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Caffeine is an ergogenic substance that is consumed globally in many forms. The use of buccally absorbable formulations instead of gastrointestinal uptake has become increasingly popular over the years, especially when accelerated absorption with minimal gastrointestinal stress is desired. This study investigated the impact of five different formulations and administration routes of caffeine on the whole blood concentrations of caffeine, paraxanthine, and theobromine: caffeinated capsules, tablets, shots, pouches, and chewing gums. A uniform dose of caffeine (200 mg) was administered to 16 healthy recreational athletes (26.0 ± 2.1 years) using a randomized crossover design. Samples were taken in the form of dried blood spots at 16 different time points in a 2-hr timeframe after drug administration. The samples were analyzed using a validated liquid chromatography–tandem mass spectrometry method. The results for caffeine showed no significant differences in the overall bioavailability (area under the concentration–time curve), maximal concentration, and time to maximum concentration. However, when analyzing the bioavailability of caffeine in the first 5, 10, and 15 min, the liquid caffeine formulation was superior to other administered forms (p <.05). This indicates that caffeine solubility has a major influence on its absorption rate. In sports, the rate of caffeine absorption must be considered, not only when ingesting anhydrous caffeine, but also when choosing buccal absorption. These findings imply that general guidelines for ergogenic caffeine use should consider the formulation used and, accordingly, the corresponding route of absorption. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the effect of exercise intensity on the proportion and rate of carbohydrate oxidation and glucoregulatory hormone responses during recovery from exercise. Six physically active participants completed 1 hr of low-intensity (LI; 50% lactate threshold) or moderate-intensity (MI; 100% lactate threshold) exercise on separate days following a randomized counterbalanced design. During exercise and for 6 hr of recovery, samples of expired air were collected to determine oxygen consumption, respiratory exchange ratio, energy expenditure, and substrate oxidation rates. Blood samples were also collected to measure glucoregulatory hormones (catecholamines, GH) and metabolites (glucose, free fatty acids, lactate, pH, and bicarbonate). During exercise, respiratory exchange ratio, energy expenditure, and the proportion and rate of carbohydrate (CHO) oxidation were higher during MI compared with LI. However, during recovery from MI, respiratory exchange ratio and the proportion and rate of CHO oxidation were lower than preexercise levels and corresponding LI. During exercise and early recovery, catecholamines and growth hormone were higher in MI than LI, and there was a trend for higher levels of free fatty acids in the early recovery from MI compared with LI. In summary, CHO oxidation during exercise increases with exercise intensity but there is a preference for CHO sparing (and fat oxidation) during recovery from MI exercise compared with LI exercise. This exercise intensity-dependent shift in substrate oxidation during recovery is explained, in part, by the pattern of change of key glucoregulatory hormones including catecholamines and growth hormone and plasma fatty acid concentrations. [ABSTRACT FROM AUTHOR]

Today, colorectal cancer (CRC) diagnosis is performed using colonoscopy, which is the current, most effective screening method. However, colonoscopy poses risks of harm to the patient and is an invasive process. Recent research has proven metabolomics as a potential, non-invasive detection method, which can use identified biomarkers to detect potential cancer in a patients body. The aim of this study is to develop a machine-learning (ML) model based on chemical descriptors that will recognize CRC-associated metabolites. We selected a set of metabolites found as the biomarkers of CRC, confirmed that they participate in cancer-related pathways, and used them for training a machine-learning model for the diagnostics of CRC. Using a set of selective metabolites and random compounds, we developed a range of ML models. The best performing ML model trained on Stage 0-2 CRC metabolite data predicted a metabolite class with 89.55% accuracy. The best performing ML model trained on Stage 3-4 CRC metabolite data predicted a metabolite class with 95.21% accuracy. Lastly, the best-performing ML model trained on Stage 0-4 CRC metabolite data predicted a metabolite class with 93.04% accuracy. These models were then tested on independent datasets, including random and unrelated-disease metabolites. In addition, six pathways related to these CRC metabolites were also distinguished: aminoacyl-tRNA biosynthesis; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; and alanine, aspartate, and glutamate metabolism. Thus, in this research study, we created machine-learning models based on metabolite-related descriptors that may be helpful in developing a non-invasive diagnosis method for CRC.

Oxylipins are a group of bioactive fatty acid metabolites generated via enzymatic oxygenation. They are notably involved in inflammation, pain, vascular tone, hemostasis, thrombosis, immunity, and coagulation. Oxylipins have become the focus of therapeutic intervention since they are implicated in many conditions, such as nonalcoholic fatty liver disease, cardiovascular disease, and aging. The liver plays a crucial role in lipid metabolism and distribution throughout the organism. Long-term exposure to pesticides is suspected to contribute to hepatic carcinogenesis via notable disruption of lipid metabolism. Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. The amounts of prometryn documented in the environment, mainly waters, soil and plants used for human and domestic consumption are significantly high. Previous research revealed that prometryn decreased liver development during zebrafish embryogenesis. To understand the mechanisms by which prometryn could induce hepatotoxicity, the effect of prometryn (185 mg/kg every 48 h for seven days) was investigated on hepatic and plasma oxylipin levels in mice. Using an unbiased LC-MS/MS-based lipidomics approach, prometryn was found to alter oxylipins metabolites that are mainly derived from cytochrome P450 (CYP) and lipoxygenase (LOX) in both mice liver and plasma. Lipidomic analysis revealed that the hepatotoxic effects of prometryn are associated with increased epoxide hydrolase (EH) products, increased sEH and mEH enzymatic activities, and induction of oxidative stress. Furthermore, 9-HODE and 13-HODE levels were significantly increased in prometryn treated mice liver, suggesting increased levels of oxidation products. Together, these results support that sEH may be an important component of pesticide-induced liver toxicity.

Rationale: This study focuses on the advantage of using the novel electron‐activated dissociation (EAD) technology on the QTOF system for structural elucidation of conjugation metabolites. In drug metabolite identification, conceptual "boxes" are generally used to represent potential sites of modifications, which are proposed based on MS/MS data. Electron‐activated dissociation (EAD) provides unique fragmentation patterns, potentially allowing for more precise localization of the metabolic modification sites compared to CID, particularly for conjugations. Method: Known compounds were incubated with rat liver microsomes in the presence of nicotinamide adenine dinucleotide phosphate (NADPH), uridine dihosphate‐glucuronic acid (UDPGA), and glutathione. Conjugation metabolites were analyzed using the QTOF system. High‐resolution MS/MS spectra were collected using EAD and CID fragmentations along with TOF MS full scan for tested drugs and metabolites. Fragmentation patterns were compared to evaluate their efficiency in structural elucidation. Results: Metabolite profiling identified conjugation metabolites (glucuronides and GSH adducts), using characteristic mass shifts. A comparison of EAD and CID fragmentation revealed EAD‐specific fragments for most conjugates. EAD was able to break the relatively stable bonds on parent drug motifs while keeping relatively weak conjugation bonds intact, despite the generally low intensity of EAD. EAD effectively narrowed the conceptual "box" representing modification sites, providing more definitive information on conjugation sites and facilitating the structural elucidation of conjugated metabolites. Conclusion: EAD is a powerful tool for metabolite profiling in drug development, particularly for identifying conjugation sites. EAD‐enabled MS/MS spectra offer a greater variety of signature fragments compared to CID, resulting in more comprehensive and unique structural information for metabolic modification analysis. Overall, EAD, complementary to CID, has the potential to narrow down potential modification sites, significantly enhancing the precision of conjugation metabolite structure elucidation. [ABSTRACT FROM AUTHOR]

Mycotoxins are secondary metabolites produced by fungi during their growth. They not only seriously affect the yield of food crops but also pose a threat to human and animal health. Physical and chemical methods have been widely used to reduce the production and accumulation of mycotoxins in the field or after harvest, but these methods have difficulty in completely removing mycotoxins while keeping the nutrients at the same time. Biodegradation methods using isolated enzymes have shown superiority and potential for modest reaction conditions, high degradation efficiency and degradation products with low toxicity. Therefore, the occurrence, chemical structures, and toxicology of six prevalent mycotoxins (deoxynivalenol, zearalenone, aflatoxin, patulin, fumonisin, and ochratoxin) were described in this manuscript. The identification and application of mycotoxin-degrading enzymes were thoroughly reviewed. It is believed that in the near future, mycotoxin-degrading enzymes are expected to be commercially developed and used in the feed and food industries. [ABSTRACT FROM AUTHOR]

Exposure to mycotoxins through the dietary route occurs on a daily basis while their deleterious effects are exhibited in the form of ailments, such as inflammation, cancer, and hormonal imbalance. The negative impact of mycotoxins can be attributed to their interaction with various biomolecules and their interference in metabolic pathways. The activity of biomolecules, such as enzymes/receptors, which engage the intricate mechanism of endogenous metabolism, is more susceptible to disruption by metabolites of high toxicity, which gives rise to adverse health effects. Metabolomics is a useful analytical approach that can assist in unraveling such information. It can simultaneously and comprehensively analyze a large number of endogenous and exogenous molecules present in biofluids and can, thus, reveal biologically relevant perturbations following mycotoxin exposure. Information provided by genome, transcriptome and proteome analyses, which have been utilized for the elucidation of biological mechanisms so far, are further complemented by the addition of metabolomics in the available bioanalytics toolbox. Metabolomics can offer insight into complex biological processes and their respective response to several (co-)exposures. This review focuses on the most extensively studied mycotoxins reported in literature and their respective impact on the metabolome upon exposure. [ABSTRACT FROM AUTHOR]

Enzymes are biologically active complex protein molecules that catalyze most chemical reactions in living organisms, and their inhibitors accelerate biological processes. This review emphasizes medicinal food plants and their isolated chemicals inhibiting clinically important enzymes in common diseases. A mechanistic overview was investigated to explain the mechanism of these food bases enzyme inhibitors. The enzyme inhibition potential of medicinal food plants and their isolated substances was searched in Ovid, PubMed, Science Direct, Scopus, and Google Scholar. Cholinesterase, amylase, glucosidase, xanthine oxidase, tyrosinase, urease, lipoxygenase, and others were inhibited by crude extracts, solvent fractions, or isolated pure chemicals from medicinal food plants. Several natural compounds have shown tyrosinase inhibition potential, including quercetin, glabridin, phloretin-4-O-β-D-glucopyranoside, lupinalbin, and others. Some of these compounds' inhibitory kinetics and molecular mechanisms are also discussed. Phenolics and flavonoids inhibit enzyme activity best among the secondary metabolites investigated. Several studies showed flavonoids' significant antioxidant and anti-inflammatory activities, highlighting their medicinal potential. Overall, many medicinal food plants, their crude extracts/fractions, and isolated compounds have been studied, and some promising compounds depending on the enzyme have been found. Still, more studies are recommended to derive potential pharmacologically active functional foods. [ABSTRACT FROM AUTHOR]

Acrolein, a highly reactive toxic aldehyde, is a common dietary and environmental contaminant which can also be generated endogenously. Exposure to acrolein has been positively associated with some pathological conditions, such as atherosclerosis, diabetes mellitus, stroke, and Alzheimer's disease. At the cellular level, acrolein induces various harmful effects, particularly protein adduction and oxidative damages. Polyphenols are a group of secondary plant metabolites ubiquitously presented in fruits, vegetables, and herbs. Recent evidence has gradually solidified the protective role of polyphenols by working as acrolein scavengers and regulator of acrolein toxicities. This was largely attributed to the ability of polyphenols as antioxidants and sacrificial nucleophiles in trapping acrolein. This review discussed the exposure and toxicity of acrolein, summarized the known and anticipated contribution of polyphenols in ameliorating acrolein contamination and its health hazards. [ABSTRACT FROM AUTHOR]

Liquid chromatography-mass spectrometry (LC–MS) has emerged as a powerful analytical technique for analyzing complex biological samples. Among various chromatographic stationary phases, porous graphitic carbon (PGC) columns have attracted significant attention due to their unique properties—such as the ability to separate both polar and non-polar compounds and their stability through all pH ranges and to high temperatures—besides the compatibility with LC–MS. This review discusses the applicability of PGC for SPE and separation in LC–MS-based analyses of human biological samples, highlighting the diverse applications of PGC-LC–MS in analyzing endogenous metabolites, pharmaceuticals, and biomarkers, such as glycans, proteins, oligosaccharides, sugar phosphates, and nucleotides. Additionally, the fundamental principles underlying PGC column chemistry and its advantages, challenges, and advances in method development are explored. This comprehensive review aims to provide researchers and practitioners with a valuable resource for understanding the capabilities and limitations of PGC columns in LC–MS-based analysis of human biological samples, thereby facilitating advancements in analytical methodologies and biomedical research. [ABSTRACT FROM AUTHOR]

In the human body, the positive effects of phenolic compounds are increasingly observed through their presence in tissues and organs in their native form or in the form of metabolites or catabolites formed during digestion, microbial metabolism, and host biotransformation. The full extent of these effects is still unclear. The aim of this paper is to review the current knowledge of beneficial effects of native phenolic compounds or their metabolites and catabolites focusing on their role in the health of the digestive system, including disorders of the gastrointestinal and urinary tracts and liver. Studies are mostly connecting beneficial effects in the gastrointestinal and urinary tract to the whole food rich in phenolics, or to the amount of phenolic compounds/antioxidants in food. Indeed, the bioactivity of parent phenolic compounds should not be ignored due to their presence in the digestive tract, and the impact on the gut microbiota. However, the influence of their metabolites and catabolites might be more important for the liver and urinary tract. Distinguishing between the effects of parent phenolics vs metabolites and catabolites at the site of action are important for novel areas of food industry, nutrition and medicine. [ABSTRACT FROM AUTHOR]

The methanolic extract of the marine sponge Hemimycale sp. yielded two new compounds; 1-(2'-methyl heptadecyl) phenol (1) and a new pyrazole derivative; 4-(hydroxymethyl)-1H-pyrazol-3-ol (2), together with previously isolated (2′R)-2′-hydroxy-N-((2S,3S,4R)-1,3,4-trihydroxy-16-methylpentadecan-2-yl)docosanamide (3), cholesterol (4), 5, 8-epi-dioxycholest-6-en-3-ol (5) and 3-acetylsesterstatin 3 (6), which were firstly reported from family Hymedesmiidae. Their structure elucidation was based on extensive nuclear magnetic resonance spectroscopy and high resolution-electrospray ionization-mass spectrometry. The isolated compounds were evaluated for their anti-leishmanial and cytotoxic activities. Compound 5 showed remarkable anti-leishmanial activity with IC50 value of 15.8 ± 0.92 µg/mL comparable with the standard miltefosine (IC50 = 3.2 ± 0.07 µg/mL), while compound 3 exhibited noteworthy cytotoxicity against A594 cell line with IC50 value of 29.6 ± 1.68 µg/mL compared to etoposide (IC50 = 10.9 ± 1.30 µg/mL). [ABSTRACT FROM AUTHOR]

Background: The metabolism of gut microbiota produces bioactive metabolites that modulate host physiology and promote self-growth. Erysipelotrichaceae is one of the most common anaerobic microorganism families in the gut, which has been discovered to play a vital role in host metabolic disorders and inflammatory diseases. Our previous study found that N-acetylgalactosamine (GalNAc) in caecal content of pigs significantly affected the abundance of Erysipelotrichaceae strains. However, it remains unknown how GalNAc feeding in vitro culture affects the expression levels of genes in the GalNAc metabolic pathway and the concentrations of intermediate metabolites in the Erysipelotrichaceae strain. Whether GalNAc feeding should influence the metabolism of other nutrients, such as amino acids, remains unrevealed. Results: In this study, whole-genome sequence, transcriptome, and metabolome data were analyzed to assess the utilization of a Erysipelotrichaceae strain on GalNAc. The results showed the presence of a complete GalNAc catabolism pathway in the genome of this Erysipelotrichaceae strain. GalNAc feeding to this Erysipelotrichaceae strain significantly changed the expression levels of genes involved in glycolysis and tricarboxylic acid (TCA) cycle. Meanwhile, the concentrations of lactate, pyruvate, citrate, succinate and malate from the glycolysis and TCA cycle were significantly increased. In addition, transcriptome analysis indicated that the genes involved in the metabolism of amino acids were affected by GalNAc, including lysA (a gene involved in lysine biosynthesis) that was significantly down-regulated. The intracellular concentrations of 14 amino acids in the Erysipelotrichaceae strain were significantly increased after feeding GalNAc. Conclusions: Our findings comfirmed and extended our previous works that demonstrated the utilization of GalNAc by Erysipelotrichaceae strain, and explained the possible mechanism of GalNAc affecting the abundance of Erysipelotrichaceae strain in vitro. [ABSTRACT FROM AUTHOR]

The recent growing interest in the biological properties of lichen metabolites has evidenced different needs and challenges for further exploration, including the development of green processing with safer solvents and more efficient use of energy. Microwave assisted hydrothermal processing, applied after supercritical CO2 extraction, was proposed for the sequential extraction of bioactives and biopolymer fractions. Alternatively, it was combined with natural deep eutectics (NaDES) as cosolvents. Lichenic acids, antioxidants and oligosaccharides were simultaneously extracted using NaDES, and the recovered polysaccharides showed adequate mechanical properties for the formulation of films with antimicrobial action against Gram positive bacteria. An environmental assessment of the three different processes using the Eco-Scale suggested that the NaDES microwave extraction was, due to its low toxicity and good extraction yield of polysaccharides, the most sustainable of the three processes. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by poor prognosis due to the absence of effective targeted therapies. Emerging evidence indicates that the gut microbiota and its metabolites play a key role in the occurrence and development of TNBC. This study aimed to explore the metabolic changes and potential mechanisms associated with TNBC. Objectives: This study aimed to explore the potential relationship between targeted metabolites and the gut microbiota in TNBC. Design: We recruited 8 participants, including 4 with TNBC and 4 with benign fibroadenomas as controls. Methods: The gut microbiota was analyzed using metagenomics on fecal samples. Liquid chromatography–mass spectrometry (LC-MS) was employed to identify differential metabolites in serum and fecal samples. The correlation between the gut microbiota and metabolites was analyzed using Spearman's correlation analysis. Results: Analysis of altered serum metabolites in the TNBC group revealed changes, particularly in carboxylic acids and derivatives, benzene, and substituted derivatives. Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis revealed significant enrichment in 18 pathways. Regarding fecal metabolites, differences between the 2 groups also included carboxylic acids and derivatives, benzene, and substituted derivatives, with 28 metabolic pathways enriched based on KEGG pathway analysis. Metagenomics analysis showed differences in the relative abundance of Anaerococcus, Fischerella, and Schizosaccharomyces at the genus level, which have been previously associated with breast cancer. Furthermore, 4 serum metabolites—L-glutamine, citrate, creatinine, and creatine—along with 9 fecal metabolites, were associated with the aforementioned microbiota. Conclusion: Our findings highlight distinct metabolite profiles in the serum and feces of patients with TNBC. The identification of gut microbiota and their associated metabolites provides new insights into the pathophysiological mechanisms underlying TNBC. [ABSTRACT FROM AUTHOR]

Background: Bacillus strains are well recognized for their inherent production of bioactive compounds that exhibit antibacterial and anticancer properties. This study aims to evaluate the antimicrobial and anticancer effects of the secondary metabolite isolated from Bacillus licheniformis and Bacillus siamensis strain. Material and method: We developed and purified a new soil-derived Bacillus strain to study its metabolites on cancer cells and bacteria. After evaluating the antimicrobial effects of the selected strains' secondary metabolites by well diffusion, growth conditions and temperature optimised using liquid-liquid extraction, secondary metabolites isolated, and active compounds identified using GC-MS. Evaluation of PC-3 and HPrEpC cytotoxicity. AV/PI staining and comet assay assessed necrosis and apoptosis. Real-time PCR measured apoptotic gene expression. Finally, the scratch test measured cell movement. Results: Bacillus strain metabolites exhibit dual-purpose antimicrobial and anticancer properties. Bacillus licheniformis isolate 56 and S2-G12 isolate 60 demonstrated the greatest antibacterial activity. Among all Bacillus isolates, isolates 56 (Bacillus licheniformis) and 60 (Bacillus siamensis strain) had the highest antibacterial activity. Crude extracts obtained from strains 56 and 60 decreased PC-3 cell viability in a dose-dependent manner. At 200 µg/mL, the survival rate of cells treated with strain 56 and 60 crude extract was 23% and 25%, respectively (p < 0.001). The treatment of PC-3 cells with strains 56 and 60 crude extract led to considerable apoptosis (46.2% and 50.09%, respectively) compared to the control group. After treatment with the crude extract from strains 56 and 60 at an IC50 concentration, a significant number of PC-3 cells showed comet formation, indicating DNA fragmentation. Metabolites extracted from strain 56 and 60 enhanced caspase 3, caspase 8, and Bax genes expression and reduced Bcl-2 expression (p < 0.001). Cell migration was also prevented. Conclusion: Our findings show that the secondary metabolites of B. licheniformis and B. siamensis have antibiotic and anticancer properties. However in vivo studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Turbinaria ornata, Polycladia myrica, and Padina pavonica is a perennial Mediterranean-native seaweed that is commonly used for mass display. The principal aims of this reconnaissance were the isolation of various compounds from methanolic seaweeds extraction and screening the potential effect as antibacterial, and antioxidant. The micro-dilution method was used to measure antibacterial activity. Gas chromatography-mass spectrophotometry (GC. Mass) abused to analyze the chemical components of the methanolic seaweed extract. The existence of 19 secondary metabolites was discovered using GC–MS analysis: 8 different compounds for each seaweed's species. Among these bioactive compounds, 4 compounds from P. pavonica extract showed the binding affinity and ability to react with Beta-ketoacyl synthase (PDB ID 1EK4) of Escherichia coli. The phytocompounds' drug-like and poisonous characteristics were predicted. Auto Dock was used to examine the ligand receptor complexes' binding strength. T. ornate and P. pavonica had the highest activity against K. pneumonia, with 22.50 mm (0.78 µg/ml) and 22.23 mm (5.10 µg/ml) obtained, respectively. In a concentration-dependent manner, the extract components demonstrated substantial antioxidant activity. P. pavonica had the highest scavenging activity (78.00%, IC50 = 6.35 µg/ml), while ascorbic acid had a 96.45% scavenging impact. Because the chemicals bind to the Lipinski Ro5, they have drug-like characteristics. The compounds had no hepatotoxic effects. P. pavonica extract has the prospect of being used as a source of medicinal drug-like chemicals. The docking investigation found a strong correlation between the experimental results and the docking results. Finally, brown seaweed extract, particularly P. pavonica extract, demonstrated strong antibacterial, antioxidant, and free radical scavenging properties. [ABSTRACT FROM AUTHOR]

Dinanath grass (Pennisetum pedicellatum Trin.) is an extensively grown forage grass known for its significant drought resilience. In order to comprehensively grasp the adaptive mechanism of Dinanath grass in response to water deficient conditions, transcriptomic and metabolomics were applied in the leaves of Dinanath grass exposed to two distinct drought intensities (48-hour and 96-hour). Transcriptomic analysis of Dinanath grass leaves revealed that a total of 218 and 704 genes were differentially expressed under 48- and 96-hour drought conditions, respectively. The genes that were expressed differently (DEGs) and the metabolites that accumulated in response to 48-hour drought stress mainly showed enrichment in the biosynthesis of secondary metabolites, particularly phenolics and flavonoids. Conversely, under 96-hour drought conditions, the enriched pathways predominantly involved lipid metabolism, specifically sterol lipids. In particular, phenylpropanoid pathway and brassinosteroid signaling played a crucial role in drought response to 48- and 96-hour water deficit conditions, respectively. This variation in drought response indicates that the adaptation mechanism in Dinanath grass is highly dependent on the intensity of drought stress. In addition, different genes associated with phenylpropanoid and fatty acid biosynthesis, as well as signal transduction pathways namely phenylalanine ammonia-lyase, putrescine hydroxycinnamoyl transferase, abscisic acid 8'-hydroxylase 2, syntaxin-61, lipoxygenase 5, calcium-dependent protein kinase and phospholipase D alpha one, positively regulated with drought tolerance. Combined transcriptomic and metabolomic analyses highlights the outstanding involvement of regulatory pathways related to secondary cell wall thickening and lignin biosynthesis in imparting drought tolerance to Dinanath grass leaves. These findings collectively contribute to an enhanced understanding of candidate genes and key metabolites relevant to drought response in Dinanath grass. Furthermore, they establish a groundwork for the creation of a transcriptome database aimed at developing abiotic stress-tolerant grasses and major crop varieties through both transgenic and genome editing approaches. [ABSTRACT FROM AUTHOR]

Background and purpose: While there is evidence that gut microbiota (GM) and blood metabolites are associated with ovarian cancer (OC), the precise mechanisms underlying this relationship are still unclear. This study used Mendelian randomization (MR) to elucidate the causal connections between GM, blood metabolite biomarkers, and OC. Methods: In this study, we leveraged summary data for GM (5,959 individuals with genotype-matched GM), blood metabolites (233 circulating metabolic traits with 136,016 participants), and OC (63,702 participants with 23,564 cases and 40,138 controls) from genome-wide association studies (GWASs). We performed MR analysis to explore the causal relationship between GM and OC. Further, we harnessed univariable MR (UVMR) analysis to evaluate the causal associations between GM and circulating metabolites. Finally, we employed a two-step approach based on multivariable MR (MVMR) to evaluate the total genetic prediction effect of metabolites mediating the GM on the risk of OC to discover a potential causal relationship. Results: In the MR analysis, 24 gut bacteria were causally associated with the pathogenesis of OC, including 10 gut bacteria (Dorea phocaeense, Succinivibrionaceae, Raoultella, Phascolarctobacterium sp003150755, Paenibacillus J, NK4A144, K10, UCG-010 sp003150215, Pseudomonas aeruginosa, and Planococcaceae) that were risk factors, and 14 gut bacteria (CAG-177 sp002438685, GCA-900066135 sp900066135, Enorma massiliensis, Odoribacter laneus, Ruminococcus E sp003521625, Streptococcus sanguinis, Turicibacter sp001543345, Bacillus velezensis, CAG-977, CyanobacteriaStaphylococcus A fleurettii, Caloranaerobacteraceae, RUG472 sp900319345, and CAG-269 sp001915995) that were protective factors. The UVMR analysis showed that these 24 positive gut bacteria were causally related to lipoproteins, lipids, and amino acids. According to the MVMR analysis, Enorma massiliensis could reduce the risk of OC by raising the total cholesterol to total lipids ratio in large low-density lipoprotein (LDL) and cholesteryl esters to total lipids ratio in intermediate-density lipoprotein (IDL). Turicibacter sp001543345, however, could reduce the risk of OC by lowering free cholesterol in small high-density lipoprotein (HDL) and increasing the ratios of saturated fatty acids to total fatty acids, total cholesterol to total lipids ratio in very small very-low-density lipoprotein (VLDL), and cholesteryl esters to total lipids ratio in very small VLDL. Conclusion: The current MR study provides evidence that genetically predicted blood metabolites can mediate relationships between GM and OC. [ABSTRACT FROM AUTHOR]

Within host environments, iron availability is limited, which instigates competition for this essential trace element. In response, bacteria produce siderophores, secondary metabolites that scavenge iron and deliver it to bacterial cells via specific receptors. This role in iron acquisition contributes significantly to bacterial pathogenesis, thereby designating siderophores as virulence factors. While prior research has primarily focused on unravelling the molecular mechanisms underlying siderophore biosynthesis, uptake, and iron sequestration, recent investigations have unveiled additional non-iron chelating functions of siderophores. These emerging roles are being consistently shown to support bacterial pathogenesis. In this review, we present the current understanding of siderophores in various roles: acquiring non-iron metal ions, supporting tolerance to metal-induced and reactive oxygen species (ROS)-induced stresses, mediating siderophore signalling, inducing ROS formation, and functioning in class IIb microcins. By integrating recent findings, this review aims to provide an overview of the diverse roles of siderophores in bacterial pathogenesis. [ABSTRACT FROM AUTHOR]

Dopamine's role as the principal neurotransmitter in motor functions has long been accepted. We broaden this conventional perspective by demonstrating the involvement of non-dopaminergic mechanisms. In mouse models of Parkinson's disease, we observed that L- DOPA elicited a substantial motor response even when its conversion to dopamine was blocked by inhibiting the enzyme aromatic amino acid decarboxylase (AADC). Remarkably, the motor activity response to L- DOPA in the presence of an AADC inhibitor (NSD1015) showed a delayed onset, yet greater intensity and longer duration, peaking at 7 h, compared to when L- DOPA was administered alone. This suggests an alternative pathway or mechanism, independent of dopamine signalling, mediating the motor functions. We sought to determine the metabolites associated with the pronounced hyperactivity observed, using comprehensive metabolomics analysis. Our results revealed that the peak in motor activity induced by NSD1015/ L- DOPA in Parkinson's disease mice is associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (also known as ophthalmate in its anionic form). Interestingly, we found that administering ophthalmate directly to the brain rescued motor deficits in Parkinson's disease mice in a dose-dependent manner. We investigated the molecular mechanisms underlying ophthalmate's action and discovered, through radioligand binding and cAMP-luminescence assays, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR). Additionally, our findings demonstrated that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate, further solidifying the evidence that ophthalmate modulates motor functions through the activation of the CaSR. The discovery of ophthalmate as a novel regulator of motor function presents significant potential to transform our understanding of brain mechanisms of movement control and the therapeutic management of related disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mycotoxin surveys play an essential role in our food safety system. The obtained occurrence data form the basis for the assessment of the exposure of humans and animals to these toxic fungal secondary metabolites. Liquid chromatography coupled with tandem mass spectrometry (LC‐MS/MS) has become the gold standard for mycotoxin determination because it enables selective and sensitive multi‐toxin analysis. Simultaneous determination of several hundreds of secondary fungal metabolites is feasible using this technique. In this study, we combined a targeted dilute‐and‐shoot LC‐MS/MS‐based multi‐analyte approach with multivariate statistics for the analysis of Austrian wheat from two different years and different geographical origins. RESULTS: We quantified 47 secondary fungal metabolites, including regulated emerging and masked mycotoxins. The resulting multi‐mycotoxin occurrence data were further analyzed using both multivariate and univariate statistics. Principal component analysis (PCA) and analysis of variance (ANOVA) simultaneous component analysis (ASCA) were employed to identify regional and yearly trends within the dataset and to quantify the variance in metabolite occurrence attributed to the different effects. In addition, secondary fungal metabolites significantly impacted by these factors were selected via ANOVA. Of the 47 secondary metabolites identified, 39 were affected by the year, region or a combined effect. Moreover, our findings show that 43 of the secondary fungal metabolites were significantly influenced by the weather conditions. CONCLUSION: The results presented in this study underline the added value of combining targeted LC‐MS/MS with multivariate statistics for monitoring a broad spectrum of secondary fungal metabolites in food crops. Through multivariate statistics, trends associated with the year or region can be readily studied. The approach presented could pave the way for a better understanding of the impact of climate change on plant pathogenic fungi and its implications for food safety. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Komagataella phaffii (K. phaffii), formerly known as Pichia pastoris, is a widely utilized yeast for recombinant protein production. However, due to the formation of overflow metabolites, carbon yields may be reduced and product recovery becomes challenging. This study investigates the impact of oxygen availability, different glucose concentrations and feeding strategies on overflow metabolite formation and recombinant protein production in K. phaffii. Results: High glucose concentrations in batch fermentation, as applied in literature, lead to substantial ethanol accumulation, adversely affecting biomass yield and product formation. Increasing dissolved oxygen setpoints does not significantly reduce ethanol formation, indicating that glucose surplus, rather than oxygen availability, drives overflow metabolism. Decreasing the initial glucose concentration to 5 g/L and adapting the feeding strategy of the fed-batch phase, effectively mitigates overflow metabolite formation, improving biomass yield by up to 9% and product concentration by 40% without increasing process time. Conclusions: These findings underscore the importance of a suitable glucose-feeding strategy in K. phaffii fermentation processes and highlight the detrimental effects of overflow metabolites on productivity. By optimizing carbon source utilization, it is possible to enhance fermentation efficiency and recombinant protein production with K. phaffii. [ABSTRACT FROM AUTHOR]

Microbial secondary metabolites are a rich source for pharmaceutical discoveries and play crucial ecological functions. While tools exist to identify secondary metabolite clusters in genomes, precise sequencetofunction mapping remains challenging because neither function nor substrate specificity of biosynthesis enzymes can accurately be predicted. Here, we developed a knowledgeguided bioinformatic pipeline to solve these issues. We analyzed 1928 genomes of Pseudomonas bacteria and focused on iron-scavenging pyoverdines as model metabolites. Our pipeline predicted 188 chemically different pyoverdines with nearly 100% structural accuracy and the presence of 94 distinct receptor groups required for the uptake of ironloaded pyoverdines. Our pipeline unveils an enormous yet overlooked diversity of siderophores (151 new structures) and receptors (91 new groups). Our approach, combining feature sequence with phylogenetic approaches, is extendable to other metabolites and microbial genera, and thus emerges as powerful tool to reconstruct bacterial secondary metabolism pathways based on sequence data. [ABSTRACT FROM AUTHOR]

Summary: During the primary fermentation of beer, the yeast simultaneously carries out a series of processes such as cell growth, pH shift, and the formation and degradation of essential flavour components. Harvested yeast from a previous fermentation can be used to inoculate the fermentation or fresh cells can be produced through aerobic propagation. This study investigated the influence of different aeration conditions during Saccharomyces pastorianus ssp. carlsbergensis propagation on the cell count development and the production of secondary metabolites during the subsequent primary beer fermentation. Propagations were conducted by applying six different dissolved oxygen concentrations, and the cells were used as inoculum for the subsequent fermentation. Cell count, pH shift, and the development of key aroma compounds were monitored throughout the primary fermentation to evaluate any difference between the conducted fermentations. The outcomes revealed significant distinctions between fermentations using yeast propagated under elevated oxygen levels and those propagated under reduced oxygen levels. Cells propagated using lower oxygen concentrations showed earlier cell growth with 40% lower final cell counts, resulting in 50% reduced biomass yields. Additionally, lower oxygen concentrations during propagation led to lower pH shifts during primary fermentation with 20% more higher alcohols and elevated formation of acetaldehyde, and esters. [ABSTRACT FROM AUTHOR]

Summary: Aflatoxins are toxic secondary metabolites produced by Aspergillus spp., found in staple food commodities. Aflatoxins are carcinogenic, teratogenic, and mutagenic and pose a serious threat to the health of humans. The identification and quantification of aflatoxins in foods is a major challenge to guarantee food safety. Therefore, developing feasible, sensitive, and robust methods for decontamination is paramount, with short processing time and negligible impact on quality. This review evaluates recent novel technologies for aflatoxins decontamination by physical methods (microwave heating, Gama and electron beam irradiation, pulse light and ultraviolet), chemical methods (ozone, natural plant extracts, and organic acids), and biological methods (atoxigenic Aspergillus strains, Trichoderma spp., and bacteria and yeast). The study highlights on the cutting‐edge technologies of smart packaging and artificial intelligence (AI). To achieve more efficiency and adaptability to different food matrices in aflatoxins decontamination, the study suggests integrating multiple strategies. The study also recommends integrating Partnership for Delivery (P4D) to share the responsibility to increase the chance for success and control aflatoxins in foods. [ABSTRACT FROM AUTHOR]

Summary: The cases of fake Moutai‐flavour liquor have occurred frequently, seriously disrupting market economic order, therefore it is of great significance to realise the Moutai‐flavour liquor identification. Herein, an approach based on GC–MS technology coupled with chemometrics was established to achieve products identification and origins traceability. The normalised metabolite data were analysed by PCA, OPLS‐DA and volcano plot to screen differential metabolites. The heatmap visualisation and boxplot were used to explore the correlation between chemical markers and liquor samples. PLS‐DA model realised the accurate classification of Moutai‐flavour liquor samples using the screened chemical markers. All Moutai‐flavour liquor samples of the prediction set were accurately differentiated with 100% accuracy during the external verification. This study indicated that an approach based on GC–MS coupled with chemometrics has great potential for products identification and source tracing, thus providing technical support for combating crime of fake Moutai‐flavour liquor. [ABSTRACT FROM AUTHOR]

Objectives Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs). Methods Serum NMR metabolomic profiles from female SLE patients (n  = 164, age = 14–76) and HCs (n  = 123, age = 13–72) were assessed across age by linear regression and by age group between patients/HCs (Group 1, age ≤ 25, n  = 62/46; Group 2, age = 26–49, n  = 50/46; Group 3, age ≥ 50, n  = 52/31) using multiple t tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed. Results Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group 1), increased very-low-density lipoproteins (Group 2), and increased low-density lipoproteins (Group 3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein (Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type 1 and type 2 diabetes by disease-wide association. Conclusions Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies. [ABSTRACT FROM AUTHOR]

In this work, the stems, leaves, and flowers of Ruta chalepensis L., R. graveolens L., and R. montana L. harvested in Morocco were subject to a comparative study to determine the phytochemical composition, antioxidant capacities, and the content of total phenols and flavonoids. For this purpose, 45 crude extracts (CEs) were prepared using different solvents, including water, ethyl acetate, methanol, ethanol, and hexane. Upon undergoing secondary metabolites screening, it was discovered that the different parts of three Ruta species contain a high level of secondary metabolites such as alkaloids, catechic tannins, flavonoids, coumarins, sterols, and triterpenes. This was confirmed by the results of the quantitative analysis, which proved that the three Ruta species contain a significant amount of total phenolic compounds, ranging from 27.05 to 213.42 mg GAE/g CE. With regard to antioxidant capacities, antiradical power (ARP) results prove that the majority of CEs have great ARP (were within the range of 0.42–1.99) compared to the BHT (butylated hydroxytoluene) standard (0.33 APR). In addition, the results of total antioxidant capacity (TAC) analysis of Ruta CEs showed good TAC (varies between 37.67 and 396.80 mg AAE/g CE). [ABSTRACT FROM AUTHOR]

Fusarium oxysporum f.sp. cubense (Foc) is a fungus that not only causes disease while bananas are being grown, but it also causes begetting after bananas are harvested, which limits the production of bananas. Zingiberaceae plants contain a high number of extractable secondary metabolites that are regarded to have effective antifungal activities. However, in order for the compounds to be suitable for use, they must be tested by modifying the polarity in the extracting solvent. In this study, four Zingiberaceae species were examined, namely Zingiber officinale, Curcuma longa, C. zanthorrhiza, and Alpinia galanga. The extraction of rhizomes of each plant was accomplished by using solvents with distinct polarity index (PI) viz. water (PI 9.0); a mixture of 50% water and 50% ethanol (PI 7.1); ethanol (PI 5.2); and n-hexane (PI 0.0). The anti-Fusarium evaluation of these 16 extracts was carried out in vitro by implementing the pour plate method in potato dextrose agar (PDA). Our results showed that the C. zanthorrhiza n-hexane extract possessed the greatest antifungal activity among other extracts. The fungal inhibition ability of the extracts was negatively correlated with the increase in solvent polarity index. In order to comprehend our understanding of the antifungal activity, the chemical compositions of each extract were identified through non-targeted Gas Chromatography–Mass Spectrometry (GC-MS), showing the main components of the n-hexane extracts were terpenes and terpenoids. Particularly, C. zanthorrhiza n-hexane extract contained, with the percentage of abundance in parentheses, germacrene B (22.99%), β-farnesene (14.72%), curzerene (10.87%), 2-bornanone (9.60%), α-curcumene (9.32%), zingiberene (8.30%), β-curcumene (6.36%), β-elemene (5.31%), caryophyllene (3.36%), cedrene (2.73%), α-bergamotene (1.36%), and humulene (0.20%). As conclusion, this crude extract or its pure chemical constituents have potential application as biofumigant to control Foc in postharvest banana. [ABSTRACT FROM AUTHOR]

The culture of a cyanobacterium 'Anabaena' sp. was isolated from alluvial meadow soils in the south of Russia and deposited in the IPPAS collection of cultures of microalgae and cyanobacteria, Timiryazev Institute of Plant Physiology, Russian Academy of Sciences, under the number IPPAS B-2020. Phylogenetic analysis showed that the studied strain belongs to a clade comprising the genera Sphaerospermopsis, Amphiheterocytum, Raphidiopsis, Wollea, and Neowollea, but cannot currently be assigned to any of them. The phytotoxicity and fungicidal and antioxidant activities of the strain were studied. The culture turned out to be non-toxic. Water–alcohol extract and biomass of 'Anabaena' sp. IPPAS B-2020 completely suppressed the micromycetes Fusarium culmorum, F. graminearum, and F. sporotrichioides with the maximum diameter of growth inhibition zone of 2.5 cm. The water extract of cyanobacteria 'Anabaena' sp. IPPAS B-2020 had a pronounced antioxidant activity (39.3%). Among the metabolites of 'Anabaena' sp. IPPAS B-2020, there were organic acids (citric, lactic, acetic), terpenes, alkanes, alcohols, and other low molecular weight organic compounds. The 'Anabaena' sp. IPPAS B-2020 culture is of interest for biotechnology as a producer of such important biologically active compounds as tributyl phosphate, D-limonene, squalene, and α-pinene. [ABSTRACT FROM AUTHOR]

Shrimp head by-product (SHP) has been increasingly studied for applications in bacterial fermentation and the production of secondary metabolites. In this work study, Bacillus velezensis EB.KN15 was grown via fermentation using SHP as a novel substrate on a large scale and its potential fungicidal effect against durian pathogen fungi was evaluated. SHP was found rich in protein content (29.18%) and several mineral elements suitable for EB.KN15 fermentation. The appropriate cultural medium for B. velezensis EB.KN15 growth in the small-scale fermentation using 250 mL-Erlenmeyer flask included 2% SHP/LB (7/3), 0.05% MnSO4, and 0.1% KH2PO4 at 34 °C, pH 7 for 36 h. When scaling up fermentation in a 14 L-bioreactor system, this strain exhibited better productivity (1.2 × 1012 CFU/mL) in a shorter fermentation time (only 10 h). Anti-fungal activity tests revealed for the first time, that EB.KN15 has potential fungicidal effect against Fusarium incarnatum, Phytophthora palmivora, and Fusarium solani with high inhibition values of 70%, 78.95%, and 80%, respectively. Gas chromatography mass spectrometry could identify 11 major volatiles produced by B. velezensis EB.KN15 in the supernatant. The molecular docking indicated effective interaction of these major volatiles with the target protein responsible for F. solani inhibition with good binding energy (DS ≤ 7.1 kcal/mol) and an acceptable root-mean-square deviation value (1.05–1.96 Å). This study suggests that SHP is a new substrate for the fermentation of B. velezensis EB.KN15 and recorded this strain as a novel potential candidate to effectively manage durian pathogen fungi. [ABSTRACT FROM AUTHOR]

Plant–microbe interactions significantly influence plant growth dynamics and adaptability. This study explores the impact of metabolites on microbial biodiversity in shoot tips and wood of Populus nigra under greenhouse conditions, using high‐throughput sequencing and metabolite profiling. Branches from P. nigra were harvested, rooted, and transplanted into pots for growth. After 3 months, tissue samples from shoot tips and wood were collected, and metabolites extracted and analysed using GC‐MS and LC‐MS. Genomic DNA was extracted and subjected to high‐throughput sequencing for bacterial biodiversity profiling. Both datasets were analysed using bioinformatic and statistical pipelines. Metabolite profiling indicated that shoot tips had a higher relative abundance of primary and secondary metabolites, including sugars, fatty acids, organic acids, phenolic acid derivatives and salicinoids, while wood was enriched in flavonoids. Bacterial biodiversity also differed significantly between these tissues, with Clostridiales, Bacteroidales and Bacillales dominating in shoot tips, associated with rapid growth and anaerobic fermentation, while wood tissues were characterized by diazotrophs from Rhizobiales, Sphingomonadales and Frankiales. PCoA clustering confirmed tissue‐specific microbial differences. Functional analysis revealed an enrichment of fundamental cellular processes in shoot tips, while wood exhibited pathways related to degradation and mortality. Metabolite profiling revealed significant variations in primary and secondary metabolites, highlighting their influence on microbial biodiversity across plant tissues. The dominance of specific bacterial orders and distinct functional pathways in each tissue suggests a tailored microbial response to the unique environments of shoot tips and wood. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) depletion has been postulated as a contributor to the severity of COVID‐19; however, no study has prospectively characterized NAD+ and its metabolites in relation to disease severity in patients with COVID‐19. We measured NAD+ and its metabolites in 56 hospitalized patients with COVID‐19 and in two control groups without COVID‐19: (1) 31 age‐ and sex‐matched adults with comorbidities, and (2) 30 adults without comorbidities. Blood NAD+ concentrations in COVID‐19 group were only slightly lower than in the control groups (p < 0.05); however, plasma 1‐methylnicotinamide concentrations were significantly higher in patients with COVID‐19 (439.7 ng/mL, 95% CI: 234.0, 645.4 ng/mL) than in age‐ and sex‐matched controls (44.5 ng/mL, 95% CI: 15.6, 73.4) and in healthy controls (18.1 ng/mL, 95% CI 15.4, 20.8; p < 0.001 for each comparison). Plasma nicotinamide concentrations were also higher in COVID‐19 group and in controls with comorbidities than in healthy control group. Plasma concentrations of 2‐methyl‐2‐pyridone‐5‐carboxamide (2‐PY), but not NAD+, were significantly associated with increased risk of death (HR = 3.65; 95% CI 1.09, 12.2; p = 0.036) and escalation in level of care (HR = 2.90, 95% CI 1.01, 8.38, p = 0.049). RNAseq and RTqPCR analyses of PBMC mRNA found upregulation of multiple genes involved in NAD+ synthesis as well as degradation, and dysregulation of NAD+‐dependent processes including immune response, DNA repair, metabolism, apoptosis/autophagy, redox reactions, and mitochondrial function. Blood NAD+ concentrations are modestly reduced in COVID‐19; however, NAD+ turnover is substantially increased with upregulation of genes involved in both NAD+ biosynthesis and degradation, supporting the rationale for NAD+ augmentation to attenuate disease severity. [ABSTRACT FROM AUTHOR]

The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post‐marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects. This single‐center, open‐label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre‐dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated. All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies. Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded. [ABSTRACT FROM AUTHOR]

Microorganisms produce siderophores, which are secondary metabolites with a high affinity for iron. Siderophores have received significant attention due to their diverse applications in ecological and clinical research. In this study, siderophores production by Escherichia coli OQ866153 was optimized using two-stage statistical approach involving Plackett–Burman design (PBD) and response surface methodology (RSM) using central composite design (CCD). Out of 23 variables, succinate, tryptophan, Na2HPO4, CaCl2, agitation, and KH2PO4 were found to have the most significant effect on siderophores production in the first optimization stage with the highest SU% of 43.67%. In the second stage, RSM using CCD was utilized, and the optimal conditions were determined to be 0.3 g/l succinate, 0 g/l tryptophan, 6 g/l Na2HPO4, 0.1 g/l CaCl2, 150 RPM agitation, and 0.6 g/l KH2PO4, resulting in a maximum siderophore units (SU%) of 89.13%. The model was significant, as indicated by the model f-value of 314.14 (p-value = 0.0004) and coefficient of determination R2 of 0.9950. During validation experiments, the obtained maximum SU% was increased up to 87.1472%, which was two times as the value obtained under ordinary conditions (46.62%). The produced siderophores were purified and characterized using 1H, 13C NMR, IR spectroscopy. The obtained results indicated that the compound was enterobactin and entABCDEF genes were further detected in Escherichia coli OQ866153 extracted DNA. To our knowledge, this is the first report of statistical optimization for enterobactin synthesis by an E. coli strain isolated from a clinical source in Egypt. [ABSTRACT FROM AUTHOR]

Integrating grain yield, component traits and metabolite profiles aids in selecting drought‐adapted and climate‐smart crop varieties preferred by end users. Understanding the trends and magnitude of grain‐based metabolites is vital for selecting wheat genotypes with higher grain yield, drought tolerance, water use efficiency and product profiles. The aim of this study was to determine the response of newly developed wheat genotypes for grain yield and component traits and metabolites under drought stress to guide selection. One hundred wheat genotypes were preliminarily evaluated for agro‐morphological traits and water use efficiency under drought‐stressed and non‐stressed conditions during the 2022 and 2023 growing seasons using a 5 × 20 alpha lattice design with two replications. Ten high‐yielding genotypes were selected based on grain yield and were validated for agronomic traits and water use efficiency (WUE), and grain samples were assayed to profile their key metabolites under drought‐stressed conditions. Significant differences existed (p < 0.05) among the tested wheat genotypes for yield and yield components, WUE, drought tolerance and major metabolites to discern trait associations. The grain yield of the 10 genotypes ranged from 590.00 g m−2 (genotype LM70 × BW140) to 800.00 g m−2 (BW141 × LM71) under drought‐stressed treatment, whilst under non‐stressed it ranged from 760.06 g m −2 (LM70 × BW140) to 908.33 g m−2 (LM71 × BW162). Grain yield‐based water use efficiency of the assessed genotypes was higher under non‐stressed (0.18 g mm−1) than drought‐stressed (0.17 g mm−1) conditions. The highest drought tolerance index (211.67) and stress susceptibility index (0.77) were recorded for BW162 × LM71, whilst the lowest tolerance index (23.33) and stress susceptibility index (0.09) were recorded in BW141 × LM71. Grain metabolites, including the apigenin‐8‐C‐glucoside (log2Fold = 3.00) and malate (log2Fold = 3.60) were present in higher proportions in the high‐yielding genotypes (BW141 × LM71 and LM71 × BW162) under drought‐stressed conditions, whilst fructose (log2Fold = −0.50) and cellulose (log2Fold = −3.90) showed marked decline in the two genotypes. Based on phenotypic and metabolite profile analyses, genotypes BW141 × LM71 and LM71 × BW162 were selected for being drought‐tolerant, water‐use efficient and recommended for production or breeding. The findings revealed associations between yield components, water use efficiency and grain metabolites to guide the selection of best‐performing and drought‐tolerant wheat varieties. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic flexibility (MetF), defined as the ability to switch between fat and glucose oxidation, is increasingly recognised as a critical marker for assessing responses to dietary interventions. Previously, we showed that the consumption of multifibre bread improved insulin sensitivity and reduced low‐density lipoprotein cholesterol (LDLc) levels in overweight and obese individuals. As a secondary objective, we aimed to explore whether our intervention could also improve MetF. Methods: In this study, 39 subjects at cardiometabolic risk participated in a double‐blind, randomised, crossover trial lasting 8 weeks, repeated twice. During each phase, participants consumed either 150 g of standard bread daily or bread enriched with a mixture of seven dietary fibres. MetF response was assessed using a mixed‐meal tolerance test (MMTT), analysing changes in respiratory quotient (∆RQ) measured using indirect calorimetry. Results: Although there were no significant differences in ∆RQ changes induced by dietary fibre between the two diets, these changes were positively correlated with postprandial triglyceride excursion (∆TG) at baseline. Subgroup analysis of baseline fasting and postprandial plasma metabolites was conducted to characterise MetF responders. These responders exhibited higher baseline fasting LDLc levels and greater post‐MMTT ∆TG. Conclusion: In conclusion, although dietary fibres did not directly impact MetF in this study, our findings highlight potential determinants of MetF response, warranting further investigation in dedicated future interventions. Highlights: The term 'metabolic flexibility' (MetF) was initially used to describe the ability of helminths to generate energy through either aerobic respiration or anaerobic respiration, enabling them to adapt to environmental changes. This concept was later applied to human metabolism, emphasising the body's capacity to switch between different energy sources, such as carbohydrates and fats, based on energy requirements.MetF has been studied in the context of transitions between fasting and fed states, or in response to insulin stimulation. It refers to the body's ability to adapt its energy utilisation in response to changing metabolic demands.Research has shown that insulin resistance, often linked to type 2 diabetes and obesity, may be associated with reduced MetF, characterised by altered patterns of carbohydrate and fat oxidation. [ABSTRACT FROM AUTHOR]

Metabolic conversion of benzene (Bz) is thought to be required for the hematotoxic effects observed following Bz exposures. Most safe exposure limits set for Bz utilize epidemiology data on the hematotoxic effects of Bz for the dose–response assessments. These hematotoxic effects occurred among workers exposed to elevated Bz levels, thus dose extrapolation is required for assessing relevant risks for populations exposed orders of magnitude lower. Thus, understanding how Bz is metabolized over a wide range of air Bz levels is an important topic for risk assessments for Bz. Here, we analyze biomonitoring data for workers exposed to Bz to make evaluations of how the metabolism of Bz varies across a wide range of exposures. Our analysis indicates that the presence of metabolites derived from exposures to sources other than Bz (nonspecific metabolites of Bz) are significant confounders among biomonitoring studies and this precludes making any assessments of how Bz metabolism differs below approximately 3 ppm air Bz exposures using such nonspecific metabolites. [ABSTRACT FROM AUTHOR]

[Display omitted] • We elaborate on the role of gut microbiota and microbial metabolites in the efficacy and adverse effects of chemotherapeutics. • We further summarize the clinical potential of various ways to harness gut microbiota for cancer chemotherapy. • The potential of gut microbiota severing as predictive markers for chemotherapy efficacy is discussed. • Finally, we discuss current limitations and suggest potential approaches to facilitate utilization of gut microbiota in chemotherapy. The microbiota inhabits the epithelial surfaces of hosts, which influences physiological functions from helping digest food and acquiring nutrition to regulate metabolism and shaping host immunity. With the deep insight into the microbiota, an increasing amount of research reveals that it is also involved in the initiation and progression of cancer. Intriguingly, gut microbiota can mediate the biotransformation of drugs, thereby altering their bioavailability, bioactivity, or toxicity. The review aims to elaborate on the role of gut microbiota and microbial metabolites in the efficacy and adverse effects of chemotherapeutics. Furthermore, we discuss the clinical potential of various ways to harness gut microbiota for cancer chemotherapy. Recent evidence shows that gut microbiota modulates the efficacy and toxicity of chemotherapy agents, leading to diverse host responses to chemotherapy. Thereinto, targeting the microbiota to improve efficacy and diminish the toxicity of chemotherapeutic drugs may be a promising strategy in tumor treatment. [ABSTRACT FROM AUTHOR]

Introduction: The human salivary metabolome is a rich source of information for metabolomics studies. Among other influences, individual differences in sleep-wake history and time of day may affect the metabolome. Objectives: We aimed to characterize the influence of a single night of sleep deprivation compared to sufficient sleep on the metabolites present in oral fluid and to assess the implications of sampling time points for the design of metabolomics studies. Methods: Oral fluid specimens of 13 healthy young males were obtained in Salivette® devices at regular intervals in both a control condition (repeated 8-hour sleep) and a sleep deprivation condition (total sleep deprivation of 8 h, recovery sleep of 8 h) and their metabolic contents compared in a semi-targeted metabolomics approach. Results: Analysis of variance results showed factor 'time' (i.e., sampling time point) representing the major influencer (median 9.24%, range 3.02–42.91%), surpassing the intervention of sleep deprivation (median 1.81%, range 0.19–12.46%). In addition, we found about 10% of all metabolic features to have significantly changed in at least one time point after a night of sleep deprivation when compared to 8 h of sleep. Conclusion: The majority of significant alterations in metabolites' abundances were found when sampled in the morning hours, which can lead to subsequent misinterpretations of experimental effects in metabolomics studies. Beyond applying a within-subject design with identical sample collection times, we highly recommend monitoring participants' sleep-wake schedules prior to and during experiments, even if the study focus is not sleep-related (e.g., via actigraphy). [ABSTRACT FROM AUTHOR]

Background: Different types of analytical methods, with different characteristics, are applied in metabolomics and lipidomics research and include untargeted, targeted and semi-targeted methods. Ultra High Performance Liquid Chromatography-Mass Spectrometry is one of the most frequently applied measurement instruments in metabolomics because of its ability to detect a large number of water-soluble and lipid metabolites over a wide range of concentrations in short analysis times. Methods applied for the detection and quantification of metabolites differ and can either report a (normalised) peak area or an absolute concentration. Aim of review: In this tutorial we aim to (1) define similarities and differences between different analytical approaches applied in metabolomics and (2) define how amounts or absolute concentrations of endogenous metabolites can be determined together with the advantages and limitations of each approach in relation to the accuracy and precision when concentrations are reported. Key scientific concepts of review: The pre-analysis knowledge of metabolites to be targeted, the requirement for (normalised) peak responses or absolute concentrations to be reported and the number of metabolites to be reported define whether an untargeted, targeted or semi-targeted method is applied. Fully untargeted methods can only provide (normalised) peak responses and fold changes which can be reported even when the structural identity of the metabolite is not known. Targeted methods, where the analytes are known prior to the analysis, can also report fold changes. Semi-targeted methods apply a mix of characteristics of both untargeted and targeted assays. For the reporting of absolute concentrations of metabolites, the analytes are not only predefined but optimized analytical methods should be developed and validated for each analyte so that the accuracy and precision of concentration data collected for biological samples can be reported as fit for purpose and be reviewed by the scientific community. [ABSTRACT FROM AUTHOR]

Introduction: Fungi biosynthesize chemically diverse secondary metabolites with a wide range of biological activities. Natural product scientists have increasingly turned towards bioinformatics approaches, combining metabolomics and genomics to target secondary metabolites and their biosynthetic machinery. We recently applied an integrated metabologenomics workflow to 110 fungi and identified more than 230 high-confidence linkages between metabolites and their biosynthetic pathways. Objectives: To prioritize the discovery of bioactive natural products and their biosynthetic pathways from these hundreds of high-confidence linkages, we developed a bioactivity-driven metabologenomics workflow combining quantitative chemical information, antiproliferative bioactivity data, and genome sequences. Methods: The 110 fungi from our metabologenomics study were tested against multiple cancer cell lines to identify which strains produced antiproliferative natural products. Three strains were selected for further study, fractionated using flash chromatography, and subjected to an additional round of bioactivity testing and mass spectral analysis. Data were overlaid using biochemometrics analysis to predict active constituents early in the fractionation process following which their biosynthetic pathways were identified using metabologenomics. Results: We isolated three new-to-nature stemphone analogs, 19-acetylstemphones G (1), B (2) and E (3), that demonstrated antiproliferative activity ranging from 3 to 5 µM against human melanoma (MDA-MB-435) and ovarian cancer (OVACR3) cells. We proposed a rational biosynthetic pathway for these compounds, highlighting the potential of using bioactivity as a filter for the analysis of integrated—Omics datasets. Conclusions: This work demonstrates how the incorporation of biochemometrics as a third dimension into the metabologenomics workflow can identify bioactive metabolites and link them to their biosynthetic machinery. [ABSTRACT FROM AUTHOR]

Summary: In severely phosphorus (P)‐impoverished environments, plants have evolved to use P very efficiently. Yet, it is unclear how P allocation in leaves contributes to their photosynthetic P‐use efficiency (PPUE) and position along the leaf economics spectrum (LES). We address this question in 10 species of Banksia and Hakea, two highly P‐efficient Proteaceae genera.We characterised traits in leaves of Banksia and Hakea associated with the LES: leaf mass per area, light‐saturated photosynthetic rates, P and nitrogen concentrations, and PPUE. We also determined leaf P partitioning to five biochemical fractions (lipid, nucleic acid, metabolite, inorganic and residual P) and their possible association with the LES.For both genera, PPUE was negatively correlated with fractional allocation of P to lipids, but positively correlated with that to metabolites. For Banksia only, PPUE was negatively correlated with residual P, highlighting a strategy contrasting to that of Hakea. Phosphorus‐allocation patterns significantly explained PPUE but were not linked to the resource acquisition vs resource conservation gradient defined by the LES.We conclude that distinct P‐allocation patterns enable species from different genera to achieve high PPUE and discuss the implications of different P investments. We surmise that different LES axes representing different ecological strategies coexist in extremely P‐impoverished environments. [ABSTRACT FROM AUTHOR]

As a treasure trove of natural products (NPs), various fungal species possess great potential as cell factories for valuable NPs bioproduction. However, they have many silent biosynthetic gene clusters (BGCs), and activation of BGCs expression is critical to the discovery of their indetectable NPs, especially secondary metabolites, in which epigenetic regulation plays a significant role. Thanks to the development of sequencing technologies, more and more epigenetic regulators have been characterized and adopted for boosting fungal NPs production. In this review, at first we summarize various kinds of epigenetic regulation and relevant strategies for triggering fungal NPs biosynthesis. Then, we discuss the limitations of the current strategies, and propose future trends in the discovery of fungi derived NPs by manipulating epigenetics. • Epigenetic regulation plays a significant role in discovery of the undetectable natural products from fungal species. • Manipulating histone-modifying proteins is a novel manner to activate the expression of biosynthetic gene clusters. • This work provides a systematical view on triggering fungal natural products biosynthesis by epigenetic regulation. [ABSTRACT FROM AUTHOR]

Diabetes mellitus has emerged as a pressing global public health concern in the 21st century, necessitating the exploration of effective and safer therapeutic alternatives to conventional synthetic anti-diabetic medications. This study aimed to comprehensively evaluate the anti-diabetic potential of Castanopsis tribuloide s through a multi-faceted approach encompassing in vitro , in vivo , and in silico experiments. In vitro assessments revealed that the methanol extract of C. tribuloides bark (CtbME) exhibited remarkable α-glucosidase inhibitory activity, as demonstrated by a low IC 50 value of 550 μg/mL, surpassing that of acarbose (600 μg/mL). Furthermore, CtbME administration led to a significant and dose-dependent reduction in hyperglycemic blood glucose levels. Twenty-three secondary metabolites were identified in GC-MS analysis. Molecular docking analysis was employed to elucidate the molecular interactions between C. tribuloides constituents and α-glucosidase. Rutin hydrate, catechin hydrate, and betulin exhibited higher binding affinity than acarbose, where rutin hydrate demonstrated exceptional stability throughout molecular dynamics simulation (MDS), affirming the accuracy of the docking data. The findings of this research underscore the potential of C. tribuloides as a source of anti-diabetic agents and provide valuable insights into the molecular mechanisms underlying its efficacy. [Display omitted] • CtbME exhibited remarkable α-glucosidase inhibitory activity. • CtbME significantly reduced hyperglycemic blood glucose levels in diabetic mice. • GC-MS analysis of CtbME identified 23 secondary metabolites. • Rutin hydrate and betulin showed strong binding affinity to α-glucosidase. • The α-glucosidase inhibitory mechanism was confirmed by MD simulation. [ABSTRACT FROM AUTHOR]

Alternative plasticizers such as diisononyl-1,2-cyclohexanedicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), and di(2-ethylhexyl) adipate (DEHA) are progressively replacing phthalates in many consumer and professional products because of adverse effects on reproduction associated with some phthalates. Human exposures to these phthalate substitutes can occur through ingestion, skin absorption and inhalation. Skin uptake can lead to greater concentration at the target organs compared to ingestion because the skin exposure route bypasses the first-pass effect. Skin absorption studies are almost absent for these alternative plasticizers. We therefore wanted first, to characterize skin absorption of a mixture containing DINCH, DEHA and DEHTP in vitro using a flow-through diffusion cell system with ex vivo human skin, quantifying their respective monoester metabolites (mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH), mono-2-ethylhexyl adipate (MEHA), mono-2-ethylhexyl terephthalate (MEHTP), respectively); second, to validate these results by exposing five human volunteers to this mixture on their forearm and quantifying the corresponding urinary metabolites (including the monoesters and their oxidation products). Our study showed that two of these alternative plasticizers, DEHTP and DINCH, did not permeate skin showing as quantifiable metabolite levels in vitro and only traces of DEHA were quantified as its monoester metabolite, MEHA. Permeation coefficient (Kp) 0.06 and 55.8*10−7 cm/h for neat and emulsified DEHA, respectively, while the permeation rate (J) remained low for both (0.005 and 0.001 µg/cm2/h, respectively). Participants exposed to a mixture of these three plasticizers did not have noteworthy urinary concentrations of their respective metabolites after 24 hours post-application. However, the alternative plasticizer mixture was completely absorbed after six hours post-application on the forearms of the human volunteers, and the urinary elimination curves showed a slight increase after 24 hours post-application. Further studies on skin absorption of these substances should follow the urinary elimination kinetics of these metabolites more than 24 hours post-application. We also recommend quantifying the parent compounds in the in vitro diffusion experiments. [Display omitted] • Urinary excretion of DINCH monoester was slow in skin-exposed participants. • DEHTP and DEHA monoesters were not detected in urine from participants. • DEHA permeated skin in vitro as its monoester. • DEHTP and DINCH did not permeate skin in vitro as their monoesters. [ABSTRACT FROM AUTHOR]

Objective: Upper gastrointestinal (UGI) cancers, particularly esophageal cancer (EC) and gastric cancer (GC) represent a significant health burden with complex etiologies. Metabolic alterations are known to play a crucial role in cancer development and progression. Identifying key metabolic biomarkers may offer insights into the pathophysiology of UGI cancers and potential therapeutic targets. This study aimed to investigate the causal associations between 1,400 types of metabolites, specifically phosphate-to-alanine and bilirubin-to-androsterone glucuronide, and the risk of developing UGI cancers using Mendelian randomisation (MR) analysis. Method: We conducted a two-sample MR study utilising genetic instruments identified from large-scale genome-wide association studies (GWASs) for metabolic traits. The outcomes were derived from GWAS datasets of UGI cancer patients, including EC and GC. Several MR methods were employed to ensure the robustness of the findings, including inverse variance weighted (IVW), MR-Egger and weighted median approaches. Results: Our analysis found a total of 44 metabolites associated with EC and 15 metabolites associated with GC. The MR analyses revealed a significant causal relationship between the phosphate-to-alanine ratio (EC: OR = 1.002,95% CI = 1.00034-1.0037, p = 0.0037; GC: OR = 1.24,95% CI = 1.046-1.476, p = 0.01) and increased risk of UGI cancers. In contrast, the bilirubin-to-androsterone glucuronide ratio (EC: OR = 0.998,95% CI = 0.997-0.999, p = 0.03; GC: OR = 0.80,95% CI = 0.656-0.991, p = 0.04) was inversely associated with the risk, suggesting a potential protective effect. Conclusion: Our findings suggest that the phosphate-to-alanine ratio and bilirubin-to-androsterone glucuronide ratio are key hub metabolites in the etiology of UGI cancers. These metabolic ratios could serve as potential biomarkers for early detection or targets for therapeutic intervention. Further research is warranted to elucidate the underlying biological mechanisms and to validate the clinical utility of these associations. [ABSTRACT FROM AUTHOR]