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Orphan solute carrier (SLC) represents a group of membrane transporters whose exact functions and substrate specificities are not known. Elucidating the function and regulation of orphan SLC transporters is not only crucial for advancing our knowledge of cellular and molecular biology but can potentially lead to the development of new therapeutic strategies. Here, we provide evidence for the biological function of a ubiquitous orphan lysosomal SLC, the Major Facilitator Superfamily Domain-containing Protein 1 (MFSD1), which has remained phylogenetically unassigned. Targeted metabolomics revealed that dipeptides containing either lysine or arginine residues accumulate in lysosomes of cells lacking MFSD1. Whole-cell patch-clamp electrophysiological recordings of HEK293-cells expressing MFSD1 on the cell surface displayed transport affinities for positively charged dipeptides in the lower mM range, while dipeptides that carry a negative net charge were not transported. This was also true for single amino acids and tripeptides, which MFSD1 failed to transport. Our results identify MFSD1 as a highly selective lysosomal lysine/arginine/histidine-containing dipeptide exporter, which functions as a uniporter.

This manuscript presents a multiomics investigation into the metabolic and proteomic responses of wheat to molybdenum (Mo)- and copper (Cu)-based engineered nanomaterials (ENMs) exposure via root and leaf application methods. Wheat plants underwent a four-week growth period with a 16 h photoperiod (light intensity set at 150 μmol·m-2·s-1), at 22 °C and 60% humidity. Six distinct treatments were applied, including control conditions alongside exposure to Mo- and Cu-based ENMs through both root and leaf routes. The exposure dosage amounted to 6.25 mg of the respective element per plant. An additional treatment with a lower dose (0.6 mg Mo/plant) of Mo ENM exclusively through the root system was introduced upon the detection of phytotoxicity. Utilizing LC-MS/MS analysis, 82 metabolites across various classes and 24 proteins were assessed in different plant tissues (roots, stems, leaves) under diverse treatments. The investigation identified 58 responsive metabolites and 19 responsive proteins for Cu treatments, 71 responsive metabolites, and 24 responsive proteins for Mo treatments, mostly through leaf exposure for Cu and root exposure for Mo. Distinct tissue-specific preferences for metabolite accumulation were revealed, highlighting the prevalence of organic acids and fatty acids in stem or root tissues, while sugars and amino acids were abundant in leaves, mirroring their roles in energy storage and photosynthesis. Joint-pathway analysis was conducted and unveiled 23 perturbed pathways across treatments. Among these, Mo exposure via roots impacted all identified pathways, whereas exposure via leaf affected 15 pathways, underscoring the reliance on exposure route of metabolic and proteomic responses. The coordinated response observed in protein and metabolite concentrations, particularly in amino acids, highlighted a dynamic and interconnected proteomic-to-metabolic-to-proteomic relationship. Furthermore, the contrasting expression patterns observed in glutamate dehydrogenase (upregulation at 1.38 ≤ FC ≤ 1.63 with high Mo dose, and downregulation at 0.13 ≤ FC ≤ 0.54 with low Mo dose) and its consequential impact on glutamine expression (7.67 ≤ FC ≤ 39.60 with high Mo dose and 1.50 ≤ FC ≤ 1.95 with low Mo dose) following Mo root exposure highlighted dose-dependent regulatory trends influencing proteins and metabolites. These findings offer a multidimensional understanding of plant responses to ENMs exposure, guiding agricultural practices and environmental safety protocols while advancing knowledge on nanomaterial impacts on plant biology.

Introduction: Biliary atresia (BA) is a rare progressive neonatal cholangiopathy with unknown pathophysiology and time of onset. Newborn Screening (NBS) in Germany is routinely performed in the first days of life to identify rare congenital diseases utilizing dried blood spot (DBS) card analyses. Infants with biliary atresia (BA) are known to have altered amino acid profiles (AAP) at the time point of diagnosis, but it is unclear whether these alterations are present at the time point of NBS. Objectives: We aimed to analyze amino acid profiles in NBS–DBS of infants with Biliary Atresia. Methods: Original NBS-DBS cards of 41 infants who were later on diagnosed with BA were retrospectively obtained. NBS–DBS cards from healthy newborns (n = 40) served as controls. In some BA infants (n = 14) a second DBS card was obtained at time of Kasai surgery. AAP in DBS cards were analyzed by targeted metabolomics. Results: DBS metabolomics in the NBS of at that time point seemingly healthy infants later diagnosed with BA revealed significantly higher levels of Methionine (14.6 ± 8.6 μmol/l), Histidine (23.5 ± 50.3 μmol/l), Threonine (123.9 ± 72.8 μmol/l) and Arginine (14.1 ± 11.8 μmol/l) compared to healthy controls (Met: 8.1 ± 2.6 μmol/l, His: 18.6 ± 10.1 μmol/l, Thr: 98.1 ± 34.3 μmol/l, Arg: 9.3 ± 6.6 μmol/l). Methionine, Arginine and Histidine showed a further increase at time point of Kasai procedure. No correlation between amino acid levels and clinical course was observed. Conclusion: Our data demonstrate that BA patients exhibit an altered AAP within 72 h after birth, long before the infants become symptomatic. This supports the theory of a prenatal onset of the disease and, thus, the possibility of developing a sensitive and specific NBS. Methionine might be particularly relevant due to its involvement in glutathione metabolism. Further investigation of AAP in BA may help in understanding the underlying pathophysiology. [ABSTRACT FROM AUTHOR]

The fight against coronavirus disease 2019 (COVID-19) continues. Since the pandemic's onset, several biomarkers have been proposed to assess the diagnosis and prognosis of this disease. This research aimed to identify potential disease severity biomarkers in serum samples of patients with COVID-19 during the disease course. Data were collected using untargeted and targeted mass spectrometry methods. The results were interpreted by performing univariate and multivariate analyses. Important metabolite classes were identified by qualitative untargeted metabolomics in 15 serum samples from survivors of COVID-19. Quantitative targeted metabolomics on a larger patient cohort including 15 non-survivors confirmed serum 3-sulfate bile acids (i.e. GLCA-3S) were significantly increased in non-survivors compared to survivors during the early disease stage (p-value < 0.0001). Notably, it was associated with a higher risk of mortality (odds ratio of 26). A principal component analysis showed the ability to discriminate between survivors and non-survivors using the BA concentrations. Furthermore, increased BA-S is highly correlated with known parameters altered in severe clinical conditions. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, immune-mediated skin condition with significant metabolic complications. Although lipid metabolism is linked to its pathogenesis, reliable biomarkers and the impact of modifiable factors remain underexplored. The aim of the present study was to identify potential biomarkers, study the affected metabolic networks, and assess the role of dietary and lifestyle factors in psoriasis. Plasma samples from 56 patients with psoriasis and 49 healthy controls were analyzed, as part of the Metabolic Biomarkers in Hashimoto's Thyroiditis and Psoriasis (METHAP) clinical trial. Using Gas Chromatography-Mass Spectrometry 23 fatty acids and their ratios were quantified, revealing significant changes in psoriasis. Specifically, lower levels of α-linoleic acid (C18:3n3), linoleic acid (C18:2n6), and gamma-linolenic acid (C18:3n6) were observed along with higher levels of eicosatrienoic acid (C20:3n3), eicosapentaenoic acid (C20:5n3), and erucic acid (C22:1n9). Total polyunsaturated fatty acids (PUFA) were significantly decreased, and the ratio of saturated to total fatty acids (SFA/Total) was increased in psoriasis (p-values < 0.0001). Linear regression identified α-linoleic acid, linoleic acid, eicosatrienoic acid, and eicosapentaenoic acid as potential biomarkers for psoriasis, adjusting for demographic, dietary, and lifestyle confounders. Network analysis revealed key contributors in the metabolic reprogramming of psoriasis. These findings highlight the association between psoriasis and fatty acid biomarkers of inflammation, insulin resistance and micronutrients deficiency, suggesting their potency in disease management. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is among the most commonly diagnosed cancers. Besides mammography, breast ultrasonography and the routinely monitored protein markers, the variations of small molecular metabolites in blood may be of great diagnostic value. This study aimed to quantify specific metabolite markers with potential application in BC detection. The study enrolled 50 participants, 25 BC patients and 25 healthy controls (CTRL). Dried blood spots (DBS) were utilized as biological media and were quantified via a simplified liquid chromatography tandem mass spectrometry (LC-MS/MS) method, used in expanded newborn screening. The targeted metabolomic analysis included 12 amino acids and 32 acylcarnitines. Statistical analysis revealed a significant variation of metabolic profiles between BC patients and CTRL. Among the 44 metabolites, 18 acylcarnitines and 10 amino acids remained significant after Bonferroni correction, showing increase or decrease and enabled classification of BC patients and CTRL. The well-established LC-MS/MS protocol could provide results within few minutes. Therefore, the combination of an easy-to-handle material-DBS and LC-MS/MS protocol could facilitate BC screening/diagnosis and in the next step applied to other cancer patients, as well. [ABSTRACT FROM AUTHOR]

Early diagnosis of inborn errors of metabolism (IEM) is crucial to ensure early detection of conditions which are treatable. This study reports on targeted metabolomic procedures for the diagnosis of IEM of amino acids, acylcarnitines, creatine/guanidinoacetate, purines/pyrimidines and oligosaccharides, and describes its validation through external quality assessment schemes (EQA). Analysis was performed on a Waters ACQUITY UPLC H-class system coupled to a Waters Xevo triple-quadrupole (TQD) mass spectrometer, operating in both positive and negative electrospray ionization mode. Chromatographic separation was performed on a CORTECS C18 column (2.1 × 150, 1.6 µm). Data were collected by multiple reaction monitoring. The internal and EQA results were generally adequate, with a few exceptions. We calculated the relative measurement error (RME) and only a few metabolites displayed a RME higher than 30 % (asparagine and some acylcarnitine species). For oligosaccharides, semi-quantitative analysis of an educational panel clearly identified the 8 different diseases included. Overall, we have validated our analytical system through an external quality control assessment. This validation will contribute to harmonization between laboratories, thus improving identification and management of patients with IEM. [ABSTRACT FROM AUTHOR]

Background: Over the years, it was noticed that patients with diabetes have reached an alarming number worldwide. Diabetes presents many complications, including diabetic kidney disease (DKD), which can be considered the leading cause of end-stage renal disease. Current biomarkers such as serum creatinine and albuminuria have limitations for early detection of DKD. Methods: In our study, we used UHPLC-QTOF-ESI+-MS techniques to quantify previously analyzed metabolites. Based on one-way ANOVA and Fisher's LSD, untargeted analysis allowed the discrimination of six metabolites between subgroups P1 versus P2 and P3: tryptophan, kynurenic acid, taurine, l-acetylcarnitine, glycine, and tiglylglycine. Results: Our results showed several metabolites that exhibited significant differences among the patient groups and can be considered putative biomarkers in early DKD, including glycine and kynurenic acid in serum (p < 0.001) and tryptophan and tiglylglycine (p < 0.001) in urine. Conclusions: Although we identified metabolites as potential biomarkers in the present study, additional studies are needed to validate these results. [ABSTRACT FROM AUTHOR]

Ischemic stroke is one of the leading causes of death and permanent disability in the world. Rapid diagnosis and intervention are crucial for reducing its consequences on individuals and societies. Therefore, identifying reliable biomarkers for early detection, prognostics, and therapy can facilitate the early prediction and prevention of stroke. Metabolomics has been shown as a promising tool for biomarker discovery since many post-ischemic metabolites can be found in the plasma or serum of the patient. In this research, we performed a comparative targeted metabolomic analysis of stroke thrombi, stroke patient serums, and healthy control serums in order to determine the alteration in the patients' metabolomes, which might serve as biomarkers for early prediction or stroke prevention. The most statistically altered metabolites characterized in the patient serums compared with the control serums were glutamate and serotonin, followed by phospholipids and triacylglycerols. In stroke thrombi compared with the patients' serums, the most significantly altered metabolites were classified as lipids, with choline-containing phospholipids and sphingomyelins having the highest discriminatory score. The results of this preliminary study could help in understanding the roles of different metabolic changes that occur during thrombosis and cerebral ischemia and possibly suggest new metabolic biomarkers for ischemic stroke. [ABSTRACT FROM AUTHOR]

Infant botulism in a 4-month-old boy in China who continued to excrete toxins for over a month despite antitoxin therapy was further treated with fecal microbiota transplantation. After treatment, we noted increased gut microbial diversity and altered fecal metabolites, which may help reduce intestinal pH and enhance anti-inflammatory capabilities.

AbstractChinese herbal formula (CHF) has the potential to improve the performance of aged laying hens through integrated regulation of various physiological functions. The present study aimed to investigate the effects of dietary CHF supplementation on the yolk fatty acid profile in aged laying hens. A total of 144 healthy 307-day-old Xinyang black-feather laying hens were randomly allocated into two groups: a control group (CON, fed a basal diet) and a CHF group (fed a basal diet supplemented with 1% CHF; contained 0.30% Leonurus japonicus Houtt., 0.20% Salvia miltiorrhiza Bge., 0.25% Ligustrum lucidum Ait., and 0.25% Taraxacum mongolicum Hand.-Mazz. for 120 days). The fatty acid concentrations in egg yolks were analyzed using a targeted metabolomics technology at days 60 and 120 of the trial. The results showed that dietary CHF supplementation increased (p

Abstract The Balanophorae are not only traditional Chinese herbal medicines but also functional foods with diverse sources. This study aimed to distinguish pharmacognostic characteristics and secondary metabolites among different species of Balanophorae. Eight species of Balanophorae herbs were harvested, including 21 batches with 209 samples. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to analyze secondary metabolites of Balanophorae from 21 sources. Targeted metabolomic analysis was performed to compare differences among the groups. Rhopalocnemis phalloide and B. indica can be identified by their pharmacognostic characteristics. Then, 41 secondary metabolites were identified or characterized in the mixed extracts of the 209 samples, mainly phenolic acids, flavonoids, and their derivatives. The distribution of these secondary metabolites revealed apparent differences among different species. In addition, targeted metabolomic analysis suggested that the secondary metabolite profiles of seven species of Balanophorae showed noticeable differences, and differences were also observed among different growing regions. Finally, five important metabolic markers were screened to successfully distinguish B. laxiflora, B. harlandii, and B. polyandra, including three phenolic acids and two flavonoids. This is the first study to systematically compare both the morphology and secondary metabolites among different sources of Balanophorae, which could provide effective information for identifying diverse species.

Abstract Background Oxidative stress is currently one of the main threats to animal health, and flavonoids in forage have good antioxidant activity. However, the impact of fermentation on flavonoids and their antioxidant activity in forage is still unclear. This study aims to investigate the effect of lactic acid bacteria inoculation on the biological transformation of flavonoids in alfalfa silage fermentation and its relationship with antioxidant activity. Results Compared with the raw materials, silage fermentation can increase the total flavonoid content of alfalfa. The addition of Pediococcus pentosaceus (CP115739.1) and Lactiplantibacillus plantarum (CP115741.1) can significantly increase the total flavonoid content in alfalfa silage (P

Introduction: The formidable survival mechanisms employed by Mycobacterium tuberculosis (Mtb), combined with the low bioavailability of anti-tubercular drugs and their associated hepatotoxicity, worsen tuberculosis management. Traditional medicinal plants offer potential solutions to these challenges. This study focuses on exploring the anti-tubercular potential of Solanum virginianum against Mycobacterium smegmatis, mc²155. Methods and results: HPTLC and UHPLC phytochemically characterized the hydro-methanolic extract of Solanum virginianum (SVE). SVE curtails the growth and viability of mc²155 under normal and in vitro stress conditions. The compromised cell wall integrity of mc²155 with SVE is depicted through scanning electron microscopy (SEM) while EtBr permeability assays and TLCbased comparative changes in lipids extraction addressed the integrity of the cell wall. Furthermore, SVE augmented the susceptibility of mc²155 towards Isoniazid (INH) through enhanced bioavailability. Adjunct treatment of SVE with INH demonstrated a markedly reduced survival of the intracellular bacilli. The study also uncovered the hepatoprotective potential of SVE in HepG2 cells. Conclusion: This research paves the way for deeper exploration into the potential of Solanum virginianum against virulent Mtb strains, emphasizing over the significance of traditional medicinal plants in tuberculosis treatment. Collectively, the findings suggest SVE as a potent candidate for independent or adjunct anti-tubercular therapy. [ABSTRACT FROM AUTHOR]

AbstractPlant metabolomics, a rapidly advancing field within plant biology, is dedicated to comprehensively exploring the intricate array of small molecules in plant systems. This entails precisely gathering comprehensive chemical data, detecting numerous metabolites, and ensuring accurate molecular identification. Nuclear magnetic resonance (NMR) spectroscopy, with its detailed chemical insights, is crucial in obtaining metabolite profiles. Its widespread application spans various research disciplines, aiding in comprehending chemical reactions, kinetics, and molecule characterization. Biotechnological advancements have further expanded NMR's utility in metabolomics, particularly in identifying disease biomarkers across diverse fields such as agriculture, medicine, and pharmacology. This review covers the stages of NMR-based metabolomics, including historical aspects and limitations, with sample preparation, data acquisition, spectral processing, analysis, and their application parts. [ABSTRACT FROM AUTHOR]

Objects: This study aims to explore the etiology of peri‐implantitis by comparing the metabolic profiles in peri‐implant crevicular fluid (PICF) from patients with healthy implants (PH) and those with peri‐implantitis (PI). Materials and Methods: Fifty‐six patients were enrolled in this cross‐sectional study. PICF samples were collected and analyzed using both non‐targeted and targeted metabolomics approaches. The relationship between metabolites and clinical indices including probing depth (PD), bleeding on probing (BOP), and marginal bone loss (MBL) was examined. Additionally, submucosal microbiota was collected and analyzed using 16S rRNA gene sequencing to elucidate the association between the metabolites and microbial communities. Results: Significant differences in metabolic profiles were observed between the PH and PI groups, with 179 distinct metabolites identified. In the PI group, specific amino acids and fatty acids were significantly elevated compared to the PH group. Organic acids including succinic acid, fructose‐6‐phosphate, and glucose‐6‐phosphate were markedly higher in the PI group, showing positive correlations with mean PD, BOP, and MBL. Metabolites that increased in the PI group positively correlated with the presence of Porphyromonas and Treponema and negatively with Streptococcus and Haemophilus. Conclusions: This study establishes a clear association between metabolic compositions and peri‐implant condition, highlighting enhanced metabolite activity in peri‐implantitis. These findings open avenues for further research into metabolic mechanisms of peri‐implantitis and their potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes mellitus, and early detection is crucial for effective management. Metabolomics profiling has emerged as a promising approach for identifying potential biomarkers associated with DR progression. This study aimed to develop a hybrid explainable artificial intelligence (XAI) model for targeted metabolomics analysis of patients with DR, utilizing a focused approach to identify specific metabolites exhibiting varying concentrations among individuals without DR (NDR), those with non-proliferative DR (NPDR), and individuals with proliferative DR (PDR) who have type 2 diabetes mellitus (T2DM). Methods: A total of 317 T2DM patients, including 143 NDR, 123 NPDR, and 51 PDR cases, were included in the study. Serum samples underwent targeted metabolomics analysis using liquid chromatography and mass spectrometry. Several machine learning models, including Support Vector Machines (SVC), Random Forest (RF), Decision Tree (DT), Logistic Regression (LR), and Multilayer Perceptrons (MLP), were implemented as solo models and in a two-stage ensemble hybrid approach. The models were trained and validated using 10-fold cross-validation. SHapley Additive exPlanations (SHAP) were employed to interpret the contributions of each feature to the model predictions. Statistical analyses were conducted using the Shapiro–Wilk test for normality, the Kruskal–Wallis H test for group differences, and the Mann–Whitney U test with Bonferroni correction for post-hoc comparisons. Results: The hybrid SVC + MLP model achieved the highest performance, with an accuracy of 89.58%, a precision of 87.18%, an F1-score of 88.20%, and an F-beta score of 87.55%. SHAP analysis revealed that glucose, glycine, and age were consistently important features across all DR classes, while creatinine and various phosphatidylcholines exhibited higher importance in the PDR class, suggesting their potential as biomarkers for severe DR. Conclusion: The hybrid XAI models, particularly the SVC + MLP ensemble, demonstrated superior performance in predicting DR progression compared to solo models. The application of SHAP facilitates the interpretation of feature importance, providing valuable insights into the metabolic and physiological markers associated with different stages of DR. These findings highlight the potential of hybrid XAI models combined with explainable techniques for early detection, targeted interventions, and personalized treatment strategies in DR management. [ABSTRACT FROM AUTHOR]

Background: Clonorchiasis remains a serious public health problem. However, the molecular mechanism underlying clonorchiasis remains largely unknown. Amino acid (AA) metabolism plays key roles in protein synthesis and energy sources, and improves immunity in pathological conditions. Therefore, this study aimed to explore the AA profiles of spleen in clonorchiasis and speculate the interaction between the host and parasite. Methods: Here targeted ultrahigh performance liquid chromatography multiple reaction monitoring mass spectrometry was applied to discover the AA profiles in spleen of rats infected with Clonorchis sinensis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (KEGG) was performed to characterize the dysregulated metabolic pathways. Results: Pathway analysis revealed that phenylalanine, tyrosine, and tryptophan biosynthesis and β-alanine metabolism were significantly altered in clonorchiasis. There were no significant correlations between 14 significant differential AAs and interleukin (IL)-1β. Although arginine, asparagine, histidine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine were positively correlated with IL-6, IL-10, tumor necrosis factor (TNF)-α as well as aspartate aminotransferase and alanine aminotransferase; β-alanine and 4-hydroxyproline were negatively correlated with IL-6, IL-10, and TNF-α. Conclusion: This study reveals the dysregulation of AA metabolism in clonorchiasis and provides a useful insight of metabolic mechanisms at the molecular level. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Our aim was to characterise the in-depth metabolic response to aerobic exercise and the impact of residual pancreatic beta cell function in type 1 diabetes. We also aimed to use the metabolome to distinguish individuals with type 1 diabetes with reduced maximal aerobic capacity in exercise defined by V ˙ O 2peak . Methods: Thirty participants with type 1 diabetes (≥3 years duration) and 30 control participants were recruited. Groups did not differ in age or sex. After quantification of peak stimulated C-peptide, participants were categorised into those with undetectable (<3 pmol/l), low (3–200 pmol/l) or high (>200 pmol/l) residual beta cell function. Maximal aerobic capacity was assessed by V ˙ O 2peak test and did not differ between control and type 1 diabetes groups. All participants completed 45 min of incline treadmill walking (60% V ˙ O 2peak ) with venous blood taken prior to exercise, immediately post exercise and after 60 min recovery. Serum was analysed using targeted metabolomics. Metabolomic data were analysed by multivariate statistics to define the metabolic phenotype of exercise in type 1 diabetes. Receiver operating characteristic (ROC) curves were used to identify circulating metabolomic markers of maximal aerobic capacity ( V ˙ O 2peak ) during exercise in health and type 1 diabetes. Results: Maximal aerobic capacity ( V ˙ O 2peak ) inversely correlated with HbA1c in the type 1 diabetes group (r2=0.17, p=0.024). Higher resting serum tricarboxylic acid cycle metabolites malic acid (fold change 1.4, p=0.001) and lactate (fold change 1.22, p=1.23×10−5) differentiated people with type 1 diabetes. Higher serum acylcarnitines (AC) (AC C14:1, F value=12.25, p=0.001345; AC C12, F value=11.055, p=0.0018) were unique to the metabolic response to exercise in people with type 1 diabetes. C-peptide status differentially affected metabolic responses in serum ACs during exercise (AC C18:1, leverage 0.066; squared prediction error 3.07). The malic acid/pyruvate ratio in rested serum was diagnostic for maximal aerobic capacity ( V ˙ O 2peak ) in people with type 1 diabetes (ROC curve AUC 0.867 [95% CI 0.716, 0.956]). Conclusions/interpretation: The serum metabolome distinguishes high and low maximal aerobic capacity and has diagnostic potential for facilitating personalised medicine approaches to manage aerobic exercise and fitness in type 1 diabetes. [ABSTRACT FROM AUTHOR]

This study aims to provide the first report on the soluble and polyphenolic profiles of "Farmacista Honorati" (FH) persimmons, which is a marketed cultivar with no existing data on its nutraceutical value. Total soluble tannins (TSTs) and major soluble (poly)phenols in FH fruits before and after post-harvest commercial treatments with carbon dioxide and ethylene were analyzed. Fruits at commercial harvest had a TST content of 1022 ± 286 mg GAL/100 g d.w. Whereas, after deastringency treatments, an 85% and 83% reduction were observed for carbon dioxide- and ethylene-treated fruits, respectively. Carbon dioxide treatment resulted in the insolubilization of tannins around comparable values in most fruit cultivars, despite the variable soluble tannin content in untreated fruit. By targeted metabolomic profiling, nineteen (poly)phenolic substances were quantified in the investigated untreated and treated fruits. Gallic acid (99 mg/100 g d.w.), (+)-catechin (1.8 mg/100 g d.w.), ellagic acid (1.2 mg/100 g d.w.), and (−)-epicatechin (1.1 mg/100 g d.w.) were the predominant compounds in the untreated FH samples. After the application of post-harvest treatments, a non-nutraceutical relevant decrease of 8-19% in the targeted (poly)phenolic content was generally observed. Ethylene induced the most significant reduction in the individual (poly)phenolic compounds in the FH fruits. [ABSTRACT FROM AUTHOR]

Increasing dietary Met, Lys, and His supply without increasing the dietary protein content was reported to partially alleviate the productive and physiological impact of heat stress. Nevertheless, the metabolic pathways involved are yet to be identified. Thus, we aimed to explore the metabolic pathways associated with these positive effects and develop new metabolomics-based hypotheses. Twelve lactating Holstein cows (primiparous, n = 6; multiparous, n = 6; 42.2 ± 10.6 kg/d milk yield; 83 ± 28 days in milk) were enrolled in two 3×3 replicated Latin squares consisting of 14-day treatment periods: heat stress [HS; max. Temperature Humidity Index (THI) 84, 16.8% crude protein (CP), 1,741 g/d metabolizable protein (MP), 108 Lys, 33 Met, and 37 His (g/d)], pair feeding in thermo-neutrality (TN; max. THI 64, same diet as HS), and HS with increased Lys, Met and His supply [HS+AA; max. THI 84; 17.0% CP, 1,730 g/d MP, 179 Lys, 58 Met, and 45 His (g/d)]. Blood plasma and milk were sampled on day 14 for metabolomics profiling. Several amino acids (AA) and derivatives differed between the treatments. Plasma and milk Met, Val, Trp and a-amino adipic acid concentrations were highest in HS+AA (false discovery rate-P (FDR) < 0.05). Moreover, only plasma Lys and milk His were highest in HS+AA (FDR < 0.05). Some phosphatidylcholines (PC) and diglycerides had lower concentrations in HS than TN (FDR < 0.05), while HS+AA had similar concentrations as TN. The pathway enrichment analysis revealed that the AA-related pathways were more significantly affected in multiparous than in primiparous cows. Our results suggest that increased supply of Met stimulated PC synthesis in HS+AA to similar concentrations as in TN. Increased Lys supply likely elevated the oxidation rate of Lys and downregulated the catabolism of other essential AA (EAA) such as Val and Trp, stimulating milk protein synthesis. No clear associations were found related to His availability. In conclusion, partial amelioration of productive and physiological effects of heat stress associated with increased dietary Met and Lys supply were likely explained by stimulated PC synthesis and increased plasma and milk concentrations of other EEA. [ABSTRACT FROM AUTHOR]

Introduction: Proliferative diabetic retinopathy (PDR) is a common diabetes complication, significantly impacting vision and quality of life. Previous studies have suggested a potential link between arginine pathway metabolites and diabetic retinopathy (DR). Connective tissue growth factor (CTGF) plays a role in the occurrence and development of fibrovascular proliferation (FVP) in PDR patients. However, the relationship between arginine pathway metabolites and FVP in PDR remains undefined. This study aimed to explore the correlation between four arginine pathway metabolites (arginine, asymmetric dimethylarginine[ADMA], ornithine, and citrulline) and the severity of FVP in PDR patients. Methods: In this study, plasma and aqueous humor samples were respectively collected from 30 patients with age-related cataracts without diabetes mellitus (DM) and from 85 PDR patients. The PDR patients were categorized as mild-tomoderate or severe based on the severity of fundal FVP. The study used KruskalWallis test to compare arginine, ADMA, ornithine, and citrulline levels across three groups. Binary logistic regression identified risk factors for severe PDR. Spearman correlation analysis assessed associations between plasma and aqueous humor metabolite levels, and between ADMA and CTGF levels in aqueous humor among PDR patients. Results: ADMA levels in the aqueous humor were significantly greater in patients with severe PDR than in those with mild-to-moderate PDR(P=0.0004). However, the plasma and aqueous humor levels of arginine, ornithine, and citrulline did not significantly differ between mild-to-moderate PDR patients and severe PDR patients (P>0.05). Binary logistic regression analysis indicated that the plasma (P=0.01) and aqueous humor (P=0.006) ADMA levels in PDR patients were risk factors for severe PDR. Furthermore, significant correlations were found between plasma and aqueous humor ADMA levels (r=0.263, P=0.015) and between aqueous humor ADMA and CTGF levels (r=0.837, P<0.001). Conclusion: Elevated ADMA levels in plasma and aqueous humor positively correlate with the severity of FVP in PDR, indicating ADMA as a risk factor for severe PDR. [ABSTRACT FROM AUTHOR]

The Balanophorae are not only traditional Chinese herbal medicines but also functional foods with diverse sources. This study aimed to distinguish pharmacognostic characteristics and secondary metabolites among different species of Balanophorae. Eight species of Balanophorae herbs were harvested, including 21 batches with 209 samples. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to analyze secondary metabolites of Balanophorae from 21 sources. Targeted metabolomic analysis was performed to compare differences among the groups. Rhopalocnemis phalloide and B. indica can be identified by their pharmacognostic characteristics. Then, 41 secondary metabolites were identified or characterized in the mixed extracts of the 209 samples, mainly phenolic acids, flavonoids, and their derivatives. The distribution of these secondary metabolites revealed apparent differences among different species. In addition, targeted metabolomic analysis suggested that the secondary metabolite profiles of seven species of Balanophorae showed noticeable differences, and differences were also observed among different growing regions. Finally, five important metabolic markers were screened to successfully distinguish B. laxiflora, B. harlandii, and B. polyandra, including three phenolic acids and two flavonoids. This is the first study to systematically compare both the morphology and secondary metabolites among different sources of Balanophorae, which could provide effective information for identifying diverse species. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is currently one of the main threats to animal health, and flavonoids in forage have good antioxidant activity. However, the impact of fermentation on flavonoids and their antioxidant activity in forage is still unclear. This study aims to investigate the effect of lactic acid bacteria inoculation on the biological transformation of flavonoids in alfalfa silage fermentation and its relationship with antioxidant activity. Results: Compared with the raw materials, silage fermentation can increase the total flavonoid content of alfalfa. The addition of Pediococcus pentosaceus (CP115739.1) and Lactiplantibacillus plantarum (CP115741.1) can significantly increase the total flavonoid content in alfalfa silage (P < 0.05). The addition of lactic acid bacteria significantly improved the antioxidant capacity of alfalfa silage (P < 0.05). Pearson correlation analysis showed a significant correlation between total flavonoids and DPPH (R = 0.62, P < 0.05), and a highly significant correlation between total flavonoids and FRAP (R = 0.70, P < 0.01). Compared with natural silage fermentation, the addition of lactic acid bacteria leads to changes in the biological transformation process of flavonoids in alfalfa. Its unique products, 3,7,4′-trioxyflavonoids, as well as acacetin and taxifolin 7-O-rhamnoside, are significantly positively correlated with antioxidant activity. Conclusions: Silage fermentation contributes to the transformation of flavonoids, and inoculation with certain lactic acid bacteria can increase the content of flavonoids (including apigenin, luteolin, and other free flavonoids). It is worth noting that after fermentation, the antioxidant capacity of alfalfa is significantly improved, which may be attributed to the biotransformation of flavonoids related to acacetin, 3,7,4′-trihydroxyflavonoids, and taxifolin 7-O-rhamnoside. This study provides a potential pathway for obtaining value-added silage fermentation products by selecting specific lactic acid bacteria inoculants. [ABSTRACT FROM AUTHOR]

The increase in UV-B radiation at the Earth's surface due to the depletion of the stratospheric ozone layer is a notable facet of contemporary climate change patterns. The macroalgae inhabiting the intertidal zone exhibit a diverse array of adaptive strategies to cope with dramatic environmental changes. In this study, we integrated physiological, transcriptomic and metabolomic data from energy metabolism perspective to elucidate the responses and recovery mechanism of N. haitanensis to UV-B radiation exposure. UV-B radiation has a harmful impact on the photosynthetic performance of N. haitanensis. However, an increase in photosynthetic performance and upregulated expression of genes related to photosynthesis were observed during recovery, suggesting that the effect of UVBon N. haitanensis was dynamic photoinhibition. Recovery experiments revealed that most genes and metabolites related to glycolysis were significantly upregulated, suggesting that glycolysis was activated to promote energy production. In addition, the TCA cycle was also activated, as evidenced by the increase in key substances and the upregulated expression of key enzymeencoding genes during recovery. Correspondingly, ATP was also abundantly accumulated. These results suggested that the TCA cycle provided ATP for N. haitanensis to repair UV-B damage. Meanwhile, amino acid metabolism was enhanced during recovery as a source of intermediates for the TCA cycle. Therefore, photosynthesis, glycolysis, the TCA cycle, and amino acid metabolism synergistically cooperate to provide material and energy for recovery after UV-B radiation. This study is important for understanding the adaptive strategies of intertidal macroalgae in response to UV-B radiation. [ABSTRACT FROM AUTHOR]

Abstract Background Vitamin D deficiency is common in pregnancy, however, its effects has not been fully elucidated. Here, we conducted targeted metabolomics profiling to study the relationship. Methods This study enrolled 111 pregnant women, including sufficient group (n = 9), inadequate group (n = 49) and deficient group (n = 53). Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabonomics were used to characterize metabolite profiles associated with vitamin D deficiency in pregnancy. Results Many metabolites decreased in the inadequate and deficient group, including lipids, amino acids and others. The lipid species included fatty acyls (FA 14:3, FA 26:0; O), glycerolipids (MG 18:2), glycerophospholipids (LPG 20:5, PE-Cer 40:1; O2, PG 29:0), sterol lipids (CE 20:5, ST 28:0; O4, ST 28:1; O4). Decreased amino acids included aromatic amino acids (tryptophan, phenylalanine, tyrosine) and branched-chain amino acids (valine, isoleucine, leucine), proline, methionine, arginine, lysine, alanine, L-kynurenine,5-hydroxy-L-tryptophan, allysine. Conclusions This targeted metabolomics profiling indicated that vitamin D supplementation can significantly affect lipids and amino acids metabolism in pregnancy.

Background: Vitamin D deficiency is common in pregnancy, however, its effects has not been fully elucidated. Here, we conducted targeted metabolomics profiling to study the relationship. Methods: This study enrolled 111 pregnant women, including sufficient group (n = 9), inadequate group (n = 49) and deficient group (n = 53). Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabonomics were used to characterize metabolite profiles associated with vitamin D deficiency in pregnancy. Results: Many metabolites decreased in the inadequate and deficient group, including lipids, amino acids and others. The lipid species included fatty acyls (FA 14:3, FA 26:0; O), glycerolipids (MG 18:2), glycerophospholipids (LPG 20:5, PE-Cer 40:1; O2, PG 29:0), sterol lipids (CE 20:5, ST 28:0; O4, ST 28:1; O4). Decreased amino acids included aromatic amino acids (tryptophan, phenylalanine, tyrosine) and branched-chain amino acids (valine, isoleucine, leucine), proline, methionine, arginine, lysine, alanine, L-kynurenine,5-hydroxy-L-tryptophan, allysine. Conclusions: This targeted metabolomics profiling indicated that vitamin D supplementation can significantly affect lipids and amino acids metabolism in pregnancy. [ABSTRACT FROM AUTHOR]

Objective To investigate the diagnostic values of L-carnitine and acetyl-carnitine (ACar 2: 0) in esophageal squamous cell carcinoma (ESCC). Methods The serum of 31 ESCC patients from Guangxi Medical University Cancer Hospital from April 2022 to October 2022 were collected and 30 healthy volunteers during the same period were recruited. Ultra-high performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS) was used to targetedly analyze the serum metabolic changes of L - carnitine and acetyl - carnitine. The diagnostic efficiency was evaluated by receiver operating characteristic (ROC) curve. Results Compared with the case in healthy controls, there was no significant difference in serum carnitine level in ESCC patients (P=0.149), and the levels of two acetyl-carnitine isomers (ACar 2∶0 isomer1 and ACar 2∶0 isomer 2) were increased (both P<0.001). Multivariable analysis showed that ACar 2∶0 isomer 1 >0.0163 μmol/L (OR=19.456, 95%CI: 1.971-192.104, P=0.011) and ACar 2∶0 isomer 2 >0.0148 μmol/L (OR=7.720, 95%CI: 1.047-56.915, P=0.045) were the risk factors for ESCC, while L-carnitine (OR=1.310, 95%CI: 0.051-33.951, P=0.871) was not significantly associated with ESCC. The two acetyl - carnitine isomers had a good ability to distinguish between ESCC and healthy controls. The area under curve (AUC), sensitivity and specificity of ACar 2∶0 isomer 1 in the diagnosis of ESCC were 0.957, 0.900 and 0.862, respectively. The AUC, sensitivity and specificity of ACar 2∶0 isomer 2 in the diagnosis of ESCC were 0.901, 0.867 and 0.821, respectively. The AUC, sensitivity and specificity of combining ACar 2∶0 isomer 1 and ACar 2∶0 isomer 2 in the diagnosis of ESCC were 0.952, 0.867 and 0.889, respectively. Conclusions Serum acetylcarnitine level increases in ESCC, showing a good efficacy in the diagnosis of ESCC, and may become a potential diagnostic marker. [ABSTRACT FROM AUTHOR]

Simple Summary: The vaginal microbiome may play a role in racial disparities in ovarian cancer; there is evidence suggesting that it differs according to race and contributes to inflammation by producing or consuming compounds that can shape how ovarian cancer progresses. Our cross-sectional study aimed to investigate the extent to which chemical compounds, or metabolites, from vaginal fluid, also differ by race, and whether these metabolites are linked to systemic inflammation. Our study of 20 White and 16 Black patients identified 1 out of 99 metabolites, arachidonoylcarnitine (C20:4), as occurring at lower levels in Black and higher levels in White patients with ovarian cancer. More than one-third of vaginal fluid metabolites considered showed correlations with biomarkers of systemic inflammation. Our findings suggest that vaginal fluid metabolites likely differ by race, and may play an important role in inflammatory processes, which may be relevant to racial differences in ovarian cancer outcomes. These pilot findings have the potential to improve our understanding of biological mechanisms underlying racial disparities in ovarian cancer but need verification with larger sample sizes. The vaginal microbiome differs by race and contributes to inflammation by directly producing or consuming metabolites or by indirectly inducing host immune response, but its potential contributions to ovarian cancer (OC) disparities remain unclear. In this exploratory cross-sectional study, we examine whether vaginal fluid metabolites differ by race among patients with OC, if they are associated with systemic inflammation, and if such associations differ by race. Study participants were recruited from the Ovarian Cancer Epidemiology, Healthcare Access, and Disparities Study between March 2021 and September 2022. Our study included 36 study participants with ovarian cancer who provided biospecimens; 20 randomly selected White patients and all 16 eligible Black patients, aged 50–70 years. Acylcarnitines (n = 45 species), sphingomyelins (n = 34), and ceramides (n = 21) were assayed on cervicovaginal fluid, while four cytokines (IL-1β, IL-10, TNF-α, and IL-6) were assayed on saliva. Seven metabolites showed >2-fold differences, two showed significant differences using the Wilcoxon rank-sum test (p < 0.05; False Discovery Rate > 0.05), and 30 metabolites had coefficients > ±0.1 in a Penalized Discriminant Analysis that achieved two distinct clusters by race. Arachidonoylcarnitine, the carnitine adduct of arachidonic acid, appeared to be consistently different by race. Thirty-eight vaginal fluid metabolites were significantly correlated with systemic inflammation biomarkers, irrespective of race. These findings suggest that vaginal fluid metabolites may differ by race, are linked with systemic inflammation, and hint at a potential role for mitochondrial dysfunction and sphingolipid metabolism in OC disparities. Larger studies are needed to verify these findings and further establish specific biological mechanisms that may link the vaginal microbiome with OC racial disparities. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify differential metabolites and key metabolic pathways between lung adenocarcinoma (LUAD) tissues and normal lung (NL) tissues using metabolomics techniques, to discover potential biomarkers for the early diagnosis of lung cancer. Material and Methods: Forty-five patients with primary ground-glass nodules (GGN) identified on computed tomography imaging and who were willing to undergo surgery at Shanghai General Hospital from December 2021 to December 2022 were recruited to the study. All participants underwent video thoracoscopy surgery with segmental or wedge resection of the lung. Tissue samples for pathological examination were collected from the site of ground-glass nodules (GGN) lesion and 3 cm away from the lesion (NL). The pathology results were 35 lung adenocarcinoma (LUAD) cases (13 invasive adenocarcinoma, 14 minimally invasive adenocarcinoma, and eight adenocarcinoma in situ), 10 benign samples, and 45 NL tissues. For the untargeted metabolomics technique, 25 LUAD samples were assigned as the case group and 30 NL tissues as the control group. For the targeted metabolomics technique, ten LUAD samples were assigned as the case group and 15 NL tissues as the control group. Samples were analyzed by untargeted and targeted metabolomics, with liquid chromatography-tandem mass spectrometry detection used as part of the experimental procedure. Results: Untargeted metabolomics revealed 164 differential metabolites between the case and control groups, comprising 110 up regulations and 54 down regulations. The main metabolic differences found by the untargeted method were organic acids and their derivatives. Targeted metabolomics revealed 77 differential metabolites between the case and control groups, comprising 69 up regulations and eight down regulations. The main metabolic changes found by the targeted method were fatty acids, amino acids, and organic acids. The levels of organic acids such as lactic acid, fumaric acid, and malic acid were significantly increased in LUAD tissue compared to NL. Specifically, an increased level of L-lactic acid was found by both untargeted (variable importance in projection [VIP] = 1.332, fold-change [FC] = 1.678, q = 0.000) and targeted metabolomics (VIP = 1.240, FC = 1.451, q = 0.043). Targeted metabolomics also revealed increased levels of fumaric acid (VIP = 1.481, FC = 1.764, q = 0.106) and L-malic acid (VIP = 1.376, FC = 1.562, q = 0.012). Most of the 20 differential fatty acids identified were downregulated, including dodecanoic acid (VIP = 1.416, FC = 0.378, q = 0.043) and tridecane acid (VIP = 0.880, FC = 0.780, q = 0.106). Furthermore, increased levels of differential amino acids were found in LUAD samples. Conclusion: Lung cancer is a complex and heterogeneous disease with diverse genetic alterations. The study of metabolic profiles is a promising research field in this cancer type. Targeted and untargeted metabolomics revealed significant differences in metabolites between LUAD and NL tissues, including elevated levels of organic acids, decreased levels of fatty acids, and increased levels of amino acids. These metabolic features provide valuable insights into LUAD pathogenesis and can potentially serve as biomarkers for prognosis and therapy response. [ABSTRACT FROM AUTHOR]

Introduction: Depression is a complex psychiatric disorder with substantial societal impact. While current antidepressants offer moderate efficacy, their adverse effects and limited understanding of depression's pathophysiology hinder the development of more effective treatments. Amidst this complexity, the role of neuroinflammation, a recognized but poorly understood associate of depression, has gained increasing attention. This study investigates hydroxytyrosol (HT), an olive-derived phenolic antioxidant, for its antidepressant and anti-neuroinflammatory properties based on mitochondrial protection. Methods: In vitro studies on neuronal injury models, the protective effect of HT on mitochondrial ultrastructure from inflammatory damage was investigated in combination with high-resolution imaging of mitochondrial substructures. In animal models, depressive-like behaviors of chronic restraint stress (CRS) mice and chronic unpredictable mild stress (CUMS) rats were examined to investigate the alleviating effects of HT. Targeted metabolomics and RNA-Seq in CUMS rats were used to analyze the potential antidepressant pathways of HT. Results: HT protected mitochondrial ultrastructure from inflammatory damage, thus exerting neuroprotective effects in neuronal injury models. Moreover, HT reduced depressive-like behaviors in mice and rats exposed to CRS and CUMS, respectively. HT's influence in the CRS model included alleviating hippocampal neuronal damage and modulating cytokine production, mitochondrial dysfunction, and brain-derived neurotrophic factor (BDNF) signaling. Targeted metabolomics in CUMS rats revealed HT's effect on neurotransmitter levels and tryptophan-kynurenine metabolism. RNA-Seq data underscored HT's antidepressant mechanism through the BDNF/TrkB signaling pathways, key in nerve fiber functions, myelin formation, microglial differentiation, and neural regeneration. Discussion: The findings underscore HT's potential as an anti-neuroinflammatory treatment for depression, shedding light on its antidepressant effects and its relevance in nutritional psychiatry. Further investigations are warranted to comprehensively delineate its mechanisms and optimize its clinical application in depression treatment. [ABSTRACT FROM AUTHOR]

In‐depth profiling of embryogenesis‐associated endogenous and exogenous metabolic changes can reveal potential bio‐effects resulting from human‐made chemicals and underlying mechanisms. Due to the lack of potent tools for monitoring spatiotemporal distribution and bio‐transformation behavior of dynamic metabolites at single‐cell resolution, however, how and to what extent environmental chemicals may influence or interfere embryogenesis largely remain unclear. Herein, a zero‐sample‐loss micro‐biopsy‐based mass spectrometric platform is presented for quantitative, chemo‐selective, high‐coverage, and minimal‐destructive profiling of development‐associated cis‐diol metabolites, which are critical for signal transduction and epigenome regulation, at both cellular level and tissue level of Xenopus laevis. Using this platform, three extraordinary findings that are otherwise hard to achieve are revealed: 1) there are characteristically different cis‐diol metabolic signatures among oocytes, anterior and posterior part of tailbud‐stage embryos; 2) halogenated cis‐diols heavily accumulate at the posterior part of tailbud‐stage embryos of Xenopus laevis; 3) dimethachlon, a kind of exogenous fungicide that is widely used as pesticide, may be bio‐transformed and accumulated in vertebrate animals in environment. Thus, this study opens a new avenue to simultaneously monitoring intercellular and intraembryonic heterogeneity of endogenous and exogenous metabolites, providing new insights into metabolic remolding during embryogenesis and putting a warning on potential environmental risk. [ABSTRACT FROM AUTHOR]

Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α‐reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so‐called post‐finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α‐reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO2 levels, and a decrease in ornithine transcarbamylase (OTC) activity, measured by citrulline/ornithine ratio. Interestingly, the T levels are negatively correlated with NOS activity, while those of DHT are positively correlated with OTC activity. Finasteride treatment also induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug. Altogether, the results reported here indicate that finasteride treatment, but not its withdrawal, affects T metabolism in the rat corpus cavernosum, and this alteration was linked to mechanisms associated with erectile dysfunction. Data here reported could also suggest that the PFS sexual side effects are more related to dysfunction in a sexual central control rather than peripheral compromised condition. [ABSTRACT FROM AUTHOR]

Introduction: The Automated Quantification Algorithm (AQuA) is a rapid and efficient method for targeted NMR-based metabolomics, currently optimised for blood plasma. AQuA quantifies metabolites from 1D-1H NMR spectra based on the height of only one signal per metabolite, which minimises the computational time and workload of the method without compromising the quantification accuracy. Objectives: To develop a fast and computationally efficient extension of AQuA for quantification of selected metabolites in highly complex samples, with minimal prior sample preparation. In particular, the method should be capable of handling interferences caused by broad background signals. Methods: An automatic baseline correction function was combined with AQuA into an automated workflow, the extended AQuA, for quantification of metabolites in plant root exudate NMR spectra that contained broad background signals and baseline distortions. The approach was evaluated using simulations as well as a spike-in experiment in which known metabolite amounts were added to a complex sample matrix. Results: The extended AQuA enables accurate quantification of metabolites in 1D-1H NMR spectra with varying complexity. The method is very fast (< 1 s per spectrum) and can be fully automated. Conclusions: The extended AQuA is an automated quantification method intended for 1D-1H NMR spectra containing broad background signals and baseline distortions. Although the method was developed for plant root exudates, it should be readily applicable to any NMR spectra displaying similar issues as it is purely computational and applied to NMR spectra post-acquisition. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In - vivo and in - vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment. [Display omitted] • Energy homeostasis is disturbed in diabetic peripheral neuropathy. • JMT alleviates experimental diabetic peripheral neuropathy. • JMT regulates energy homeostasis via AMPK activation. [ABSTRACT FROM AUTHOR]

IntroductionThe formidable survival mechanisms employed by Mycobacterium tuberculosis (Mtb), combined with the low bioavailability of anti-tubercular drugs and their associated hepatotoxicity, worsen tuberculosis management. Traditional medicinal plants offer potential solutions to these challenges. This study focuses on exploring the anti-tubercular potential of Solanum virginianum against Mycobacterium smegmatis, mc2155.Methods and resultsHPTLC and UHPLC phytochemically characterized the hydro-methanolic extract of Solanum virginianum (SVE). SVE curtails the growth and viability of mc2155 under normal and in vitro stress conditions. The compromised cell wall integrity of mc2155 with SVE is depicted through scanning electron microscopy (SEM) while EtBr permeability assays and TLC-based comparative changes in lipids extraction addressed the integrity of the cell wall. Furthermore, SVE augmented the susceptibility of mc2155 towards Isoniazid (INH) through enhanced bioavailability. Adjunct treatment of SVE with INH demonstrated a markedly reduced survival of the intracellular bacilli. The study also uncovered the hepatoprotective potential of SVE in HepG2 cells.ConclusionThis research paves the way for deeper exploration into the potential of Solanum virginianum against virulent Mtb strains, emphasizing over the significance of traditional medicinal plants in tuberculosis treatment. Collectively, the findings suggest SVE as a potent candidate for independent or adjunct anti-tubercular therapy.

Increasing dietary Met, Lys, and His supply without increasing the dietary protein content was reported to partially alleviate the productive and physiological impact of heat stress. Nevertheless, the metabolic pathways involved are yet to be identified. Thus, we aimed to explore the metabolic pathways associated with these positive effects and develop new metabolomics-based hypotheses. Twelve lactating Holstein cows (primiparous, n = 6; multiparous, n = 6; 42.2 ± 10.6 kg/d milk yield; 83 ± 28 days in milk) were enrolled in two 3×3 replicated Latin squares consisting of 14-day treatment periods: heat stress [HS; max. Temperature Humidity Index (THI) 84, 16.8% crude protein (CP), 1,741 g/d metabolizable protein (MP), 108 Lys, 33 Met, and 37 His (g/d)], pair feeding in thermo-neutrality (TN; max. THI 64, same diet as HS), and HS with increased Lys, Met and His supply [HS+AA; max. THI 84; 17.0% CP, 1,730 g/d MP, 179 Lys, 58 Met, and 45 His (g/d)]. Blood plasma and milk were sampled on day 14 for metabolomics profiling. Several amino acids (AA) and derivatives differed between the treatments. Plasma and milk Met, Val, Trp and α-amino adipic acid concentrations were highest in HS+AA (false discovery rate-P (FDR) < 0.05). Moreover, only plasma Lys and milk His were highest in HS+AA (FDR < 0.05). Some phosphatidylcholines (PC) and diglycerides had lower concentrations in HS than TN (FDR < 0.05), while HS+AA had similar concentrations as TN. The pathway enrichment analysis revealed that the AA-related pathways were more significantly affected in multiparous than in primiparous cows. Our results suggest that increased supply of Met stimulated PC synthesis in HS+AA to similar concentrations as in TN. Increased Lys supply likely elevated the oxidation rate of Lys and downregulated the catabolism of other essential AA (EAA) such as Val and Trp, stimulating milk protein synthesis. No clear associations were found related to His availability. In conclusion, partial amelioration of productive and physiological effects of heat stress associated with increased dietary Met and Lys supply were likely explained by stimulated PC synthesis and increased plasma and milk concentrations of other EEA.

This work investigated the effects of the combined use of thermosonication-preconditioned lactic acid bacteria (LAB) with the addition of ultrasound-assisted pineapple peel extracts (UU group) on the post-acidification potential, physicochemical and functional qualities of yogurt products, aimed at achieving prolonged preservation and enhancing functional attributes. Accordingly, the physical–chemical features, adhesion properties, and sensory profiles, acidification kinetics, the contents of major organic acids, and antioxidant activities of the differentially processed yogurts during refrigeration were characterized. Following a 14-day chilled storage process, UU group exhibited acidity levels of 0.5–2 oT lower than the control group and a higher lactose content of 0.07 mg/ml as well as unmodified adhesion potential, indicating that the proposed combination method efficiently inhibited post-acidification and delayed lactose metabolism without leading to significant impairment of the probiotic properties. The results of physicochemical analysis showed no significant changes in viscosity, hardness, and color of yogurt. Furthermore, the total phenolic content of UU-treated samples was 98 μg/mL, 1.78 times higher than that of the control, corresponding with the significantly lower IC50 values of DPPH and ABTS radical scavenging activities of the UU group than those of the control group. Observations by fluorescence inverted microscopy demonstrated the obvious adhesion phenomenon with no significant difference found among differentially prepared yogurts. The results of targeted metabolomics indicated the proposed combination strategy significantly modified the microbial metabolism, leading to the delayed utilization of lactose and the inhibited conversion into glucose during post-fermentation, as well as the decreased lactic acid production and a notable shift towards the formation of relatively weak acids such as succinic acid and citric acid. This study confirmed the feasibility of thermosonication-preconditioned LAB inocula, in combination with the use of natural active components from fruit processing byproducts, to alleviate post-acidification in yogurt and to enhance its antioxidant activities as well as simultaneously maintaining sensory features.

Li Bao,1,2 Bowen Wu,3 Chunjing Yang,1,2 Xiqiao Xu,1,2 Zhengyuan Shi,1,2 Dechun Jiang1,2 1Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing, People’s Republic of China; 3Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Zhengyuan Shi; Dechun Jiang, Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi-Road, Haidian District, Beijing, 10038, People’s Republic of China, Tel +86-10-63926405 ; +86-10-63926723, Email shizhengyuan2980@bjsjth.cn; jdc@bjsjth.cnPurpose: Amino acids are the important metabolites in the body and play a crucial role in biological processes. The purpose of this study is to provide a profile of amino acids change in the serum of T2DM patients and identify potential biomarkers.Patients and Methods: In this study, we quantitatively determined the serum amino acid profiles of 30 T2DM patients and 30 healthy volunteers. T test and multivariate statistical analysis were used to identify candidate biomarkers with GraphPad Prism 9.5 software and MetaboAnalyst 5.0 on-line platform.Results: Thirty-four amino acids were quantified, and 19 amino acid levels differed significantly between T2DM and Healthy groups. Screened by the specific screening criteria (VIP> 1.0; P< 0.05; FC> 1.5, or FC< 0.67) in MetaboAnalyst 5.0 platform, 8 amino acids were identified as potential biomarkers. Pearson rank correlation test showed 14 differential amino acids were significantly correlated with T2DM-related physiological parameters.Conclusion: The results of this study provide theoretical basis for the subsequent development of dietary supplements for the prevention or treatment of T2DM and its complications.Keywords: diabetes mellitus type 2, T2DM, targeted metabolomics, amino acids, biomarker

Abstract Background Alterations in the production of short-chain fatty acids (SCFAs) may reflect disturbances in the gut microbiota and have been linked to metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed plasma SCFAs in patients with MASLD and healthy controls. Methods Fasting venous blood samples were collected and eight SCFAs were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). Relative between-group differences in circulating SCFA concentrations were estimated by linear regression, and the relation between SCFA concentrations, MASLD, and fibrosis severity was investigated using logistic regression. Results The study includes 100 patients with MASLD (51% with mild/no fibrosis and 49% with significant fibrosis) and 50 healthy controls. Compared with healthy controls, MASLD patients had higher plasma concentrations of propionate (21.8%, 95% CI 3.33 to 43.6, p = 0.02), formate (21.9%, 95% CI 6.99 to 38.9, p = 0.003), valerate (35.7%, 95% CI 4.53 to 76.2, p = 0.02), and α-methylbutyrate (16.2%, 95% CI 3.66 to 30.3, p = 0.01) but lower plasma acetate concentrations (− 30.0%, 95% CI − 40.4 to − 17.9, p

Abstract Background Long-chain fatty acids (LCFAs) are involved in regulating multiple physiological processes as signalling molecules. Gas chromatography–mass spectrometry (GC–MS) is widely used to quantify LCFAs. However, current quantitative methods for LCFAs using GC–MS have demonstrated complicated issues. Psoriasis is a chronic inflammatory skin disease, and its pathogenesis may be related to the overproduction of interleukin-17A (IL-17A). Clinical efficacy of anti-IL-17A monoclonal antibody (mAb) treatment in psoriasis patients has been demonstrated. Recent studies suggest that LCFAs play varying roles in the pathogenesis of psoriasis. However, more comprehensive research is needed to illuminate the mechanism of LCFAs in psoriasis. Methods The established in situ derivatization method for analysing LCFAs with a GC–MS platform was utilized to conduct serum lipidomics analysis of healthy volunteers and psoriasis patients receiving pretherapy and posttreatment with of anti-IL-17A mAb. Imiquimod (IMQ)-treated wild type (WT) and T-cell receptor delta chain knock-out (Tcrd −/− ) mice were used to investigate the correlation between IL-17A and abnormal changes in LCFAs in psoriasis patients. Results A rapid and sensitive in situ extraction derivatization method for quantifying LCFAs using GC–MS was established. Serum lipidomic results showed that psoriasis patients had higher levels of saturated fatty acids (SFAs) and ω-6 polyunsaturated fatty acids (PUFAs) but lower levels of monounsaturated fatty acids (MUFAs) and ω-3 PUFAs than healthy individuals, indicating impaired serum LCFA metabolism. Anti-IL-17A mAb treatment affected most of these LCFA changes. Analysis of LCFAs in IMQ-treated mice showed that LCFAs increased in the serum of WT mice, while there were no significant changes in the Tcrd −/− mice. SFAs increased in IMQ-treated WT mice, while MUFAs showed the opposite trend, and PUFAs did not change significantly. Conclusions This study presented a dependable method for quantifying LCFAs that enhanced sensitivity and reduced analysis time. The lipidomic analysis results showed that anti-IL-17A mAb not only ameliorated skin lesions in psoriasis patients but also affected abnormal LCFAs metabolism. Furthermore, the study indicated a potential correlation between IL-17A and abnormal LCFA metabolism in psoriasis patients, which was supported by the alterations in serum LCFAs observed in IMQ-treated WT and Tcrd −/− mice.

Abstract Background The morbidity of cancer keeps growing worldwide, and among that, the colorectal cancer (CRC) has jumped to third. Existing early screening tests for CRC are limited. The aim of this study was to develop a diagnostic strategy for CRC by plasma metabolomics. Methods A targeted amino acids metabolomics method was developed to quantify 32 plasma amino acids in 130 CRC patients and 216 healthy volunteers, to identify potential biomarkers for CRC, and an independent sample cohort comprising 116 CRC subjects, 33 precancerosiss patients and 195 healthy volunteers was further used to validate the diagnostic model. Amino acids-related genes were retrieved from Gene Expression Omnibus and Molecular Signatures Database and analyzed. Results Three were chosen out of the 32 plasma amino acids examined. The tryptophan / sarcosine / glutamic acid -based receiver operating characteristic (ROC) curve showed the area under the curve (AUC) of 0.955 (specificity 83.3% and sensitivity 96.8%) for all participants, and the logistic regression model were used to distinguish between early stage (I and II) of CRC and precancerosiss patients, which showed superiority to the commonly used carcinoembryonic antigen. The GO and KEGG enrichment analysis proved many alterations in amino acids metabolic pathways in tumorigenesis. Conclusion This altered plasma amino acid profile could effectively distinguish CRC patients from precancerosiss patients and healthy volunteers with high accuracy. Prognostic tests based on the tryptophan/sarcosine/glutamic acid biomarkers in the large population could assess the clinical significance of CRC early detection and intervention. Graphical Abstract

Psoriasis is a chronic, immune-mediated skin condition with significant metabolic complications. Although lipid metabolism is linked to its pathogenesis, reliable biomarkers and the impact of modifiable factors remain underexplored. The aim of the present study was to identify potential biomarkers, study the affected metabolic networks, and assess the role of dietary and lifestyle factors in psoriasis. Plasma samples from 56 patients with psoriasis and 49 healthy controls were analyzed, as part of the Metabolic Biomarkers in Hashimoto’s Thyroiditis and Psoriasis (METHAP) clinical trial. Using Gas Chromatography-Mass Spectrometry 23 fatty acids and their ratios were quantified, revealing significant changes in psoriasis. Specifically, lower levels of α-linoleic acid (C18:3n3), linoleic acid (C18:2n6), and gamma-linolenic acid (C18:3n6) were observed along with higher levels of eicosatrienoic acid (C20:3n3), eicosapentaenoic acid (C20:5n3), and erucic acid (C22:1n9). Total polyunsaturated fatty acids (PUFA) were significantly decreased, and the ratio of saturated to total fatty acids (SFA/Total) was increased in psoriasis (p-values < 0.0001). Linear regression identified α-linoleic acid, linoleic acid, eicosatrienoic acid, and eicosapentaenoic acid as potential biomarkers for psoriasis, adjusting for demographic, dietary, and lifestyle confounders. Network analysis revealed key contributors in the metabolic reprogramming of psoriasis. These findings highlight the association between psoriasis and fatty acid biomarkers of inflammation, insulin resistance and micronutrients deficiency, suggesting their potency in disease management.

The fight against coronavirus disease 2019 (COVID-19) continues. Since the pandemic’s onset, several biomarkers have been proposed to assess the diagnosis and prognosis of this disease. This research aimed to identify potential disease severity biomarkers in serum samples of patients with COVID-19 during the disease course. Data were collected using untargeted and targeted mass spectrometry methods. The results were interpreted by performing univariate and multivariate analyses. Important metabolite classes were identified by qualitative untargeted metabolomics in 15 serum samples from survivors of COVID-19. Quantitative targeted metabolomics on a larger patient cohort including 15 non-survivors confirmed serum 3-sulfate bile acids (i.e. GLCA-3S) were significantly increased in non-survivors compared to survivors during the early disease stage (p-value < 0.0001). Notably, it was associated with a higher risk of mortality (odds ratio of 26). A principal component analysis showed the ability to discriminate between survivors and non-survivors using the BA concentrations. Furthermore, increased BA-S is highly correlated with known parameters altered in severe clinical conditions.

Ischemic stroke is one of the leading causes of death and permanent disability in the world. Rapid diagnosis and intervention are crucial for reducing its consequences on individuals and societies. Therefore, identifying reliable biomarkers for early detection, prognostics, and therapy can facilitate the early prediction and prevention of stroke. Metabolomics has been shown as a promising tool for biomarker discovery since many post-ischemic metabolites can be found in the plasma or serum of the patient. In this research, we performed a comparative targeted metabolomic analysis of stroke thrombi, stroke patient serums, and healthy control serums in order to determine the alteration in the patients’ metabolomes, which might serve as biomarkers for early prediction or stroke prevention. The most statistically altered metabolites characterized in the patient serums compared with the control serums were glutamate and serotonin, followed by phospholipids and triacylglycerols. In stroke thrombi compared with the patients’ serums, the most significantly altered metabolites were classified as lipids, with choline-containing phospholipids and sphingomyelins having the highest discriminatory score. The results of this preliminary study could help in understanding the roles of different metabolic changes that occur during thrombosis and cerebral ischemia and possibly suggest new metabolic biomarkers for ischemic stroke.

Background: Alterations in the production of short-chain fatty acids (SCFAs) may reflect disturbances in the gut microbiota and have been linked to metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed plasma SCFAs in patients with MASLD and healthy controls. Methods: Fasting venous blood samples were collected and eight SCFAs were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). Relative between-group differences in circulating SCFA concentrations were estimated by linear regression, and the relation between SCFA concentrations, MASLD, and fibrosis severity was investigated using logistic regression. Results: The study includes 100 patients with MASLD (51% with mild/no fibrosis and 49% with significant fibrosis) and 50 healthy controls. Compared with healthy controls, MASLD patients had higher plasma concentrations of propionate (21.8%, 95% CI 3.33 to 43.6, p = 0.02), formate (21.9%, 95% CI 6.99 to 38.9, p = 0.003), valerate (35.7%, 95% CI 4.53 to 76.2, p = 0.02), and α-methylbutyrate (16.2%, 95% CI 3.66 to 30.3, p = 0.01) but lower plasma acetate concentrations (− 30.0%, 95% CI − 40.4 to − 17.9, p < 0.001). Among patients with MASLD, significant fibrosis was positively associated with propionate (p = 0.02), butyrate (p = 0.03), valerate (p = 0.03), and α-methylbutyrate (p = 0.02). Six of eight SCFAs were significantly increased in F4 fibrosis. Conclusions: In the present study, SCFAs were associated with MASLD and fibrosis severity, but further research is needed to elucidate the potential mechanisms underlying our observations and to assess the possible benefit of therapies modulating gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Long-chain fatty acids (LCFAs) are involved in regulating multiple physiological processes as signalling molecules. Gas chromatography–mass spectrometry (GC–MS) is widely used to quantify LCFAs. However, current quantitative methods for LCFAs using GC–MS have demonstrated complicated issues. Psoriasis is a chronic inflammatory skin disease, and its pathogenesis may be related to the overproduction of interleukin-17A (IL-17A). Clinical efficacy of anti-IL-17A monoclonal antibody (mAb) treatment in psoriasis patients has been demonstrated. Recent studies suggest that LCFAs play varying roles in the pathogenesis of psoriasis. However, more comprehensive research is needed to illuminate the mechanism of LCFAs in psoriasis. Methods: The established in situ derivatization method for analysing LCFAs with a GC–MS platform was utilized to conduct serum lipidomics analysis of healthy volunteers and psoriasis patients receiving pretherapy and posttreatment with of anti-IL-17A mAb. Imiquimod (IMQ)-treated wild type (WT) and T-cell receptor delta chain knock-out (Tcrd−/−) mice were used to investigate the correlation between IL-17A and abnormal changes in LCFAs in psoriasis patients. Results: A rapid and sensitive in situ extraction derivatization method for quantifying LCFAs using GC–MS was established. Serum lipidomic results showed that psoriasis patients had higher levels of saturated fatty acids (SFAs) and ω-6 polyunsaturated fatty acids (PUFAs) but lower levels of monounsaturated fatty acids (MUFAs) and ω-3 PUFAs than healthy individuals, indicating impaired serum LCFA metabolism. Anti-IL-17A mAb treatment affected most of these LCFA changes. Analysis of LCFAs in IMQ-treated mice showed that LCFAs increased in the serum of WT mice, while there were no significant changes in the Tcrd−/− mice. SFAs increased in IMQ-treated WT mice, while MUFAs showed the opposite trend, and PUFAs did not change significantly. Conclusions: This study presented a dependable method for quantifying LCFAs that enhanced sensitivity and reduced analysis time. The lipidomic analysis results showed that anti-IL-17A mAb not only ameliorated skin lesions in psoriasis patients but also affected abnormal LCFAs metabolism. Furthermore, the study indicated a potential correlation between IL-17A and abnormal LCFA metabolism in psoriasis patients, which was supported by the alterations in serum LCFAs observed in IMQ-treated WT and Tcrd−/− mice. [ABSTRACT FROM AUTHOR]