PubMed

Biosci Rep. 2024 Dec 13:BSR20240842. doi: 10.1042/BSR20240842. Online ahead of print.ABSTRACTAs a rate-limiting enzyme in endogenous serine de novo synthesis pathway, PHGDH has been widely concerned about its role in a variety of tumors including colon cancer and the development of inhibitors. In our previous study, we studied PHGDH in colon cancer cell lines. However, with the development of personalized therapy, we realized that in scientific research, 2D cell lines lost a lot of original characteristic information during long-term culture, and the results obtained may not be enough to support the conclusion. Patient-derived tumor organoids maintain genomic stability and make up for information missing from cell lines due to monoclonal growth. Therefore, in our study, a colon cancer organoid with high PHGDH expression was selected, and was analyzed for transcriptomic and metabolomic changes through targeted inhibition of PHGDH. The results showed that inhibition of PHGDH significantly inhibited the proliferation of colon cancer organoids. The transcriptome, metabolome and combined omics analysis showed that the changes of colon cancer organoids after inhibition of PHGDH were mainly involved in PRSS1 and PRSS56, steroid hormone biosynthesis, phenylalanine metabolism, ascorbate and aldarate metabolism and tyrosine metabolism. In our study, the role of PHGDH in serine metabolism in colon cancer organoids was clarified by multi-omics analysis to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer.PMID:39670663 | DOI:10.1042/BSR20240842

Plant Biotechnol J. 2024 Dec 13. doi: 10.1111/pbi.14542. Online ahead of print.ABSTRACTChicoric acid, a phenolic compound derived from plants, exhibits a range of pharmacological activities. Light significantly influences the chicoric acid biosynthesis in Taraxacum mongolicum; however, the transcriptional regulatory network governing this process remains unclear. A combined analysis of the metabolome and transcriptome revealed that blue light markedly enhances chicoric acid accumulation compared to red light. The blue light-sensitive transcription factor ELONGATED HYPOCOTYL5 (HY5) is closely associated with multiple core proteins, transcription factors and chicoric acid synthase genes involved in light signalling. Both in vivo and in vitro experiments demonstrated that TmHY5 directly regulates several chicoric acid biosynthetic genes, including TmPAL3, Tm4CL1 and TmHQT2. Additionally, TmHY5 promotes the accumulation of luteolin and anthocyanins by increasing the expression of TmCHS2 and TmANS2. The E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) forms a protein complex with TmHY5, significantly inhibiting chicoric acid biosynthesis. Blue light inhibits TmCOP1-TmHY5 complex protein formation while enhancing the expression levels of TmCOP1 through TmHY5. Furthermore, TmHY5 elevates the expression levels of TmbZIP1, which indirectly activates Tm4CL1 expression. In vivo, TmCOP1 directly inhibits the expression of the TmHY5-Tm4CL1 complex. Therefore, we speculate that TmCOP1-TmHY5-mediated blue light signalling effectively activates chicoric acid biosynthesis, providing a foundation for the application of blue light supplementation technology in industrial production.PMID:39670431 | DOI:10.1111/pbi.14542

Front Plant Sci. 2024 Nov 28;15:1452804. doi: 10.3389/fpls.2024.1452804. eCollection 2024.ABSTRACTNepeta nuda L. shares a typical secondary chemistry with other Nepeta species (fam. Lamiaceae), characterized by the tendency to intensively produce monoterpenoid iridoids, whereas the phenylpropanoid chemistry is steered towards the production of a caffeic acid ester, rosmarinic acid. Combining complementary state-of-the-art analytical techniques, N. nuda metabolome was here comprehensively characterized in the quest for the organ-specific composition of phenolics and terpenoids that possess well-defined functions in plant-biotic interactions as well as therapeutic potential. N. nuda inflorescences showed generally higher constitutive levels of specialized metabolites, as compared to leaves, and the composition of major iridoids and phenolics in reproductive organs was found to be more conserved than in leaves across 13 populations from the Central Balkans. The results suggest that N. nuda plants most likely invest more in constitutive than inducible biosynthesis of functional metabolites in flowers, since they are of essential importance for both pollination and defense against herbivores and pathogens. Conversely, specialized metabolism of leaves is found to be more susceptible to reprograming in response to differential growth conditions. The defense strategy of leaves, primarily functioning in CO2 fixation during photosynthesis, more likely relies on the induction of metabolite levels following plant-environment interplay. Organ-specific biosynthesis of iridoids in N. nuda is found to be tightly regulated at the transcriptional level, and high constitutive levels of these compounds in inflorescences most likely result from the up-regulated expression of several key genes (NnG8H, NnNEPS1, NnNEPS2, and NnNEPS3) determining the metabolic flux through the pathway. The organ-specific content of rosmarinic acid and co-expression patterns of the corresponding biosynthetic genes were much less correlated, which suggests independent organ-specific transcriptional regulation of the iridoid and phenolic pathways. Knowledge gathered within the present study can assist growers to select productive genotypes and manipulate phenology of N. nuda towards maximizing yields and facilitating its integration into pest management systems and other applications related to human health.PMID:39670275 | PMC:PMC11634604 | DOI:10.3389/fpls.2024.1452804

Front Plant Sci. 2024 Nov 25;15:1490633. doi: 10.3389/fpls.2024.1490633. eCollection 2024.ABSTRACTINTRODUCTION: Currently, research on tobacco's response to chilling stress is mostly limited to laboratory simulations, where temperature is controlled to study physiological and molecular responses. However, laboratory conditions cannot fully replicate the complex environment of field chilling stress, so conducting research under field conditions is crucial for understanding the multi-level adaptive mechanisms of tobacco to chilling stress in natural environments.METHODS: This study aims to use field trials, starting from physiological responses, combined with proteomics and untargeted metabolomics, to systematically reveal the physiological and biochemical characteristics and key molecular mechanisms of tobacco leaves under chilling stress. It provides new insights into tobacco's adaptation strategies under chilling stress.RESULTS: The results showed that (1) chilling stress damages the appearance of tobacco leaves, reduces the chlorophyll content, increases H2O2 and malondialdehyde (MDA) levels in cold-injured tobacco leaves, and damages the plasma membrane system. Although catalase (CAT) activity increases to cope with the accumulation of reactive oxygen species (ROS), the activities of key antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD) significantly decrease, indicating that the antioxidant system of tobacco leaves fails in environments with sudden temperature drops. (2) Proteomics analysis indicated that 410 differentially expressed proteins were identified in cold-stressed tobacco leaves, with 176 upregulated and 234 downregulated. Tobacco leaves under chilling stress attempt to maintain energy supply and physiological stability by enhancing glycolysis, starch, and sucrose metabolism pathways. Concurrently, chilling stress triggers the expression of proteins related to cell wall reinforcement and antioxidant defense. However, due to impaired ribosomal function, protein synthesis is significantly inhibited, which aggravates damage to photosynthesis and cellular functions. (3) Metabolomics analysis revealed that the differential metabolites in cold-stressed tobacco leaves were mainly enriched in tyrosine metabolism, isoquinoline alkaloid biosynthesis, and fatty acid degradation pathways. This indicates that under chilling stress, tobacco leaves enhance adaptability by regulating energy metabolism, increasing antioxidant capacity, and stabilizing cell membrane structure.CONCLUSIONS: Therefore, under chilling stress, tobacco leaves exhibit complex physiological adaptability through multiple regulatory mechanisms involving proteins and metabolites. The research results provide important insights into the metabolic regulatory mechanisms of tobacco in response to extreme environments and also enhance the theoretical foundation for addressing low-temperature stress in practical production.PMID:39670264 | PMC:PMC11635995 | DOI:10.3389/fpls.2024.1490633

Front Plant Sci. 2024 Nov 28;15:1466659. doi: 10.3389/fpls.2024.1466659. eCollection 2024.ABSTRACTINTRODUCTION: Phytoremediation is a safe and green technology for the remediation of heavy metal pollution, a global environmental problem. Bryophytes are well known for their special physiological properties, but there is little research on the use of bryophytes for phytoremediation.METHODS: In this indoor experiment, the impacts of 40 days of Cd pollution (1 (T1), 5 (T2), 10 (T3) mg·L-1) on Cd absorption, growth and physiological characteristics, and phyllosphere bacterial diversity of Tortella tortuosa were explored.RESULTS: The results showed that the maximum Cd absorption capacity of T. tortuosa was 5.0135 mg·kg-1. The contents of leaf chlorophyll a (Chl a) and chlorophyll b (Chl b) in T. tortuosa decreased (p < 0.05) with the increase of Cd concentration. Especially, the Chl a and Chl b contents of the T3 treatment reduced by 88% and 91%, respectively compared with those of the CK (Cd: 0 mg·L-1). The catalase (CAT) and peroxidase (POD) activities of the T3 treatment reduced by 55% and 85%, respectively (p < 0.05), and the malondialdehyde (MDA) content increased by 167%, compared with those of the CK. Under Cd exposure, Cyanobacteria (63.49%) and Proteobacteria (26.62%) were the dominant bacterial phyla. The highly abundant phyllosphere bacteria were negatively correlated with the Cd concentration, antioxidant enzyme activity, and chlorophyll content in T. tortuosa, and positively correlated with the relative abundances of Neomycin and N-Acetyl-L-Glutamic acid.DISCUSSION: Although the severe Cd pollution could affect the physiological and metabolic characteristics of T. tortuosa, T. tortuosa had a strong absorption capacity for Cd. Therefore, it could be used for phytoremediation of heavy metal pollution. This study will provide a reference for the remediation of soil heavy metal pollution.PMID:39670261 | PMC:PMC11635300 | DOI:10.3389/fpls.2024.1466659

ISME Commun. 2024 Nov 26;4(1):ycae149. doi: 10.1093/ismeco/ycae149. eCollection 2024 Jan.ABSTRACTHydraulic fracturing has unlocked vast amounts of hydrocarbons trapped within unconventional shale formations. This large-scale engineering approach inadvertently introduces microorganisms into the hydrocarbon reservoir, allowing them to inhabit a new physical space and thrive in the unique biogeochemical resources present in the environment. Advancing our fundamental understanding of microbial growth and physiology in this extreme subsurface environment is critical to improving biofouling control efficacy and maximizing opportunities for beneficial natural resource exploitation. Here, we used metaproteomics and exometabolomics to investigate the biochemical mechanisms underpinning the adaptation of model bacterium Halanaerobium congolense WG10 and mixed microbial consortia enriched from shale-produced fluids to hypersalinity and very low reservoir flow rates (metabolic stress). We also queried the metabolic foundation for biofilm formation in this system, a major impediment to subsurface energy exploration. For the first time, we report that H. congolense WG10 accumulates tyrosine for osmoprotection, an indication of the flexible robustness of stress tolerance that enables its long-term persistence in fractured shale environments. We also identified aromatic amino acid synthesis and cell wall maintenance as critical to biofilm formation. Finally, regulation of transmembrane transport is key to metabolic stress adaptation in shale bacteria under very low well flow rates. These results provide unique insights that enable better management of hydraulically fractured shale systems, for more efficient and sustainable energy extraction.PMID:39670059 | PMC:PMC11637423 | DOI:10.1093/ismeco/ycae149

Front Med (Lausanne). 2024 Nov 28;11:1447566. doi: 10.3389/fmed.2024.1447566. eCollection 2024.ABSTRACTBACKGROUND: Gastric ulcer (GU), a globally prevalent disease, represents a significant burden to human health. Bletilla ochracea Schltr. (BOS), an herbal medicine, shows promising therapeutic potential in the treatment of chronic GU.METHODS: This study utilized a rat model of chronic gastric ulceration induced by acetic acid to evaluate the protective effects of Bletilla ochracea Schltr. (BOS) on gastric tissue through the analysis of gross morphological and histopathological changes. Non-targeted metabolomic techniques were employed to identify differential metabolites, followed by the use of metabolic analysis software to enrich the pathways associated with these metabolites, thereby revealing the potential mechanisms underlying the anti-gastric ulcer effects of BOS.RESULTS: The results suggest that the primary mechanism underlying BOS regulation of GU involves modulation of endogenous metabolites, including dimethylglycine, l-2,4-diaminobutyric acid, uridine propionic acid and l-asparagine. These diverse metabolites may have anti-inflammatory, antioxidant and reparative properties. In addition, KEGG enrichment analysis indicated potential anti-GU effects of BOS through diverse pathways such as energy metabolism, immune metabolism and amino acid metabolism.CONCLUSION: The study demonstrates BOS protective effects on GU in rats, potentially through modulating key metabolites and pathways, highlighting its therapeutic potential and warranting further investigation for clinical applications.PMID:39669987 | PMC:PMC11634584 | DOI:10.3389/fmed.2024.1447566

Front Microbiol. 2024 Nov 28;15:1466024. doi: 10.3389/fmicb.2024.1466024. eCollection 2024.ABSTRACTThis study aimed to investigate the effects of multi-enzyme (alkaline protease, xylanase, glucanase, β-mannanase, cellulase, acid protease, glucoamylase, and α-galactosidase) on antioxidant capacity, egg quality, amino acid profiles in yolk, cecal microflora and metabolites in laying hens. A total of 384 Jingfen No.6 laying hens aged 65 weeks were randomly divided into 4 treatments groups (6 replicates per group) and fed diets containing 0, 150, 300, or 600 mg kg-1 multi-enzyme over an 8-week feeding duration. Our findings revealed that supplementation with 600 mg kg-1 of multi-enzyme significantly increased the albumen height (P < 0.05) and haugh unit (P < 0.05). Moreover, as the levels of multi-enzyme supplementation in the diet increased, there were significant increases in activities of total antioxidant capacity (T-AOC) in serum (P < 0.05) and glutathione peroxidase (GSH-Px) in the liver (P < 0.05). Different levels of multi-enzyme supplementation significantly affected the composition of amino acid profiles in the yolk. Furthermore, the results from 16S rRNA sequencing and untargeted metabolomics analysis of cecal content revealed that multi-enzyme supplementation altered the cecal microflora and metabolite profiles. We found the relative abundance of the Bacteroidota phyla in T600 group was significantly increased (P < 0.05) compared to CON and T150 groups, but the relative abundance of the Firmicutes phylum in T600 group were significantly lower than T150 group (P < 0.05). At the genus level, the relative abundance of the Parabacteroides genera in T300 group, the Faecalibacterium genera in T300 and T600 groups, the norank_f_Prevotellaceae genera in treatment groups (T150, T300 and T600), the norank_f_Peptococcaceae genera in T600 group, and the Monoglobus genera in T1 group were significantly increased. The KEGG pathway analysis showed that the common enrichment metabolic pathways of each treatment group compared to the CON group were glycine, serine and threonine metabolism, foxo signaling pathway and mTOR signaling pathway, and the enrichment metabolic pathways shared by T300 vs CON and T600 vs CON was galactose metabolism and glycolysis/gluconeogenesis pathways. Correlation analysis identified notable relationships between specific microbes and metabolites with T-AOC in serum, GSH-Px activity in the liver, amino acids in yolk, albumen height, and haugh units. Overall, this study suggests that multi-enzyme supplementation regulated the cecal microbial community and metabolism, potentially influencing amino acid profiles in yolk, antioxidant capacity, and egg quality.PMID:39669781 | PMC:PMC11634838 | DOI:10.3389/fmicb.2024.1466024

Front Microbiol. 2024 Nov 28;15:1475984. doi: 10.3389/fmicb.2024.1475984. eCollection 2024.ABSTRACTKeloid scarring is a fibroproliferative disease of the skin, which can significantly impact one's quality of life through cosmetic concerns, physical discomfort (itchy; painful), restricted movement, and psychological distress. Owing to the poorly understood pathogenesis of keloids and their high recurrence rate, the efficacy of keloid treatment remains unsatisfactory, particularly in patients susceptible to multiple keloids. We conducted fecal metagenomic analyzes and both untargeted and targeted plasma metabolomics in patients with multiple keloids (MK, n = 56) and controls with normal scars (NS, n = 60); tissue-untargeted metabolomics (MK, n = 35; NS, n = 32), tissue-targeted metabolomics (MK, n = 41; NS, n = 36), and single-cell sequencing analyzes (GSE163973). Differences in the gut microbiota composition, plasma metabolites, and tissue metabolites were observed between the MK and NS groups; the core gut microbiota, Oxalobacter formigenes, Bacteroides plebeius, and Parabacteroides distasonis, were identified via the gut microbiome co-occurrence network. Single-cell data helped clarify the specific cells affected by plasma metabolites. An area under the curve analysis using a random forest model based on fecal metagenomics, plasma metabolomics, and tissue metabolomics revealed that gut bacteria, plasma, and tissue metabolites were effective in distinguishing between MK and NS groups. Decreased Bacteroides plebeius could lower uracil levels, altering systemic lipid metabolism, which may change the metabolic phenotype of secretory reticular fibroblasts in wounds, potentially leading to MK. These findings may open new avenues for understanding the multifactorial nature of keloid formation from the gut-skin axis and highlight the potential for novel therapeutic strategies targeting keloid lesions and the underlying systemic imbalances affected by the gut microbiome.PMID:39669776 | PMC:PMC11636970 | DOI:10.3389/fmicb.2024.1475984

Front Mol Biosci. 2024 Nov 28;11:1528799. doi: 10.3389/fmolb.2024.1528799. eCollection 2024.NO ABSTRACTPMID:39669675 | PMC:PMC11634746 | DOI:10.3389/fmolb.2024.1528799

Heliyon. 2024 Feb 28;10(5):e26643. doi: 10.1016/j.heliyon.2024.e26643. eCollection 2024 Mar 15.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is an incurable neurodegenerative disease that has become one of the most important diseases threatening global public health security. Dihuang Yinzi (DHYZ) is a traditional Chinese medicine that has been widely used for the treatment of AD and has significant therapeutic effects, but its specific mechanism of action is still unclear.The aim of the study is to investigate the specific mechanism of DHYZ in treating AD based on brain metabolomics and network pharmacology.MATERIALS AND METHODS: In this study, the classic APPswe/PS1E9 (APP/PS1) mice were selected as the AD animal model, and the mechanism of DHYZ was studied. The learning and memory ability of mice was detected by Y-maze test, and the ultrastructure of neural cells in the brain of the mice was observed by transmission electron microscope (TEM). Then, the mechanism of DHYZ intervention in AD was analyzed by constructing network pharmacology, and combined with brain metabolomics based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS) to detect differential metabolic markers and their metabolic pathways. In addition, a joint analysis of differential metabolites and potential targets for DHYZ treatment of AD is conducted to deeply explore the relationship between key targets, differential metabolites, and metabolic pathways.RESULTS: After 30 days of DHYZ treatment, the spatial work and reference memory ability of APP/PS1 mice were significantly improved, the structure of mitochondria and synapses in the neurons of the brain were basically normal. 202 potential targets for DHYZ treatment of AD were screened through network pharmacology, and after enrichment analysis, these targets showed correlation with redox reactions, mitochondrial and synaptic functional pathways. And 7 differential metabolites were identified in brain metabolomics are Nicotinic acid, N-Formyl-L-glutamic acid, 5-(2-Hydroxyethyl)-4-methylthiazole, D-Gulono-1,4-lactone, Norepinephrine, 3-Methylotrophicacid, Palmitic acid. These differential metabolites mainly involve nicotinite and nicotinamide metabolism, pertussis, cAMP signaling pathway, cysteine and methionine metabolism. Notablely, through matching analysis of targets and metabolites, a total of 20 genes were found to match Nicotinic acid, 51 genes were found to match norepinephrine, and 14 genes intersected with the two metabolites, enrichment analysis of the intersected genes showed that neuroactive light receptor interaction, serotonergic synapse, and cAMP signaling were significantly affected, which is consistent with previous network pharmacology results.CONCLUSION: This study identified the main chemical ingredients of DHYZ intervention in AD may originated from Polygala tenuifolia Wild, Dendrobium nobile Line and Ophiogon japonicus (L.f) Ker-Gawl. Combined with Y Maze, TEM and brain metabolomics, revealed that DHYZ can improve the learning and memory abilities and brain pathological morphology of APP/PS1 mice by regulating nicotinic acid, 3-Methylthiopropionic acid, pertussis and their metabolic pathways, including nicotinate and nicotinamide metabolism, cAMP signaling pathway and cysteine and methionine metabolism. In short, this study provides a new research foundation and direction for the treatment of AD with traditional Chinese medicine.PMID:39669488 | PMC:PMC11636838 | DOI:10.1016/j.heliyon.2024.e26643

Int J Endocrinol. 2024 Dec 5;2024:1634072. doi: 10.1155/ije/1634072. eCollection 2024.ABSTRACTIn this study, we evaluated the effects of intrabursal administration of cabergoline and N-acetylcysteine on ovarian hyperstimulation syndrome (OHSS) in an immature rat model. The study assessed body, ovarian, and uterine weights, as well as the concentrations of vascular endothelial growth factor A (VEGF-A). Moreover, levels of MDA, 4-HDA, and nitrites were assessed in ovarian homogenates, and vascular permeability was quantified in the peritoneal cavity. Ovarian morphology was characterized using histology and hematoxylin-eosin staining, determining the count of ovarian follicles and corpus luteum. Our results demonstrated a significant increase in lipoperoxidation, nitrite levels, and VEGF-A concentrations in the OHSS group compared to the control group. These biochemical alterations corroborate the successful induction of OHSS in the experimental model. Direct injection into the ovarian bursa resulted in reduced vascular permeability and VEGF-A levels, suggesting that the effects of cabergoline are predominantly ovarian. Particularly, cabergoline did not significantly alter other parameters such as ovarian weight, lipoperoxidation, nitrite levels, or morphology. Conversely, low concentrations of N-acetylcysteine (25-50 µg/kg) significantly reduced ovarian and uterine weights, VEGF-A levels, and vascular permeability. Interestingly, this dose-response relationship was not observed at higher NAC concentrations (100-200 μg/kg), suggesting a potential threshold beyond which NAC loses efficacy in these specific parameters. Our results suggest that the localized administration of N-acetylcysteine shows promise as a therapeutic strategy for OHSS by modulating key parameters associated with the syndrome. These promising results warrant further investigation into its mechanisms and efficacy, potentially expanding therapeutic options for OHSS management.PMID:39669379 | PMC:PMC11637629 | DOI:10.1155/ije/1634072

Front Pharmacol. 2024 Nov 28;15:1510098. doi: 10.3389/fphar.2024.1510098. eCollection 2024.ABSTRACTINTRODUCTION: Chronic kidney disease (CKD) is a substantial global health issue with high morbidity and mortality. Yishen Paidu Pills (YSPDP) are effective concentrated water pills composed of four herbs developed by Wuhan Union Hospital to treat CKD. However, the mechanism of YSPDP action is largely unknown. This study combined metabolomics, network pharmacology, transcriptomics, and experimental verification to elucidate and identify the effects and potential mechanisms of YSPDP against CKD.METHODS: Firstly, we used metabolomics analyses to identify the chemical components of YSPDP. Then, network pharmacology was conducted and indicated the predicted signaling pathways regulated by YSPDP. Next, we conducted a 5/6 subtotal nephrectomy (5/6 SNx) rat model and treated these rats with YSPDP or Losartan for 10 weeks to evaluate the effect of YSPDP on CKD. To further analyze the underlying mechanism of YSPDP in CKD, the kidney tissues of 5/6 SNx rats treated with vehicle and YSPDP were performed with transcriptome sequencing. Finally, the western blot was performed to validate the signaling pathways of YSPDP against CKD.RESULTS: Twenty-four classes of chemicals were identified by metabolomics in YSPDP. YSPDP markedly hindered CKD progression, characterized by the restoration of body weight and serum albumin levels, improved renal function, diminished tissue injury, and hampered renal fibrosis in 5/6 SNx rats. The efficacy of YSPDP in ameliorating the progression of CKD was comparable to that of losartan. Furthermore, network pharmacology, transcriptomics, and functional enrichment analysis indicated the PI3K/AKT/mTOR signaling pathway was the key pathway regulated by YSPDP. Western blot validated the inhibition of PI3K/AKT/mTOR signaling in the kidney of 5/6 SNx rats treated by YSPDP.CONCLUSION: The study identified the chemicals of YSPDP and revealed that YSPDP prevented the progression of CKD by inhibiting PI3K/AKT/mTOR signaling in 5/6 SNx rats.PMID:39669205 | PMC:PMC11634598 | DOI:10.3389/fphar.2024.1510098

Front Pharmacol. 2024 Nov 28;15:1506767. doi: 10.3389/fphar.2024.1506767. eCollection 2024.ABSTRACTMetformin has become the frontline treatment in addressing the significant global health challenge of type 2 diabetes due to its proven effectiveness in lowering blood glucose levels. However, the reality is that many patients struggle to achieve their glycemic targets with the medication and the cause behind this variability has not been investigated thoroughly. While genetic factors account for only about a third of this response variability, the potential influence of metabolomics and the gut microbiome on drug efficacy opens new avenues for investigation. This review explores the different molecular signatures to uncover how the complex interplay between genetics, metabolic profiles, and gut microbiota can shape individual responses to metformin. By highlighting the insights from recent studies and identifying knowledge gaps regarding metformin-microbiota interplay, we aim to highlight the path toward more personalized and effective diabetes management strategies and moving beyond the one-size-fits-all approach.PMID:39669200 | PMC:PMC11634602 | DOI:10.3389/fphar.2024.1506767

Hepatobiliary Surg Nutr. 2024 Dec 1;13(6):962-973. doi: 10.21037/hbsn-23-645. Epub 2024 Aug 22.ABSTRACTBACKGROUND: Sarcopenia at the time of liver transplantation (LT) is an established risk factor for mortality following LT. However, most studies in this context have defined sarcopenia by one-time, static measurements. The aims of this study were (I) to determine the impact of the rate of muscle loss in waitlisted LT recipients on post-LT outcomes and (II) to identify patterns of serum metabolites associated with patients with more progressive sarcopenia.METHODS: Patients undergoing liver transplant from 2008 to 2018 who received more than one computed tomography (CT) scans within 12 months prior to liver transplant were included (n=61). The psoas muscle index (PMI) was calculated using Slice-O-Matic software and corrected for patient height (m2). Patients were classified into two groups based the rate of reduction in PMI-high wasting [HW; change in PMI (ΔPMI) ≤-1%/month] and low wasting (LW; ΔPMI >-1%/month). Pre-transplant serum metabolic profiles were collected using nuclear magnetic resonance (NMR) spectroscopy. Living kidney donor sera was used as healthy controls.RESULTS: Median ΔPMI was -2.0%/month in HW and -0.15%/month in LW patients (P<0.001). Post-transplant 1-year mortality was significantly higher in HW patients. There were no significant differences in metabolite concentrations between HW and LW patients. However, perturbations in taurine, sarcosine, betaine and the aromatic amino acids (AAAs), were observed in patients with liver disease as compared to healthy controls. Liver disease was also associated with a decrease in lipoprotein profiles, especially high-density lipoprotein (HDL) particles.CONCLUSIONS: In patients undergoing LT, the rate of progression of sarcopenia is a strong prognostic indicator of post-LT death. Serum metabolite profiles were not characteristically unique to HW patients, and most closely resemble derangements associated with chronic liver disease.PMID:39669082 | PMC:PMC11634410 | DOI:10.21037/hbsn-23-645

Front Nutr. 2024 Nov 28;11:1438876. doi: 10.3389/fnut.2024.1438876. eCollection 2024.ABSTRACTBACKGROUND: The global prevalence of the metabolic disease Type 2 Diabetes (T2D) is increasing. Risk factors contributing to the development of T2D include overweight and obesity, lack of physical activity (PA), and an unhealthy diet. In addition, the gut microbiota has been shown to affect metabolic regulation. Since T2D is preventable, efforts should be put into the discovery of new biomarkers for early detection of individuals at risk of developing the disease.OBJECTIVE: The objective of the cross-sectional study was to explore the relationship between gut microbiota and physical activity (PA) and/or metabolic markers such as selected amino acids (AA), markers of glycaemic regulation and lipid metabolism and anthropometric measures.DESIGN: Healthy adults (18 and 65 years) with BMI between 18.5 and 27.5 kg/m2 originally recruited to a randomised controlled trial (RCT) (n = 17: six males, eleven females), were included in this exploratory cross-sectional study. Physical activity data was calculated based on a 3-days registration, and blood metabolome, gut microbiota analyses and anthropometric measures from one visit of the intervention were used in this cross-sectional study.RESULTS: Of the 47 gut bacteria analysed, there were a total of 87 significant correlations with AA, PA, body composition and/or metabolic markers. Several of the gut bacteria correlated with both PA, metabolic or anthropometric markers.CONCLUSION: In this study, we demonstrate associations between gut bacteria and PA and/or metabolic markers including AA in healthy individuals. The results may guide future studies aiming at identifying new and early biomarkers of metabolic health and diseases.PMID:39668899 | PMC:PMC11635997 | DOI:10.3389/fnut.2024.1438876

Anal Methods. 2024 Dec 13. doi: 10.1039/d4ay01672f. Online ahead of print.ABSTRACTLiupao tea (LPT) is a Chinese dark tea known to possess a unique flavour. Microbial fermentation plays a crucial role in flavour development and enrichment. Currently, the phytochemical profiles and bioactivities of LPT with and without fermentation are not fully known. In this study, we compared the chemical composition of raw tea (SF), stale-aroma (SA), and betelnut-aroma (BA) type LPT through the application of GC/LC-MS-based metabolomics, and experimentally investigated their bioactivities via antioxidant, anti-inflammatory, hypolipidemic, and hypoglycemic assays in vitro. The results indicated that fermentation enhanced the flavour of LPT as evidenced by the sweetness-producing substances, decreased bitterness and astringency-related compounds and enriched abundance of aroma-generating compounds. Two and four volatiles were detected to be major contributors to the aroma in SA and BA, respectively. Fatty acids and phosphatidylcholines were the primary lipids, among which the lysing diacylglycerol trimethyl homoserines were found to be a new class of lipids in LPT. Notably, the fermentation resulted in the degradation of compounds, particularly glycerophospholipids and saccharolipids. SF had the highest level of bioactivity, followed by BA and SA. These findings expand the present understanding regarding the development of flavour, nutrition, and medicinal value of LPT. Moreover, they provide a theoretical basis for the identification of BA and SA and serve as a reference value for consumers in their selection of LPT products.PMID:39668786 | DOI:10.1039/d4ay01672f

Food Funct. 2024 Dec 13. doi: 10.1039/d4fo04660a. Online ahead of print.ABSTRACTBifidobacterium species are known for their efficacy in alleviating constipation. This study aimed to compare the constipation-relieving effects of different Bifidobacterium species (Bifidobacterium longum subsp. longum, Bifidobacterium bifidum, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, and Bifidobacterium adolescentis) and to explore the underlying mechanisms from both the bacterial and host perspectives. We evaluated six Bifidobacterium species for their physiological properties, including growth rate, oligosaccharide utilization, osmotic pressure resistance, cell adhesion, and bile acid dissociation capability. Mice with severe constipation induced by loperamide hydrochloride were treated with these bacteria at a density of 109 CFU per mL for 17 days. Gastrointestinal indices such as fecal water content, time to first black stool defecation, and small intestine propulsion rate were measured to assess constipation relief. Microbiome and metabolome (bile acid and tryptophan) analyses were conducted to elucidate the differences in constipation relief among the species. Our results demonstrated that Bifidobacterium longum subsp. longum exhibited superior physiological traits, including rapid growth, extensive oligosaccharide utilization, and high bile salt dissociation capacity. Notably, only Bifidobacterium longum subsp. longum significantly ameliorated constipation symptoms in the mouse model. Furthermore, this strain markedly restored bile acid and short-chain fatty acid levels in the intestines of constipated mice and altered the composition of the intestinal microbiota. These findings suggest that the enhanced efficacy of Bifidobacterium longum subsp. longum in relieving constipation is associated with its ability to modulate intestinal physiology and microbiota structure and metabolism.PMID:39668691 | DOI:10.1039/d4fo04660a

Br J Pharmacol. 2024 Dec 12. doi: 10.1111/bph.17409. Online ahead of print.ABSTRACTBACKGROUND AND PURPOSE: Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease, and the range of current clinical treatments is not ideal. We previously found that polysaccharide of Atractylodes macrocephala Koidz (PAMK) is beneficial in DSS-induced colitis, and we aimed to investigate the underlying mechanisms in this study.EXPERIMENTAL APPROACH: PAMK was used to treat DSS-induced colitis in mice, 16S rRNA sequencing analysis was used to detect changes in the intestinal microbiota, targeted metabolomics analysis was used to determine the content of tryptophan-metabolizing bacteria, and western blotting was used to determine aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) levels. Furthermore, antibiotic-mediated depletion of gut microbiota and faecal microbiota transplantation were performed to assess the role of the gut microbiota in PAMK alleviation of colitis.KEY RESULTS: PAMK treatment relieved intestinal microbiota dysbiosis in mice with colitis, contributed to the proliferation of tryptophan-metabolizing bacteria, and increased the levels of tryptophan metabolites, resulting in a significant increase in the nuclear translocation of PXR and expression of PXR and its target genes, but not AhR. The gut microbiota is important in PAMK treatment of colitis, including in the alleviation of symptoms, inhibition of inflammation, maintenance of the integrity of the intestinal barrier, and the regulation of the Th17/Treg cell balance.CONCLUSION AND IMPLICATIONS: Based on our findings, we elucidate a novel mechanism by which PAMK alleviates DSS-induced colitis and thus provides evidence to support the potential development of PAMK as a new clinical drug against UC.PMID:39667762 | DOI:10.1111/bph.17409

Fitoterapia. 2024 Dec 10:106343. doi: 10.1016/j.fitote.2024.106343. Online ahead of print.ABSTRACTPostprandial hyperglycemia is a hallmark of diabetes, and inhibition of key carbohydrate digestion enzymes such as α-amylase (α-AMY) and α-glucosidase (α-GLU) is an effective therapeutic target. A potential unexplored source of inhibitory compounds of these enzymes is Brassica oleracea var. capitata L (BOCE). This study explored the in vitro inhibition mechanism of BOCE and studied in silico the interaction of its compounds identified and quantified by UPLC-QTOF-MS on α-AMY and α-GLU. BOCE demonstrated IC50 values of 3.08 mg/mL for α-AMY and 22.63 mg/mL for α-GLU, indicating competitive and mixed-type inhibitions, respectively. Untargeted metabolomics identified 21 compounds, primarily phenolic acids such as t-cinnamic, sinapic, and caffeoylquinic acid. In the targeted analysis, 11 compounds were quantified, mainly phenolic acids. The most impactful biosynthetic pathways identified were phenylpropanoids and brassinosteroids. In silico analysis revealed that for α-AMY and α-GLU, castasterone and 26-hydroxybrassinolide displayed the lowest binding free energies with specific hydrogen bond patterns to catalytic residues in the binding site, respectively. B. oleracea is a promising source of compounds with the ability to modulate key enzymes related to hyperglycemia. Specifically, compounds such as castasterone and 26-hydroxybrassinolide show potential against α-AMY and α-GLU inhibition, offering a novel approach to diabetes.PMID:39667674 | DOI:10.1016/j.fitote.2024.106343