Di Sarno, Fiammetta Romano, Rossana Arianna, Domenico Serpico, Mariarosaria Lavorgna, Silvia Savastano, Annamaria Colao and Carolina Di Somma

Metabolites 2025, 15(4), 282; https://doi.org/10.3390/metabo15040282 - 18 Apr 2025

Abstract

Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, [...] Read more.

Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer’s disease (AD), Parkisons’s disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue. Full article

(This article belongs to the Special Issue Lipid Metabolism in Age-Related Diseases)

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12 pages, 1097 KiB

Open AccessArticle

Quality Evaluation of the Traditional Chinese Medicine Moutan Cortex Based on UPLC Fingerprinting and Chemometrics Analysis

by Wentao Fang, Qianqian Song, Han Luo, Rui Wang and Chengwu Fang

Metabolites 2025, 15(4), 281; https://doi.org/10.3390/metabo15040281 - 18 Apr 2025

Abstract

Background: This study aims to develop a fingerprint analysis method using ultra-high performance liquid chromatography (UPLC) for Moutan Cortex sourced from different regions. The objective is to establish quality control standards validated through the integration of chemometric methods and component structure theory. Methods: [...] Read more.

Background: This study aims to develop a fingerprint analysis method using ultra-high performance liquid chromatography (UPLC) for Moutan Cortex sourced from different regions. The objective is to establish quality control standards validated through the integration of chemometric methods and component structure theory. Methods: The mobile phase for UPLC consisted of acetonitrile (A) and a 0.1% aqueous formic acid solution (B), with gradient elution set as follows: 0–1 min, 8% A → 15% A; 1–8 min, 15% A → 18% A; 8–10 min, 18% A → 30% A; 10–15 min, 30% A → 35% A; 15–20 min, 35% A → 85% A; 20–21 min, 85% A → 8% A; and 21–26 min, 8% A → 8% A. Chemical markers significantly affecting Moutan Cortex from various regions were screened, and their identification was based on comparison with reference materials and content determination. Results: A total of 15 chemical markers were identified, including gallic acid, oxypaeoniflorin, catechin, methyl gallate, paeonolide, apiopaeonoside, albiflorin, paeoniflorin, benzoic acid, 1,2,3,6-tetra-O-galloyl-D-glucose, 1,2,3,4,6-pentagalloylglucose, mudanpioside C, benzoyloxypaeoniflorin, benzoylpaeoniflorin, and paeonol. These markers align with component structure theory, allowing for an analysis of the structural characteristics of Moutan Cortex from different regions. Conclusions: The findings provide a valuable reference for the future quality evaluation of traditional Chinese medicine preparations, enhancing the understanding of the material basis components in Moutan Cortex from diverse sources. Full article

(This article belongs to the Special Issue Advances in Secondary Metabolites: Phytochemical Analysis and Bioactivity Assays)

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13 pages, 715 KiB

Open AccessArticle

Association Between Alpha-1-Acid Glycoprotein and Non-Alcoholic Fatty Liver Disease and Liver Fibrosis in Adult Women

by Yansong Fu, Siyi Zhang, Xin Zeng and Hong Qin

Metabolites 2025, 15(4), 280; https://doi.org/10.3390/metabo15040280 - 17 Apr 2025

Abstract

Background: Alpha-1-acid glycoprotein (AGP) is a glycoprotein synthesized mainly by the liver. Nonalcoholic fatty liver disease (NAFLD) and liver fibrosis (LF) are associated with metabolic disorders. The aim of this study was to examine the potential correlation between AGP and both NAFLD and [...] Read more.

Background: Alpha-1-acid glycoprotein (AGP) is a glycoprotein synthesized mainly by the liver. Nonalcoholic fatty liver disease (NAFLD) and liver fibrosis (LF) are associated with metabolic disorders. The aim of this study was to examine the potential correlation between AGP and both NAFLD and LF. Methods: The data were derived from the 2017–2023 National Health and Nutrition Examination Survey (NHANES). The linear association between AGP and NAFLD and LF was examined by multivariate logistic regression models. Non-linear relationships were described by fitting smoothed curves and threshold effect analysis. Subgroup analysis was also performed to assess potential regulatory factors. Results: The study included 2270 females. AGP was found to be significantly and positively associated with NAFLD [OR = 12.00, 95% CI (6.73, 21.39), p < 0.001] and LF [OR = 2.20, 95% CI (1.07, 4.50), p = 0.042]. Furthermore, the association between AGP and NAFLD was significantly different in the diabetic subgroup (p < 0.05 for interaction). Additionally, we found an inverted U-shaped relationship between AGP and controlled attenuation parameter (CAP), with an inflection point at 1.20 g/L. Conclusions: We found a significant positive correlation between AGP and both NAFLD and LF, and there was an inverted U-shaped relationship between AGP and CAP. Full article

(This article belongs to the Special Issue Metabolic Syndrome and Non-Alcoholic Liver Disease)

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15 pages, 2601 KiB

Open AccessArticle

A Scoring Model Using Multi-Metabolites Based on Untargeted Metabolomics for Assessing Dyslipidemia in Korean Individuals with Obesity

by Su-Geun Yang and Hye Jin Yoo

Metabolites 2025, 15(4), 279; https://doi.org/10.3390/metabo15040279 - 17 Apr 2025

Abstract

Background/Objectives: Metabolite risk score (MRS), which considers the collective effects of metabolites closely reflecting a phenotype, is a new approach for disease assessment, moving away from focusing solely on individual biomarkers. This study aimed to investigate a metabolite panel for dyslipidemia and verify [...] Read more.

Background/Objectives: Metabolite risk score (MRS), which considers the collective effects of metabolites closely reflecting a phenotype, is a new approach for disease assessment, moving away from focusing solely on individual biomarkers. This study aimed to investigate a metabolite panel for dyslipidemia and verify the diagnostic efficacy of MRS on dyslipidemia. Methods: Key metabolite identification and MRS establishment were conducted in the discovery set, and MRS validation was performed in the replication set, with 50 healthy individuals and 50 dyslipidemia patients in each set. The MRS was constructed using key metabolites, identified via UPLC-MS/MS analysis, employing a weighted approach based on linear regression analysis. Results: N-acetylisoputreanine-γ-lactam and eicosapentaenoic acid were identified as key metabolites for dyslipidemia and were utilized for establishing the MRS. In addition to the MRS model, a conventional dyslipidemia diagnostic model based on lipid profiles, as well as a combined model (MRS + lipid profiles), were also established. In the discovery set, the MRS model diagnosed dyslipidemia with 85.4% accuracy. When combined with lipid profiles, accuracy improved to 91.8%. In the replication set, the MRS demonstrated diagnostic power with 76.1% accuracy, while the combined model achieved 86.0% accuracy for dyslipidemia assessment. Conclusions: The MRS alone indicated sufficient assessment power in a real-world setting, despite a slight reduction in assessment ability when validated in the replication set. At this stage, therefore, the MRS serves as an auxiliary tool for disease diagnosis. This first attempt to apply MRS for dyslipidemia may offer a foundational concept for MRS in this disease. Full article

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

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19 pages, 2384 KiB

Open AccessArticle

Effects of a 6-Week Concurrent Training Program Combining Resistance and Various Modalities of Aerobic Exercise in Obese Women with Prehypertension: A Randomized Controlled Trial

by Jinhyuk Yu, Eunjoo Lee, Jae-Ho Choi, Yerin Sun, Seungyeon Woo, Sohyang Cho, Deunsol Hwang, Sung-Woo Kim, Jisu Kim, Kiwon Lim and Hun-Young Park

Metabolites 2025, 15(4), 278; https://doi.org/10.3390/metabo15040278 - 17 Apr 2025

Abstract

Background/Objectives: Our study aimed to verify the effects of 6 weeks of concurrent training composed of resistance training (RT) and different modalities of aerobic exercise (moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT)) on body composition, blood pressure, vascular function, autonomic [...] Read more.

Background/Objectives: Our study aimed to verify the effects of 6 weeks of concurrent training composed of resistance training (RT) and different modalities of aerobic exercise (moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT)) on body composition, blood pressure, vascular function, autonomic nervous system (ANS) function, blood lipid levels, cardiometabolic index (CMI), and health-related fitness in obese middle-aged women with prehypertension. Methods: We selected 26 middle-aged women with obesity and prehypertension and divided them equally into the RT + MICT (n = 13) and RT + HIIT (n = 13) groups. The concurrent training program consisted of warm-up, RT, aerobic exercise (MICT or HIIT), and cool-down, and was performed for 6 weeks, three times a week, 85–100 min per session. The measured dependent parameters were analyzed before and after training. Results: Concurrent training (RT + MICT and RT + HIIT) for 6 weeks showed significant improvements in body composition, blood pressure, vascular function, ANS function, CMI, and health-related fitness. However, the RT + HIIT group showed a relatively greater improvement in blood lipid levels compared to the RT + MICT group. Conclusions: Our study confirmed that both RT + MICT and RT + HIIT yielded similar positive effects on most health-related parameters in obese middle-aged women with prehypertension. Among them, RT + HIIT appeared to be relatively more effective in improving blood lipid profiles. Full article

(This article belongs to the Special Issue Effects of Various Exercise Methods on Metabolic Health)

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17 pages, 1407 KiB

Open AccessArticle

Metabolic Effects of the Cancer Metastasis Modulator MEMO1

by Marziyeh Ghanbarian, Natalia Dolgova, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Deborah Michel, Anas El-Aneed and Oleg Y. Dmitriev

Metabolites 2025, 15(4), 277; https://doi.org/10.3390/metabo15040277 - 17 Apr 2025

Abstract

Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, and dysregulation of the TCA cycle is a frequent hallmark of cancer cell metabolism. MEMO1, a modulator [...] Read more.

Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, and dysregulation of the TCA cycle is a frequent hallmark of cancer cell metabolism. MEMO1, a modulator of cancer metastasis, has been shown to bind iron and regulate iron homeostasis in the cells. MEMO1 knockout changed mitochondrial morphology and iron content in breast cancer cells. Our previous genome-wide analysis of MEMO1 genetic interactions across multiple cancer cell lines revealed that gene sets involved in mitochondrial respiration and the TCA cycle are enriched among the gain-of-function interaction partners of MEMO1. Based on these findings, we measured the TCA cycle metabolite levels in breast cancer cells with varying levels of MEMO1 expression. Methods: ShRNA knockdown assay was performed to test essentiality of key TCA cycle enzymes. TCA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in MDA-MB-231 (high MEMO1), M67-2 (MEMO1 knockdown), and M67-9 (MEMO1 knockout) cells under iron-depleted, basal iron, and iron-supplemented conditions. Results:ACO2 and OGDH knockdowns inhibit cell proliferation, indicating an essential role of the TCA cycle in MDA-MB-231 metabolism. α-Ketoglutarate and citrate levels exhibited an inverse relationship with MEMO1 expression, increasing significantly in MEMO1 knockout cells regardless of iron availability. In contrast, fumarate, malate, and glutamate levels were elevated in MEMO1 knockout cells specifically under low iron conditions, suggesting an iron-dependent effect. Conclusions: Overall, our results indicate that MEMO1 plays a role in regulating the TCA in cancer cells in an iron-dependent manner. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Energy Metabolic Alterations in Health and Disease)

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27 pages, 3031 KiB

Open AccessReview

Plant Secondary Metabolites—Central Regulators Against Abiotic and Biotic Stresses

by Ameer Khan, Farah Kanwal, Sana Ullah, Muhammad Fahad, Leeza Tariq, Muhammad Tanveer Altaf, Asad Riaz and Guoping Zhang

Metabolites 2025, 15(4), 276; https://doi.org/10.3390/metabo15040276 - 16 Apr 2025

Abstract

As global climates shift, plants are increasingly exposed to biotic and abiotic stresses that adversely affect their growth and development, ultimately reducing agricultural productivity. To counter these stresses, plants produce secondary metabolites (SMs), which are critical biochemical and essential compounds that serve as [...] Read more.

As global climates shift, plants are increasingly exposed to biotic and abiotic stresses that adversely affect their growth and development, ultimately reducing agricultural productivity. To counter these stresses, plants produce secondary metabolites (SMs), which are critical biochemical and essential compounds that serve as primary defense mechanisms. These diverse compounds, such as alkaloids, flavonoids, phenolic compounds, and nitrogen/sulfur-containing compounds, act as natural protectants against herbivores, pathogens, and oxidative stress. Despite the well-documented protective roles of SMs, the precise mechanisms by which environmental factors modulate their accumulation under different stress conditions are not fully understood. This review provides comprehensive insights into the recent advances in understanding the functions of SMs in plant defense against abiotic and biotic stresses, emphasizing their regulatory networks and biosynthetic pathways. Furthermore, we explored the unique contributions of individual SM classes to stress responses while integrating the findings across the entire spectrum of SM diversity, providing a comprehensive understanding of their roles in plant resilience under multiple stress conditions. Finally, we highlight the emerging strategies for harnessing SMs to improve crop resilience through genetic engineering and present novel solutions to enhance agricultural sustainability in a changing climate. Full article

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23 pages, 3688 KiB

Open AccessArticle

Targeted and Non-Targeted Metabolomic Evaluation of Cerebrospinal Fluid in Early Phase Schizophrenia: A Pilot Study from the Hopkins First Episode Psychosis Project

by George E. Jaskiw, Mark E. Obrenovich, Curtis J. Donskey, Farren B. S. Briggs, Sun Sunnie Chung, Anastasiya I. Kalinina, Austin Bolomey, Lindsay N. Hayes, Kun Yang, Robert H. Yolken and Akira Sawa

Metabolites 2025, 15(4), 275; https://doi.org/10.3390/metabo15040275 - 15 Apr 2025

Abstract

(1) Background: The lack of reliable biomarkers remains a significant barrier to improving outcomes for patients with schizophrenia. While metabolomic analyses of blood, urine, and feces have been explored, results have been inconsistent. Compared to peripheral compartments, cerebrospinal fluid (CSF) more closely reflects [...] Read more.

(1) Background: The lack of reliable biomarkers remains a significant barrier to improving outcomes for patients with schizophrenia. While metabolomic analyses of blood, urine, and feces have been explored, results have been inconsistent. Compared to peripheral compartments, cerebrospinal fluid (CSF) more closely reflects the chemical composition of brain extracellular fluid. Given that brain dysregulation may be more pronounced during the first episode of psychosis (FEP), we hypothesized that metabolomic analysis of CSF from FEP patients could reveal disease-associated biomarkers. (2) Methods: We recruited 15 patients within 24 months of psychosis onset (DSM-4 criteria) and 14 control participants through the Johns Hopkins Schizophrenia Center. CSF samples were analyzed using both non-targeted and targeted liquid chromatography–mass spectrometry. (3) Results: The non-targeted analysis identified lower levels of N-acetylneuraminic acid and N-acetyl-L-aspartic acid in the FEP group, while levels of uric acid were elevated. The targeted analysis focused on indolic and phenolic molecules previously linked to neuropsychiatric disorders. Notably, L-phenylalanine and 4-hydroxycinnamic acid levels were lower in the FEP group, and this difference remained significant after adjusting for age and sex. However, none of the significant differences in analyte levels between the groups survived an adjustment for multiple comparisons. (4) Conclusions: Our intriguing but preliminary associations align with results from other investigational approaches and highlight potential CSF analytes that warrant further study in larger samples. Full article

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

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16 pages, 1293 KiB

Open AccessArticle

Comprehensive Characterization of Serum Lipids of Dairy Cows: Effects of Negative Energy Balance on Lipid Remodelling

by Zhiqian Liu, Wenjiao Wang, Joanne E. Hemsworth, Coralie M. Reich, Carolyn R. Bath, Monique J. Berkhout, Muhammad S. Tahir, Vilnis Ezernieks, Leah C. Marett, Amanda J. Chamberlain, Mike E. Goddard and Simone J. Rochfort

Metabolites 2025, 15(4), 274; https://doi.org/10.3390/metabo15040274 - 15 Apr 2025

Abstract

Background: The presence and concentration of lipids in serum of dairy cows have significant implications for both animal health and productivity and are potential biomarkers for several common diseases. However, information on serum lipid composition is rather fragmented, and lipid remodelling during the [...] Read more.

Background: The presence and concentration of lipids in serum of dairy cows have significant implications for both animal health and productivity and are potential biomarkers for several common diseases. However, information on serum lipid composition is rather fragmented, and lipid remodelling during the transition period is only partially understood. Methods: Using a combination of reversed-phase liquid chromatography-mass spectrometry (RP-LC-MS), hydrophilic interaction-mass spectrometry (HILIC-MS), and lipid annotation software, we performed a comprehensive identification and quantification of serum of dairy cows in pasture-based Holstein-Friesian cows. The lipid remodelling induced by negative energy balance was investigated by comparing the levels of all identified lipids between the fresh lactation (5–14 days in milk, DIM) and full lactation (65–80 DIM) stages. Results: We identified 535 lipid molecular species belonging to 19 classes. The most abundant lipid class was cholesteryl ester (CE), followed by phosphatidylcholine (PC), sphingomyelin (SM), and free fatty acid (FFA), whereas the least abundant lipids included phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylglycerol (PG), acylcarnitine (AcylCar), ceramide (Cer), glucosylceramide (GluCer), and lactosylceramide (LacCer). Conclusions: A remarkable increase in most lipids and a dramatic decrease in FFAs, AcylCar, and DHA-containing species were observed at the full lactation compared to fresh lactation stage. Several serum lipid biomarkers for detecting negative energy balance in cows were also identified. Full article

(This article belongs to the Special Issue Effects of Stress on Animal Metabolism)

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