PubMed

Thorax. 2024 Aug 7:thorax-2024-221460. doi: 10.1136/thorax-2024-221460. Online ahead of print.ABSTRACTBACKGROUND: Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms.METHODS: Children (n=633) from the COPSAC2010 mother-child cohort were monitored daily with symptom diaries of infection episodes during the first 3 years and prospectively diagnosed with asthma until age 6 years. Rural and urban environments were based on the CORINE land cover database. Child airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling were assessed at pregnancy week 24 and at birth, respectively.RESULTS: We observed a mean (SD) total number of infections of 16.3 (8.4) consisting mainly of upper respiratory infections until age 3 years. Urban versus rural living increased infection risk (17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05-1.26), p=0.002) and altered the child airway immune profile, which increased infection risk (principal component 1 (PC1): 1.03 (1.00-1.06), p=0.038 and PC2: 1.04 (1.01-1.07), p=0.022). Urban living also altered the maternal and child metabolomic profiles, which also increased infection risk. The association between urbanicity and infection risk was partly mediated through the maternal metabolomic and child airway immune profiles. Finally, urbanicity increased the risk of asthma by age 6 years, which was mediated through early infection load (pACME<0.001).CONCLUSION: This study suggests urbanicity as an independent risk factor for early infections partly explained by changes in the early metabolic and immunological development with implications for later risk of asthma.PMID:39117420 | DOI:10.1136/thorax-2024-221460

Sci Total Environ. 2024 Aug 6:175314. doi: 10.1016/j.scitotenv.2024.175314. Online ahead of print.ABSTRACTMelia azedarach L. is a Meliaceae that has shown important insecticidal activities. However, few researchers have extensively studied the toxicology of aqueous extracts of M. azedarach (MAE). Therefore, the main objective of this study was to characterize the phyto-eco-toxicological profile of MAE. First, a botanical and phytochemical characterization of MAE was performed using a histological, and metabolomic multi-analytical approach. Second, the toxicological effects on pollinating insects (Apis mellifera ligustica) and soil collembola (Folsomia candida) were evaluated. In addition, acute toxicity was evaluated in zebrafish (Danio rerio) to assess effects on aquatic fauna, and toxicity was determined in human neuroblastoma (SH-SY5Y) and fibroblast (FB-21) cell models. Finally, phytotoxic effects on germination of Cucumis sativus L., Brassica rapa L. and Sorghum vulgare L. were considered. Metabolomic analyses revealed the presence of not only limonoids but also numerous alkaloids, flavonoids and terpenoids in MAE. Histological analyses allowed us to better localize the areas of leaf deposition of the identified secondary metabolites. Regarding the ecotoxicological data, no significant toxicity was observed in bees and collembola at all doses tested. In contrast, severe cardiac abnormalities were observed in zebrafish embryos at concentrations as low as 25 μg/mL. In addition, MAE showed toxicity at 1.6 μg/mL and 6.25 μg/mL in FB-21 and SH-SY5Y cells, respectively. Finally, MAE inhibited seed germination with inhibitory concentrations starting from 5.50 μg/mL in B. rapa, 20 μg/mL in S. vulgare, and 31 μg/mL in C. sativus. Although M. azedarach extracts are considered valuable natural insecticides, their ecological impact cannot be underestimated. Even the use of an environmentally friendly solvent (an aqueous solution), for the first time, is not without side effects. Therefore, the data collected in this study show the importance of evaluating the dosages, modes of administration and production methods of M. azedarach phytoextracts in agricultural settings.PMID:39117217 | DOI:10.1016/j.scitotenv.2024.175314

Comp Biochem Physiol Part D Genomics Proteomics. 2024 Aug 2;52:101304. doi: 10.1016/j.cbd.2024.101304. Online ahead of print.ABSTRACTPinctada fucata martensii is an economically important bivalve mollusk, as this species makes a major contribution to seawater pearl production. Pearl production efficiency varies between the sexes of P. f. martensii, but many aspects of the molecular mechanisms underlying sex determination and sex differentiation in P. f. martensii remain unclear. Here, transcriptomic and metabonomic analyses were conducted to identify the major genes and metabolic changes associated with sex determination and gametogenesis. We identified a total of 3426 differentially expressed genes (DEGs) between females and males. These included Fem-1c and Foxl2, which are involved in sex determination and sex differentiation, and SOHLH2, Nanos1 and TSSK4, which are involved in gametogenesis. We also identified a total of 5231 significant differential metabolites (SDMs) between females and males. These DEGs were enriched in 47 metabolic pathways, including "ABC transporters," "purine metabolism," and "glycerophospholipid metabolism." Our findings provide new insights into the molecular mechanisms underlying sex determination, sex differentiation, and gametogenesis and will aid future studies of P. f. martensii.PMID:39116717 | DOI:10.1016/j.cbd.2024.101304

Biochem Biophys Res Commun. 2024 Aug 3;736:150492. doi: 10.1016/j.bbrc.2024.150492. Online ahead of print.ABSTRACTBACKGROUND: The risk of developing dementia is higher in individuals who suffer from perioperative neurocognitive disorder (PND), including postoperative cognitive dysfunction (POCD) and delirium. Recent studies have indicated correlations between anesthesia, surgery and PND. Acute metabolic changes induced by anesthesia and surgery may be related to cognitive impairments. Despite a paucity of research on acute metabolic changes in the hippocampus during surgery, there are conflicting about specific metabolites.METHODS: We developed a mouse model of cognitive impairment induced by isoflurane anesthesia and unilateral nephrectomy. Cognition was evaluated by Y maze and fear conditioning test (FCT). The hippocampus was harvested after the surgery. LC-MS (liquid chromatography-mass spectrometry) was performed. The differential metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were analyzed.RESULTS: Anesthesia and surgery exposure induced cognition decline. A total of 49 metabolites were significantly up-regulated and 122 down-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the metabolites identified purine, glutathione, nicotinate and nicotinamide metabolism. Metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were identified including nicotinamide adenine dinucleotide (NAD), 1-Methylnicotinamide, propionic acid, histidine, adenosine, and guanosine cyclic monophosphate. Some metabolites exhibited a consistent change trend in the hippocampus of aging mice.CONCLUSIONS: The study indicates that anesthesia and surgery can induce acute alterations in hippocampal metabolomics, including metabolites involved in lipid, amino acid, nucleotide, and carbohydrate metabolism. These metabolites may play a role in modulating PND through the regulation of neuroinflammation, oxidative stress, blood-brain barrier (BBB) permeability.PMID:39116679 | DOI:10.1016/j.bbrc.2024.150492

Clin Nutr. 2024 Jul 25;43(9):2125-2135. doi: 10.1016/j.clnu.2024.07.025. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Healthy dietary patterns and exercise practices have been associated with improved metabolic and inflammatory profiles. However, studies regarding the combined effect of these interventions on plasma biomarkers and metabolome in older adults are sparser. The primary aim of this study was to investigate the impact of a combined Mediterranean Diet-based Sustainable Healthy Diet (SHD) and Multicomponent Training (MT) intervention on the plasma biomarkers and metabolome and how dietary intake and exercise could modulate these effects.METHODS: SHD intervention included a weekly supply of Mediterranean Diet-based SHD food and four nutrition sessions involving a Mediterranean-Diet culinary workshop, and the exercise program included 50-min MT group sessions, held three times a week, lasting both 12 weeks. Plasma biomarkers were obtained through standard biochemical analysis. A proton (1H) nuclear magnetic resonance (NMR) spectroscopy-based metabolomics approach was used to study the metabolome in blood plasma. Repeated measures ANOVA were performed and adjusted for confounders.RESULTS: SHD + MT intervention significantly decreased HDL-C and calcium. SHD + MT showed some changes in common with the SHD and MT group, namely a significant decrease in citrate levels (p = 0.009 for SHD + MT; p = 0.037 for SHDT) and an increase in pyruvate (p < 0.001 for MT and SHD + MT). The SHD + MT group also revealed specific changes in the levels of some amino acids (decrease in alanine, glutamine and lysine: p = 0.026; p < 0.001; p = 0.038, respectively). Increases in formate (p = 0.025) and unsaturated lipids (p = 0.011) are consistent with changes in energy and lipoprotein metabolism.CONCLUSION: Our data show that a combined lifestyle intervention program, including a Mediterranean Diet-based SHD and MT, could modulate biomarker and metabolome and there seems to be a metabolic path associated to these interventions in older adults. Due to its wide-ranging relevance, it is pertinent to assess to what extent combined SHD and MT can contribute to better clinical profiles.PMID:39116619 | DOI:10.1016/j.clnu.2024.07.025

Environ Int. 2024 Jul 25;190:108912. doi: 10.1016/j.envint.2024.108912. Online ahead of print.ABSTRACTBACKGROUND: Bisphenol A (BPA; or 4,4'-isopropylidenediphenol) is an endocrine disrupting chemical. It was widely used in a variety of plastic-based manufactured products for several years. The European Food Safety Authority (EFSA) recently reduced the Tolerable Daily Intake (TDI) for BPA by 20,000 times due to concerns about immune-toxicity.OBJECTIVE: We used human biomonitoring (HBM) data to investigate the general level of BPA exposure from 2007 to 2014 of European women aged 18-73 years (n = 4,226) and its determinants.METHODS: Fifteen studies from 12 countries (Austria, Belgium, Denmark, France, Germany, Greece, Israel, Luxembourg, Slovenia, Spain, Sweden, and the United Kingdom) were included in the BPA Study protocol developed within the European Joint Programme HBM4EU. Seventy variables related to the BPA exposure were collected through a rigorous post-harmonization process. Linear mixed regression models were used to investigate the determinants of total urine BPA in the combined population.RESULTS: Total BPA was quantified in 85-100 % of women in 14 out of 15 contributing studies. Only the Austrian PBAT study (Western Europe), which had a limit of quantification 2.5 to 25-fold higher than the other studies (LOQ=2.5 µg/L), found total BPA in less than 5 % of the urine samples analyzed. The geometric mean (GM) of total urine BPA ranged from 0.77 to 2.47 µg/L among the contributing studies. The lowest GM of total BPA was observed in France (Western Europe) from the ELFE subset (GM=0.77 µg/L (0.98 µg/g creatinine), n = 1741), and the highest levels were found in Belgium (Western Europe) and Greece (Southern Europe), from DEMOCOPHES (GM=2.47 µg/L (2.26 µg/g creatinine), n = 129) and HELIX-RHEA (GM=2.47 µg/L (2.44 µg/g creatinine), n = 194) subsets, respectively. One hundred percent of women in 14 out of 15 data collections in this study exceeded the health-based human biomonitoring guidance value for the general population (HBM-GVGenPop) of 0.0115 µg total BPA/L urine derived from the updated EFSA's BPA TDI. Variables related to the measurement of total urine BPA and those related to the main socio-demographic characteristics (age, height, weight, education, smoking status) were collected in almost all studies, while several variables related to BPA exposure factors were not gathered in most of the original studies (consumption of beverages contained in plastic bottles, consumption of canned food or beverages, consumption of food in contact with plastic packaging, use of plastic film or plastic containers for food, having a plastic floor covering in the house, use of thermal paper…). No clear determinants of total urine BPA concentrations among European women were found. A broader range of data planned for collection in the original questionnaires of the contributing studies would have resulted in a more thorough investigation of the determinants of BPA exposure in European women.CONCLUSION: This study highlights the urgent need for action to further reduce exposure to BPA to protect the population, as is already the case in the European Union. The study also underscores the importance of pre-harmonizing HBM design and data for producing comparable data and interpretable results at a European-wide level, and to increase HBM uptake by regulatory agencies.PMID:39116556 | DOI:10.1016/j.envint.2024.108912

Meat Sci. 2024 Aug 3;217:109621. doi: 10.1016/j.meatsci.2024.109621. Online ahead of print.ABSTRACTThe objective of this exploratory study was to assess the changes on lipidome and metabolome profiling of Longissimus lumborum bull muscle with different ultimate pH (pHu) and aging periods. The bull muscles classified as normal, intermediate, or high pHu were collected from a Brazilian commercial slaughterhouse, cut into steaks, individually vacuum-packaged, and aged for 3 days (3-d) or 21 days (21-d) at 2 °C. Muscle extracts were analyzed for the profiles of both lipids, by mass spectrometry (via direct flow-injection), and metabolites, by nuclear magnetic resonance, with downstream multivariate data analysis. As major results, pairwise comparisons identified C12:0 and C14:0 acylcarnitines as potential biomarkers of the intermediate pHu-muscle, which are related to lipid catabolism for alternative energy metabolism and indicate less protein breakage postmortem. Interestingly, the concentration of arginine at early postmortem aging (3-d) may influence the previously reported improved tenderness in normal and high pHu-muscles. Moreover, upregulation of fumarate, formate, and acetate with increased pHu muscle at 21-d aging indicate more intense tricarboxylic acid cycle, amino acid degradation, and pyruvate oxidation by reactive oxygen species, respectively. These three compounds (fumarate, formate, and acetate) discriminated statistically the muscle with high pHu at 21-d aging. The normal pHu-muscle showed higher concentrations of glycogenolysis and glycolysis metabolites, including glucose, mannose, and pyruvate. Hence, our results enhance knowledge of postmortem biochemical changes of beef within different pHu groups aged up to 21 days, which is essential to understand the mechanisms underpinning bull meat quality changes.PMID:39116534 | DOI:10.1016/j.meatsci.2024.109621

J Pharm Biomed Anal. 2024 Aug 3;249:116395. doi: 10.1016/j.jpba.2024.116395. Online ahead of print.ABSTRACTMultiloop splitter-based non-cryogenic artificial trapping (M-SNAT) modulation technique was developed, miniaturized and applied in comprehensive two-dimensional gas chromatography (GC×GC) for analysis of cannabis samples. The approach employed deactivated fuse silica (DFS) columns configured into multiple loop splitter system halving the perimeters of the progressively upstream loops. This splitter device was located between the first (1D) semi-nonpolar column outlet and a microfluidic Deans switch (DS). Each splitter loop splits a peak into two subpeaks having the same area with different void times. Three loops were then applied resulting in the number of the split subpeaks (nsplit) of 8 for each peak, and retention time differences between any two adjacent subpeaks (∆tR,split) were the same. By applying periodic heartcut event (H/C) within every artificial modulation period (PAM) of nsplit×∆tR,split, comprehensive split-and-trapped modulation profiles of analytes could be selectively transferred onto the second (2D) polar column (30 m) without cryogen consumption. This artificial modulation system was applied for analysis of cannabis samples with enhanced 2D peak capacity (2nc∼15). The established method was applied to analyse cannabis extracts using vegetable oils with or without frying process. This reveals 454 different peaks with 76, 92, 35 and 70 specific components specifically observed by using olive oil extraction (OE), fried OE, coconut oil extraction (CE) and fried CE, respectively.PMID:39116505 | DOI:10.1016/j.jpba.2024.116395

J Pharm Biomed Anal. 2024 Aug 3;249:116391. doi: 10.1016/j.jpba.2024.116391. Online ahead of print.ABSTRACTSinomenii Caulis (SC), a commonly used traditional Chinese medicine for its therapeutic effects on rheumatoid arthritis, contains rich chemical components. At present, most studies mainly focus on sinomenine, with little research on other alkaloids. In this study, a comprehensive profile of compounds in SC extract, and biological samples of rats (including bile, urine, feces, and plasma) after oral administration of SC extract was conducted via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The fragmentation patterns and potential biotransformation pathways of six main types of alkaloids in SC were summarized, and the corresponding characteristic product ions, relative ion intensity, and neutral losses were obtained to achieve rapid classification and identification of complex components of SC from in vitro to in vivo. As a result, a total of 114 alkaloid compounds were identified, including 12 benzyl alkaloids, 4 isoquinolone alkaloids, 32 aporphine alkaloids, 28 protoberberine alkaloids, 34 morphinan alkaloids and 4 organic amine alkaloids. After administration of SC extract to rats, a total of 324 prototypes and metabolites were identified from rat plasma, urine, feces and bile, including 81 aporphines, 95 protoberberines, 117 morphinans and 31 benzylisoquinolines. The main types of metabolites were demethylation, hydrogenation, dehydrogenation, aldehydation, oxidation, methylation, sulfate esterification, glucuronidation, glucose conjugation, glycine conjugation, acetylation, and dihydroxylation. In summary, this integrated strategy provides an additional approach for the incomplete identification caused by compound diversity and low abundance, laying the foundation for the discovery of new bioactive compounds of SC against rheumatoid arthritis.PMID:39116504 | DOI:10.1016/j.jpba.2024.116391

Environ Sci Technol. 2024 Aug 8. doi: 10.1021/acs.est.4c03608. Online ahead of print.ABSTRACTUnderstanding the chemical nature of soil organic carbon (SOC) with great potential to bind iron (Fe) minerals is critical for predicting the stability of SOC. Organic ligands of Fe are among the top candidates for SOCs able to strongly sorb on Fe minerals, but most of them are still molecularly uncharacterized. To shed insights into the chemical nature of organic ligands in soil and their fate, this study developed a protocol for identifying organic ligands using ultrahigh-performance liquid chromatography-high-resolution tandem mass spectrometry (UHPLC-HRMS/MS) and metabolomic tools. The protocol was used for investigating the Fe complexes formed by model compounds of lignin-derived organic ligands, namely, caffeic acid (CA), p-coumaric acid (CMA), vanillin (VNL), and cinnamic acid (CNA). Isotopologue analysis of 54/56Fe was used to screen out the potential UHPLC-HRMS (m/z) features for complexes formed between organic ligands and Fe, with multiple features captured for CA, CMA, VNL, and CNA when 35/37Cl isotopologue analysis was used as supplementary evidence for the complexes with Cl. MS/MS spectra, fragment analysis, and structure prediction with SIRIUS were used to annotate the structures of mono/bidentate mono/biligand complexes. The analysis determined the structures of monodentate and bidentate complexes of FeLxCly (L: organic ligand, x = 1-4, y = 0-3) formed by model compounds. The protocol developed in this study can be used to identify unknown organic ligands occurring in complex environmental samples and shed light on the molecular-level processes governing the stability of the SOC.PMID:39116213 | DOI:10.1021/acs.est.4c03608

Cell Oncol (Dordr). 2024 Aug 8. doi: 10.1007/s13402-024-00967-1. Online ahead of print.ABSTRACTPURPOSE: Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma.METHODS: In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance.RESULTS: Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO.CONCLUSION: Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an "One-two Punch" therapy of metastatic and recurrent osteosarcoma.PMID:39115605 | DOI:10.1007/s13402-024-00967-1

J Cell Biol. 2024 Oct 7;223(10):e202401024. doi: 10.1083/jcb.202401024. Epub 2024 Aug 8.ABSTRACTDendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.PMID:39115541 | DOI:10.1083/jcb.202401024

Environ Toxicol Chem. 2024 Aug 8. doi: 10.1002/etc.5959. Online ahead of print.NO ABSTRACTPMID:39115466 | DOI:10.1002/etc.5959

Food Funct. 2024 Aug 8. doi: 10.1039/d4fo02391a. Online ahead of print.ABSTRACTThe incidence of hyperuricemia (HUA) shows a gradually increasing trend towards affecting younger individuals, and it can significantly harm the overall health status of the body. Based on a metabolomics perspective, this study reveals the mechanism of the uric acid-lowering action of Prunus salicina Lindl. cv. "furong" polyphenols (PSLP) on a hyperuricemia mouse model induced by hypoxanthine and potassium oxybutyrate. The results demonstrate that PSLP comprise an effective treatment strategy for reducing the levels of serum uric acid (SUA), serum creatinine (SCr) and blood urea nitrogen (BUN) in HUA mice (p < 0.05), wherein the maximum decrease rates are up to 44.50%, 29.46%, and 32.95%, respectively. PSLP are observed to exert a pronounced inhibitory effect on the activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) in the livers of HUA mice, with reductions of up to 16.36% and 20.13%, respectively. These findings illustrate that PSLP exert a significant uric acid-lowering effect. Subsequent metabolomic analysis of mouse serum identified 28 potential biomarkers for hyperuricemia, whose levels were markedly diminished by PSLP. This process involved alterations in purine, glycine, the pentose phosphate pathway, and galactose metabolism. Twenty-eight potential biomarkers were identified for hyperuricemia by subsequent metabolomic analysis of mouse serum, whose levels were markedly reversed by PSLP intervention. The regulation of HUA by PSLP involved alterations in purine metabolism, glycerolipid metabolism, the pentose phosphate pathway, and galactose metabolism. The mechanism of PSLP ameliorated hyperuricemia might be attributed to reduction of the level of the uric acid precursor ribose-5-phosphate in the pentose phosphate pathway, the inhibition of the activities of uric acid synthase XOD and ADA in purine metabolism, and reduction of the synthesis of the end product uric acid. This study provides a theoretical basis for the development of functional foods based on PSLP, which can potentially reduce uric acid levels.PMID:39115429 | DOI:10.1039/d4fo02391a

J Vet Intern Med. 2024 Aug 8. doi: 10.1111/jvim.17148. Online ahead of print.ABSTRACTBACKGROUND: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx).HYPOTHESIS/OBJECTIVES: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs).ANIMALS: Ten healthy dogs, 21 dogs with PCC.METHODS: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection.RESULTS: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%-98%] vs 14% [11%-26%]; P < .001), and significantly lower tissue proportion of epinephrine (12% [1%-62%] vs 86% [74%-89%]; P < .001). Pheochromocytomas exhibited significantly lower fumarate (0.4-fold; P < .001), and malate (0.5-fold; P = .008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6-fold; P = .015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25-fold higher than in the other PCCs, suggesting an SDHx mutation.CONCLUSIONS AND CLINICAL IMPORTANCE: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs.PMID:39115145 | DOI:10.1111/jvim.17148

Front Immunol. 2024 Jul 23;15:1435180. doi: 10.3389/fimmu.2024.1435180. eCollection 2024.ABSTRACTINTRODUCTION: Introduction: The influenza virus primarily targets the respiratory tract, yet both the respiratory and intestinal systems suffer damage during infection. The connection between lung and intestinal damage remains unclear.METHODS: Our experiment employs 16S rRNA technology and Liquid Chromatography-Mass Spectrometry (LC-MS) to detect the impact of influenza virus infection on the fecal content and metabolites in mice. Additionally, it investigates the effect of influenza virus infection on intestinal damage and its underlying mechanisms through HE staining, Western blot, Q-PCR, and flow cytometry.RESULTS: Our study found that influenza virus infection caused significant damage to both the lungs and intestines, with the virus detected exclusively in the lungs. Antibiotic treatment worsened the severity of lung and intestinal damage. Moreover, mRNA levels of Toll-like receptor 7 (TLR7) and Interferon-b (IFN-b) significantly increased in the lungs post-infection. Analysis of intestinal microbiota revealed notable shifts in composition after influenza infection, including increased Enterobacteriaceae and decreased Lactobacillaceae. Conversely, antibiotic treatment reduced microbial diversity, notably affecting Firmicutes, Proteobacteria, and Bacteroidetes. Metabolomics showed altered amino acid metabolism pathways due to influenza infection and antibiotics. Abnormal expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon disrupted the balance between helper T17 cells (Th17) and regulatory T cells (Treg cells) in the intestine. Mice infected with the influenza virus and supplemented with tryptophan and Lactobacillus showed reduced lung and intestinal damage, decreased Enterobacteriaceae levels in the intestine, and decreased IDO1 activity.DISCUSSION: Overall, influenza infection caused damage to lung and intestinal tissues, disrupted intestinal microbiota and metabolites, and affected Th17/Treg balance. Antibiotic treatment exacerbated these effects. Supplementation with tryptophan and Lactobacillus improved lung and intestinal health, highlighting a new understanding of the lung-intestine connection in influenza-induced intestinal disease.PMID:39114658 | PMC:PMC11304505 | DOI:10.3389/fimmu.2024.1435180

Front Plant Sci. 2024 Jul 24;15:1402451. doi: 10.3389/fpls.2024.1402451. eCollection 2024.ABSTRACTAerospace breeding is a breeding technique that utilizes a spacecraft to position plants in a space environment for mutagenesis, which is conducive to rapid mutagenesis for the screening of superior plant varieties. In this study, tea trees with aviation mutagenesis (TM) and those without aviation mutagenesis (CK) were selected as research subjects to analyze the effects of aviation mutagenesis on the growth, physiological properties, and hormone metabolism of tea trees, and to further screen the characteristic hormones and validate their functions. The results showed that the leaf length, leaf width, and leaf area of TM tea trees were significantly larger than those of CK. The growth indexes, the photosynthetic physiological indexes (i.e., chlorophyll content, intercellular CO2 concentration, stomatal conductance, transpiration rate, and photosynthetic rate), and the resistance physiological indexes (i.e., superoxide dismutase, peroxidase, catalase, and soluble sugar) were significantly higher in TM than in CK. Hormone metabolome analysis showed that four characteristic hormones distinguished CK from TM, namely, l-tryptophan, indole, salicylic acid, and salicylic acid 2-O-β-glucoside, all of which were significantly more abundant in TM than in CK. These four characteristic hormones were significantly and positively correlated with the growth indexes, tea yield, and the photosynthetic and resistance physiological indexes of tea trees. The leaf area, chlorophyll content, photosynthetic rate, and superoxide dismutase activity of tea tree seedlings after spraying with the four characteristic hormones were significantly increased, in which salicylic acid and salicylic acid 2-O-β-glucoside were more favorable to increase the leaf area and superoxide dismutase activity, while l-tryptophan and indole were more favorable to increase the leaf chlorophyll content and photosynthetic rate. It can be observed that aviation mutagenesis improves the accumulation of the characteristic hormones of tea trees, enhances their photosynthetic capacity, improves their resistance, promotes their growth, and then improves the tea yield.PMID:39114474 | PMC:PMC11303228 | DOI:10.3389/fpls.2024.1402451

Front Pharmacol. 2024 Jul 24;15:1423060. doi: 10.3389/fphar.2024.1423060. eCollection 2024.ABSTRACTAlzheimer's disease (AD) has an increasing prevalence, complicated pathogenesis and no effective cure. Emerging evidences show that flavonoid compounds such as xanthohumol (Xn) could play an important role as a dietary supplement or traditional Chinese herbal medicine in the management of diseases such as AD. This study aims to analyze the target molecules of Xn in the prevention and treatment of AD, and its potential mechanism from the perspective of metabolites. APP/PS1 mice 2- and 6-months old were treated with Xn for 3 months, respectively, the younger animals to test for AD-like brain disease prevention and the older animals to address therapeutic effects on the disease. Memantine (Mem) was selected as positive control. Behavioral tests were performed to assess the course of cognitive function. Urine samples were collected and analyzed by high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) coupled with online Compound Discoverer software. Morris Water Maze (MWM) tests showed that Xn, like Mem, had a therapeutic but not a preventive effect on cognitive impairment. The expression levels of urinary metabolites appeared to show an opposite trend at different stages of Xn treatment, downregulated in the prevention phase while upregulated in the therapy phase. In addition, the metabolic mechanisms of Xn during preventive treatment were also different from that during therapeutic treatment. The signaling pathways metabolites nordiazepam and genistein were specifically regulated by Xn but not by Mem in the disease prevention stage. The signaling pathway metabolite ascorbic acid was specifically regulated by Xn in the therapeutic stage. In conclusion, dietary treatment with Xn altered the urinary metabolite profile at different stages of administration in APP/PS1 mice. The identified potential endogenous metabolic biomarkers and signal pathways open new avenues to investigate the pathogenesis and treatment of AD.PMID:39114364 | PMC:PMC11303171 | DOI:10.3389/fphar.2024.1423060

Front Pharmacol. 2024 Jul 24;15:1368776. doi: 10.3389/fphar.2024.1368776. eCollection 2024.ABSTRACTBackground: The fibrous root of ginseng (GFR) is the dried thin branch root or whisker root of Ginseng (Panax ginseng C. A. Mey). It is known for its properties such as tonifying qi, producing body fluid, and quenching thirst. Clinically, it is used to treat conditions such as cough, hemoptysis, thirst, stomach deficiency, and vomiting. While GFR and Ginseng share similar metabolites, they differ in their metabolites ratios and efficacy. Furthermore, the specific role of GFR in protecting the body remains unclear. Methods: We employed ultra-high performance liquid chromatography-triple quadrupole mass spectrometry to examine alterations in brain neurotransmitters and elucidate the impact of GFR on the central nervous system. Additionally, we analyzed the serum and brain metabolic profiles of rats using ultra-high performance liquid chromatography-quadrupole-orbitrap mass spectrometry to discern the effect and underlying mechanism of GFR in delaying aging in naturally aged rats. Results: The findings of the serum biochemical indicators indicate that the intervention of GFR can enhance cardiovascular, oxidative stress, and energy metabolism related indicators in naturally aging rats. Research on brain neurotransmitters suggests that GFR can augment physiological functions such as learning and memory, while also inhibiting central nervous system excitation to a certain degree by maintaining the equilibrium of central neurotransmitters in aged individuals. Twenty-four abnormal metabolites in serum and seventeen abnormal metabolites in brain could be used as potential biomarkers and were involved in multiple metabolic pathways. Among them, in the brain metabolic pathways, alanine, aspartate and glutamate metabolism, arginine and proline metabolism, histidine metabolism, and tyrosine metabolism were closely related to central neurotransmitters. Butanoate metabolism improves energy supply for life activities in the aging body. Cysteine and methionine metabolism contributes to the production of glutathione and taurine and played an antioxidant role. In serum, the regulation of glycerophospholipid metabolism pathway and proline metabolism demonstrated the antioxidant capacity of GFR decoction. Conclution: In summary, GFR plays a role in delaying aging by regulating central neurotransmitters, cardiovascular function, oxidative stress, energy metabolism, and other aspects of the aging body, which lays a foundation for the application of GFR.PMID:39114359 | PMC:PMC11303238 | DOI:10.3389/fphar.2024.1368776

Integr Med (Encinitas). 2024 Jul;23(3):12-23.ABSTRACTEpidemiological studies have found 2 significant factors associated with the increased incidence of autism spectrum disorder (ASD): the increased use of acetaminophen in the 1970s when this drug largely replaced the use of aspirin for many patients because of a fear of Reye syndrome, and the agricultural use in the 1990s of the herbicide glyphosate on crops that were genetically modified (GM) to tolerate glyphosate. The incidence of autism in the United States, where acetaminophen is widely available, is more than 1000 times greater than in Cuba, where acetaminophen is available only by prescription. Metabolites of both glyphosate and acetaminophen likely alter the function of the developmental protein sonic hedgehog (SHH). Glyphosate likely affects SHH indirectly by decreasing the beneficial flora of the gastrointestinal tract and increasing pathogenic Clostridia bacteria, which are resistant to glyphosate. The marked increase of certain Clostridia species caused by glyphosate results in Clostridia production of large amounts of 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA) and 4-cresol (p-cresol). The 4-cresol metabolite 4-methyl-o-hydroquinone and the acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) likely react with the sulfhydryl group of the N-terminal cysteine of SHH, blocking the function of this critical amino acid required for the activation of SHH. HPHPA and 4-cresol also inhibit dopamine β-hydroxylase, resulting in overproduction of dopamine and its toxic metabolites, such as aminochrome, that cause biochemical damage to mitochondria and structural proteins in brain cells. Elevated amounts of these Clostridia products in body fluids in people with autism and in animals with autistic signs have been documented in laboratories throughout the world. The synthesis of the HPHPA molecule in extremely large quantities depletes the body of free coenzyme A, which is needed for the palmitoylation of SHH. SHH covalently coupled to palmitic acid is 30 times more active than SHH without palmitic acid. These possible modifications of SHH help to explain the significantly altered quantities of SHH in the blood serum of patients with autism. The severity of autism is related to the degree of SHH abnormality. The spread of pathogenic Clostridia worldwide from soil to food animals to humans, which may be promoted by glyphosate use, is a great public health concern, not only for autism but perhaps for all the neuropsychiatric diseases that appear to be related to gastrointestinal Clostridia overgrowth These diseases include seizures, tremors, tic disorders, Parkinson disease, chronic fatigue syndrome, obsessive compulsive disorder, schizophrenia, bipolar and unipolar depression, ADHD, and anorexia nervosa.PMID:39114279 | PMC:PMC11302971