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Keywords = arginine metabolism 4

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32 pages, 5791 KB  
Article
Metabolomics and Transcriptomics Reveal the Effects of Fermented Lycium barbarum (Goji) Berry Residue on Muscle Nutrition and Flavor Quality in Fattening Tan Sheep
by Cong Zhan, Meng Li, Dan Li, Pan Li, Qiming Zhang, Mirou Wu, Guowei Zhong and Xiaochun Xu
Metabolites 2026, 16(1), 39; https://doi.org/10.3390/metabo16010039 - 1 Jan 2026
Viewed by 483
Abstract
Background/Objectives: In the context of increasing consumer demand for high-quality meat, this study aimed to evaluate the effects of 4% fermented goji berry residue supplementation on meat quality and flavor characteristics in finishing Tan sheep. Methods: Thirty-six male lambs were randomly assigned to [...] Read more.
Background/Objectives: In the context of increasing consumer demand for high-quality meat, this study aimed to evaluate the effects of 4% fermented goji berry residue supplementation on meat quality and flavor characteristics in finishing Tan sheep. Methods: Thirty-six male lambs were randomly assigned to a control and FGB group and fed for 68 days. Results: FGB supplementation significantly enhanced Longissimus Dorsi (LD) brightness (L*), redness (a*), and crude protein content, while reducing crude fat (p < 0.05). Amino acid analysis revealed significant increases in lysine, methionine, histidine, glycine, proline, arginine, cysteine, and total sweet-tasting amino acids in the FGB group (p < 0.05). Lactate and inosine monophosphate (IMP) levels were significantly elevated, whereas hypoxanthine levels decreased (p < 0.05). Metabolomics identified 189 metabolites, with 12 differentially expressed, mainly enriched in butanoate metabolism, glycolysis/gluconeogenesis, PI3K-Akt, and HIF-1 signaling pathways. Transcriptomics revealed 382 differentially expressed genes, including key regulators of lipid metabolism (FOXO1, SLC2A4, LPIN1, IGF1, SPP1) and amino acid metabolism (COL3A1, GLUL, PSMC1). Conclusions: Fermented goji residue altered amino acid and lipid metabolism in the LD muscle of Tan sheep, affecting meat quality and flavor traits. However, effects on color (L*, a*, b*), protein content, and shear force varied across the four muscles studied, indicating that responses to supplementation are muscle-specific. These findings offer a sustainable strategy for improving meat quality and provide insights into the molecular mechanisms underlying flavor development in ruminants. Full article
(This article belongs to the Section Animal Metabolism)
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22 pages, 3661 KB  
Article
Bifidobacterium adolescentis Strengthens Gut Barrier in Post-Voyage Functional Constipation
by Huidie Zhao, Hongli Wang, Xinyuan Zhao, Yishan Song, Dong Liang, Yuhao Ma and Zheng Xu
Int. J. Mol. Sci. 2025, 26(24), 12142; https://doi.org/10.3390/ijms262412142 - 17 Dec 2025
Cited by 1 | Viewed by 596
Abstract
Prolonged periods of sailing may contribute to the development of functional constipation, which can significantly impair an individual’s work efficiency. Currently, the efficacy of Bifidobacteria in treating functional constipation is gaining recognition. However, since the therapeutic effects of Bifidobacteria are strain-specific, further research [...] Read more.
Prolonged periods of sailing may contribute to the development of functional constipation, which can significantly impair an individual’s work efficiency. Currently, the efficacy of Bifidobacteria in treating functional constipation is gaining recognition. However, since the therapeutic effects of Bifidobacteria are strain-specific, further research is required on strains isolated from pre-voyage fecal samples. This study examines the role of gut microbiota in post-stroke constipation, aiming to identify specific microbial biomarkers for the development of targeted therapeutic strategies. B. adolescentis was identified through metagenomic analysis and subsequently isolated for validation. In the experimental group (EG), C57BL/6J mice received fecal suspension treatment following a 12-day navigation period, which was subsequently followed by a 12-day oral administration of B. adolescentis. After treatment, EG significantly improved fecal volume, intestinal motility, and goblet cells; reversed microbial ecological imbalance; reduced pathogens (E. coli and Klebsiella) by restoring arginine/bile acid metabolism, decreasing Tauro-ursodeoxycholic acid (TUDCA) content, 5-Hydroxytryptamine 4 Receptor (5-HT4R)/Slc8a1 signaling, and Ca2+ signaling pathway; and restoring beneficial species (B. adolescentis, Pseudomonas aeruginosa). This study provides new insights into probiotics in improving human intestinal health. Full article
(This article belongs to the Special Issue Current Advances in Gut Microbiota in Human Diseases and Health)
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20 pages, 6072 KB  
Article
Reversing the Warburg Effect: YW3-56 Induces Leukemia Differentiation via AKT-Mediated Glucose Metabolic Reprogramming
by Di Zhu, Dan Gao, Yu Lu, Na Chen, Li Zhang, Lan Zhang and Yuji Wang
Pharmaceuticals 2025, 18(11), 1646; https://doi.org/10.3390/ph18111646 - 31 Oct 2025
Viewed by 584
Abstract
Background: Protein arginine deiminase 4 (PAD4) has emerged as a promising therapeutic target for acute promyelocytic leukemia (APL) because of its role in epigenetic regulation and leukemogenesis. All-trans retinoic acid, a standard differentiation agent in APL therapy, has been shown to upregulate [...] Read more.
Background: Protein arginine deiminase 4 (PAD4) has emerged as a promising therapeutic target for acute promyelocytic leukemia (APL) because of its role in epigenetic regulation and leukemogenesis. All-trans retinoic acid, a standard differentiation agent in APL therapy, has been shown to upregulate PAD4 expression during leukemic cell maturation. Interestingly, first-generation PAD4 inhibitors also promote differentiation, but simultaneously trigger compensatory PAD4 overexpression, underscoring the unresolved complexity of PAD4 modulation in leukemia therapy. Methods: In this study, we employed mass cytometry and transcriptomic–proteomic integrated analysis to investigate the underlying mechanisms of YW3-56, a dual-function PAD4 inhibitor against protein expression and enzymatic function, in NB4 leukemia cells. Functional validation was conducted using Western blot and metabolic assays. Results: Mass cytometry analysis revealed that YW3-56 reduced leukemia stemness (CD44/CD133), while enhancing myeloid differentiation (CD11b/CD14) and immunogenic activation (CD80/CD86). Multiomics analysis revealed a YW3-56-induced metabolic shift characterized by downregulation of glycolytic enzymes and upregulation of the tricarboxylic acid cycle and pentose phosphate pathway components, indicating a reversal of the Warburg effect. Mechanistically, this metabolic reprogramming was driven by reduced AKT expression and phosphorylation at Thr308, impaired GLUT1 expression and membrane localization, and decreased glucose uptake, which collectively promoted the differentiation of NB4 cells. Additionally, YW3-56 suppressed the downstream mTOR pathway, inducing caspase-3/PARP-mediated apoptosis and inhibiting cell proliferation. Conclusions: Our study demonstrated that YW3-56 exerts multimodal antileukemic effects in APL by simultaneously targeting PAD4-mediated epigenetic regulation, AKT-driven metabolic reprogramming and cellular differentiation, highlighting PAD4-AKT signaling as a promising target for APL combination therapy. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 5067 KB  
Article
Rectal Microbiomes and Serum Metabolomics Reveal Changes in Serum Antioxidant Status and Immune Responses of Dezhou Donkeys in Late Gestation to Parturition
by Fang Hui, Yanli Zhao, Zaccheaus Pazamilala Akonyani, Yongmei Guo, Xiaoyu Guo, Qingyue Zhang, Fanzhu Meng, Li Li, Binlin Shi and Sumei Yan
Antioxidants 2025, 14(10), 1253; https://doi.org/10.3390/antiox14101253 - 18 Oct 2025
Viewed by 946
Abstract
Parturition is a critical event in the reproductive cycle of dairy animals, accompanied by multiple physiological changes in sex hormones, metabolism, antioxidant capacity, and immune function. However, the changes in the rectal microbiota and metabolic products of Jennies from late gestation to parturition [...] Read more.
Parturition is a critical event in the reproductive cycle of dairy animals, accompanied by multiple physiological changes in sex hormones, metabolism, antioxidant capacity, and immune function. However, the changes in the rectal microbiota and metabolic products of Jennies from late gestation to parturition affect serum antioxidant capacity and anti-inflammatory responses, but it is still unclear. The present study aimed to investigate the serum antioxidant capacity and anti-inflammatory responses of Dezhou donkeys from late gestation to parturition by analyzing rectal microbiomes and serum metabolomics. Nine pregnant multiparous Dezhou Jennies, aged 6.0 ± 0.1 years, with a body weight of 292 ± 33 kg, an average parity number of 2.7 ± 0.1, and similar expected dates of confinement (35 ± 4 days), were selected for this study. The study investigates the changes in antioxidant capacity and inflammatory responses, as well as the alterations in rectal microbiota structure and serum metabolites, in Jennies at 35 days prepartum (B1), 7 days prepartum (B2), and at 0 h postpartum (B3). The results showed that from groups B1 to B2, serum activity of GSH-Px, IL-10, and GLU concentrations were decreased significantly. In contrast, the concentrations of MDA, IgG, LF, IL-1β, IL-2, IL-6, TNF-α, and ROS increased significantly. From groups B2 to B3, serum activities of GSH-Px, CAT, SOD, and T-AOC, as well as the concentrations of MDA, IgG, IL-2, AST, ALP, and BHBA, were significantly increased, whereas the concentrations of IL-4, IL-10, and CRE decreased considerably. Therefore, from 35 days prepartum to parturition, Jennies experienced a gradually intensifying oxidative stress and inflammatory states, with the inflammatory response being the most severe at parturition, and with enhanced antioxidant capacity corresponding to increased oxidative damage. Microbiome analysis revealed that the group B1 significantly increased the relative abundance of Prevotella and Fibrobacteres. Group B2 significantly increased the relative abundance of Prevotellaceae_UCG-001, Streptococcus, and Acetitomaculum. Group B3 showed a significant upregulation of the relative abundance of Norank_f__F082, Lachnospiraceae_UCG-009, and Prevotellaceae_UCG-004. At the same time, metabolomics analysis revealed that, compared with group B1, group B3 may alleviate inflammation and enhance the body’s antioxidant function by upregulating the tryptophan and arginine metabolic pathways and enriching the differential metabolites (L-tryptophan, L-kynurenine, 3-Indoleacetonitrile, N-acetylglutamic acid). Concurrently, the elevation of these differential metabolites may be associated with the relative abundance of the beneficial bacterium Lachnospiraceae_UCG-009. However, the increase in LysoPC, a fatty acid oxidation product in glycerophospholipid metabolism, as well as the correlation between the sucrose content in the galactose metabolic pathway and the abundance of Paracoccus, indicates the reason why the Jennies are in a state of oxidative stress. Furthermore, group B1 may enhance the serum anti-inflammatory response in Jennies during late gestation by increasing the levels of estrogen in the steroid hormone biosynthesis metabolic pathway. These results could provide useful information for improving the health levels at the specific physiological stages and processes in Dezhou donkeys. Full article
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17 pages, 1131 KB  
Article
Dose–Response Effect of Watermelon Consumption on Ambulatory Blood Pressure in Adults with Elevated Blood Pressure: A Randomized Controlled Pilot Trial
by Kanishka Singh, Huiling Liao, Indika Edirisinghe, Britt Burton-Freeman and Amandeep K. Sandhu
Nutrients 2025, 17(19), 3073; https://doi.org/10.3390/nu17193073 - 26 Sep 2025
Viewed by 2455
Abstract
Background/Objectives: Watermelon (Citrullus lanatus) is a natural dietary source of L-citrulline and L-arginine, the two amino acids involved in nitric oxide (NO) production and vasodilation. Pre-clinical and clinical studies using isolated amino acids or watermelon extracts suggest blood pressure (BP)-lowering [...] Read more.
Background/Objectives: Watermelon (Citrullus lanatus) is a natural dietary source of L-citrulline and L-arginine, the two amino acids involved in nitric oxide (NO) production and vasodilation. Pre-clinical and clinical studies using isolated amino acids or watermelon extracts suggest blood pressure (BP)-lowering potential; however, limited research has been conducted on the impact of watermelon flesh (WM) on BP in adults at risk for hypertension. Therefore, the primary objective of this study was to assess the effect of daily WM intake for four weeks on 24 h ambulatory BP in adults with elevated blood pressure. The secondary outcomes of this study include changes in glucose and insulin markers, lipid profile, NO, L-citrulline, L-arginine, asymmetric dimethylarginine (ADMA) concentrations, and the L-arginine/ADMA ratio. Methods: In this randomized, placebo controlled parallel study design, 39 adults (age: 41 ± 14 years, BMI: 31 ± 6 kg/m2, mean ± SD) with elevated BP were randomly assigned to one of three groups for a 4-week intervention: control (0 g WM), WM-1 cup (152 g/day), or WM-2 cups (304 g/day). Ambulatory BP was measured over 24 h at baseline and the end of the intervention period. Fasting plasma samples were analyzed for metabolic biomarkers on a clinical analyzer and NO using a colorimetric assay. L-citrulline, L-arginine, and ADMA were analyzed using an ultra-high-performance liquid chromatography triple quadrupole mass spectrometer (UHPLC-QQQ-MS/MS). Statistical analyses were conducted using SPSS software (IBM SPSS Statistics, Version 29.0.0). Results: After 4 weeks, mean 24 h ambulatory BP was 130.2 ± 3.9 mm Hg (control), 130 ± 3.2 mm Hg (WM-1 cup), and 124.9 ± 3.9 mm Hg (WM-2 cups), with no statistically significant differences between study interventions (p > 0.05). Similarly, no significant changes were observed in fasting plasma glucose, insulin, lipid profile, or NO concentrations. However, plasma L-arginine concentrations and L-arginine/ADMA ratios significantly increased in the WM groups compared to the control (p = 0.009) after adjusting for age, BMI, race, and gender in the statistical model. Conclusion: Overall, BP was not significantly different after two different doses of watermelon compared to control; however, improvements in NO synthesis pathway precursors (L-arginine, ADMA) suggest potential for dietary modulation to support endothelial function and BP regulation. Full article
(This article belongs to the Section Clinical Nutrition)
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23 pages, 3886 KB  
Article
Monitoring of Allograft Adaptation After Kidney Transplantation in Pediatric Patients by Targeted Plasma Metabolomics
by Jelena Klawitter, Bruce E. Kirkpatrick, Ryan Shillingburg, Jost Klawitter, Garrett Wheeler, Touraj Shokati, Melissa A. Cadnapaphornchai, Jeffrey L. Galinkin, Joshua M. Thurman and Uwe Christians
Int. J. Mol. Sci. 2025, 26(18), 9190; https://doi.org/10.3390/ijms26189190 - 20 Sep 2025
Viewed by 982
Abstract
End-stage kidney disease is preferably treated by kidney transplantation. The function of the allograft often determines kidney-controlled processes and requires long-term monitoring. Kidneys are organs with a very high metabolic rate, and, thus, a metabolomics approach is suitable to observe systemic metabolic changes [...] Read more.
End-stage kidney disease is preferably treated by kidney transplantation. The function of the allograft often determines kidney-controlled processes and requires long-term monitoring. Kidneys are organs with a very high metabolic rate, and, thus, a metabolomics approach is suitable to observe systemic metabolic changes that are related to graft adaptation. To understand these ongoing changes in post-transplant pediatric patients, we applied a targeted liquid chromatography/tandem mass spectrometry-based metabolomics approach. Time-dependent changes of 140 metabolites in plasma samples prospectively collected from 23 pediatric kidney graft recipients receiving tacrolimus-based immunosuppression were monitored over the first 4 years after transplantation and compared to levels prior to transplantation. Furthermore, by comparing the pre-transplant metabolite levels to those measured in healthy children, we were able to obtain insights into the pathways associated with kidney failure. Arginine biosynthesis, alanine, aspartate, glutamine, and glutamate metabolism, taurine and tryptophan metabolism were the most affected pathways that separate the pediatric patients with and without kidney failure. Accumulation of uremic toxins such as various tryptophan/kynurenine and tryptophan/indole metabolism pathway intermediates, and betaine and methionine cycle metabolites was evident in patients with restricted kidney function. Furthermore, reduced nicotinamide production, insufficient hydroxylation of phenylalanine to tyrosine, lowered cysteine, arginine, glutamine, taurine, and overall amino acid utilization, as well as diminished levels of protective antioxidants such as glutathione and vitamins B6 and C, were all the result of progressive kidney failure leading to transplantation. Importantly, following kidney transplantation and recovery of kidney function, the levels of most of the previously described metabolites normalized toward the levels observed in healthy participants. The here identified metabolic patterns could be used as markers to monitor the progression of pediatric chronic kidney disease patients towards kidney failure, and assuming their direct association with kidney function, they could serve as markers of successful graft adaptation. Full article
(This article belongs to the Special Issue Research Progress of Metabolomics in Health and Disease)
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18 pages, 6558 KB  
Article
Integrated Omics Reveal Dendrobium nobile Lindl.’s Anti-Diabetic Mechanisms via Arginine/Proline and Glycerophospholipid Pathways
by Zhibo Wang, Xian Wang, Sifan Guo, Ying Cai, Dandan Xie, Yujuan Wang, Aihua Zhang, Jun Dai and Shi Qiu
Pharmaceuticals 2025, 18(7), 1061; https://doi.org/10.3390/ph18071061 - 18 Jul 2025
Cited by 2 | Viewed by 1136
Abstract
Background/Objectives: Dendrobium nobile Lindl. (DNL), a traditional dietary supplement, exhibits therapeutic potential for type 2 diabetes mellitus (T2DM), yet its mechanisms remain unclear. Methods: T2DM was induced in db/db mice. DNL (10 g/kg/d) or metformin (65 mg/kg/d) was administered [...] Read more.
Background/Objectives: Dendrobium nobile Lindl. (DNL), a traditional dietary supplement, exhibits therapeutic potential for type 2 diabetes mellitus (T2DM), yet its mechanisms remain unclear. Methods: T2DM was induced in db/db mice. DNL (10 g/kg/d) or metformin (65 mg/kg/d) was administered for 4 weeks. This study integrated pharmacodynamic evaluation and multi-omics to elucidate DNL’s anti-diabetic effects in db/db mice. Results: DNL intervention significantly ameliorated T2DM phenotypes, reducing hyperglycemia, insulin resistance, and renal dysfunction. Metabolomics analysis identified 39 differential metabolites (19 upregulated, 20 downregulated) linked to citrate cycle, oxidative phosphorylation, and glycerophospholipid metabolism, while proteomics revealed 113 differentially expressed proteins, with multi-omics integration highlighting DNL’s modulation of three proteins (Ckm, Ache, Selenbp1) and four metabolites (4-guanidinobutanoic acid, phosphorylcholine, homocysteine, succinic acid) across arginine/proline metabolism, glycerophospholipid metabolism, and sulfur metabolism. Pathway analysis demonstrated DNL’s restoration of dysregulated processes, including inflammation suppression via NF-κB and PI3K-Akt pathways, enhanced insulin sensitivity through glycerophospholipid balance, and mitigation of oxidative stress via sulfur metabolism. Key correlations between metabolites and proteins underscored DNL’s multi-target action. Conclusions: These findings systematically decode therapeutic mechanisms of Dendrobium nobile Lindl., emphasizing its role in rectifying metabolic disorders and inflammatory signaling, thereby providing a molecular basis for its clinical application in T2DM management. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 2630 KB  
Article
Nitrogen Metabolism in Two Flor Yeast Strains at Mid-Second Bottle Fermentation in Sparkling Wine Production
by Juan Carlos García-García, Miguel E. G-García, Juan Carbonero-Pacheco, Inés M. Santos-Dueñas, Juan Carlos Mauricio, María Trinidad Alcalá-Jiménez, Juan Moreno and Teresa García-Martínez
Appl. Sci. 2025, 15(10), 5579; https://doi.org/10.3390/app15105579 - 16 May 2025
Cited by 1 | Viewed by 1212
Abstract
This study investigates nitrogen metabolism during the middle of the second fermentation in stopped bottles of sparkling wine, focusing on two flor Saccharomyces cerevisiae yeast strains (G1 and N62) isolated from the velum of biologically aged wine. Nitrogen compounds, including amino acids, biogenic [...] Read more.
This study investigates nitrogen metabolism during the middle of the second fermentation in stopped bottles of sparkling wine, focusing on two flor Saccharomyces cerevisiae yeast strains (G1 and N62) isolated from the velum of biologically aged wine. Nitrogen compounds, including amino acids, biogenic amines, and ammonium chloride, were quantified, revealing strain-specific differences in nitrogen utilization and production. Proteomic analysis identified 1053 proteins, with 127 showing significant differences between strains. Strain G1 demonstrated enhanced cell wall remodeling and prioritized nitrogen conservation via arginine and lysine biosynthesis, while strain N62 exhibited increased translational activity and alternative carbon utilization pathways. Notably, strain N62 produced higher concentrations of biogenic amines (putrescine and tyramine), likely due to its greater decarboxylation capacity. Principal Component Analysis (PCA) highlighted clear differentiation in the nitrogen compound profiles across the base wine and wines inoculated with the two strains. The proteome of strain N62 showed increased mitochondrial activity and TCA cycle involvement, facilitating faster fermentation (27 days vs. 52 days for G1), growth (46 × 106 cells/mL vs. 21 × 106 cells/mL for G1) and cell viability (4 × 106 cells/mL vs. 0.7 × 106 cells/mL for G1). These findings suggest that yeast strain selection significantly influences nitrogen metabolism and potentially aroma profiles and and fermentation dynamics in sparkling wine production. Understanding these metabolic adaptations provides valuable insights for optimizing yeast performance to enhance wine quality and preserve regional characteristics. Full article
(This article belongs to the Special Issue Wine Technology and Sensory Analysis)
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24 pages, 3890 KB  
Article
Dietary Insulinogenic Amino Acid Restriction Improves Glucose Metabolism in a Neonatal Piglet Model
by Matthew W. Gorton, Parniyan Goodarzi, Xia Lei, Michael Anderson, Mohammad Habibi, Nedra Wilson and Adel Pezeshki
Nutrients 2025, 17(10), 1675; https://doi.org/10.3390/nu17101675 - 15 May 2025
Viewed by 1769
Abstract
Background: Dietary consumption of insulinogenic amino acids (IAA) is known to contribute to the development of insulin resistance. It remains to be studied whether dietary IAA restriction improves glucose metabolism and insulin sensitivity and whether this improvement is related to alterations in glucose [...] Read more.
Background: Dietary consumption of insulinogenic amino acids (IAA) is known to contribute to the development of insulin resistance. It remains to be studied whether dietary IAA restriction improves glucose metabolism and insulin sensitivity and whether this improvement is related to alterations in glucose metabolism in peripheral tissues. The objective of this study was to examine the effect of IAA restriction on glucose metabolism in a piglet model. Methods: Following the acclimation period, thirty-two seven-day-old male piglets were randomly assigned into one of three groups for three weeks as follows (n = 10–11/group): (1) NR (control): basal diet without IAA restriction; (2) R50: basal diet with IAA restricted by 50%; (3) R75: basal diet with IAA restricted by 75%. IAA were alanine (Ala), arginine (Arg), isoleucine (Ile), leucine (Leu), lysine (Lys), threonine (Thr), phenylalanine (Phe), and valine (Val) as suggested by previous studies. Thermal images, body weight, and growth parameters were recorded weekly, oral glucose tolerance tests were performed on week 2 of the study, and blood and tissue samples were collected on week 3 after a meal test. Results: R75 improved glucose tolerance and, together with R50, reduced blood insulin concentration and homeostatic model assessment for insulin resistance (HOMA-IR) value, which is suggestive of improved insulin sensitivity following IAA restriction. R75 increased thermal radiation and decreased adipocyte number in white adipose tissue (WAT). R75 had a greater transcript of glucose transporter 1 (GLUT1), phosphofructokinase, liver type (PFKL), and pyruvate kinase, liver, and RBC (PKLR) in the liver and glucokinase (GCK) in WAT indicating a higher uptake of glucose in the liver and greater glycolysis in both liver and WAT. R75 increased the mRNA abundance of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT1) in skeletal muscle suggestive of enhanced insulin signaling. Further, R75 had a higher mRNA of fibroblast growth factor 21 (FGF-21) in both the liver and hypothalamus and its upstream molecules such as activating transcription factor 4 (ATF4) and inhibin subunit beta E (INHBE) which may contribute to increased energy expenditure and improved glucose tolerance during IAA restriction. Conclusions: IAA restriction improves glucose tolerance and insulin sensitivity in piglets while not reducing body weight, likely through improved hepatic glycolysis and insulin signaling in skeletal muscle, and induced FGF-21 signaling in both the liver and hypothalamus. Full article
(This article belongs to the Section Proteins and Amino Acids)
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24 pages, 3715 KB  
Article
Placental Protein Citrullination Signatures Are Modified in Early- and Late-Onset Fetal Growth Restriction
by Owen R. Vaughan, Kasia Maksym, Sara Hillman, Rebecca N. Spencer, Mariya Hristova, Anna L. David and Sigrun Lange
Int. J. Mol. Sci. 2025, 26(9), 4247; https://doi.org/10.3390/ijms26094247 - 29 Apr 2025
Cited by 2 | Viewed by 1728
Abstract
Fetal growth restriction (FGR) is an obstetric condition most frequently caused by placental dysfunction. It is a major cause of perinatal morbidity with limited treatment options, so identifying the underpinning mechanisms is important. Peptidylarginine deiminases (PADs) are calcium-activated enzymes that mediate post-translational citrullination [...] Read more.
Fetal growth restriction (FGR) is an obstetric condition most frequently caused by placental dysfunction. It is a major cause of perinatal morbidity with limited treatment options, so identifying the underpinning mechanisms is important. Peptidylarginine deiminases (PADs) are calcium-activated enzymes that mediate post-translational citrullination (deimination) of proteins, through conversion of arginine to citrulline. Protein citrullination leads to irreversible changes in protein structure and function and is implicated in many pathobiological processes. Whether placental protein citrullination occurs in FGR is poorly understood. We assessed protein citrullination and PAD isozyme abundance (PAD1, 2, 3, 4 and 6) in human placental samples from pregnancies complicated by early- and late-onset FGR, compared to appropriate-for-gestational-age (AGA) controls. Proteomic mass spectrometry demonstrated that the placental citrullinome profile changed in both early- and late-onset FGR, with 112 and 345 uniquely citrullinated proteins identified in early- and late-onset samples, respectively. Forty-four proteins were citrullinated only in control AGA placentas. The proteins that were uniquely citrullinated in FGR placentas were enriched for gene ontology (GO) terms related to neurological, developmental, immune and metabolic pathways. A greater number of GO and human phenotype pathways were functionally enriched for citrullinated proteins in late- compared with early-onset FGR. Correspondingly, late-onset but not early-onset FGR was associated with significantly increased placental abundance of PAD2 and citrullinated histone H3, determined by Western blotting. PAD3 was downregulated in early-onset FGR while abundance of PAD 1, 4 and 6 was less altered in FGR. Our findings show that placental protein citrullination is altered in FGR placentas, potentially contributing to the pathobiology of placental dysfunction. Full article
(This article belongs to the Section Molecular Biology)
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17 pages, 2138 KB  
Article
Fucoidan Alleviates Porcine Epidemic Diarrhea Virus-Induced Intestinal Damage in Piglets by Enhancing Antioxidant Capacity and Modulating Arginine Metabolism
by Qian Zhang, Maojing Wang, Zhonghua Li, Di Zhao, Yongqing Hou and Tao Wu
Animals 2025, 15(7), 1001; https://doi.org/10.3390/ani15071001 - 30 Mar 2025
Cited by 1 | Viewed by 1096
Abstract
Porcine epidemic diarrhea virus (PEDV) causes severe intestinal damage, posing significant threats to the swine industry. Fucoidan (FUC), a biologically active compound, exhibits antiviral activity against multiple viruses. This study aimed to investigate the protective effects of FUC on PEDV-induced intestinal injury in [...] Read more.
Porcine epidemic diarrhea virus (PEDV) causes severe intestinal damage, posing significant threats to the swine industry. Fucoidan (FUC), a biologically active compound, exhibits antiviral activity against multiple viruses. This study aimed to investigate the protective effects of FUC on PEDV-induced intestinal injury in piglets and explore its underlying mechanisms. A total of 28 healthy crossbred piglets were randomly allocated into four experimental groups using a 2 × 2 factorial design: (1) a control group, (2) an FUC group, (3) a PEDV group, and (4) an FUC+PEDV group. From day 4 to day 10, the piglets in the FUC and FUC+PEDV groups were orally administered fucoidan at a dosage of 20 mg/kg body weight (BW) each day. On day 8, the piglets in the PEDV and FUC+PEDV groups were orally administered PEDV at a dose of 3 × 105.5 TCID50. The results show that FUC supplementation significantly decreased plasma DAO activity (p < 0.05) and increased the villus height, villus area, as well as the villus height/crypt depth (p < 0.05) in the intestine when compared to the PEDV-infected piglets. This indicates that FUC could alleviate the disruption of intestinal morphology and function caused by PEDV infection. FUC enhanced the antioxidant capacity of the piglets by increasing SOD and GSH-Px activity. Transcriptional profiling combined with quantitative analysis revealed that FUC regulates immune responses, substance transport, and arginine metabolism. Notably, FUC downregulated arginase 1 expression, which may redirect arginine toward nitric oxide synthesis, thereby establishing an antiviral state in the host. These findings highlight the potential application of FUC as a natural agent for mitigating PEDV-induced intestinal damage and improving gut health. Additionally, monitoring the health status of piglets is necessary when FUC is applied in practical applications. Full article
(This article belongs to the Special Issue Gastrointestinal Tract Health in Pigs—2nd Edition)
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15 pages, 4661 KB  
Article
Analysis of Metabolomic Reprogramming Induced by Infection with Kaposi’s Sarcoma-Associated Herpesvirus Using Untargeted Metabolomic Profiling
by Abdulkarim Alfaez, Michael W. Christopher, Timothy J. Garrett and Bernadett Papp
Int. J. Mol. Sci. 2025, 26(7), 3109; https://doi.org/10.3390/ijms26073109 - 28 Mar 2025
Viewed by 1478
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus. There are no vaccines or antiviral therapies for KSHV. Identifying the cellular metabolic pathways that KSHV manipulates can broaden the knowledge of how these pathways contribute to sustaining lytic infection, which can be [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus. There are no vaccines or antiviral therapies for KSHV. Identifying the cellular metabolic pathways that KSHV manipulates can broaden the knowledge of how these pathways contribute to sustaining lytic infection, which can be targeted in future therapies to prevent viral spread. In this study, we performed an untargeted metabolomic analysis of KSHV infected telomerase-immortalized gingival keratinocytes (TIGK) cells at 4 h post-infection compared to mock-infected cells. We found that the metabolomic landscape of KSHV-infected TIGK differed from that of the mock. Specifically, a total of 804 differential metabolic features were detected in the two groups, with 741 metabolites that were significantly upregulated, and 63 that were significantly downregulated in KSHV-infected TIGK cells. The differential metabolites included ornithine, arginine, putrescine, dimethylarginine, orotate, glutamate, and glutamine, and were associated with pathways, such as the urea cycle, polyamine synthesis, dimethylarginine synthesis, and de novo pyrimidine synthesis. Overall, our untargeted metabolomics analysis revealed that KSHV infection results in marked rapid alterations in the metabolic profile of the oral epithelial cells. We envision that a subset of these rapid metabolic changes might result in altered cellular functions that can promote viral lytic replication and transmission in the oral cavity. Full article
(This article belongs to the Section Molecular Microbiology)
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28 pages, 6044 KB  
Article
Untargeted Metabolomics and Chemometrics Elucidate Dynamic Plasma Profile Changes Induced by Cocoa Shell in Female Rats
by David Ramiro-Cortijo, Miguel Rebollo-Hernanz, Pilar Rodríguez-Rodríguez, Santiago Ruvira, Silvia M. Arribas and Maria A. Martin-Cabrejas
Nutrients 2025, 17(5), 885; https://doi.org/10.3390/nu17050885 - 28 Feb 2025
Cited by 1 | Viewed by 2027
Abstract
Objective: This study aimed to explore the effects of cocoa shell extract (CSE) supplementation on the plasma metabolome of female rats. Methods: Female rats were supplemented with CSE (250 mg/kg/day) over seven days, and plasma samples were collected at baseline, day 4, and [...] Read more.
Objective: This study aimed to explore the effects of cocoa shell extract (CSE) supplementation on the plasma metabolome of female rats. Methods: Female rats were supplemented with CSE (250 mg/kg/day) over seven days, and plasma samples were collected at baseline, day 4, and day 7 for untargeted metabolomic profiling using LC-ESI-QTOF. Results: A total of 244 plasma metabolites were identified, while 180 were detected in the CSE. Among these, only 21 compounds were consistently detected in both the CSE and the plasma at baseline and day 7. Notably, just three compounds, caffeine, theobromine, and N-isovaleroylglycine, were bioavailable, detected only in plasma after supplementation on day 7, confirming their absorption and systemic distribution. Pathways related to caffeine metabolism, glycerophospholipid biosynthesis, nicotinate, and nicotinamide metabolism were significantly upregulated, indicating enhanced lipid metabolism and energy homeostasis. Conversely, reductions were observed in pathways involving tryptophan, glutathione, arginine, and proline, pointing to shifts in amino acid metabolism and antioxidant defense mechanisms. Network analysis revealed significant changes in the cholinergic synapse, retrograde endocannabinoid signaling, and glutamatergic synapse pathways, which are crucial for cellular communication and neurotransmission. Conclusions: The observed metabolic reconfiguration demonstrates CSE’s rapid modulation of the metabolome, highlighting the bioavailability of its key components. These findings suggest potential mechanisms for CSE as a functional food ingredient with health-promoting effects, potentially supporting cognitive function and metabolic health through energy metabolism, neurotransmission, and lipid signaling pathways. Full article
(This article belongs to the Special Issue Nutritional Value and Health Benefits of Dietary Bioactive Compounds)
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13 pages, 1973 KB  
Article
Energy Metabolism-Related Arginine Kinase Gene Expression in Mud Crab (Macrophthalmus japonicus) Following Irgarol Exposure
by Won-Seok Kim, Kiyun Park, Jiwon Park and Ihn-Sil Kwak
Appl. Sci. 2025, 15(5), 2489; https://doi.org/10.3390/app15052489 - 25 Feb 2025
Viewed by 1378
Abstract
Antifouling paints are essentially used to prevent biological fouling of marine vessels and structures, but their release into the environment has resulted in various marine ecosystem problems. Irgarol, a representative antifouling paint substance, is well known for its direct effects on plankton productivity, [...] Read more.
Antifouling paints are essentially used to prevent biological fouling of marine vessels and structures, but their release into the environment has resulted in various marine ecosystem problems. Irgarol, a representative antifouling paint substance, is well known for its direct effects on plankton productivity, but studies on its harmful effects on estuarine organisms are limited. This study aimed to determine the impact of irgarol exposure at the transcriptional level in Macrophthalmus japonicus, a highly dominant crab species in estuaries. To this end, we characterized the M. japonicus arginine kinase (AK) gene, which plays a role in energy metabolism in invertebrates, and examined its expression levels in response to irgarol exposure. Consequently, AK was identified as a highly prevalent enzyme in invertebrate species, including crustaceans and insects. Following irgarol exposure, the gills of M. japonicus exhibited relatively elevated AK gene expression compared to the control group at 4 and 7 days of exposure. In addition, elevated AK gene expression was observed in the hepatopancreas. Notably, the relatively low irgarol exposure concentrations of 1 and 10 μg L−1 demonstrated comparatively higher AK gene expression in the hepatopancreas than the relatively high irgarol concentration of 30 μg L−1. The results of this study imply that irgarol exposure may disrupt the equilibrium of energy metabolic processes regulated by AK gene expression in the M. japonicus crab. Moreover, the sustained environmental accumulation of irgarol indicates that it may serve as a significant disturbance factor within estuarine ecosystems. Full article
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17 pages, 6555 KB  
Article
Exploring the Mechanism of Clostridium autoethanogenum Protein for Broiler Growth Based on Gut Microbiota and Serum Metabolomics
by Chunqiao Shan, Yan Liu, Sisi Liu, Chuang Li, Chaoxin Ma, Hongmin Yu, Juan Li, Guotuo Jiang and Jing Tian
Biology 2025, 14(1), 29; https://doi.org/10.3390/biology14010029 - 2 Jan 2025
Cited by 2 | Viewed by 1864
Abstract
Intestinal health is vital for poultry production, and protein plays a key role in intestinal nutrition. The present study used 16S rRNA gene sequencing and serum metabolomics to investigate the effect of CAP on the cecal microflora structure and serum metabolites in 42-day-old [...] Read more.
Intestinal health is vital for poultry production, and protein plays a key role in intestinal nutrition. The present study used 16S rRNA gene sequencing and serum metabolomics to investigate the effect of CAP on the cecal microflora structure and serum metabolites in 42-day-old broiler chickens. A total of 480 one-day-old Arbor Acres broiler chickens were randomly divided into four treatments with twelve replicates comprising 10 chickens each, evenly divided by sex. The four groups were basal diet group (CAP0), treatment group 1 (CAP2), treatment group 2 (CAP3), and treatment group 3 (CAP4). The broilers in the CAP0 group were fed a basal diet (without CAP), while those in the CAP2, CAP3, and CAP4 groups received diets containing 2%, 3%, and 4% CAP, respectively. Growth performance results showed that dietary CAP supplementation significantly ameliorated the feed conversion rate (FCR) of broilers at 42 days in the CAP3 and CAP4 groups (p < 0.05). Microbial results revealed that CAP did not alter the dominant microorganisms in the cecum at the phylum, family, and genus levels. LEfSe analysis showed significantly higher relative abundances of p_Desulfobacterota, f_Desulfovibrionaceae, and g_Ruminococcus in the CAP3 group compared to the CAP0 and CAP4 groups. Metabolomic analyses indicated that the effect of incorporating CAP into the diet on serum metabolites primarily focused on organic acids and their derivatives, small peptides, amino acid derivatives, and oxidized lipids. The addition of 3% or 4% CAP to the diet can enhance metabolic pathways such as the citrate cycle (TCA cycle) and arginine and proline metabolism. In summary, incorporating CAP into the diet can increase the relative abundance of beneficial bacteria in the cecum and improve the feed conversion efficiency of broilers by enhancing amino acid and energy metabolism. Full article
(This article belongs to the Special Issue Metabolic Interactions between the Gut Microbiome and Host)
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