PubMed

Biofactors. 2023 Dec 8. doi: 10.1002/biof.2022. Online ahead of print.ABSTRACTGlycosaminoglycans are complex carbohydrates used as nutraceuticals for diverse applications. We studied the potential of the glycosaminoglycan dermatan sulfate (DS) to counteract the development of diet-induced obesity (DIO) using obesity-prone mice fed a high-fat diet (HFD) as a model. Oral DS supplementation protected the animals against HFD-induced increases in whole-body adiposity, visceral fat mass, adipocyte size, blood glucose levels, insulin resistance, and pro-inflammatory lipids levels in brown adipose tissue (BAT) and the liver, where it largely counteracted the HFD-induced changes in the nonpolar metabolome. Protection against DIO in the DS-supplemented mice occurred despite higher energy intake and appeared to be associated with increased energy expenditure, higher uncoupling protein 1 expression in BAT, decreased BAT "whitening," and an enhanced channeling of fuel substrates toward skeletal muscle. This work is the first preclinical study to examine the anti-obesity activity of DS tested individually in vivo. The results support possible uses of DS as an active component in functional foods/supplements to manage obesity and associated metabolic diseases.PMID:38063391 | DOI:10.1002/biof.2022

Microbiol Spectr. 2023 Dec 8:e0324823. doi: 10.1128/spectrum.03248-23. Online ahead of print.ABSTRACTCharacterization of the skin microbiome and metabolome across geography will help uncover the climate factors behind the prevalence of skin disorders and provide suggestions for skincare products for people living in different geographic regions.PMID:38063390 | DOI:10.1128/spectrum.03248-23

J Extracell Vesicles. 2023 Dec;12(12):e12385. doi: 10.1002/jev2.12385.ABSTRACTBlood is the most commonly used body fluid for extracellular vesicle (EV) research. The composition of a blood sample and its derivatives (i.e., plasma and serum) are not only donor-dependent but also influenced by collection and preparation protocols. Since there are hundreds of pre-analytical protocols and over forty variables, the development of standard operating procedures for EV research is very challenging. To improve the reproducibility of blood EV research, the International Society for Extracellular Vesicles (ISEV) Blood EV Task Force proposes standardized reporting of (i) the applied blood collection and preparation protocol and (ii) the quality of the prepared plasma and serum samples. Gathering detailed information will provide insight into the performance of the protocols and more effectively identify potential confounders in the prepared plasma and serum samples. To collect this information, the ISEV Blood EV Task Force created the Minimal Information for Blood EV research (MIBlood-EV), a tool to record and report information about pre-analytical protocols used for plasma and serum preparation as well as assays used to assess the quality of these preparations. This tool does not require modifications of established local pre-analytical protocols and can be easily implemented to enhance existing databases thereby enabling evidence-based optimization of pre-analytical protocols through meta-analysis. Taken together, insight into the quality of prepared plasma and serum samples will (i) improve the quality of biobanks for EV research, (ii) guide the exchange of plasma and serum samples between biobanks and laboratories, (iii) facilitate inter-laboratory comparative EV studies, and (iv) improve the peer review process.PMID:38063210 | DOI:10.1002/jev2.12385

JCI Insight. 2023 Dec 8;8(23):e171417. doi: 10.1172/jci.insight.171417.ABSTRACTGout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.PMID:38063198 | DOI:10.1172/jci.insight.171417

J Cell Mol Med. 2023 Dec 8. doi: 10.1111/jcmm.18073. Online ahead of print.ABSTRACTDiabetic kidney disease (DKD) can lead to accumulation of glucose upstream metabolites due to dysfunctional glycolysis. But the effects of accumulated glycolysis metabolites on podocytes in DKD remain unknown. The present study examined the effect of dihydroxyacetone phosphate (DHAP) on high glucose induced podocyte pyroptosis. By metabolomics, levels of DHAP, GAP, glucose-6-phosphate and fructose 1, 6-bisphosphate were significantly increased in glomeruli of db/db mice. Furthermore, the expression of LDHA and PKM2 were decreased. mRNA sequencing showed upregulation of pyroptosis-related genes (Nlrp3, Casp1, etc.). Targeted metabolomics demonstrated higher level of DHAP in HG-treated podocytes. In vitro, ALDOB expression in HG-treated podocytes was significantly increased. siALDOB-transfected podocytes showed less DHAP level, mTORC1 activation, reactive oxygen species (ROS) production, and pyroptosis, while overexpression of ALDOB had opposite effects. Furthermore, GAP had no effect on mTORC1 activation, and mTORC1 inhibitor rapamycin alleviated ROS production and pyroptosis in HG-stimulated podocytes. Our findings demonstrate that DHAP represents a critical metabolic product for pyroptosis in HG-stimulated podocytes through regulation of mTORC1 pathway. In addition, the results provide evidence that podocyte injury in DKD may be treated by reducing DHAP.PMID:38063077 | DOI:10.1111/jcmm.18073

Plant Biotechnol J. 2023 Dec 8. doi: 10.1111/pbi.14259. Online ahead of print.ABSTRACTRutin, a flavonoid rich in buckwheat, is important for human health and plant resistance to external stresses. The hydrolysis of rutin to quercetin underlies the bitter taste of Tartary buckwheat. In order to identify rutin hydrolysis genes, a 200 genotypes mini-core Tartary buckwheat germplasm resource was re-sequenced with 30-fold coverage depth. By combining the content of the intermediate metabolites of rutin metabolism with genome resequencing data, metabolite genome-wide association analyses (GWAS) eventually identified a glycosyl hydrolase gene FtGH1, which could hydrolyse rutin to quercetin. This function was validated both in Tartary buckwheat overexpression hairy roots and in vitro enzyme activity assays. Mutation of the two key active sites, which were determined by molecular docking and experimentally verified via overexpression in hairy roots and transient expression in tobacco leaves, exhibited abnormal subcellular localization, suggesting functional changes. Sequence analysis revealed that mutation of the FtGH1 promoter in accessions of two haplotypes might be necessary for enzymatic activity. Co-expression analysis and GWAS revealed that FtbHLH165 not only repressed FtGH1 expression, but also increased seed length. This work reveals a potential mechanism behind rutin metabolism, which should provide both theoretical support in the study of flavonoid metabolism and in the molecular breeding of Tartary buckwheat.PMID:38062934 | DOI:10.1111/pbi.14259

Curr Pharm Des. 2023 Dec 7. doi: 10.2174/0113816128268061231012073704. Online ahead of print.ABSTRACTBACKGROUND: Cervical cancer is a prevalent malignancy among women globally.OBJECTIVE: We aimed to uncover the mechanism of action of kaempferol in the treatment of cervical cancer using an integrated approach that combines metabolomics with network pharmacology.METHODS: Initially, we investigated the specific metabolites and potential pathways influenced by kaempferol in the pathological progression of cervical cancer, employing UHPLC-Q-Orbitrap MS metabolomics. In addition, network pharmacology analysis was performed to ascertain the pivotal targets of kaempferol in the context of CC therapy.RESULTS: Metabolomics analysis indicated that the therapeutic effect of kaempferol on cervical cancer is primarily associated with 11 differential metabolites and 7 metabolite pathways. These pathways include arginine and proline metabolism, the tricarboxylic acid cycle, phenylalanine, tyrosine, and tryptophan biosynthesis, fatty acid biosynthesis, glycerophospholipid metabolism, pantothenate and CoA biosynthesis, and tyrosine metabolism. Additionally, kaempferol was found to regulate 3 differential metabolites, namely palmitic acid, citric acid, and L-tyrosine, by directly targeting 7 specific proteins, including AKR1B1, CS, EGFR, PLA2G1B, PPARG, SLCO2B1, and SRC. Furthermore, molecular docking demonstrated strong binding affinities between kaempferol and 7 crucial targets.CONCLUSION: This study elucidates the intricate mechanisms by which kaempferol acts against cervical cancer. Furthermore, this research offers a novel approach to investigating the potential pharmacological mechanisms of action exhibited by natural compounds.PMID:38062663 | DOI:10.2174/0113816128268061231012073704

Hum Genomics. 2023 Dec 8;17(1):109. doi: 10.1186/s40246-023-00561-w.ABSTRACTThe unique physiological and genetic characteristics of individuals influence their reactions to different dietary constituents and nutrients. This notion is the foundation of personalized nutrition. The field of nutrigenetics has witnessed significant progress in understanding the impact of genetic variants on macronutrient and micronutrient levels and the individual's responsiveness to dietary intake. These variants hold significant value in facilitating the development of personalized nutritional interventions, thereby enabling the effective translation from conventional dietary guidelines to genome-guided nutrition. Nevertheless, certain obstacles could impede the extensive implementation of individualized nutrition, which is still in its infancy, such as the polygenic nature of nutrition-related pathologies. Consequently, many disorders are susceptible to the collective influence of multiple genes and environmental interplay, wherein each gene exerts a moderate to modest effect. Furthermore, it is widely accepted that diseases emerge because of the intricate interplay between genetic predisposition and external environmental influences. In the context of this specific paradigm, the utilization of advanced "omic" technologies, including epigenomics, transcriptomics, proteomics, metabolomics, and microbiome analysis, in conjunction with comprehensive phenotyping, has the potential to unveil hitherto undisclosed hereditary elements and interactions between genes and the environment. This review aims to provide up-to-date information regarding the fundamentals of personalized nutrition, specifically emphasizing the complex triangulation interplay among microbiota, dietary metabolites, and genes. Furthermore, it highlights the intestinal microbiota's unique makeup, its influence on nutrigenomics, and the tailoring of dietary suggestions. Finally, this article provides an overview of genotyping versus microbiomics, focusing on investigating the potential applications of this knowledge in the context of tailored dietary plans that aim to improve human well-being and overall health.PMID:38062537 | DOI:10.1186/s40246-023-00561-w

J Appl Microbiol. 2023 Dec 7:lxad284. doi: 10.1093/jambio/lxad284. Online ahead of print.ABSTRACTAIMS: This study explores the phosphate (Pi)-solubilizing characteristics and mechanisms of a novel phosphate-solubilizing bacterium, Agrobacterium deltaense C1 (C1hereafter).METHODS AND RESULTS: The growth-promoting effects of C1 were investigated by gnotobiotic experiments, and the Pi-solubilizing mechanism was revealed by extracellular metabolomics, liquid chromatography analysis, and reverse transcription quantitative polymerase chain reaction (RT‒qPCR). Results showed that C1 significantly increased Arabidopsis biomass and total phosphorus (P) content under P deficiency. Under Ca3(PO4)2 condition, the presence of C1 resulted in a significant and negative correlation between available P content and medium pH changes, implying that Pi dissolution occurs through acid release. Metabolomics revealed C1's ability to release 99 organic acids, with gluconic acid (GA), citric acid, and α-ketoglutaric acid contributing 64.86%, 9.58%, and 0.94% to Pi solubilization. These acids were significantly induced by P deficiency. Moreover, C1's Pi solubilization may remain significant even in the presence of available P, as evidenced by substantial pH reduction and high gcd gene expression. Additionally, C1 produced over 10 plant growth-promoting substances.CONCLUSIONS: C1 dissolves Pi primarily by releasing GA, which enhances plant growth under P deficiency. Notably, its Pi solubilization effect is not significantly limited by available Pi.PMID:38061837 | DOI:10.1093/jambio/lxad284

Sci Total Environ. 2023 Dec 5:169048. doi: 10.1016/j.scitotenv.2023.169048. Online ahead of print.ABSTRACTBiodegradable plastics (BPs) have gained increased attention as a promising solution to plastics pollution problem. However, BPs often exhibited limited in situ biodegradation in the soil environment, so they may also release microplastics (MPs) into soils just like conventional non-degradable plastics. Therefore, it is necessary to evaluate the impacts of biodegradable MPs (BMPs) on soil ecosystem. Here, we explored the effects of biodegradable poly(butylene adipate-co-terephthalate) (PBAT) MPs and conventional polyethylene (PE) MPs on soil-plant (pakchoi) system at three doses (0.02 %, 0.2 %, and 2 %, w/w). Results showed that PBAT MPs reduced plant growth in a dose-dependent pattern, while PE MPs exhibited no significant phytotoxicity. High-dose PBAT MPs negatively affected the rhizosphere soil nutrient availability, e.g., decreased available phosphorus and available potassium. Metagenomics analysis revealed that PBAT MPs caused more serious interference with the rhizosphere microbial community composition and function than PE MPs. In particular, compared with PE MPs, PBAT MPs induced greater changes in functional potential of carbon, nitrogen, phosphorus, and sulfur cycles, which may lead to alterations in soil biogeochemical processes and ecological functions. Moreover, untargeted metabolomics showed that PBAT MPs and PE MPs differentially affect plant root exudates. Mantel tests, correlation analysis, and partial least squares path model analysis showed that changes in plant growth and root exudates were significantly correlated with soil properties and rhizosphere microbiome driven by the MPs-rhizosphere interactions. This work improves our knowledge of how biodegradable and conventional non-degradable MPs affect plant growth and the rhizosphere ecology, highlighting that BMPs might pose greater threat to soil ecosystems than non-degradable MPs.PMID:38061654 | DOI:10.1016/j.scitotenv.2023.169048

Comp Biochem Physiol C Toxicol Pharmacol. 2023 Dec 5:109808. doi: 10.1016/j.cbpc.2023.109808. Online ahead of print.ABSTRACTSilica nanoparticles (SNPs) are widely explored as drug carriers, gene delivery vehicles, and as nanoparticles intended for bone and tissue engineering. SNPs are highly evident through various clinical trials for a wide range of biomedical applications. SNPs are biocompatible and promising nanoparticles for next-generation therapeutics. However, despite the well-established importance of SNPs, metabolomics methods for the SNPs remain elusive which renders its maximal clinical translation. We applied 1H nuclear magnetic resonance (1H NMR) spectroscopy to investigate the metabolomics profile in Zebrafish (Danio rerio) exposed to SNPs. Zebrafish were exposed to the SNPs (10.0, 25.0, and 50.0 μg/mL) for 72 h and whole-body samples were subjected for targeted profiling. Pattern recognition of 1H NMR spectral data depicted alterations in the metabolomic profiles between control and SNPs exposed zebrafish. We found that tryptophane, lysine, methionine, phenylalanine, tyrosine, sn-glycero-3-phosphocholine (G3PC), and o-phosphocholine were decreased. The metabolic expression of niacinamide, nicotinamide adenine dinucleotide (NAD+), citrate, adenosine triphosphate (ATP), and xanthine were increased in zebrafish with SNPs treatment. We are report for the first time on metabolite alterations and phenotypic expression in zebrafish via 1H NMR. These results demonstrate that SNPs can adversely affect the significant metabolic pathways involved in energy, amino acids, cellular membrane, lipids, and fatty acid metabolisms. Metabolomics profiling may be able to detect metabolic dysregulation in SNPs-treated zebrafish and establish a foundation for further toxicological studies.PMID:38061618 | DOI:10.1016/j.cbpc.2023.109808

Comp Biochem Physiol C Toxicol Pharmacol. 2023 Dec 5:109815. doi: 10.1016/j.cbpc.2023.109815. Online ahead of print.ABSTRACTAflatoxin B1 (AFB1) is the most prevalent and toxic class of aflatoxins, which is considered a significant risk factor for food safety. Curcumin, a phytoconstituent with anti-inflammatory and antioxidant properties, has potential therapeutic value for intestinal inflammatory diseases. In this study, the duckling model susceptible to AFB1 was selected for toxicity testing, aiming to explore the effect of curcumin on AFB1 enterotoxicity and its possible mechanism of action. The results showed that curcumin promoted the growth and development of ducklings and mitigated the changes in morphology and permeability serological index (DAO and D-LA) after AFB1 exposure. Curcumin also mitigated AFB1-induced oxidative stress by activating the Nrf2 pathway, and ameliorated intestinal inflammation by inhibiting the NF-κB/IκB signaling pathway and boosting intestinal autophagy. In terms of gut flora and their metabolites, we found that curcumin supplementation significantly increased the intestinal flora's abundance index and diversity index compared to the AFB1 group, mitigating the decline in the abundance of Actinobacteria and the rise in that of harmful bacteria Clostridia. Furthermore, untargeted metabolomic analysis revealed that the protective effect of curcumin on the intestine was mainly through the regulation of AFB1-induced disorders of lipid metabolism, involving linoleic acid metabolism, α-linolenic acid metabolism, and glycerolipid metabolism. Overall, the enteroprotective effects of curcumin may be of significant value in the future for treating chronic AFB1 poisoning and also provide new therapeutic ideas for other mycotoxicosis.PMID:38061615 | DOI:10.1016/j.cbpc.2023.109815

Pharmacol Res. 2023 Dec 5:107033. doi: 10.1016/j.phrs.2023.107033. Online ahead of print.ABSTRACTBaicalin is a small molecule medication used to treat hepatitis. Our research group discovered that administering baicalin orally to mice following fecal microbiota transplantation from patients resistant to ICIs supported anti-PD-1 activity. However, the precise mechanisms behind this effect are presently unknown. In this present study, ATB-treated C57BL/6J mice received FMT from patients with advanced NSCLC amenable to αPD-1. Additionally, subcutaneous LLC cells were injected into the mice. Baicalin oral gavage and αPD-1 injection were administered to the mice on days 3 and 9 after tumour inoculation. 16S rRNA, metabolomics, and flow cytometry were utilized to clarify the mechanisms of baicalin's relief of immunosuppression. The results indicated that oral administration of baicalin enriched bacteria such as Akkermansia and Clostridia_UCG-014, resulted in an increase in SCFAs, which improved the ratio of PD-1+ (CD8+ T cell/Treg) and promoted the levels of IFN-γ+ CD8+ T cells and TNF-α+ CD8+ T cells within the tumour microenvironment. In conclusion, baicalin regulates the metabolites of the gut microbiota to improve the PD-1+ (CD8+ T cell/Treg) balance and circumvent anti-PD-1 resistance. This is achieved through the regulation of short-chain fatty acids.PMID:38061593 | DOI:10.1016/j.phrs.2023.107033

Environ Res. 2023 Dec 5:117843. doi: 10.1016/j.envres.2023.117843. Online ahead of print.ABSTRACTBACKGROUND: The utilization of short-term natural exposure as a health intervention has great potential in the field of public health. However, previous studies have mostly focused on outdoor urban green spaces, with limited research on indoor biophilic environments, and the physiological regulatory mechanisms involved remain unclear.OBJECTIVES: To explore the affective and physiological impact of short-term exposure to indoor biophilic environments and their potential regulatory mechanisms.METHODS: A between-group design experiment was conducted, and the psychophysiological responses of participants to the indoor plants (Vicks Plant) were measured by a method combined the subjective survey, electrophysiological measurements, and salivary biochemical analysis. Volatile organic compounds (VOCs) from plants were also detected to analyze the main substances that caused olfactory stimuli.RESULTS: Compared with the non-biophilic environment, short-term exposure to the indoor biophilic environment was associated with psychological and physiological relaxation, including reduced negative emotions, improved positive emotions, lower heart rate, skin conductance level, salivary cortisol and pro-inflammatory cytokines, and increased alpha brainwave power. Salivary metabolomics analysis revealed that the differential metabolites observed between the groups exhibited enrichment in two metabolic pathways related to neural function and immune response: phenylalanine, tyrosine and tryptophan biosynthesis, and ubiquinone and other terpenoid-quinone biosynthesis. These changes may be associated with the combined visual and olfactory stimuli of the biophilic environment, in which D-limonene was the dominant substance in plant-derived VOCs.CONCLUSION: This research demonstrated the benefits of short-term exposure to indoor biophilic environments on psychophysiological health through evidence from both the nervous and endocrine systems.PMID:38061588 | DOI:10.1016/j.envres.2023.117843

Int J Biol Macromol. 2023 Dec 5:128632. doi: 10.1016/j.ijbiomac.2023.128632. Online ahead of print.ABSTRACTRuminant rumen plays an important role in the digestibility of cellulose, hemicellulose, starch and fat. In this study, the yaks under graze and stall feeding were chosen as the models of different rumen bacteria and intramuscular fat (IMF). The characteristics of IMF deposition, serum indexes in yaks were detected; the bacteria, metabolites in rumen was explored by 16S rRNA sequencing technology, untargeted metabolomics based on liquid chromatography-mass spectrometer and gas chromatography, respectively; the transcriptome of longissimus thoracis was identified by RNA-Sequencing analysis. Based on above results, a hypothesis that yak IMF deposition is regulated by the combined action of microbiome-gut-brain and muscle axis was proposed. The short-chain fatty acids (SCFAs) and neurotransmitters precursors like acetylcholine produced in yak rumen promoted insulin secretion via central nervous system. These insulin resulted in the high expression of SREBF1 gene by gut-brain axis; SCFAs can directly arrive to muscular tissue via blood circulation system, then activated the expression of PPARγ gene by gut-muscle axis. The expression of lipogenesis gene SCD, FABP3, CPT1, FASN and ACC2 was accordingly up-regulated. This study firstly introduce the theory of microbiome-gut-brain/muscle axis into the study of ruminant, and comprehensively expounded the regulatory mechanism of yak IMF deposition.PMID:38061511 | DOI:10.1016/j.ijbiomac.2023.128632

Toxicol Lett. 2023 Dec 5:S0378-4274(23)01108-6. doi: 10.1016/j.toxlet.2023.12.002. Online ahead of print.ABSTRACTSilicosis is a common occupational disease caused by the long-term inhalation of large amounts of silica dust. Lipid metabolism plays an important role in the progression of silicosis, but its contributing mechanism remains unclear. The aim of this study was to investigate the differential lipid metabolites and active metabolic pathways in silicosis rat lung tissue. We first constructed a silicosis rat model, and randomly divided 24 male SD rats into control group (C), silicosis group for 1 week (S1W), silicosis group for 2 weeks (S2W) and silicosis group for 4 weeks (S4W) with 6 rats in each group. 1ml SiO2 suspension (50mg/ml) or normal saline were injected into the trachea, and the rats were killed at 1 week, 2 weeks and 4 weeks, respectively. The lung tissue pathology of the rats was observed by HE staining and VG staining, and the plasma TC and FC levels were detected by the kit. Western blot was used to detect the expression of lipid-related factors CD36, PGC1α and LXR. In addition, lipidomics analysis of lung tissue samples was performed using UPLC-IMS-QTOF mass spectrometer to screen out potential differential metabolites in silicosis models and analyze lipid enrichment, and verified the expression of differential gene CHPT1 in the metabolic pathway. HE and VG staining showed that the number of nodules and fibrosis increased in a time-dependent manner in the silicosis model group, and the levels of TC, FC and CE in silicosis plasma increased. Western blot results showed that PGC1α and LXR decreased in the silicosis model group, while CD36 expression increased. In addition, metabolomics screened out 28 differential metabolites in the S1W group, 32 in the S2W group, and 22 in the S4W group, and found that the differential metabolites were mainly enriched in metabolic pathways such as glycerophospholipid metabolism and ether lipid metabolism, and the expression of differential gene CHPT1 in the metabolic pathway was decreased in the silicosis model group. These results suggest that there are significant changes in lipid metabolites in lung tissue in silicosis rat models, and glycerophospholipid metabolism was significantly enriched, suggesting that glycerophospholipids play an important role in the progression of silicosis. The differential metabolites and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.PMID:38061438 | DOI:10.1016/j.toxlet.2023.12.002

Curr Opin Biotechnol. 2023 Dec 6;85:103027. doi: 10.1016/j.copbio.2023.103027. Online ahead of print.ABSTRACTMany biological phenotypes are rooted in metabolic pathway activity rather than the concentrations of individual metabolites. Despite this, most metabolomics studies only capture steady-state metabolism - not metabolic flux. Although sophisticated metabolic flux analysis strategies have been developed, these methods are technically challenging and difficult to implement in large-cohort studies. Recently, a new boundary flux analysis (BFA) approach has emerged that captures large-scale metabolic flux phenotypes by quantifying changes in metabolite levels in the media of cultured cells. This approach is advantageous because it is relatively easy to implement yet captures complex metabolic flux phenotypes. We describe the opportunities and challenges of BFA and illustrate how it can be harnessed to investigate a wide transect of biological phenomena.PMID:38061263 | DOI:10.1016/j.copbio.2023.103027

EBioMedicine. 2023 Dec 6;99:104904. doi: 10.1016/j.ebiom.2023.104904. Online ahead of print.ABSTRACTBACKGROUND: The pathology of keloid and especially the roles of bacteria on it were not well understood.METHODS: In this study, multi-omics analyses including microbiome, metaproteomics, metabolomic, single-cell transcriptome and cell-derived xenograft (CDX) mice model were used to explore the roles of bacteria on keloid disease.FINDINGS: We found that the types of bacteria are significantly different between keloid and healthy skin. The 16S rRNA sequencing and metaproteomics showed that more catalase (CAT) negative bacteria, Clostridium and Roseburia existed in keloid compared with the adjacent healthy skin. In addition, protein mass spectrometry shows that CAT is one of the differentially expressed proteins (DEPs). Overexpression of CAT inhibited the proliferation, migration and invasion of keloid fibroblasts, and these characteristics were opposite when CAT was knocked down. Furthermore, the CDX model showed that Clostridium butyricum promote the growth of patient's keloid fibroblasts in BALB/c female nude mice, while CAT positive bacteria Bacillus subtilis inhibited it. Single-cell RNA sequencing verified that oxidative stress was up-regulated and CAT was down-regulated in mesenchymal-like fibroblasts of keloid.INTERPRETATION: In conclusion, our findings suggest that bacteria and CAT contribute to keloid disease.FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.PMID:38061241 | DOI:10.1016/j.ebiom.2023.104904

J Pharm Biomed Anal. 2023 Nov 29;239:115875. doi: 10.1016/j.jpba.2023.115875. Online ahead of print.ABSTRACTHuachansu (HCS) tablets, classified as well-known traditional Chinese medicine (TCM) preparation, have been proved to be effective in the treatment of hepatocellular carcinoma (HCC) in clinical studies. However, the underlying mechanism of HCS tablets against HCC has not been comprehensively elucidated. In this study, a rat model of HCC was established with diethylnitrosamine (DEN) inducer. The efficacy of HCS tablets against HCC was assessed through liver histopathological examination and evaluation of biochemical indicators. A metabolomics method based on UPLC-Q-TOF/MS combined with multivariate data analysis was established to identify differential metabolites related to the inhibition effect of HCS tablets on HCC, and then the relevant metabolic pathway analysis was performed to investigate the anti-HCC mechanisms of HCS tablets. The results showed that compared to the control group, the HCC model group showed a significant increase in the values of HCC-related biochemical indicators and the number of tumor nodules, indicating the successful establishment of the HCC rat model. Upon treatment with HCS tablets, the values of HCC-related biochemical indicators decreased, liver fibrosis and nuclear deformation were also significantly alleviated. A total of 15 differential metabolites associated with the anti-tumor effect of HCS tablets on HCC were screened and annotated through hepatic tissue metabolomics studies. Analysis of metabolic pathways revealed that the therapeutic effects of HCS tablets on HCC mainly involved the pentose and glucuronate interconversions and arachidonic acid metabolism. Further western blotting corroborated that the alteration in arachidonic acid (AA) level after the intervention of HCS tablets was related to the inhibition of cPLA2α expression in rat liver tissues. In conclusion, HCS tablets exhibit a certain anti-tumor effect on HCC, and the metabolomics method based on UPLC-Q-TOF/MS combined with further verification at the biochemical level is a promising way to reveal its underlying mechanism.PMID:38061172 | DOI:10.1016/j.jpba.2023.115875

J Neuroinflammation. 2023 Dec 7;20(1):293. doi: 10.1186/s12974-023-02976-7.ABSTRACTBACKGROUND: Depression is two-to-three times more frequent among women. The hypothalamus, a sexually dimorphic area, has been implicated in the pathophysiology of depression. Neuroinflammation-induced hypothalamic dysfunction underlies behaviors associated with depression. The lipopolysaccharide (LPS)-induced mouse model of depression has been well-validated in numerous laboratories, including our own, and is widely used to investigate the relationship between neuroinflammation and depression. However, the sex-specific differences in metabolic alterations underlying depression-associated hypothalamic neuroinflammation remain unknown.METHODS: Here, we employed the LPS-induced mouse model of depression to investigate hypothalamic metabolic changes in both male and female mice using a metabolomics approach. Through bioinformatics analysis, we confirmed the molecular pathways and biological processes associated with the identified metabolites. Furthermore, we employed quantitative real-time PCR, enzyme-linked immunosorbent assay, western blotting, and pharmacological interventions to further elucidate the underlying mechanisms.RESULTS: A total of 124 and 61 differential metabolites (DMs) were detected in male and female mice with depressive-like behavior, respectively, compared to their respective sex-matched control groups. Moreover, a comparison between female and male model mice identified 37 DMs. We capitalized on biochemical clustering and functional enrichment analyses to define the major metabolic changes in these DMs. More than 55% of the DMs clustered into lipids and lipid-like molecules, and an imbalance in lipids metabolism was presented in the hypothalamus. Furthermore, steroidogenic pathway was confirmed as a potential sex-specific pathway in the hypothalamus of female mice with depression. Pregnenolone, an upstream component of the steroid hormone biosynthesis pathway, was downregulated in female mice with depressive-like phenotypes but not in males and had considerable relevance to depressive-like behaviors in females. Moreover, exogenous pregnenolone infusion reversed depressive-like behaviors in female mice with depression. The 5α-reductase type I (SRD5A1), a steroidogenic hub enzyme involved in pregnenolone metabolism, was increased in the hypothalamus of female mice with depression. Its inhibition increased hypothalamic pregnenolone levels and ameliorated depressive-like behaviors in female mice with depression.CONCLUSIONS: Our study findings demonstrate a marked sexual dimorphism at the metabolic level in depression, particularly in hypothalamic steroidogenic metabolism, identifying a potential sex-specific pathway in female mice with depressive-like behaviors.PMID:38062440 | DOI:10.1186/s12974-023-02976-7