PubMed

Nat Commun. 2024 Nov 4;15(1):9522. doi: 10.1038/s41467-024-53733-0.ABSTRACTFat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.PMID:39496584 | DOI:10.1038/s41467-024-53733-0

CNS Neurosci Ther. 2024 Nov;30(11):e70094. doi: 10.1111/cns.70094.ABSTRACTThis case report provides the first evidence that coenzyme Q10 may improve muscle weakness in patients with 22q11.2DS. The patient's genetic copy number deletion mutation region mainly contains COMT, PRODH functional genes related with mitochondria dynamics. The level of L-arginine was significantly increased after treatment by coenzyme Q10 in serum.PMID:39496467 | DOI:10.1111/cns.70094

Exp Anim. 2024 Nov 5. doi: 10.1538/expanim.24-0080. Online ahead of print.ABSTRACTTo investigate the pathogenesis of hyperlipidemia in Wistar-SD Hypercholesterolemia (WSHc) rats and clarify the genetic and biological characteristics. Six 7-8-week-old WSHc rats were fed a high-fat diet (HFD), and another six were fed ordinary feed, with age-matched Wistar rats as the control group under the same treatment. After 16 weeks, serum lipid levels were measured. A transcriptomic analysis of the differences in gene expression of the liver related to cholesterol metabolism was conducted, and 119 differentially expressed genes were discovered through bioinformatics analysis and molecular biology verification. UHPLC-Q-TOF/MS was applied for lipidomic analysis of serum samples from each group. WSHc rats developed dyslipidemia after a high-fat diet was induced. Investigation of the gene profiles using the protein-protein interaction network and one-cluster clustering analysis identified SREBF1 as a HUB gene and NR1d1 as an independent key gene. SREBF1 and NR1d1 were further validated in molecular biology experiments, which was consistent with the transcriptomic results. Lipid metabolomics analysis identified seven lipid subclasses and 84 lipid molecules. The metabolic profiles of serum lipid media of the WSHc + HFD and WSHc + SC groups were significantly different compared to that of the control group by 62 and 70 lipid molecules, respectively. Differential metabolites were produced via sphingolipid and glycerophospholipid metabolism. A stable model of hypercholesterolemia in WSHc rats can be generated by feeding on a high-fat diet, and the pathogenesis mainly involves two key genes, SREBF1 and NR1d1, and the sphingolipid and glycerophospholipid metabolism pathways.PMID:39496388 | DOI:10.1538/expanim.24-0080

J Agric Food Chem. 2024 Nov 4. doi: 10.1021/acs.jafc.4c06490. Online ahead of print.ABSTRACTDysregulated muscle glycogen metabolism preslaughter contributes to aberrant postmortem muscle pH (>5.8) in dark-cutting beef phenotypes. However, the underlying mechanisms have remained elusive. Herein, we examine the glycogen dependent regulation of postmortem muscle pH decline and darkening in beef. We show that supplementation of glycogen in vitro restores postmortem pH decline in dark-cutting beef by reverting the metabolome toward a typical postmortem muscle state characterized by increased activities of enzymes glycogen phosphorylase and lactate dehydrogenase (p < 0.05) coupled with a pronounced abundance of glycolytic metabolites and reduced abundance of tricarboxylic acid cycle and amino acid metabolites. Furthermore, concurrent inhibition of mitochondrial respiration at complexes I, IV, and V with glycogen supplementation stimulates greater pH decline. Together, our findings show that supplementing glycogen at low concentrations (10 mM) can reprogram the dark-cutting beef muscle's metabolome toward typical postmortem state and promote muscle acidification. Thus, enhancing glycogen levels could represent a promising strategy for mitigating dark-cutting beef phenotypes and improving meat quality.PMID:39496138 | DOI:10.1021/acs.jafc.4c06490

Medicine (Baltimore). 2024 Nov 1;103(44):e40161. doi: 10.1097/MD.0000000000040161.ABSTRACTInflammation plays a crucial role in chronic kidney disease (CKD) and pulmonary hypertension (PH). Considering that the neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a powerful predictor of adverse outcomes in many chronic diseases, we aimed to investigate the association between NLR and all-cause mortality in patients with CKD-related PH. A total of 176 hospitalized patients with predialysis CKD-related PH were recruited retrospectively from January 2012 to June 2020 by reviewing electronic medical records. The NLR and clinical characteristics of the patients were included in the current analysis. The Kaplan-Meier method and univariate and multivariate Cox regression analyses were performed to identify the association between NLR and the incidence of all-cause mortality. Baseline NLR values were associated with hemoglobin, estimated glomerular filtration rate and C-reactive protein. During a median follow-up period of 32.5 (11.3-53.0) months, 23 patients died. Regardless of whether the NLR acted as a continuous variable with a hazard ratio of 1.408 (95% confidence interval: 1.124-1.763) or a categorical variable (NLR ≤4.3 vs NLR >4.3) with a hazard ratio of 3.100 (95% confidence interval: 1.299-7.402), an elevated NLR was significantly associated with all-cause mortality in different models. A greater NLR at baseline was remarkably associated with a higher all-cause mortality in hospitalized patients with CKD-related PH.PMID:39496051 | DOI:10.1097/MD.0000000000040161

Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2406771121. doi: 10.1073/pnas.2406771121. Epub 2024 Nov 4.ABSTRACTBurkholderia thailandensis has emerged as a nonpathogenic surrogate for Burkholderia pseudomallei, the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome of B. thailandensis. In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential for B. thailandensis in the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and β-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity against B. pseudomallei. Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens.PMID:39495920 | DOI:10.1073/pnas.2406771121

Pak J Pharm Sci. 2024 Sep;37(5):1135-1150.ABSTRACTPeperomia dindygulensis is used as an anticancer medicinal plant in China and is rich in a series of novel secolignans, including peperomin E (PE). In our prior study, we demonstrated the significant reduction in tumor weight and volume in vivo in a PCa DU145 cell xenograft tumor mouse model following PE treatment. However, the impact of PE on PCa metabolism remains unclear. Therefore, the objective of this investigation is to examine the influence of PE on metabolism regulation within a PCa mouse model. An untargeted UPLC-Q-TOF-MS plasma metabolomics approach was carried out to explore the mechanism of action of PE in a human prostate cancer DU145 cell xenograft tumour mouse model based on principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), identification of potential biomarkers and pathway analysis. A total of 71 potential plasma metabolite biomarkers were identified in the nude mouse model and 36 of which were reversed to different degrees after the treatment with PE. These identified biomarkers primarily relate to amino acid metabolism, fatty acid metabolism and cholic acid metabolism. These findings showed that PE could improve endogenous metabolism in the DU145 cell xenograft tumor mouse model and offered a reliable foundation for the design of new therapeutic drugs for treating PCa.PMID:39495855

PLoS Negl Trop Dis. 2024 Nov 4;18(11):e0012645. doi: 10.1371/journal.pntd.0012645. Online ahead of print.ABSTRACTBACKGROUND: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, and it has the potential to diminish the quality of life. Clinical and experimental evidence demonstrate protective aspects of parasitic helminth infection against IBD. However, studies on the inhibition of inflammation by helminth infection have overlooked a key determinant of health: the gut microbiota. Although infection with helminths induces alterations in the host microbiota composition, the potential influence and mechanism of helminth infections induced changes in the gut microbiota on the development of IBD has not yet been elucidated. In this study, we analyzed the intersection of helminth Trichinella spiralis and gut bacteria in the regulation of colitis and related mechanisms.METHODOLOGY/PRINCIPAL FINDINGS: T. spiralis infected mice were treated with antibiotics or cohoused with wild type mice, then challenged with dextran sodium sulfate (DSS)-colitis and disease severity, immune responses and goblet cells assessed. Gut bacteria composition was assessed by 16S rRNA sequencing and short-chain fatty acids (SCFAs) were measured. We found that protection against disease by infection with T. spiralis was abrogated by antibiotic treatment, and cohousing with T. spiralis- infected mice suppressed DSS-colitis in wild type mice. Bacterial community profiling revealed an increase in the abundance of the bacterial genus Muribaculum and unclassified_Muribaculaceae in mice with T. spiralis infection or mice cohoused with T. spiralis- infected mice. Metabolomic analysis demonstrated significantly increased propionic acid in feces from T. spiralis- infected mice. Data also showed that the gut microbiome modulated by T. spiralis exhibited enhanced goblet cell differentiation and elevated IL-10 levels in mice.CONCLUSIONS: These findings identify the gut microbiome as a critical component of the anti- colitic effect of T. spiralis and gives beneficial insights into the processes by which helminth alleviates colitis.PMID:39495798 | DOI:10.1371/journal.pntd.0012645

J Burn Care Res. 2024 Nov 4:irae162. doi: 10.1093/jbcr/irae162. Online ahead of print.ABSTRACTPreserving denatured dermis has been shown to promote wound healing and improve skin appearance and function. Angiogenesis is crucial for the healing of burn wounds. However, the metabolic mechanisms underlying angiogenesis during burn recovery remain unclear. In this study, ultra-high performance liquid chromatography-mass spectrometry analysis revealed six distinct metabolites in a heat-denatured cell model. A bioinformatics approach was used to predict the differentially expressed metabolites, and four metabolic pathways closely related to trauma repair were identified. These pathways might play a significant role in the regression of thermally injured endothelial cells. We also found that increasing D-mannose level promoted the angiogenic activity of human umbilical vein endothelial cells in the heat-denatured cell model, enhancing cell proliferation, migration, and tube formation. In summary, these findings revealed changes in metabolites and metabolic pathways in thermally injured endothelial cells, and demonstrated that D-mannose could promote angiogenesis during the recovery of thermally injured endothelial cells.PMID:39495584 | DOI:10.1093/jbcr/irae162

J Sep Sci. 2024 Nov;47(21):e70014. doi: 10.1002/jssc.70014.ABSTRACTLipid extraction of complex biological samples is essential for high-quality data in liquid chromatography-mass spectrometry (LC-MS)-based lipidomics. This study introduces a three-phase liquid extraction (3PLE)-ultra-high-performance LC coupled with quadrupole time-of-flight tandem MS method. This method was successfully applied to lipidomics analysis of breast cancer cells, including highly metastatic MDA-MB-231 and slightly metastatic MCF7 cells. The 3PLE method employed an n-hexane/methyl tert-butyl ether/acetonitrile/water solvent system that formed one aqueous and two organic phases. Neutral and polar lipids were enriched in the upper and middle organic phases, respectively, and combined for detection, thereby reducing analysis time. Compared with the Bligh and Dyer method, 3PLE achieved higher sensitivity and detected more features, with over a 50% increase in the relative abundance of nearly 50% of the differential lipids. In total, 21 differential lipids were identified in the MDA-MB-231 group and 22 in the MCF7 group compared to normal breast epithelial cells (MCF10A). Pathway analysis suggested that lipid changes in breast cancer cells were associated with glycerophospholipid metabolism, arachidonic acid metabolism, sphingolipid metabolism, and linoleic acid metabolism. The study presents a highly efficient lipidomics method, providing a scientific foundation for understanding breast cancer pathogenesis and aiding in diagnosis.PMID:39494761 | DOI:10.1002/jssc.70014

J Agric Food Chem. 2024 Nov 4. doi: 10.1021/acs.jafc.4c06928. Online ahead of print.ABSTRACTSea buckthorn (Hippophaë rhamnoides L.) known as the deciduous shrub has been reported to have effects of antioxidant, anti-inflammatory, and immunomodulatory activities. Tropomyosin (TM) induced a regulatory immune response associated with food allergy. In this study, a mouse model of food allergy sensitized to tropomyosin (TM) was established to assess the antiallergic properties of sea buckthorn flavonoid extract (SBF). SBF alleviated mice's allergic symptoms and exhibited a significant reduction in the levels of IgE and histamine. Meanwhile, SBF repaired the allergic Th2 cell overpolarization generated by TM, via downregulating the IL-4 production and upregulating IFN-γ production to restore the balance of Th1/Th2 cells. Furthermore, the 16S RNA analysis showed that SBF primarily restored the gut microbiota via increasing the abundance in Chitinophilidae and decreasing in Burkholderiaceae, Pneumatobacteriaceae, and Sphingomonadaceae. Gut metabolomes determined by liquid chromatography-mass spectrometry (LC-MS) suggested that TM upregulated PE (14:0/22:1(13Z)) and SBF decreased formimino-l-glutamic acid and urocanic acid levels. According to the KEGG pathway analysis, SBF treatment has been shown to modulate glycerophospholipid and histidine metabolism to improve allergic reactions. SBF holds great promise as a novel potential agent for the treatment of food allergies.PMID:39495351 | DOI:10.1021/acs.jafc.4c06928

Metabolomics. 2024 Nov 4;20(6):125. doi: 10.1007/s11306-024-02185-0.ABSTRACTINTRODUCTION: Human metabolomics has made significant strides in understanding metabolic changes and their implications for human health, with promising applications in diagnostics and treatment, particularly regarding the gut microbiome. However, progress is hampered by issues with data comparability and reproducibility across studies, limiting the translation of these discoveries into practical applications.OBJECTIVES: This study aims to evaluate the fit-for-purpose of a suite of human stool samples as potential candidate reference materials (RMs) and assess the state of the field regarding harmonizing gut metabolomics measurements.METHODS: An interlaboratory study was conducted with 18 participating institutions. The study allowed for the use of preferred analytical techniques, including liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR).RESULTS: Different laboratories used various methods and analytical platforms to identify the metabolites present in human stool RM samples. The study found a 40% to 70% recurrence in the reported top 20 most abundant metabolites across the four materials. In the full annotation list, the percentage of metabolites reported multiple times after nomenclature standardization was 36% (LC-MS), 58% (GC-MS) and 76% (NMR). Out of 9,300 unique metabolites, only 37 were reported across all three measurement techniques.CONCLUSION: This collaborative exercise emphasized the broad chemical survey possible with multi-technique approaches. Community engagement is essential for the evaluation and characterization of common materials designed to facilitate comparability and ensure data quality underscoring the value of determining current practices, challenges, and progress of a field through interlaboratory studies.PMID:39495321 | DOI:10.1007/s11306-024-02185-0

Metabolomics. 2024 Nov 4;20(6):126. doi: 10.1007/s11306-024-02189-w.ABSTRACTINTRODUCTION: The placenta plays influential role in the fetal development of mammals. But how the metabolic need of the fetal organs is related to that of the placenta, and whether this relationship is influenced by the sex of the fetus remain poorly understood.OBJECTIVES: This study used pigs to investigate metabolomic signatures of male and female fetal organs, and determine the relevance of gene expression of the placenta and brain to the metabolism of peripheral organs.METHODS: Untargeted metabolomics analysis was performed with the day-45 placenta, kidney, heart, liver, lung and brain of male and female pig fetuses to model sex differences in the metabolism of the peripheral organs relative to that of the brain and placenta. Transcriptomic analysis was performed to investigate the expression of metabolic genes in the placenta and fetal brain of both sexes.RESULTS: The results of this study show that the fetoplacental metabolic regulation was not only influenced by the fetal sex but also dependent on the metabolic requirement of the individual organs of the fetus. Neural network modeling of metabolomics data revealed differential relationship of the metabolic changes of the peripheral organs with the placenta and fetal brain between males and females. RNA sequencing further showed that genes associated with the metabolism of the peripheral organs were differentially expressed in the placenta and fetal brain.CONCLUSION: The findings of this study suggest a regulatory role of the fetal brain and placenta axis in the sex-bias metabolism of the peripheral organs.PMID:39495316 | DOI:10.1007/s11306-024-02189-w

Mol Biol Evol. 2024 Nov 4:msae233. doi: 10.1093/molbev/msae233. Online ahead of print.ABSTRACTAdaptation to high-altitude hypoxia is characterized by systemic and organ-specific metabolic changes. This study investigates whether intestinal metabolic rewiring is a contributing factor to hypoxia adaptation. We conducted a longitudinal analysis over 108 days, with seven timepoints, examining fecal metabolomics data from a cohort of 46 healthy male adults traveling from Chongqing (a.s.l. 243 m) to Lhasa (a.s.l. 3658 m) and back. Our findings reveal that short-term hypoxia exposure significantly alters intestinal metabolic pathways, particularly those involving purines, pyrimidines, and amino acids. A notable observation was the significantly reduced level of intestinal uric acid (UA), the end product of purine metabolism, during acclimatization (also called acclimation) and in additional two long-term exposed cohorts (Han Chinese and Tibetans) residing in Shigatse, Xizang (a.s.l. 4700 m), suggesting that low intestinal UA levels facilitate adaptation to high-altitude hypoxia. Integrative analyses with gut metagenomic data showed consistent trends in intestinal UA levels and the abundance of key UA-degrading bacteria, predominantly from the Lachnospiraceae family. The sustained high abundance of these bacteria in the long-term resident cohorts underscores their essential role in maintaining low intestinal UA levels. Collectively, these findings suggest that the rewiring of intestinal UA metabolism, potentially orchestrated by gut bacteria, is crucial for enhancing human resilience and adaptability in extreme environments.PMID:39494496 | DOI:10.1093/molbev/msae233

Int J Food Sci. 2024 Oct 26;2024:6908059. doi: 10.1155/2024/6908059. eCollection 2024.ABSTRACTThe chemical composition, including volatile metabolites of green coffee beans, is influenced by geographic origin. The aim of this study was to reveal the volatile metabolite profile of a single variety of Robusta green bean coffee from five major plantation regions in West Java and to correlate these profiles with temperature, rainfall, and altitude. By using solid phase micro extractions and gas chromatography-mass spectrometry, 143 different volatile compounds were detected, with aromatic hydrocarbon, alcohols, monoterpene, pyrazines, sesquiterpenes, carboxylic acids, and terpene the most dominant. Principal component analysis (PCA) indicated 64.3% variability, showing that the metabolite profile of Robusta green coffee from the Bogor region was distinctly different from those in Ciamis, Kuningan, Sumedang, and Tasikmalaya, which were more similar to each other. Metabolites such as benzaldehyde, isovaleric acid, toluene, diisobutyl succinate, 1-heptene, 4-dodecene, caffeine, acetic acid, and methyl benzoate were identified as key discriminants, with a VIP score greater than 1.5. Temperature increases were linked to higher levels of isovaleric acid, diisobutyl succinate, 4-dodecene, toluene, and acetic acid, while other discriminant metabolites declined. Increased rainfall was associated with higher levels of benzaldehyde, 1-heptene, caffeine, and methyl benzoate, but lower levels of the other discriminants. Altitude had a positive correlation with methyl benzoate and 1-heptene, and a negative correlation with isovaleric acid and 4-dodecene, with weaker correlations for other compounds. In summary, Robusta green coffee beans from different regions of West Java can be distinguished by their volatile metabolites. Bogor green coffee beans had higher levels of benzaldehyde, 1-heptene, caffeine, and methyl benzoate, Kuningan beans had more diisobutyl succinate and 4-dodecene, Ciamis beans had higher levels of isovaleric acid, diisobutyl succinate, and 4-dodecene, while Sumedang and Tasikmalaya beans were similar, with higher levels of isovaleric acid, diisobutyl succinate, 4-dodecene, toluene, and acetic acid. This difference is related to the climatic factors of temperature and rainfall, as well as the altitude at which Robusta coffee is grown.PMID:39494365 | PMC:PMC11531365 | DOI:10.1155/2024/6908059

Int J Biol Sci. 2024 Oct 28;20(14):5793-5811. doi: 10.7150/ijbs.102424. eCollection 2024.ABSTRACTAtherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries and involves various complex pathological mechanisms and factors. Previous studies have demonstrated a close association between atherosclerosis and inflammatory damage, metabolic disorders, and gut microbiota. It is also closely linked to several cellular processes, such as endothelial cell pyroptosis, ferroptosis, mitophagy, mitochondrial dynamics, and mitochondrial biogenesis. Mitophagy has been recognized as a previously unexplored mechanism contributing to endothelial injury in atherosclerosis. Our study aims to further elucidate the potential relationship and mechanisms between AS-induced mitophagy dysfunction and the interaction of TMBIM6 and NDUFS4. Data from the study demonstrated that atherosclerosis in AS mice was associated with substantial activation of inflammatory and oxidative stress damage, along with a marked reduction in endothelial mitophagy expression and increased pathological mitochondrial fission, leading to mitochondrial homeostasis disruption. However, under pharmacological intervention, mitophagy levels significantly increased, pathological mitochondrial fission was notably reduced, and oxidative stress and inflammatory damage were suppressed, while necroptotic pathways in endothelial cells were significantly blocked. Interestingly, the deletion of TMBIM6 or NDUFS4 in animal models or cell lines markedly impaired the therapeutic effects of the drug, disrupting its regulation of mitophagy and mitochondrial fission, and leading to the re-emergence of inflammatory responses and oxidative stress damage. Metabolomics analysis further revealed that autophagy plays a pivotal regulatory role during drug intervention and after genetic modification of TMBIM6 and NDUFS4. The activation of autophagy (macroautophagy/mitophagy) alleviated the negative effects of mitochondrial fission and inflammatory damage induced by lipid stress in endothelial cells, a regulatory mechanism likely associated with the TMBIM6-NDUFS4 axis. Subsequent animal gene modification experiments demonstrated that knocking out TMBIM6-NDUFS4 negates the therapeutic effects of the drug on lipid-induced damage and metabolic function. In summary, our research reveals a phenotypic regulatory mechanism of endothelial cell stress damage through mitophagy, influenced by the interaction of TMBIM6 and NDUFS4. Pharmacological intervention can restore mitochondrial homeostasis in endothelial cells by regulating mitophagy via the TMBIM6-NDUFS4 pathway. This novel insight suggests that TMBIM6-NDUFS4 may serve as a key therapeutic target for atherosclerosis.PMID:39494338 | PMC:PMC11528455 | DOI:10.7150/ijbs.102424

J Inflamm Res. 2024 Oct 30;17:7851-7868. doi: 10.2147/JIR.S479654. eCollection 2024.ABSTRACTBACKGROUND: Long-term use of rhubarb (RH) commonly leads to diarrhea, which can be alleviated by steaming with wine. However, the specific mechanism by which wine steaming alleviates RH-induced diarrhea remains unknown.OBJECTIVE: This study aims to reveal the underlying mechanisms of wine steaming in alleviating RH-induced diarrhea by examining small intestinal flora and serum metabolomics.METHODS: Major anthraquinone and anthrone components were detected using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Eighty-four ICR mice were randomly divided into control, RH, and RH steamed with wine (PRH) groups and were administered RH and PRH (1, 4, and 8 g/kg, i.g). for 14 consecutive days. Histopathological analysis was performed using hematoxylin-eosin staining. Levels of inflammatory factors and tight junction proteins, zonula occludens-1 (ZO-1) and occludin, in the small intestine were measured. The small intestine content was analyzed using 16S rRNA sequencing, and UPLC-MS was used to analyze endogenous metabolites.RESULTS: Levels of major anthraquinone and anthrone components decreased in PRH. Both RH and PRH groups showed varying degrees of loose stools and increased fecal water rates; the RH group exhibited more severe effects. Compared with the control group, RH caused small intestine injuries, increased levels of inflammatory cytokines, downregulated the expression of ZO-1 and occludin, and induced gut microbiota (GM) imbalance. The relative abundance of Lactobacillus decreased, while the relative abundance of Shigella and Streptococcus increased. However, PRH had a milder impact than RH. The glycerophospholipid metabolic pathway was involved in this effect. The levels of inflammatory cytokines and potential metabolites (sn-glycero-3-phosphoethanolamine) were positively correlated with Streptococcus infection, while the levels of ZO-1 and occludin were negatively correlated with Streptococcus infection. GM imbalance and abnormal glycerophospholipid metabolism contributed to impaired intestinal barrier function and inflammatory factor release, which may underlie RH-induced diarrhea, though PRH had a weaker effect.CONCLUSION: PRH alleviated RH-induced diarrhea by recovering GM balance, reducing ZO-1 and occludin expression, and decreasing the release of inflammatory factors. This mechanism may be linked to the reduced anthraquinone content. This study is the first to explore the mechanism of wine steaming in alleviating RH-induced diarrhea through small intestinal flora and serum metabolomics. It provides data to support the broader clinical use of RH and its safer application.PMID:39494199 | PMC:PMC11531732 | DOI:10.2147/JIR.S479654

ACS Omega. 2024 Oct 20;9(43):43453-43468. doi: 10.1021/acsomega.4c04795. eCollection 2024 Oct 29.ABSTRACTGiven the general increase in legume consumption worldwide, there is a need to characterize the resulting human metabolic adaptations in order to demonstrate potential legume diet/health relationships. A nuclear magnetic resonance (NMR) metabolomics urine study was carried out on a small cohort (n = 18) to characterize the excretory effects of a pilot longitudinal 8-week legume-based dietary intervention. Despite the expected high interindividual variability in the excreted metabolome, the results suggested a nonlinear metabolic response, with higher metabolic activity in the first 4 weeks and a tendency toward baseline at the end of the intervention. The excretion of isoleucine, leucine, and threonine increased, along with metabolite changes suggestive of activation of the tricarboxylic acid cycle (through anaplerosis), ketogenesis, fat catabolism, and glycoprotein biosynthesis. Gut microbiota adaptations were also suggested based on the increased excretion of 2-hydroxyisobutyrate, allantoin, and hippurate. Increased levels of trigonelline were consistent with its role as a legume intake marker, whereas malonate and pseudouridine were suggested as possible additional markers. Correlation of NMR data with nutritional parameters aided putative explanatory hypotheses to be advanced. Our results suggest a dynamic response to legume consumption, mainly through increased amino acid excretion and altered energy metabolism, while advancing potential new markers of legume intake. These results require confirmation in larger cohorts but pave the way for an informed interpretation of the effects of legume-based diets on human health.PMID:39494014 | PMC:PMC11525520 | DOI:10.1021/acsomega.4c04795

iScience. 2024 Oct 5;27(11):111103. doi: 10.1016/j.isci.2024.111103. eCollection 2024 Nov 15.ABSTRACTBrief exposure of monocytes to atherogenic molecules, such as oxidized lipoproteins, triggers a persistent pro-inflammatory phenotype, named trained immunity. In mice, transient high-fat diet leads to trained immunity, which aggravates atherogenesis. We hypothesized that a single high-fat challenge in humans induces trained immunity. In a randomized controlled cross-over study, 14 healthy individuals received a high-fat or reference shake, and blood was drawn before and after 1, 2, 4, 6, 24, and 72 h. Incubation of donor monocytes with the post-high-fat-shake serum induced trained immunity, regulated via Toll-like receptor 4. This was not mediated via triglyceride-rich lipoproteins, C12, 14, and 16, or metabolic endotoxemia. In vivo, however, the high-fat challenge did not affect monocyte phenotype and function. We conclude that a high-fat challenge leads to alterations in the serum composition that have the potential to induce trained immunity in vitro. However, this does not translate into a (persistent) hyperinflammatory monocyte phenotype in vivo.PMID:39493874 | PMC:PMC11530819 | DOI:10.1016/j.isci.2024.111103

Biomark Insights. 2024 Oct 30;19:11772719241274017. doi: 10.1177/11772719241274017. eCollection 2024.ABSTRACTBACKGROUND: Sensitivity to ionizing radiation differs between individuals, but there is a limited understanding of the biological mechanisms that account for these variations. One example of such mechanisms are the mutations in the ATM (mutated ataxia telangiectasia) gene, that cause the rare recessively inherited disease Ataxia telangiectasia (AT). Hallmark features include chromosomal instability and increased sensitivity to ionizing radiation (IR).OBJECTIVES: To deepen the molecular understanding of radiosensitivity and to identify potential new markers to predict it, human ATM-mutated and proficient cells were compared on a proteomic level.DESIGN: In this study, we analyzed 3 cell lines from AT patients, with varying radiosensitivity, and 2 cell lines from healthy volunteers, 24 hours and 72 hours post-10 Gy irradiation.METHODS: We used label-free mass spectrometry to identify differences in signaling pathways after irradiation in normal and radiosensitive individuals. Cell viability was initially determined by water soluble tetrazolium (WST) assay and DNA damage response was analyzed with 53BP1 repair foci formation along with KRAB-associated protein 1 (KAP1) phosphorylation.RESULTS: Proteomic analysis identified 4028 proteins, which were used in subsequent in silico pathway enrichment analysis to predict affected biological pathways post-IR. In AT cells, networks were heterogeneous at both time points with no common pathway identified. Mitotic cell cycle progress was the most prominent pathway altered after IR in cells from healthy donors. In particular, components of the chromosome passenger complex (INCENP and CDCA8) were significantly downregulated after 72 hours. This could also be verified at the mRNA level.CONCLUSION: Altogether, the most striking result was that proteins forming the chromosome passenger complex were downregulated after radiation exposure in healthy normosensitive control cells, but not in radiosensitive ATM-deficient cells. Thus, mitosis-associated proteins form an interesting compound to gain insights into the development and prediction of radiosensitivity.PMID:39493730 | PMC:PMC11528597 | DOI:10.1177/11772719241274017