PubMed

Anim Biosci. 2024 Aug 22. doi: 10.5713/ab.24.0015. Online ahead of print.ABSTRACTOBJECTIVE: Nicotinamide (NAM) is easily degraded in the rumen, the rumen-protected NAM (RPN) supplementation might enable the use of NAM in ruminants. This study aimed to elucidate the effects of RPN supplementation on growth performance, rumen fermentation, antioxidant status and AA metabolism in growing lambs.METHODS: A total of 128 healthy and similar lambs (21.3 ± 0.28 kg, 70 ± 6.3 days of age) were allotted to 1 of 4 groups. The treatments were 0, 0.5, 1 and 2 g/d RPN supplementation. The RPN products (50% bioavailability) were fed at 0700 h every day for 12 weeks. All lambs were fed the same pelleted total mixed rations to allow ad libitum consumption and had free access to water.RESULTS: The RPN tended to increase the average daily gain and feed efficiency. The tendencies of RPN × Day interaction were found for dry matter intake during the entire study (P = 0.078 and 0.073, respectively). The proportions of acetic acid, isobutyric acid and isovaleric acid were decreased, whereas the proportions of propionic acid and valeric acid were increased (P < 0.05). The ratio of acetic acid to propionic acid was decreased (P < 0.05). Moreover, the antioxidative status was enhanced and the glucose concentration was increased by RPN (P < 0.05). In addition, 17 amino acids (AAs) were detected in plasma, of which 11 AAs were increased by RPN (P < 0.05). Plasma metabolomics analysis identified 1395 compounds belonging to 15 classes, among which 7 peptides were significantly changed after RPN supplementation.CONCLUSION: Overall, the results suggested that RPN supplementation favoured the rumen fermentation pattern to propionic acid-type with benefited glucose metabolism, enhanced antioxidant capacity, and changed the AA and small peptide metabolism. This study provides a new perspective for studying the relationship between vitamin and AA metabolism.PMID:39210823 | DOI:10.5713/ab.24.0015

Proteins. 2024 Aug 29. doi: 10.1002/prot.26740. Online ahead of print.ABSTRACTValacyclovir, enzymatically hydrolyzed in the body to acyclovir, is a guanine-based nucleoside analog commonly prescribed as an antiviral therapy. Previous reports suggest that guanosine analogs bind to guanine deaminase; however, it is unclear whether they act as inhibitors or substrates. Data from our laboratory suggest that inhibition of guanine deaminase by small molecules attenuates spinal cord injury-induced neuropathic pain. Here, we examine whether the guanosine analogs valacyclovir and acyclovir are deaminated by cypin (cytosolic PSD-95 interactor), the major guanine deaminase in the body, or if they act as cypin inhibitors. Using purified Rattus norvegicus cypin, we use NADH-coupled assay to confirm deamination of valacyclovir and determined Michaelis-Menten constants. Subsequently, we use tryptophan fluorescence quenching assay to calculate dissociation constants for valacyclovir and acyclovir and find that inclusion of the valine motif in valacyclovir increases affinity for cypin compared to acyclovir. To our knowledge, neither Km nor KD values for cypin has been previously reported for either compound. We use Amplex Red assay and demonstrate that both valacyclovir and acyclovir are cypin substrates and that their metabolites are further processed by xanthine oxidase and uricase. Using molecular dynamics simulations, we demonstrate that an alpha helix near the active site is displaced when valacyclovir binds to cypin. Furthermore, we used LC-MS-based assay to directly confirm deamination of valacyclovir by cypin. Taken together, our results demonstrate a novel role for cypin in deamination of valacyclovir and acyclovir and suggest that therapeutics based on purine structures may be inactivated by cypin, decreasing inhibitory efficacy.PMID:39210666 | DOI:10.1002/prot.26740

Exp Dermatol. 2024 Sep;33(9):e15170. doi: 10.1111/exd.15170.ABSTRACTPrurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted-metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography-tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long-chain fatty acids, alpha-aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up-regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down-regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN.PMID:39207113 | DOI:10.1111/exd.15170

mBio. 2024 Aug 29:e0102224. doi: 10.1128/mbio.01022-24. Online ahead of print.ABSTRACTThe genus Pseudomonas is a prolific source of specialized metabolites with significant biological activities, including siderophores, antibiotics, and plant hormones. These molecules play pivotal roles in environmental interactions, influencing pathogenicity, inhibiting microorganisms, responding to nutrient limitation and abiotic challenges, and regulating plant growth. These properties mean that pseudomonads are suitable candidates as biological control agents against plant pathogens. Multiple transposon-based screens have identified a Pseudomonas biosynthetic gene cluster (BGC) associated with potent antibacterial and antifungal activities, which produces 7-hydroxytropolone (7-HT). In this study, we show that this BGC also makes 3,7-dihydroxytropolone (3,7-dHT), which has strong antimicrobial activity toward Streptomyces scabies, a potato pathogen. Through metabolomics and reporter assays, we unveil the involvement of cluster-situated genes in generating phenylacetyl-coenzyme A, a key precursor for tropolone biosynthesis via the phenylacetic acid catabolon. The clustering of these phenylacetic acid genes within tropolone BGCs is unusual in other Gram-negative bacteria. Our findings support the interception of phenylacetic acid catabolism via an enoyl-CoA dehydratase encoded in the BGC, as well as highlighting an essential role for a conserved thioesterase in biosynthesis. Biochemical assays were used to show that this thioesterase functions after a dehydrogenation-epoxidation step catalyzed by a flavoprotein. We use this information to identify diverse uncharacterized BGCs that encode proteins with homology to flavoproteins and thioesterases involved in tropolone biosynthesis. This study provides insights into tropolone biosynthesis in Pseudomonas, laying the foundation for further investigations into the ecological role of tropolone production.IMPORTANCEPseudomonas bacteria produce various potent chemicals that influence interactions in nature, such as metal-binding molecules, antibiotics, or plant hormones. This ability to synthesize bioactive molecules means that Pseudomonas bacteria may be useful as biological control agents to protect plants from agricultural pathogens, as well as a source of antibiotic candidates. We have identified a plant-associated Pseudomonas strain that can produce 3,7-dihydroxytropolone, which has broad biological activity and can inhibit the growth of Streptomyces scabies, a bacterium that causes potato scab. Following the identification of this molecule, we used a combination of genetic, chemical, and biochemical experiments to identify key steps in the production of tropolones in Pseudomonas species. Understanding this biosynthetic process led to the discovery of an array of diverse pathways that we predict will produce new tropolone-like molecules. This work should also help us shed light on the natural function of antibiotics in nature.PMID:39207110 | DOI:10.1128/mbio.01022-24

Front Biosci (Landmark Ed). 2024 Aug 22;29(8):306. doi: 10.31083/j.fbl2908306.ABSTRACTBACKGROUND: Aging is a progressive process characterized by weakness in brain function. Although metabolomics studies on the brain related with aging have been conducted, it is not yet fully understood. A systematic metabolomics study was performed to search for biomarkers and monitor altered metabolism in various brain tissues of the cortex, cerebellum, hypothalamus, and hippocampus of young (8 months old) and old rats (22 months old).METHODS: Simultaneous profiling analysis of amino acids (AAs), organic acids (OAs), and fatty acids (FAs) in the brain tissues of young and old rats were performed by gas chromatography-tandem mass spectrometry.RESULTS: Under optimal conditions, AA, OA, and FA profiling methods showed good linearity (r ≥0.995) with limit of detection of ≤30 and 73.2 ng and limit of quantification of ≤90.1 and 219.5 ng, respectively. Repeatability varied from 0.4 to 10.4 and 0.8 to 14.8% relative standard deviation and accuracy varied from -11.3 to 10.3 and -12.8 to 14.1% relative error, respectively. In the profiling analysis, total 32, 43, 45, and 30 metabolites were determined in cortex, cerebellum, hypothalamus, and hippocampus, respectively. In statistical analysis, eight AAs (alanine, valine, leucine, isoleucine, threonine, serine, proline, and phenylalanine) in the cortex and four metabolites (alanine, phenylalanine, 3-hydoxypropionic acid, and eicosadienoic acid) in the cerebellum were significantly evaluated (Q-value <0.05, variable importance in projection scores ≥1.0). In all brain tissues, the score plots of orthogonal partial least square discriminant analysis were clearly separated between the young and old groups.CONCLUSIONS: Metabolomics results indicate that mechanistic targets of rapamycin complex 1, branched chain-amino acid, and energy metabolism are related to inflammation and mitochondrial dysfunction in the brain during aging. Thus, these results may explain the characteristic metabolism of brain aging.PMID:39206923 | DOI:10.31083/j.fbl2908306

FEBS J. 2024 Aug 29. doi: 10.1111/febs.17255. Online ahead of print.ABSTRACTAmino acids are important for cellular metabolism. Their uptake across the plasma membrane is mediated by transport proteins. Despite the fact that the organic anion transporting polypeptide 4C1 (OATP4C1, Uniprot: Q6ZQN7) mediates transport of l-arginine and l-arginine derivatives, other members of the OATP family have not been characterized as amino acid transporters. The OATP family member OATP3A1 (gene symbol SLCO3A1, Uniprot: Q9UIG8) is ubiquitously expressed in human cells and highly expressed in many cancer tissues and cell lines. However, only a few substrates are known for OATP3A1. Accordingly, knowledge about its biological relevance is restricted. Our aim was to identify new substrates of OATP3A1 to gain insights into its (patho-)physiological function. In an LC-MS-based untargeted metabolomics assay using untreated OATP3A1-overexpressing HEK293 cells and control cells, we identified several amino acids as potential substrates of OATP3A1. Subsequent uptake experiments using exogenously added substrates revealed OATP3A1-mediated transport of l-tryptophan, l-tyrosine, and l-phenylalanine with 194.8 ± 28.7% (P < 0.05), 226.2 ± 18.7% (P < 0.001), and 235.2 ± 13.5% (P < 0.001), respectively, in OATP3A1-overexpressing cells compared to control cells. Furthermore, kinetic transport parameters (Km values) were determined (Trp = 61.5 ± 14.2 μm, Tyr = 220.8 ± 54.5 μm, Phe = 234.7 ± 20.6 μm). In summary, we identified the amino acids l-tryptophan, l-tyrosine, and l-phenylalanine as new substrates of OATP3A1. These findings could be used for a better understanding of (patho-)physiological processes involving increased demand of amino acids, where OATP3A1 should be considered as an important uptake transporter of l-tryptophan, l-tyrosine, and l-phenylalanine.PMID:39206635 | DOI:10.1111/febs.17255

Food Chem X. 2024 Aug 3;23:101710. doi: 10.1016/j.fochx.2024.101710. eCollection 2024 Oct 30.ABSTRACTGelatin is a protein molecule that can be hydrolyzed from collagen, animal bones, skin and it easily soluble in water. Source animals for gelatin ingredients must be evaluated, as well as their halal status. The omics method towards gelatin authentication in food and pharmaceutical products has several advantages, including high sensitivity and reliable data. Omics investigation employs the process of breaking down substances into small particles, hence enhancing the ability to detect a greater number of compounds. Omics study has the capability to identify substances at the subclass level, which makes it highly suitable for gelatin authentication. Gelatin lipids, metabolites, proteins, and volatile chemicals can be utilized as references to authenticate gelatin. In adopting gelatin authentication, lipidomics, metabolomics, proteomics, and volatilomics must be combined with chemometrics for data interpretation. Chemometrics can convert omics analysis data into easily viewable data. Chemometric approaches capable of presenting omics analysis data for gelatin authentication include PCA, HCA, PLS-DA, PLSR, SIMCA, and FACS. Visually chemometrically explain the differences in gelatin from different animal sources. The combination of omics analysis and chemometrics is a very promising technology for gelatin authentication in food and pharmaceutical products.PMID:39206450 | PMC:PMC11350464 | DOI:10.1016/j.fochx.2024.101710

Diabetes Metab Syndr Obes. 2024 Aug 23;17:3103-3110. doi: 10.2147/DMSO.S477739. eCollection 2024.ABSTRACTMetabolic syndrome (MS) is more prevalent in chronic diseases and, if left untreated, can lead to serious consequences, such as cardiovascular disease (CVD), cerebrovascular disease and type 2 diabetes, which have become significant public health issues globally. Metabolic syndrome is significantly influenced by the daily diet of patients. The dietary approaches to stop hypertension (DASH) diet, originally designed to prevent or control hypertension, offers additional metabolic benefits due to its nutrient composition. The DASH diet recommends the intake of potassium, magnesium, calcium and fibre while limiting total fat, saturated fat and sodium, which is beneficial for patients with MS. Due to its limited fat content and high levels of fibre and calcium, individuals following the DASH diet are less prone to being overweight and obese and have lower concentrations of total and low-density lipoprotein cholesterol. Moreover, the DASH diet can reduce blood pressure and is effective in correcting glucose and insulin abnormalities. This review comprehensively summarises the health benefits of the DASH diet on the risk factors of MS and describes the potential mechanisms based on available evidence.PMID:39206416 | PMC:PMC11350064 | DOI:10.2147/DMSO.S477739

Front Fungal Biol. 2024 Aug 14;5:1447588. doi: 10.3389/ffunb.2024.1447588. eCollection 2024.ABSTRACTThere is an urgent need for new antifungal drugs to treat invasive fungal diseases. Unfortunately, the echinocandin drugs that are fungicidal against other important fungal pathogens are ineffective against Cryptococcus neoformans, the causative agent of life-threatening meningoencephalitis in immunocompromised people. Contributing mechanisms for echinocandin tolerance are emerging with connections to calcineurin signaling, the cell wall, and membrane composition. In this context, we discovered that a defect in phosphate uptake impairs the tolerance of C. neoformans to the echinocandin caspofungin. Our previous analysis of mutants lacking three high affinity phosphate transporters revealed reduced elaboration of the polysaccharide capsule and attenuated virulence in mice. We investigated the underlying mechanisms and found that loss of the transporters and altered phosphate availability influences the cell wall and membrane composition. These changes contribute to the shedding of capsule polysaccharide thus explaining the reduced size of capsules on mutants lacking the phosphate transporters. We also found an influence of the calcineurin pathway including calcium sensitivity and an involvement of the endoplasmic reticulum in the response to phosphate limitation. Furthermore, we identified membrane and lipid composition changes consistent with the role of phosphate in phospholipid biosynthesis and with previous studies implicating membrane integrity in caspofungin tolerance. Finally, we discovered a contribution of phosphate to titan cell formation, a cell type that displays modified cell wall and capsule composition. Overall, our analysis reinforces the importance of phosphate as a regulator of cell wall and membrane composition with implications for capsule attachment and antifungal drug susceptibility.PMID:39206133 | PMC:PMC11349702 | DOI:10.3389/ffunb.2024.1447588

Front Mol Biosci. 2024 Aug 14;11:1407974. doi: 10.3389/fmolb.2024.1407974. eCollection 2024.ABSTRACTIn terms of time, cost, and reproducibility of clinical laboratory tests, a mass spectrometric clinical blood metabogram (CBM) enables the investigation of the blood metabolome. Metabogram's components provide clinically relevant information by describing related groups of blood metabolites connected to humoral regulation, the metabolism of lipids, carbohydrates and amines, lipid intake into the organism, and liver function. For further development of the CBM approach, the ability of CBM to detect metabolic changes in the blood in the early stages of Parkinson's disease (PD) was studied in this work. In a case-control study (n = 56), CBM enabled the detection of the signature in blood metabolites related to 1-2.5 clinical stages of PD, according to the modified Hoehn and Yahr scale, which is formed by alterations in eicosanoids, phospholipids and, presumably, in the butadione metabolism. The CBM component-based diagnostic accuracy reached 77%, with a specificity of 71% and sensitivity of 82%. The research results extend the range of disorders for which CBM is applicable and offer new opportunities for revealing PD-specific metabolic alterations and diagnosing early-stage PD.PMID:39206052 | PMC:PMC11350164 | DOI:10.3389/fmolb.2024.1407974

Front Cell Infect Microbiol. 2024 Aug 14;14:1423662. doi: 10.3389/fcimb.2024.1423662. eCollection 2024.ABSTRACTOBJECTIVE: This study aims to investigate the pathogenesis of hyperglycemia and its associated vasculopathy using multiomics analyses in diabetes and impaired glucose tolerance, and validate the mechanism using the cell experiments.METHODS: In this study, we conducted a comprehensive analysis of the metagenomic sequencing data of diabetes to explore the key genera related to its occurrence. Subsequently, participants diagnosed with impaired glucose tolerance (IGT), and healthy subjects, were recruited for fecal and blood sample collection. The dysbiosis of the gut microbiota (GM) and its associated metabolites were analyzed using 16S rDNA sequencing and liquid chromatograph mass spectrometry, respectively. The regulation of gene and protein expression was evaluated through mRNA sequencing and data-independent acquisition technology, respectively. The specific mechanism by which GM dysbiosis affects hyperglycemia and its related vasculopathy was investigated using real-time qPCR, Western blotting, and enzyme-linked immunosorbent assay techniques in HepG2 cells and neutrophils.RESULTS: Based on the published data, the key alterable genera in the GM associated with diabetes were identified as Blautia, Lactobacillus, Bacteroides, Prevotella, Faecalibacterium, Bifidobacterium, Ruminococcus, Clostridium, and Lachnoclostridium. The related metabolic pathways were identified as cholate degradation and L-histidine biosynthesis. Noteworthy, Blautia and Faecalibacterium displayed similar alterations in patients with IGT compared to those observed in patients with diabetes, and the GM metabolites, tauroursodeoxycholic acid (TUDCA) and carnosine (CARN, a downstream metabolite of histidine and alanine) were both found to be decreased, which in turn regulated the expression of proteins in plasma and mRNAs in neutrophils. Subsequent experiments focused on insulin-like growth factor-binding protein 3 and interleukin-6 due to their impact on blood glucose regulation and associated vascular inflammation. Both proteins were found to be suppressed by TUDCA and CARN in HepG2 cells and neutrophils.CONCLUSION: Dysbiosis of the GM occurred throughout the entire progression from IGT to diabetes, characterized by an increase in Blautia and a decrease in Faecalibacterium, leading to reduced levels of TUDCA and CARN, which alleviated their inhibition on the expression of insulin-like growth factor-binding protein 3 and interleukin-6, contributing to the development of hyperglycemia and associated vasculopathy.PMID:39206042 | PMC:PMC11351283 | DOI:10.3389/fcimb.2024.1423662

Front Genet. 2024 Aug 14;15:1432997. doi: 10.3389/fgene.2024.1432997. eCollection 2024.ABSTRACTLilium brownii var. viridulum, known as Longya lily, is a well-known medicinal and edible plant in China. Bulb rot is a common disease in Longya lily cultivation that severely affects the yield and quality of lilies. According field investigations, we found that different Longya lily plants in the same field had different degrees of resistance to root rot. To find the reasons leading to the difference, we performed metabolomic and transcriptomic analyses of Longya lily with different degrees of disease. The transcriptomic analyses showed that the number of differentially expressed genes increased in early and mid-stage infections (LYBH2 and LYBH3), while decreased in late-stage infection (LYBH4). A total of 2309 DEGs showed the same expression trend in diseased bulb compared healthy bulb (LYBH1). The transcription factors (TFs) analysis of DEGs showed that several common TFs, like WRKY, bHLH, AP2/ERF-ERF and MYB, were significantly activated in bulbs after decay. The metabolomic analyses showed that there were 794 differentially accumulated metabolites, and metabolites with significant changes in relative content largely were phenolic acids, followed by flavonoids and amino acids and derivatives. The combined analysis of transcriptome and metabolome indicated that phenylpropanoid biosynthesis pathway was crucial in Longya lily resistance to bulb rot. Therefore, we speculated that the different degree of resistance to bulb rot in Longya lily may be related to the transcript levels of gene and contents of metabolites in the phenylpropanoid biosynthesis pathway. Overall, these results elucidate the molecular responses of Longya lily to bulb rot and lay a theoretical foundation for breeding resistant varieties.PMID:39205945 | PMC:PMC11349735 | DOI:10.3389/fgene.2024.1432997

Front Endocrinol (Lausanne). 2024 Aug 14;15:1412684. doi: 10.3389/fendo.2024.1412684. eCollection 2024.ABSTRACTBACKGROUND: In recent years, the decline in sperm quality in men has become a global trend. There is a close relationship between sperm quality and pregnancy outcome. There is a large body of literature supporting the role of plasma lipidome in male infertility, while the complex mechanisms between them and male infertility are still less clear. Systematic study of the causal relationship between plasma lipidome and MI can help to provide new therapeutic ideas and targets for male infertility.METHODS: In this study, we used a two-sample Mendelian randomization analysis based on Genome-wide association studies pooled data of 179 causal relationships between plasma lipidome and male infertility. We used employed the inverse variance weighted method as the main analysis to assess causality between exposure and outcome, in addition to MR-Egger, Weighted median as complementary methods, and tests for multiplicity and heterogeneity.RESULTS: We identified 13 plasma lipidome comprising 4 types of plasma lipidome that were associated with male infertility. Among these, 9 plasma lipidome were found to be protective factors, while 4 were risk factors. Notably, the largest proportion of these plasma lipidome were triglyceride types, with Sphingomyelin (d40:1) exhibiting the strongest association with male infertility.CONCLUSION: These findings contribute to the current better understanding of male infertility and provide new perspectives on the underlying etiology of male infertility as well as prevention and treatment strategies. In addition, clinical trial validation is needed to assess the potential of these plasma lipidome as biomarkers.PMID:39205681 | PMC:PMC11349629 | DOI:10.3389/fendo.2024.1412684

Am J Physiol Renal Physiol. 2024 Aug 29. doi: 10.1152/ajprenal.00131.2024. Online ahead of print.ABSTRACTAbnormalities in distinct metabolic pathways have been associated with many forms of kidney disease. Metabolomics analyses can be used to determine organ-specific metabolic fingerprints. However, conventional harvesting methods depend on post-euthanasia tissue harvest, which results in ischemia conditions and metabolome changes that could introduce artifacts into the final studies. We optimized a clamp-freezing technique for kidney harvesting and freezing, significantly reducing ischemia and freezing times and granting a closer snapshot of in vivo metabolism. In this study, we characterized and compared the metabolome of kidneys harvested using our approach vs. traditional techniques to determine which metabolites are preferentially affected by a brief lapse of ischemia and freezing delay and which are more stable. We used Sprague Dawley rats as a model of wild-type (WT) kidneys and PCK, polycystic kidney disease (PKD) rats as a model of CKD kidneys. Finally, we compared the metabolic profile of clamp-frozen and delayed WT and PKD-kidneys to determine which metabolic changes are most likely observed in vivo in PKD and which could be subjected to false positive or negative results. Our data indicate that a short harvesting-freezing delay is sufficient to impart profound metabolic changes in WT and PKD kidneys. Interestingly, while the delay had a similar effect in WT and PKD, there were notable differences, leading to false positive and negative results when comparing these genotypes. The data obtained indicate that the quick clamp-freezing technique for kidney metabolomics provides a more accurate interpretation of the in vivo metabolic changes associated with the disease state.PMID:39205659 | DOI:10.1152/ajprenal.00131.2024

Gut Microbes. 2024 Jan-Dec;16(1):2390176. doi: 10.1080/19490976.2024.2390176. Epub 2024 Aug 29.ABSTRACTGut microbiota dysbiosis is involved in cholestatic liver diseases. However, the mechanisms remain to be elucidated. The purpose of this study was to examine the effects and mechanisms of Lactobacillus acidophilus (L. acidophilus) on cholestatic liver injury in both animals and humans. Bile duct ligation (BDL) was performed to mimic cholestatic liver injury in mice and serum liver function was tested. Gut microbiota were analyzed by 16S rRNA sequencing. Fecal bacteria transplantation (FMT) was used to evaluate the role of gut microbiota in cholestasis. Bile acids (BAs) profiles were analyzed by targeted metabolomics. Effects of L. acidophilus in cholestatic patients were evaluated by a randomized controlled clinical trial (NO: ChiCTR2200063330). BDL induced different severity of liver injury, which was associated with gut microbiota. 16S rRNA sequencing of feces confirmed the gut flora differences between groups, of which L. acidophilus was the most distinguished genus. Administration of L. acidophilus after BDL significantly attenuated hepatic injury in mice, decreased liver total BAs and increased fecal total BAs. Furthermore, after L. acidophilus treatment, inhibition of hepatic Cholesterol 7α-hydroxylase (CYP7α1), restored ileum Fibroblast growth factor 15 (FGF15) and Small heterodimer partner (SHP) accounted for BAs synthesis decrease, whereas enhanced BAs excretion was attributed to the increase of unconjugated BAs by enriched bile salt hydrolase (BSH) enzymes in feces. Similarly, in cholestasis patients, supplementation of L. acidophilus promoted the recovery of liver function and negatively correlated with liver function indicators, possibly in relationship with the changes in BAs profiles and gut microbiota composition. L. acidophilus treatment ameliorates cholestatic liver injury through inhibited hepatic BAs synthesis and enhances fecal BAs excretion.PMID:39205654 | DOI:10.1080/19490976.2024.2390176

J Acupunct Meridian Stud. 2024 Aug 31;17(4):133-140. doi: 10.51507/j.jams.2024.17.4.133.ABSTRACTIMPORTANCE: Choledocholithiasis, or bile duct gallstones, is effectively treated with surgery, which does not prevent relapse. A common adjuvant therapy is the stimulation of the Yanglingquan point (GB34). Acupoint catgut embedding (ACE), an acupoint stimulation therapy, may be a better treatment for choledocholithiasis.OBJECTIVES: To investigate the effect of ACE in stimulating GB34 on bile metabolism and its possible mechanism via metabonomics.METHODS: In this study, we used ultrahigh performance liquid chromatographyquadrupole time-of-flight mass spectrometry (UHPLC-MS/MS) to analyze the changes in bile metabolites, metabolic pathways, and liver function indicators in 16 patients with choledocholithiasis before and after ACE stimulation.RESULTS: We identified 10 metabolites that exhibited significant differences in the bile before and after ACE, six of which significantly increased and four that significantly decreased. Moreover, six liver function indicators showed a downward trend. We identified related metabolic pathways as glycerophospholipid metabolism, steroid biosynthesis, and the citrate cycle (TCA cycle).CONCLUSIONS AND RELEVANCE: This study shows that ACE stimulation of GB34 can effectively help treat choledocholithiasis, which may be clinically applicable to ACE.PMID:39205616 | DOI:10.51507/j.jams.2024.17.4.133

Eur J Neurosci. 2024 Aug 28. doi: 10.1111/ejn.16486. Online ahead of print.ABSTRACTWhile it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome-wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi-omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells.PMID:39205434 | DOI:10.1111/ejn.16486

Plants (Basel). 2024 Aug 20;13(16):2309. doi: 10.3390/plants13162309.ABSTRACTPlant-growth-promoting bacteria (PGPB) have beneficial effects on plants. They can promote growth and enhance plant defense against abiotic stress and disease, and these effects are associated with changes in the plant metabolite profile. The research problem addressed in this study was the impact of inoculation with PGPB on the metabolite profile of Salicornia europaea L. across controlled and field conditions. Salicornia europaea seeds, inoculated with Brevibacterium casei EB3 and Pseudomonas oryzihabitans RL18, were grown in controlled laboratory experiments and in a natural field setting. The metabolite composition of the aboveground tissues was analyzed using GC-MS and UHPLC-MS. PGPB inoculation promoted a reconfiguration in plant metabolism in both environments. Under controlled laboratory conditions, inoculation contributed to increased biomass production and the reinforcement of immune responses by significantly increasing the levels of unsaturated fatty acids, sugars, citric acid, acetic acid, chlorogenic acids, and quercetin. In field conditions, the inoculated plants exhibited a distinct phytochemical profile, with increased glucose, fructose, and phenolic compounds, especially hydroxybenzoic acid, quercetin, and apigenin, alongside decreased unsaturated fatty acids, suggesting higher stress levels. The metabolic response shifted from growth enhancement to stress resistance in the latter context. As a common pattern to both laboratory and field conditions, biopriming induced metabolic reprogramming towards the expression of apigenin, quercetin, formononetin, caffeic acid, and caffeoylquinic acid, metabolites that enhance the plant's tolerance to abiotic and biotic stress. This study unveils the intricate metabolic adaptations of Salicornia europaea under controlled and field conditions, highlighting PGPB's potential to redesign the metabolite profile of the plant. Elevated-stress-related metabolites may fortify plant defense mechanisms, laying the groundwork for stress-resistant crop development through PGPB-based inoculants, especially in saline agriculture.PMID:39204745 | PMC:PMC11360282 | DOI:10.3390/plants13162309

Plants (Basel). 2024 Aug 14;13(16):2259. doi: 10.3390/plants13162259.ABSTRACTThe benefits of citrus fruits are strongly associated with their secondary metabolites. In this study, we conducted widely targeted metabolomics analyses to compare the variability of the ingredients in four scion-rootstock combinations. A total of 376 differential metabolites were obtained by a multivariate statistical analysis, and a KEGG pathway analysis showed that the enriched metabolic pathways were mainly related to the biosynthesis of flavonoids as well as lipid metabolism. The anthocyanin-targeted metabolomic features showed that cyanidin 3-O-glucoside, cyanidin 3-O-(6-O-malonyl-beta-D-glucoside), cyanidin 3-O-sophoroside, and cyanidin 3-O-xyloside were the pigments responsible for the red color of Tarocco. A lipid metabolomics analysis revealed that when Tarocco was hetero-grafted with rootstock H, there was an increase in the content of each lipid subclass, accompanied by an increase in the levels of unsaturated fatty acids, including polyunsaturated linoleic and linolenic acids, thus impacting the ratio of unsaturated fatty acids to saturated fatty acids. Additionally, we determined their antioxidant capacity ('Trifoliate orange' (Z) > 'Citrange' (ZC) > 'Hongju' (H) > 'Ziyang Xiangcheng' (X)) using in vitro assays. Finally, we utilized a network pharmacology analysis to explore the antioxidant mechanisms and potential pharmacological ingredients; we obtained 26 core targets proteins and 42 core metabolites associated with oxidative damage, providing a basis for future preventive and therapeutic applications of these metabolites.PMID:39204695 | PMC:PMC11358934 | DOI:10.3390/plants13162259

Plants (Basel). 2024 Aug 12;13(16):2232. doi: 10.3390/plants13162232.ABSTRACTIncreased UV-B radiation due to ozone depletion adversely affects plants. This study focused on the metabolite dynamics of Rhododendron chrysanthum Pall. (R. chrysanthum) and the role of ABA in mitigating UV-B stress. Chlorophyll fluorescence metrics indicated that both JA and ABA increased UV-B resistance; however, the effect of JA was not as strong as that of ABA. Metabolomic analysis using UPLC-MS/MS (ultra-performance liquid chromatography and tandem mass spectrometry) revealed significant fluctuations in metabolites under UV-B and ABA application. UV-B decreased amino acids and increased phenolics, suggesting antioxidant defense activation. ABA treatment upregulated lipids and phenolic acids, highlighting its protective role. Multivariate analysis showed distinct metabolic clusters and pathways responding to UV-B and ABA, which impacted amino acid metabolism and hormone signal transduction. Exogenous ABA negatively regulated the JA signaling pathway in UV-B-exposed R. chrysanthum, as shown by KEGG enrichment. This study deepens understanding of plant stress-tolerance mechanisms and has implications for enhancing plant stress tolerance through metabolic and hormonal interventions.PMID:39204669 | PMC:PMC11359875 | DOI:10.3390/plants13162232