PubMed

Food Chem. 2024 Oct 26;464(Pt 2):141784. doi: 10.1016/j.foodchem.2024.141784. Online ahead of print.ABSTRACTA prolonged diet laden with purine-rich foods represents a significant contributor to renal fibrosis (RF). Eucommia ulmoides Oliver, a plant homologous to food and medicinal materials, has long been employed to recover kidney function. This investigation presents a strategy integrating chemistry, biochemistry, and metabolomics to evaluate bioactive components and efficiency mechanism of crude and salt-stir fried Eucommiae Cortex (EC) extracts against RF. Firstly, 155 chemical components were identified in the EC extracts and the contents of 19 and 27 compounds decreased and increased respectively after salt-stir frying. Secondly, various biochemical indicators displayed that salt-stir fried EC (SEC) extracts had the optimal anti-RF effects in adenine-induced RF model rats, which were associated with the attenuation of TGF-β signaling pathway. Finally, untargeted metabolomics analysis demonstrated that after treatments with EC and SEC extracts, 30 and 32 efficacy biomarkers were significantly restored in the RF + EC and RF + SEC groups respectively, involving five metabolic pathways.PMID:39476582 | DOI:10.1016/j.foodchem.2024.141784

Theriogenology. 2024 Oct 26;231:197-209. doi: 10.1016/j.theriogenology.2024.10.025. Online ahead of print.ABSTRACTPhospholipase A (PLA) in goat semen aggregates with egg yolk in semen diluent, leading to sperm death. The aim of this study is to address the issue of sperm death caused by the interaction between PLA and egg yolk, and to explore the protective effect and metabolic regulation mechanism of the combination of dexamethasone (DXMS) and azithromycin (AZM) on goat sperm under low temperature conditions. At a low temperature of 4 °C, different concentrations of DXMS were added to semen diluents containing 30 μg/mL AZM to detect the quality of goat sperm. The optimal concentration of DXMS was determined to be 20 μg/mL. On the 5th day of storage, antioxidant capacity, total cholesterol (TC) levels, energy metabolism, and metabolomics analysis were performed on the sperm of the 20 μg/mL DXMS group. The results showed that there was no aggregation caused by the interaction between PLA and egg yolk in the group containing 30 μg/mL AZM at 4 °C. 20 μg/mL DXMS significantly improved sperm motility, plasma membrane integrity, acrosome integrity, glutathione peroxidase (GPX) (P < 0.05), catalase (CAT) (P < 0.01), and superoxide dismutase (SOD) activity (P < 0.01). The content of reactive oxygen species (ROS) and Fe2+ significantly decreased (P < 0.01), while the content of ATP (P < 0.01) and TC (P < 0.05) significantly increased. Through metabolomics analysis, a total of 56 differential metabolites (P < 0.05) were screened, including 5a, 6-Anhydrotetracycline, Betamethasone, and 11-Dehydrocorticosterone, mainly enriched in 8 metabolic pathways (P < 0.05), including steroid hormone biosynthesis, glycerophospholipid metabolism, and choline metabolism in cancer. Among them, 5 metabolic pathways are related to lipid metabolism. The results indicate that AZM effectively inhibits the aggregation of PLA and yolk, and the combination of AZM and DXMS enhances the preservation quality of goat sperm during low-temperature preservation by regulating lipid metabolism.PMID:39476552 | DOI:10.1016/j.theriogenology.2024.10.025

Cancer Discov. 2024 Oct 31. doi: 10.1158/2159-8290.CD-24-0187. Online ahead of print.ABSTRACTCopper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.PMID:39476412 | DOI:10.1158/2159-8290.CD-24-0187

Plant Biol (Stuttg). 2024 Oct 30. doi: 10.1111/plb.13727. Online ahead of print.ABSTRACTCold resistance in fruit trees has a direct impact on food production and scientific studies. 'Donghe No.1' is an excellent cold-tolerant peach variety. Metabolomic changes under freezing stress were examined to understand the mechanisms of cold adaptation. The UPLC-MS/MS system was used to identify differentially expressed metabolites (DEMs) in branches of 'Donghe No.1' under freezing stress for 12 h at -5°C, -20°C, -25°C, or -30°C. In total, 1096 metabolites and 196 DEMs were obtained at -5°C vs -20°C, -25°C, and - 30°C, while 179 DEMs and eight shared DEMs obtained at -5°C vs -20°C, -20°C vs -25°C, and -25°C vs -30°C. KEGG enrichment identified 196 DEMs associated with amino acid metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis under freezing stress. A metabolic network in 1-year-old peach branches under freezing stress is proposed. Moreover, these results enhance understanding of metabolite responses and mechanisms to freezing stress in peach and will help in future breeding of freezing-tolerant varieties and investigating tolerance mechanisms.PMID:39476336 | DOI:10.1111/plb.13727

Hist Philos Life Sci. 2024 Oct 30;46(4):34. doi: 10.1007/s40656-024-00630-w.ABSTRACT'Obesity' has, for decades, been a subject of intense scientific and public interest, and remains a key target for postgenomic science. I examine the emergence of determinism in research into 'obesity' in the postgenomic field of metabolomics. I argue that determinism appears in metabolomics research in two ways: firstly, fragmentation and narrow construal of the environment is evident in metabolomics studies on weight loss interventions, resulting in particular features of the environment (notably, dietary intake) having outsized influence while the wider social environment is neglected. Secondly, studies aiming to characterize the metabolic signature of 'obesity' are guided by a commitment to a deterministic connection between 'obesity' and dysfunction, leading to a neglect or distortion of metabolic heterogeneity across individuals regardless of body size.PMID:39476192 | DOI:10.1007/s40656-024-00630-w

PLoS One. 2024 Oct 30;19(10):e0305697. doi: 10.1371/journal.pone.0305697. eCollection 2024.ABSTRACTThis study was designed as a randomized, placebo-controlled, double-blinded, cross-over trial performed to investigate the effects of a dietary supplement containing undenatured type II collagen (UCII®) and Boswellia Serrata on mobility, pain and joint metabolism in mild moderate osteoarthritis (OA) in dogs. A total of 60 dogs with mobility problems were evaluated and enrolled in the study. Seventeen of these dogs with mild/moderate OA were randomized to receive the product A (UCII® + Boswellia Serrata supplement-UCII®-BW) or product B (Placebo -PL), 1 chew per day for 8 weeks by oral route, and repeated in a crossover design after 4 weeks of washout period. All the subjects had veterinary evaluations during the trial and owners were requested to fill out a questionnaire on mobility impairment using the Liverpool Osteoarthritis in dogs scale (L.O.A.D.) at each time of the study. Objective tools were used to assess mobility, activity, and pain. Metabolomic analysis was performed on synovial fluid of most affected joint at the beginning and the end of the study. The results proved that UCII®+Boswellia serrata supplemented group over a period of eight weeks results in an improvement of mobility impairment, already at 4 weeks of administration, according to the owner´s evaluation. In contrast, its absence increased the risk of OA crisis and decreased the pain threshold on the most affected joint. Furthermore, the synovial fluid metabolic profile showed moderate differences between the beginning and the end of the supplementation period, with a particular influence associated to the time of UCII®-BW administration.PMID:39475935 | DOI:10.1371/journal.pone.0305697

Anal Chem. 2024 Oct 30. doi: 10.1021/acs.analchem.4c04187. Online ahead of print.ABSTRACTMany chiral carboxylic acids with α-amino, α-hydroxyl, and α-methyl groups are concurrently present in mammals establishing unique molecular phenotypes and multiple biological functions, especially host-microbiota symbiotic interactions. Their chirality-resolved simultaneous quantification is essential to reveal the biochemical details of physiology and pathophysiology, though challenging with their low abundances in some biological matrices and difficulty in enantiomer resolution. Here, we developed a method of the chirality-resolved metabolomics with sensitivity-enhanced quantitation via probe-promotion (Met-SeqPro) for analyzing these chiral carboxylic acids. We designed and synthesized a hydrazide-based novel chiral probe, (S)-benzoyl-proline-hydrazide (SBPH), to convert carboxylic acids into amide diastereomers to enhance their retention and chiral resolution on common C18 columns. Using the d5-SBPH-labeled enantiomers as internal standards, we then developed an optimized ultrahigh-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous quantification of 60 enantiomers of 30 chiral carboxylic acids in one run. This enantiomer-resolved method showed excellent sensitivity (LOD < 4 fmol-on-column), linearity (R2 > 0.992), precision (CV < 15%), accuracy (|RE| < 20%), and recovery (80-120%) in multiple biological matrices. With the method, we then quantified 60 chiral carboxylic acids in human urine, plasma, feces, and A549 cells to define their metabolomic phenotypes. This provides basic data for human phenomics and a promising tool for investigating the mammal-microbiome symbiotic interactions.PMID:39475527 | DOI:10.1021/acs.analchem.4c04187

J Proteome Res. 2024 Oct 30. doi: 10.1021/acs.jproteome.4c00654. Online ahead of print.ABSTRACTPharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering in vitro generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.PMID:39475502 | DOI:10.1021/acs.jproteome.4c00654

J Food Sci. 2024 Oct 30. doi: 10.1111/1750-3841.17458. Online ahead of print.ABSTRACTPlant-based meat analogs (PBMAs) are common ultra-processed foods (UPFs) included in the vegan/vegetarian diets as presumed healthy alternatives to meat and meat products. However, such health claims need to be supported by scientific evidence. To gain further insight into this topic, two commercial UPFs typically sold as meat analogs, namely, seitan (S) and tofu (T), were included in a cereal-based chow and provided to Wistar rats for 10 weeks. A group of animals had, simultaneously, an isocaloric and isoprotein experimental diet formulated with cooked beef (B). In all cases, experimental chows (∼4 kcal/g feed) had their basal protein concentration increased from 14% to 30% using proteins from S, T, or B. Upon slaughter, in vivo protein digestibility was assessed, and the entire gastrointestinal tract (digests and tissues) was analyzed for markers of oxidative stress and untargeted metabolomics. Metagenomics was also applied to assess the variation of microbiota composition as affected by dietary protein. Diets based on PBMAs showed lower protein digestibility than those containing meat and promoted an intense luminal glycoxidative stress and an inflammatory intestinal response. The fermentation of undigested oxidized proteins from T in the colon of Wistar rats likely led to formation of mutagenic metabolites such as p-cresol. The presence of these compounds in the animal models raises concerns about the potential effects of full replacement of meat by certain PBMAs in the diet. Therefore, future research might target on translational human studies to shed light on these findings.PMID:39475341 | DOI:10.1111/1750-3841.17458

Microbiol Spectr. 2024 Oct 30:e0152124. doi: 10.1128/spectrum.01521-24. Online ahead of print.ABSTRACTVulvovaginal candidiasis (VVC) is a common vaginal infectious disease caused by Candida. The high recurrence rate of VVC is a great clinical challenge, with recurrent VVC (RVVC) defined as four or more episodes within a year. In this study, we recruited 31 RVVC patients, 28 VVC patients, and 29 healthy women. Vaginal samples were collected for metagenomic and metabolic analysis. RVVC and VVC groups presented similar clinical symptoms, with only a significantly increased incidence of swelling in the VVC group. Vaginal microbiota in VVC/RVVC exhibited a decreased abundance of Lactobacillus and increased bacterial vaginosis-associated bacteria, such as Gardnerella, Prevotella, and Atopobium. Notably, Lactobacillus iners was higher in RVVC, suggesting not all Lactobacillus species are protective. Healthy women showed lower overall microbiota diversity, emphasizing single-species dominance for stability. Glycogen metabolism pathways were enriched in RVVC/VVC, and were correlated with Atopobium vaginae, Prevotella bivia, and Lactobacillus jensenii. Peptidoglycan synthesis pathways, associated with P. bivia, were enriched, with the substrate L-glutamate elevated in RVVC, possibly promoted by L. iners. These findings shed light on potential therapeutic targets for recurrent VVC, contributing to the understanding of the intricate interplay between the metabolism of vaginal microbiome and disease.IMPORTANCE: This study enhances our knowledge of the vaginal microbiota dynamics and the role of associated metabolites in individuals with vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis through shotgun sequencing and multi-omics analysis. The relationship between metabolites and vaginal microbiota and disease state was revealed. The accumulation of L-glutamate generated in glycogen metabolism, which is governed by Lactobacillus iners or bacterial vaginosis-associated bacteria, may contribute to the incidence and recurrence of VVC. Such insights have the potential to impact the treatment and prevention strategies for these common yet distressing conditions, potentially leading to targeted therapies and improved patient outcomes.PMID:39475249 | DOI:10.1128/spectrum.01521-24

Nucleic Acids Res. 2024 Oct 30:gkae961. doi: 10.1093/nar/gkae961. Online ahead of print.ABSTRACTMetabolomic microbiome research has become an important topic for understanding agricultural, ecological as well as health correlations. Only the determination of both the non-volatile and the volatile organic compound (mVOC) production by microorganisms allows a holistic view for understanding the complete potential of metabolomes and metabolic capabilities of bacteria. In the recent past, more and more bacterial headspaces and culture media were analyzed, leading to an accumulation of about 3500 mVOCs in the updated mVOC 4.0 database, including compounds synthesized by the newly discovered non-canonical terpene pathway. Approximately 10% of all mVOCs can be assigned with a biological function, some mVOCs have the potential to impact agriculture in the future (e.g. eco-friendly pesticides) or animal and human health care. mVOC 4.0 offers various options for exploring extensively annotated mVOC data from different perspectives, including improved mass spectrometry matching. The mVOC 4.0 database includes literature searches with additional relevant keywords, making it the most up-to-date and comprehensive publicly available mVOC platform at: http://bioinformatics.charite.de/mvoc.PMID:39475188 | DOI:10.1093/nar/gkae961

Proteomics Clin Appl. 2024 Oct 30:e202400048. doi: 10.1002/prca.202400048. Online ahead of print.ABSTRACTLiquid chromatography, when used in conjunction with mass spectrometry (LC/MS), is a powerful tool for conducting accurate and reproducible investigations of numerous metabolites in natural products (NPs). LC/MS has gained prominence in metabolomic research due to its high throughput, the availability of multiple ionization techniques and its ability to provide comprehensive metabolite coverage. This unique method can significantly influence various scientific domains. This review offers a comprehensive overview of the current state of LC/MS-based metabolomics in the investigation of NPs. This review provides a thorough overview of the state of the art in LC/MS-based metabolomics for the investigation of NPs. It covers the principles of LC/MS, various aspects of LC/MS-based metabolomics such as sample preparation, LC modes, method development, ionization techniques and data pre-processing. Moreover, it presents the applications of LC/MS-based metabolomics in numerous fields of NPs research such as including biomarker discovery, the agricultural research, food analysis, the study of marine NPs and microbiological research. Additionally, this review discusses the challenges and limitations of LC/MS-based metabolomics, as well as emerging trends and developments in this field.PMID:39474988 | DOI:10.1002/prca.202400048

Physiol Plant. 2024 Nov-Dec;176(6):e14585. doi: 10.1111/ppl.14585.ABSTRACTK+ accumulation in plant tissues is a crucial factor for plant growth and development. The tomato high-affinity K+ transporter SlHAK5 is essential for root K+ acquisition from low external concentrations. It is also involved in K+ accumulation in pollen and plant fertility as slhak5 KO plants show a low rate of pollen germination, impaired pollen tube growth and parthenocarpic fruits. Here, we present a thorough analysis of slhak5 flowers, which showed relevant defects at the anatomic, ionomic, metabolomic and transcriptomic levels. First, slhak5 flowers exhibited shorter styles and enlarged ovaries that, together with a low number of seeds in fruits from slhak5 X WT crosses, indicated an effect of the slhak5 mutation on female fertility. Second, a lower accumulation of Ca2+, as well as of several metabolites such as amino acids, citric acid and sugars, was observed in mutant flowers, whereas indole-3-acetic acid content was increased when compared to the wild-type. Third, RNAseq conducted on pistils and stamens of wild-type and slhak5 plants revealed that transport and signalling pathways are significantly enriched in the gene expression analyses of stamens. Thus, it can be concluded that a functional SlHAK5 transporter is required to maintain appropriate Ca2+, metabolite and gene expression levels in flowers, and its absence leads to important reductions in both male and female fertility.PMID:39474665 | DOI:10.1111/ppl.14585

Environ Health (Wash). 2023 May 30;1(1):32-40. doi: 10.1021/envhealth.3c00002. eCollection 2023 Jul 21.ABSTRACTLecithotrophic fish embryos rely on finite maternally deposited yolk resources for early development. Toxicant exposure can disrupt the uptake of yolk resources with consequences for development. In this study, we investigate the impacts of altered yolk utilization on fish embryos using the cardiotoxic compound phenanthrene. Zebrafish embryos were exposed to a cardiotoxic concentration of phenanthrene beginning at 6 hpf (hours post-fertilization) until a maximum of 72 hpf. Embryos were stained with Oil Red O to visualize neutral lipids. We then used a nontargeted approach to profile lipids in 24 and 72 hpf embryos after phenanthrene treatment. To assess changes in lipid movement within the embryo, the yolk sac was dissected from the body at 24 and 72 hpf and analyzed separately from the body at 72 hpf. Overall, total metabolites were significantly reduced in the yolk sac, and staining for neutral lipids was reduced in the embryo body at 72 hpf. This result is consistent with significant reductions in triglycerides in both the embryo body and yolk, indicating a limited contribution of impaired cardiac function to lipid mobilization at the dose tested. Additionally, lysophosphatidylcholines and lysophosphatidylethanolamines were significantly increased in the 72 hpf embryo body. Bioinformatic pathway analysis indicated that changes to these lysophospholipids could be linked to a disease model associated with inflammation and neuron demyelination consistent with previously observed injuries to neuronal and eye development in fish embryos and larvae.PMID:39474628 | PMC:PMC11504619 | DOI:10.1021/envhealth.3c00002

Front Pharmacol. 2024 Oct 15;15:1444439. doi: 10.3389/fphar.2024.1444439. eCollection 2024.ABSTRACTINTRODUCTION: Due to the high mortality rate and increasing severity of antibiotic resistance, there is a growing interest in new treatments for Klebsiella pneumoniae (KP)-induced pneumonia. Research has shown that the single herbs of SiHuangQingXinWan (SHQXW) are effective in treating pneumonia caused by KP. The PI3K/AKT signaling pathway has garnered attention for its potential role in the management of bacterial infections. This study aimed to evaluate the anti-pneumonia effect of SHQXW and to investigate its mechanism of action.MATERIALS AND METHODS: The potential plant metabolites and molecular targets of SHQXW in the context of pneumonia were determined through ultra-high performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS) and bioinformatics analysis. The therapeutic effect of SHQXW was evaluated in a KP-induced pneumonia murine model with imipenem/cilastatin as a positive control. Transcriptomics and non-targeted metabolomics were carried out to unveil potential mechanisms and targets for anti-pneumonia effects. Additionally, an in-depth exploration on the PI3K/AKT signaling pathway was conducted in this study.RESULTS: A total of 24 potential plant metabolites and 285 SHQXW-pneumonia-related targets selected by Homo sapiens were identified in this study. The tested doses of SHQXW significantly reduced mortality, improved body weight, decreased the lung index, reduced the bacterial load, and alleviated lung pathological damage in the KP-induced pneumonia murine model (p < 0.05). Notably, 1.3 g/kg/day of SHQXW provided the most effective protective outcome. Furthermore, SHQXW demonstrated the ability to suppress the production of inflammatory factors such as IL-1α, IL-1β, IL-3, IL-6, IL-12p70, G-CSF, GM-CSF, MCP-1, KC, and TNF-α. Analysis of transcriptomic and metabolomic data revealed that SHQXW could modulate inflammation-related signaling pathways (TNF, HIF-1, NF-κB, and PI3K/AKT) and metabolites to regulate pulmonary inflammation. Additional experiments using RT-qPCR and western blotting indicated that SHQXW may exert anti-inflammatory effects by activating the PI3K/AKT pathway.DISCUSSION: The findings indicate that SHQXW effectively reduces inflammation in mice with KP-induced pneumonia by modulating inflammatory signaling pathways and metabolites, rather than by directly inhibiting the growth of KP. This study introduces a novel treatment approach for KP-induced pneumonia and presents a new outlook on drug development.PMID:39474608 | PMC:PMC11519414 | DOI:10.3389/fphar.2024.1444439

World J Hepatol. 2024 Oct 27;16(10):1208-1212. doi: 10.4254/wjh.v16.i10.1208.ABSTRACTIn this letter, we comment on a recent publication by Mei et al, in the World Journal of Hepatology, investigating the hepatoprotective effects of the modified Xiaoyao San (MXS) formula in a male rat model of non-alcoholic steatohepatitis (NASH). The authors found that MXS treatment mitigated hepatic steatosis and inflammation in the NASH model, as evidenced by the reduction in lipid droplets (LDs), fibrosis markers and lipogenic factors. Interestingly, these hepatoprotective effects were associated with androgen upregulation (based on metabolomics analysis of male steroid hormone metabolites), adenosine 5'-monophosphate-activated protein kinase (AMPK) activation, and restoration of phosphatase and tensin homolog (PTEN) expression. However, the authors did not clearly discuss the relationships between MXS-induced hepatic steatosis reduction in the NASH model, and androgen upregulation, AMPK activation, and restoration of PTEN expression. This editorial emphasizes the reported mechanisms and explains how they act or interact with each other to reduce hepatic steatosis and inflammation in the NASH model. As a perspective, we propose additional mechanisms (such as autophagy/lipophagy activation in hepatocytes) for the clearance of LDs and suppression of hepatic steatosis by MXS in the NASH model. A proper understanding of the mechanisms of MXS-induced reduction of hepatic steatosis might help in the treatment of NASH and related diseases.PMID:39474573 | PMC:PMC11514612 | DOI:10.4254/wjh.v16.i10.1208

Environ Epidemiol. 2024 Oct 28;8(6):e352. doi: 10.1097/EE9.0000000000000352. eCollection 2024 Dec.ABSTRACTBACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a class of persistent synthetic chemicals that are found in human milk and are associated with negative health effects. Research suggests that PFAS affect both lactation and the human metabolome.METHODS: We measured perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in the milk of 425 participants from the New Hampshire Birth Cohort Study using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A nontargeted metabolomics assay was performed using LC with high-resolution MS, and metabolites were identified based on in-house database matching. We observed six metabolic profiles among our milk samples using self-organizing maps, and multinomial logistic regression was used to identify sociodemographic and perinatal predictors of these profiles, including infant sex, parity, participant body mass index, participant age, education, race, smoking status, gestational weight gain, and infant age at time of milk collection.RESULTS: Elevated PFOA was associated with profiles containing higher amounts of triglyceride fatty acids, glycerophospholipids and sphingolipids, and carnitine metabolites, as well as lower amounts of lactose and creatine phosphate. Lower concentrations of milk PFOS were associated with lower levels of fatty acids.CONCLUSION: Our findings suggest that elevated PFOA in human milk is related to metabolomic profiles consistent with enlarged milk fat globule membranes and altered fatty acid metabolism. Further, our study supports the theory that PFAS share mammary epithelial membrane transport mechanisms with fatty acids and associate with metabolic markers of reduced milk production.PMID:39474471 | PMC:PMC11521063 | DOI:10.1097/EE9.0000000000000352

Environ Health (Wash). 2024 Jul 1;2(10):729-738. doi: 10.1021/envhealth.4c00066. eCollection 2024 Oct 18.ABSTRACTAmbient ozone (O3) exposure may be associated with a reduction of semen quality, yet the potential biological mechanisms remain unclear. We investigated the effects of certain seminal plasma metabolites on mediating the links between O3 exposure and the deterioration of semen quality. The untargeted metabolomics analysis was performed on semen samples of 200 Chinese adult men to determine candidate metabolites associated with characteristics of semen quality. Mediation analysis was adopted to examine whether these metabolites modulated the links between O3 exposure and semen quality. We found a significant reduction in sperm concentration by -28.1% (95% CI: -41.7%, -11.3%), and sperm count by -29.2% (95% CI: -43.7%, -11.0%) associated with each 10 μg/m3 increase in ambient O3 concentration during the period of sperm development. We delineated 7 metabolites in seminal fluid that substantially mediated the links between O3 exposure and declined semen quality, including myristoleic acid, aspartyl-isoleucine, phenylethyl primeveroside, ACar (18:2), ACar (18:1), FAHFA (22:6/22:3), and LPS (22:5). Among these, myristoleic acid exhibited the most pronounced mediation effects, with its indirect effect of which accounts for 46.4% of the overall association. Our findings suggested that exposure to ozone decreased sperm quality by disrupting fatty acid metabolism, particularly myristoleic acid.PMID:39474432 | PMC:PMC11504433 | DOI:10.1021/envhealth.4c00066

Environ Health (Wash). 2024 Feb 14;2(4):221-232. doi: 10.1021/envhealth.3c00168. eCollection 2024 Apr 19.ABSTRACTEpidemiology has associated fine particulate matter (PM2.5) exposure with an increased cardiovascular risk. However, the underlying mechanism, particularly from the liver perspective, remains unclear. Here, the influence of chronic PM2.5 exposure on cardiovascular risk in mice fed a high-fat and high-cholesterol diet (HFCD) was studied by using a real-world PM2.5 exposure system. Results showed that PM2.5 exposure elevated the serum levels of nonhigh-density lipoprotein cholesterol (non-HDL-C) and oxidized low-density lipoprotein (oxLDL) in HFCD-fed mice, demonstrating increased cardiovascular risk. To investigate the molecular mechanism, lipidomics and metabolomics analyses were conducted and revealed that PM2.5 exposure enhanced lipid accumulation and disturbed purine metabolism and glutathione metabolism in the liver of HFCD-fed mice, contributing to the elevated non-HDL-C levels and intensified oxidative stress. Moreover, PM2.5 exposure increased total cholesterol levels by upregulating Hmgcr expression and downregulating Cyp7a1 expression in the livers of HFCD-fed mice. The HDL-C level was reduced by inhibiting the hepatic Abca1 and Abcg1 expression and decreasing the levels of ApoA-I and LCAT. Additionally, the PM2.5-induced pro-oxidative environment impeded the oxLDL clearance and further triggered inflammation, in turn exacerbating oxidative stress and oxLDL production. This study demonstrated a synergy of PM2.5 and HFCD on cardiovascular risk and illuminated the molecular mechanism in PM2.5-susceptible populations.PMID:39474144 | PMC:PMC11503791 | DOI:10.1021/envhealth.3c00168

iScience. 2024 Sep 11;27(10):110917. doi: 10.1016/j.isci.2024.110917. eCollection 2024 Oct 18.ABSTRACTThe portrayed effects of olanzapine on brain development and neuronal response remain unclear under the genetic background of Homo sapiens. Here, we constructed therapeutic-dosage olanzapine-treated cerebral organoid (CO) models using induced pluripotent stem cells from human samples. We found that the activation of NODAL/FOXH1 axis mediated the early response to olanzapine up to day 15, which subsequently caused thicker cortical-like structures, cell identity maturation, higher stemness of neural progenitor cells (NPCs), and mature neuronal firing of early neurons in day 24. Transcriptomics and targeted metabolomics confirmed the upregulation of neurodevelopmental-related terms and glutamate production on day 24. Gene enrichment of transcriptomics into large-scale genome-wide association studies (GWAS) showed possible relationships with intelligence, major depressive disorder, schizophrenia. We did not observe the negative effects of in-utero exposure to olanzapine in mice. Collectively, we tended to conclude that olanzapine treatment had beneficial effects instead of harmful on early brain development.PMID:39474064 | PMC:PMC11519431 | DOI:10.1016/j.isci.2024.110917