PubMed

Life Sci. 2023 Mar 30:121626. doi: 10.1016/j.lfs.2023.121626. Online ahead of print.ABSTRACTAIMS: Nonalcoholic fatty liver disease (NAFLD) is becoming more common and severe. Individuals with NAFLD have an altered composition of gut- microbial metabolites. We used metabolomics profiling to identify microbial metabolites that could indicate gut-liver metabolic severity. Noninvasive biomarkers are required for NAFLD, especially for patients at high risk of disease progression.MAIN METHODS: We compared the stool metabolomes, untargeted metabolomics, and clinical data of 80 patients. Patients with nonalcoholic fatty liver (NAFL: n = 16), nonalcoholic steatohepatitis (NASH: n = 26), and cirrhosis (n = 19) and healthy control individuals (HC: n = 19) were enrolled. The identified metabolites in NAFLD were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS) were used to analyze metabolites.KEY FINDINGS: Untargeted metabolomics was used to identify and quantify 103 metabolites. Principal component analysis (PCA) was used to assess the metabolic discrimination of NAFL, NASH, and cirrhosis. Short-chain fatty acids (SCFA) levels were significantly lower in NAFLD patients, including those of acetate (p = 0.03), butyrate (p = 0.0008), and propionate. The stool cholic acid (p = 0.001) level was significantly increased in NAFLD patients. Palmitoylcarnitine and l-carnitine levels were significantly increased in NASH and cirrhosis patients. The phenotypic expression of these metabolites was linked to β-oxidation.SIGNIFICANCE: We demonstrated a distinct metabolome profile in NAFLD patients with NAFL, NASH, and cirrhosis. We also discovered that the expression of certain metabolites and metabolic pathways was linked to NAFLD.PMID:37003543 | DOI:10.1016/j.lfs.2023.121626

J Biol Chem. 2023 Mar 30:104663. doi: 10.1016/j.jbc.2023.104663. Online ahead of print.ABSTRACTMicrotubule Associated Protein 1 Light Chain 3 Gamma (MAP1LC3C or LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as von Hippel-Lindau protein (VHL) and folliculin (FLCN). Recently We demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE). This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Additionally, metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show increased tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of Lysosomal Associated Membrane Protein 1 (LAMP1) on the plasma membrane of cancer cells in human clear cell renal cell carcinoma (ccRCC) and reduced levels of Zn, suggesting that LE occurs in ccRCC, potentially contributing to the loss of Zn. These data indicate that the reprogramming of lysosomal localization and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating cancer cells is an important aspect of tumor suppressing activity of LC3C.PMID:37003503 | DOI:10.1016/j.jbc.2023.104663

Fish Shellfish Immunol. 2023 Mar 30:108719. doi: 10.1016/j.fsi.2023.108719. Online ahead of print.ABSTRACTThe large yellow croaker (Larimichthys crocea) is the most productive mariculture fish in China, and its aquaculture scale is expanding along the southeastern coast of China, but that development is causing environmental damage by increasing the use of antibiotics and other chemicals. How to improve fish immunity through non-antibiotic substances is still a problem facing aquaculture industry. At present, the experiments have shown that Isaria cicadae spent substrate (IC) can improve the growth performance and immunity of Oreochromis niloticus. Therefore, I. cicadae may be a natural alternative to antibiotic for aquaculture. In order to study the effects of IC on growth performance, serum biochemical indices, intestinal microbiota, and intestinal metabolism of large yellow croakers, the fish were divided into three groups with three replicates in each group. Basal diet, basal diet with 2% and 6% IC supplementation (IC2 and IC6 groups), respectively. The results showed that weight gain rate (WG) and specific growth rate (SGR) of large yellow croaker significantly increased (P < 0.05) in IC6 group. The content of triglyceride (TG), low density lipoprotein cholesterol (LDL-C), total protein (TP) and albumin (ALB) increased significantly (P < 0.05), and total cholesterol (T-CHO) decreased significantly (P < 0.05) in IC2. Compared to IC0 group, the content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) increased significantly (P < 0.05) in IC2 group, the activity of total antioxidant capacity (T-AOC) and GSH-Px increased (P < 0.05) in IC6 group, and the activity of lysozyme (LZM) increased significantly in IC2 and IC6 groups. The addition of IC in the diet significantly increased the diversity of the microbial community in the intestine of large yellow croaker (P < 0.05), significantly improved the relative abundance of Acidobacteriota (P < 0.05) at the phylum level, and reduced the relative abundance of Bacteroidota, Desulfobacterota, and Synergistota (P < 0.05). At the genus level, the relative abundances of Bacteroides, Cetobacterium and Mycoplasma, which are dominant bacteria in fish gut, was significantly increased (P < 0.05). The relative abundance of Ruminofilibacter, Desulfomicrobium, DMER64, Syntrophomonas, Hydrogenophaga, and Aminobacterium were reduced (P < 0.05), Among them, Ruminofilibacter, DMER64, Syntrophomonas and Hydrogenophaga are bacteria that can participate in the hydrolysis and acidification of organic matter, while DMER64 is the hydrogen carrier. The intestinal metabolome analysis showed that IC could improve metabolic composition and function, which was related to host immunity and metabolism. In conclusion, I. cicadae may improve the growth performance, regulate the lipid metabolism and immune and antioxidant capacity of large yellow croakers by regulating intestinal microbiota and intestinal metabolism. This study provides a reference for the application of IC in aquaculture.PMID:37003497 | DOI:10.1016/j.fsi.2023.108719

J Ethnopharmacol. 2023 Mar 30:116409. doi: 10.1016/j.jep.2023.116409. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma wenyujin Y.H. Chen & C. Ling, also known as Wen-E-Zhu, has been used for cancer treatment since ancient times, with roots dating back to the Song Dynasty. Elemene (EE), a sesquiterpene extract with potent anticancer properties, is extracted from Wen-E-Zhu, with β-elemene (BE) being its main active compound, along with trace amounts of β-caryophyllene (BC), γ-elemene and δ-elemene isomers. EE has demonstrated broad-spectrum anti-cancer effects and is commonly used in clinical treatments for various types of malignant cancers, including lung cancer. Studies have shown that EE can arrest the cell cycle, inhibit cancer cell proliferation, and induce apoptosis and autophagy. However, the exact mechanism of its anti-lung cancer activity remains unclear and requires further research and investigation.AIM OF THE STUDY: In this study, the possible mechanism of EE and its main active components, BE and BC, against lung adenocarcinoma was investigated by using A549 and PC9 cell lines.MATERIALS AND METHODS: The subcutaneous tumor model of nude mice was constructed to evaluate the efficacy of EE in vivo, then the in vitro half-inhibitory concentration (IC50) of EE and its main active components, BE and BC, on A549 and PC9 cells at different concentrations were determined by CCK-8. Flow cytometry was used to detect the apoptosis and cycle of A549 and PC9 cells treated with different concentrations of BE and BC for 24 h. Non-targeted metabolomics analysis was performed on A549 cells to explore potential target pathways, which were subsequently verified through kit detection and western blot analysis.RESULTS: Injection of EE in A549 tumor-bearing mice effectively suppressed cancer growth in vivo. The IC50 of EE and its main active components, BE and BC, was around 60 μg/mL. Flow cytometry analysis showed that BE and BC blocked the G2/M and S phases of lung adenocarcinoma cells and induced apoptosis, leading to a significant reduction in mitochondrial membrane potential (MMP). Results from non-targeted metabolomics analysis indicated that the glutathione metabolism pathway in A549 cells was altered after treatment with the active components. Kit detection revealed a decrease in glutathione (GSH) levels and an increase in the levels of oxidized glutathione (GSSG) and reactive oxygen (ROS). Supplementation of GSH reduced the inhibitory activity of the active components on lung cancer and also decreased the ROS content of cells. Analysis of glutathione synthesis-related proteins showed a decrease in the expression of glutaminase, cystine/glutamate reverse transporter (SLC7A11), and glutathione synthase (GS), while the expression of glutamate cysteine ligase modified subunit (GCLM) was increased. In the apoptosis-related pathway, Bax protein and cleaved caspase-9/caspase-9 ratio were up-regulated and Bcl-2 protein was down-regulated.CONCLUSIONS: EE, BE, and BC showed significant inhibitory effects on the growth of lung adenocarcinoma cells, and the mechanism of action was linked to the glutathione system. By down-regulating the expression of proteins related to GSH synthesis, EE and its main active components BE and BC disrupted the cellular redox system and thereby promoted cell apoptosis.PMID:37003401 | DOI:10.1016/j.jep.2023.116409

J Ethnopharmacol. 2023 Mar 30:116424. doi: 10.1016/j.jep.2023.116424. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Rehmanniae Radix Praeparata (RRP), the processed root of Rehmannia glutinosa, has been widely used to treat Yin deficiency syndrome in traditional Chinese medicine. RRP is available in two forms: processed by steaming with water (SRR) or processed by stewing with yellow rice wine (WRR). Previous work has documented chemical differences in the secondary metabolomes and glycomes of SRR and WRR.AIM OF THE STUDY: This study aimed to compare SRR and WRR in terms of Yin-nourishing effects via metabolomics and microbiome analysis.MATERIALS AND METHODS: ICR mice were orally administered with thyroxine for 14 d to induce Yin deficiency. Changes in biochemical indices and histopathology were detected. Serum metabolomics analysis and microbial 16S rRNA sequencing were performed to compare the therapeutic effects and mechanisms between SRR and WRR in treating thyroxine-induced Yin deficiency.RESULTS: Both SRR and WRR decreased serum T3, T4 and MDA levels, and increased SOD activity. SRR more effectively decreased serum Cr, and ameliorated kidney injury, while WRR showed better regulation on ratio of cAMP/cGMP and serum TSH, and relieved thyroid injury. Both SRR and WRR regulated tyrosine, glycerophospholipid, and linoleic acid metabolism and the citric acid cycle. Additionally, SRR regulated fatty acid metabolism, while WRR influenced alanine, aspartate and glutamate metabolism, and bile acid biosynthesis. SRR significantly enriched the genera Staphylococcus and Bifidobacterium in the gut microbiome, while WRR significantly enriched the genera Akkermansia, Bacteroides and Parabacteroides, and decreased the abundance of Lactobacillus.CONCLUSIONS: SRR displayed better protective effects on kidney, while WRR showed stronger effects on thyroid in thyroxine-induced Yin deficient mice. These differences might be due to different regulating effects of SRR and WRR on the metabolome and gut microbiota.PMID:37003400 | DOI:10.1016/j.jep.2023.116424

J Ethnopharmacol. 2023 Mar 30:116438. doi: 10.1016/j.jep.2023.116438. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Red ginseng (RG), a processed product of ginseng (GS), is a generally used qi-tonifying medicine in Traditional Chinese Medicine (TCM). According to the TCM principle, RG is also generally applied to spleen-deficiency syndrome (SDS) clinically for its warmer property. However, the effective substances and mechanism of RG on SDS have not been well investigated.AIM OF THE STUDY: The aim of this study was to explore the effective substances and their mechanism of RG on SDS.MATERIALS AND METHODS: The SDS model was established with a compound factor method involving an irregular diet, excessive fatigue and sennae folium with a bitter-cold property. The medicine of RG was split by multi-mode separation methods and analyzed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The appearance indexes such as body weight, body temperature, swimming endurance, urine output, and water content of fecal were determined. The biochemical indexes such as D-xylose, SP, VIP and AChE in the digestive system, CRH, ACTH, CORT, E, T3, T4, T, E2 and 5-HT in the endocrine system, CS, NCR, IDH1, COX and Na+-K+-ATPase in the metabolism of substance and energy, cAMP and cGMP in the cyclic nucleotide system were analyzed by Enzyme-linked immunosorbent assay (ELISA) kits and biochemical kits. The serum metabolites were analyzed by UPLC-QTOF/MS. Furthermore, the gut microbiota and short-chain fatty acids (SCFAs) in feces were analyzed by 16S rRNA sequencing and headspace gas chromatography-mass method.RESULTS: The pharmacological experiments showed that total saponin fraction (RGTSF), less polar fraction (RGLPF), and polysaccharides faction (RGPSF) significantly modulated the "brain-gut" axis-related indexes (the levels of VIP, AChE, and 5-HT). Besides, RGTSF also significantly modulated the hypothalamic-pituitary-adrenal (HPA) axis-related indexes as well as the substance and energy metabolism-related indexes (the levels of ACTH, CORT, A, Na+-K+-ATPase, COX, NCR and CS). RGPSF also significantly modulated the hypothalamus-pituitary-thyroid (HPT) axis-related indexes (the levels of T3 and T4). Secondly, metabolomics indicated that RGTSF could significantly regulate the abnormal metabolic pathways associated with the development of SDS, which involved steroid hormone biosynthesis, taurine and hypotaurine metabolism, primary bile acid biosynthesis, and amino acid metabolism. Subsequently, the study of gut microbiota indicated that RGLPF could increase the diversities of the gut microbiota and the relative abundance of Firmicutes in rats with SDS, while RGWEF significantly increased the relative abundance of Bacteroidetes. At the genus level, RGLPF could increase the relative abundance of Lactobacillus in rats with SDS and decrease that of Akkermansia. Meanwhile, the water-eluted fraction (RGWEF) showed a stronger regulation in SCFAs.CONCLUSION: It is for the first time that the effective substances of red ginseng on spleen-deficiency syndrome were studied systematically and the different mechanisms of the RG fractions involved in substance and energy metabolism as well as the "brain-gut" axis were revealed. The present study demonstrated that RGTSF, RGPSF, and RGLPF were the effective substances of red ginseng for ameliorating spleen-deficiency syndrome, indicating that ginsenosides composed of primary and secondary saponins as well as polysaccharides were the main effective substances for red ginseng in ameliorating spleen-deficiency syndrome.PMID:37003398 | DOI:10.1016/j.jep.2023.116438

Sci Total Environ. 2023 Mar 30:163167. doi: 10.1016/j.scitotenv.2023.163167. Online ahead of print.ABSTRACTMethamphetamine (METH) is a concerning drug of abuse that produces strong psychostimulant effects. The use of this substance, along with the insufficient removal in the sewage treatment plants, leads to its occurrence in the environment at low concentrations. In this study, brown trout (Salmo trutta fario) were exposed to 1 μg/L of METH as environmental relevant concentration for 28 days in order to elucidate the complex effects resulting from the drug, including behaviour, energetics, brain and gonad histology, brain metabolomics, and their relations. Trout exposed to METH displayed lowered activity as well as metabolic rate (MR), an altered morphology of brain and gonads as well as changes in brain metabolome when compared to controls. Increased activity and MR were correlated to an increased incidence of histopathology in gonads (females - vascular fluid and gonad staging; males - apoptotic spermatozoa and peritubular cells) in exposed trout compared to controls. Higher amounts of melatonin in brain were detected in exposed fish compared to controls. Tyrosine hydroxylase expression in locus coeruleus was related to the MR in exposed fish, but not in the control. Brain metabolomics indicated significant differences in 115 brain signals between control and METH exposed individuals, described by the coordinates within the principal component analyses (PCA) axes. These coordinates were subsequently used as indicators of a direct link between brain metabolomics, physiology, and behaviour - as activity and MR varied according to their values. Exposed fish showed an increased MR correlated with the metabolite position in PC1 axes, whereas the control had proportionately lower MR and PC1 coordinates. Our findings emphasize the possible complex disturbances in aquatic fauna on multiple interconnected levels (metabolism, physiology, behaviour) as a result of the presence of METH in aquatic environments. Thus, these outcomes can be useful in the development of AOP's (Adverse Outcome Pathways).PMID:37003339 | DOI:10.1016/j.scitotenv.2023.163167

Biomed Pharmacother. 2023 Mar 30;162:114622. doi: 10.1016/j.biopha.2023.114622. Online ahead of print.ABSTRACTAtopic dermatitis (AD) is a common, chronic, and recurring inflammatory skin disease. Physalis alkekengi L. var. franchetii (Mast) Makino (PAF), a traditional Chinese medicine, is primarily used for the clinical treatment of AD. In this study, a 2,4-dinitrochlorobenzene-induced AD BALB/c mouse model was established, and a comprehensive pharmacological method was used to determine the pharmacological effects and molecular mechanisms of PAF in the treatment of AD. The results indicated that both PAF gel (PAFG) and PAFG+MF (mometasone furoate) attenuated the severity of AD and reduced the infiltration of eosinophils and mast cells in the skin. Serum metabolomics showed that PAFG combined with MF administration exerted a synergistic effect by remodeling metabolic disorders in mice. In addition, PAFG also alleviated the side effects of thymic atrophy and growth inhibition induced by MF. Network pharmacology predicted that the active ingredients of PAF were flavonoids and exerted therapeutic effects through anti-inflammatory effects. Finally, immunohistochemical analysis confirmed that PAFG inhibited the inflammatory response through the ERβ/HIF-1α/VEGF signaling pathway. Our results revealed that PAF can be used as a natural-source drug with good development prospects for the clinical treatment of AD.PMID:37003035 | DOI:10.1016/j.biopha.2023.114622

J Hazard Mater. 2023 Mar 28;452:131310. doi: 10.1016/j.jhazmat.2023.131310. Online ahead of print.ABSTRACTAs the most commonly used organochlorine pesticide nowadays, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet. This study found that the CHI based on ADI level could induce obesity in mice. In addition, CHI could induce an imbalance in the gut microbiota of mice. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the CHI could induce obesity in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, CHI could disturb the bile acids (BAs) metabolism of mice, causing the inhibition of the signal response of BAs receptor FXR and leading to glycolipid metabolism disorders in liver and epiWAT of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the CHI-induced obesity in mice. In conclusion, CHI was found to induce obesity in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of obesity, demonstrating the key role of gut microbiota in the toxic effects of pesticides.PMID:37003002 | DOI:10.1016/j.jhazmat.2023.131310

Neuroscientist. 2023 Mar 31:10738584231162508. doi: 10.1177/10738584231162508. Online ahead of print.ABSTRACTAxons are an essential component of the nervous system, and axon degeneration is an early feature of many neurodegenerative disorders. The NAD+ metabolome plays an essential role in regulating axonal integrity. Axonal levels of NAD+ and its precursor NMN are controlled in large part by the NAD+ synthesizing survival factor NMNAT2 and the pro-neurodegenerative NADase SARM1, whose activation triggers axon destruction. SARM1 has emerged as a promising axon-specific target for therapeutic intervention, and its function, regulation, structure, and role in neurodegenerative diseases have been extensively characterized in recent years. In this review, we first introduce the key molecular players involved in the SARM1-dependent axon degeneration program. Next, we summarize recent major advances in our understanding of how SARM1 is kept inactive in healthy neurons and how it becomes activated in injured or diseased neurons, which has involved important insights from structural biology. Finally, we discuss the role of SARM1 in neurodegenerative disorders and environmental neurotoxicity and its potential as a therapeutic target.PMID:37002660 | DOI:10.1177/10738584231162508

Heliyon. 2023 Mar 31;9(4):e15123. doi: 10.1016/j.heliyon.2023.e15123. eCollection 2023 Apr.ABSTRACTOBJECTIVE: Retinal hard exudates (HEs) result from lipoproteins leaking from capillaries into extracellular retinal space, and are related to decreased visual acuity in diabetic retinopathy (DR). This study aims to identify differential serum lipids and metabolites associated with HEs.MATERIALS AND METHODS: A cross-sectional study was conducted Jul 2017 ∼ Mar 2021. We assessed the amount of HEs using standard ETDRS photographs for comparison. HEs severity was rated as "no or questionable", "moderate" or "severe". Serum samples were processed via high coverage pseudotargeted lipidomics analysis, and untargeted liquid chromatography coupled with time-of-flight mass spectrometry for metabolomics study, respectively. Weighted gene co-expression network analyses, partial least squares-discriminant analysis, and multi-receiver operating characteristic analysis were applied.RESULTS: A total of 167 patients were included. Discovery group: 116 eyes (116 patients). Validation group: 51 eyes (51 patients). 888 lipids were detected and divided into 18 modules (MEs), ME1 ∼ ME18. Lipids in ME1 significantly increased in patients with HEs in DR (NPDR and PDR combined), NPDR, and PDR, respectively. ME1 enriched to triglycerides (29%), ceramides (17%), and N-acylethanolamines (15%). A combined model of 20 lipids was the best to discriminate HEs, area under curve = 0.804, 95% confidence interval = 0.674-0.916. For metabolomics analysis, 19 metabolites and 13 pathways associated with HEs were identified. Taurine and hypotaurine metabolism, cysteine and methionine metabolism were closely related to HEs (P < 0.01).CONCLUSIONS: The lipids and metabolites identified may serve as prediction biomarkers in the early stage of HEs in DR.PMID:37089301 | PMC:PMC10119565 | DOI:10.1016/j.heliyon.2023.e15123

Metabolomics. 2023 Apr 1;19(4):33. doi: 10.1007/s11306-023-01999-8.ABSTRACTINTRODUCTION: Diagnosing myocardial infarction is difficult during the initial phase. As, acute myocardial ischemia is associated with changes in metabolic pathways, metabolomics may provide ways of identifying early stages of ischemia. We investigated the changes in metabolites after induced ischemia in humans using nuclear magnetic resonance spectroscopy (NMR).METHODS: We included patients undergoing elective coronary angiography showing normal coronary arteries. These were randomized into 4 groups and underwent coronary artery occlusion for 0, 30, 60 or 90 s. Blood was collected over the next 3 h and analyzed using NMR. We used 2-way ANOVA of time from baseline- and treatment group to find metabolites that changed significantly following the intervention and principal component analysis (PCA) to investigate changes between the 90 s ischemia- and control groups at 15 and 60 min after intervention.RESULTS: We included 34 patients. The most pronounced changes were observed in the lipid metabolism where 38 of 112 lipoprotein parameters (34%) showed a significant difference between the patients exposed to ischemia and the control group. There was a decrease in total plasma triglycerides over the first hour followed by a normalization. The principal component analysis showed a effects of the treatment after just 15 min. These effects were dominated by changes in high-density lipoprotein. An increase in lactic acid levels was detected surprisingly late, 1-2 h after the ischemia.CONCLUSION: We investigated the earliest changes in metabolites of patients undergoing brief myocardial ischemia and found that ischemia led to changes throughout the lipid metabolism as early as 15 min post-intervention.PMID:37002479 | DOI:10.1007/s11306-023-01999-8

Metabolomics. 2023 Apr 1;19(4):34. doi: 10.1007/s11306-023-01986-z.ABSTRACTINTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a disorder that causes a collapse of the femoral head, requiring subsequent total hip replacement. However, the pathogenesis of ONFH remains largely unclear. Herein, exosome metabolomics analyses were conducted to explore the pathophysiology of ONFH.OBJECTIVES: This study aimed to conduct metabolic profiling of bone-derived exosomes of ONFH.METHODS: 30 ONFH patients and 30 femoral neck fracture (FNF) patients were included in this study. Exosomes were harvested from the femoral head by using ultracentrifugation. Ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed in combination with multivariate statistical analysis to reveal and provided new insight into identify the global metabolic profile of ONFH.RESULTS: The results of transmission electron microscope (TEM), nanoparticle tracking analysis (NTA), and Western blots indicated that the microvesicles isolated from the femoral head were exosomes. Several compounds were identified, including lipids and lipid-like molecules, amino acids, peptides, organooxygen compounds. 44 differential metabolites were screened between ONFH and FNF patients. The up-and down-regulation of Riboflavin metabolism, Pantothenate and CoA biosynthesis, Glycerophospholipid metabolism, and Sphingolipid metabolism were associated with ONFH pathophysiology.CONCLUSION: Our results suggest that metabolomics has huge prospects for elucidating pathophysiology of ONFH.PMID:37002424 | DOI:10.1007/s11306-023-01986-z

Sci Rep. 2023 Mar 31;13(1):5256. doi: 10.1038/s41598-023-31922-z.ABSTRACTPositive effects have been observed as a result of Aloe arborescens supplementation in the dry-off phase in dairy cows. Metabolomic approaches can provide additional information about animal physiology. Thus, we characterized plasma metabolome around dry-off in 12 cows supplemented (AL) or not (CTR) with 10 g/d of lyophilized A. arborescens with an untargeted metabolomic approach. Overall, 1658 mass features were annotated. Regardless of treatment, multivariate statistics discriminated samples taken before and after dry-off. Overall, 490 metabolites were different between late lactation and early dry period, of which 237 were shared between AL and CTR. The most discriminant compounds (pentosidine and luteolin 7-O-glucoside) were related to the more fibrous diet. Pathway analysis indicated that pyrimidine and glycerophospholipid metabolisms were down-accumulated, suggesting reduced rumen microbial activity and liver load. Samples from AL were discriminated from CTR either the day of dry-off or 7 days after. At dry-off, aloin and emodin were the most discriminant metabolites, indicating that Aloe's bioactive compounds were absorbed. Seven days later, 534 compounds were different between groups, and emodin was among the most impacted. Pathway analysis highlighted that glycerophospholipid, pyrimidine, and folate metabolisms were affected. These results might indicate that Aloe has positive effects on liver function and a modulatory effect on rumen fermentation.PMID:37002349 | DOI:10.1038/s41598-023-31922-z

Sci Rep. 2023 Mar 31;13(1):5272. doi: 10.1038/s41598-023-32337-6.ABSTRACTThe growth of endophytic bacteria is influenced by the host plants and their secondary metabolites and activities. In this study, P. megaterium P-NA14 and P. megaterium D-HT207 were isolated from potato tuber and dendrobium stem respectively. They were both identified as Priestia megaterium. The antimicrobial activities and metabolites of both strains were explored. For antimicrobial activities, results showed that P. megaterium P-NA14 exhibited a stronger inhibition effect on the pathogen of dendrobium, while P. megaterium D-HT207 exhibited a stronger inhibition effect on the pathogen of potato. The supernatant of P. megaterium P-NA14 showed an inhibition effect only on Staphylococcus aureus, while the sediment of P. megaterium D-HT207 showed an inhibition effect only on Escherichia coli. For metabolomic analysis, the content of L-phenylalanine in P. megaterium P-NA14 was higher than that of P. megaterium D-HT207, and several key downstream metabolites of L-phenylalanine were associated with inhibition of S. aureus including tyrosine, capsaicin, etc. Therefore, we speculated that the different antimicrobial activities between P. megaterium P-NA14 and P. megaterium D-HT207 were possibly related to the content of L-phenylalanine and its metabolites. This study preliminarily explored why the same strains isolated from different hosts exhibit different activities from the perspective of metabolomics.PMID:37002283 | DOI:10.1038/s41598-023-32337-6

Nat Commun. 2023 Mar 31;14(1):1813. doi: 10.1038/s41467-023-37539-0.ABSTRACTIon mobility (IM) adds a new dimension to liquid chromatography-mass spectrometry-based untargeted metabolomics which significantly enhances coverage, sensitivity, and resolving power for analyzing the metabolome, particularly metabolite isomers. However, the high dimensionality of IM-resolved metabolomics data presents a great challenge to data processing, restricting its widespread applications. Here, we develop a mass spectrum-oriented bottom-up assembly algorithm for IM-resolved metabolomics that utilizes mass spectra to assemble four-dimensional peaks in a reverse order of multidimensional separation. We further develop the end-to-end computational framework Met4DX for peak detection, quantification and identification of metabolites in IM-resolved metabolomics. Benchmarking and validation of Met4DX demonstrates superior performance compared to existing tools with regard to coverage, sensitivity, peak fidelity and quantification precision. Importantly, Met4DX successfully detects and differentiates co-eluted metabolite isomers with small differences in the chromatographic and IM dimensions. Together, Met4DX advances metabolite discovery in biological organisms by deciphering the complex 4D metabolomics data.PMID:37002244 | DOI:10.1038/s41467-023-37539-0

Med Clin North Am. 2023 May;107(3):517-531. doi: 10.1016/j.mcna.2023.01.003. Epub 2023 Feb 20.ABSTRACTHepatic encephalopathy (HE) is brain dysfunction secondary to liver insufficiency or portosystemic shunting. HE is a major burden on patients and caregivers, impairs quality of life and is associated with higher mortality. Overt HE is a clinical diagnosis while Covert HE, needs specialized diagnostic strategies. Mainstay of treatment of HE is nonabsorbable disaccharides such as lactulose as well as rifaximin; however, investigational therapies are discussed in this review. Better tools are needed to prognosticate which patients will go on to develop HE but microbiome and metabolomic-driven strategies are promising. Here we review methods to prevent the HE development and admissions.PMID:37001951 | DOI:10.1016/j.mcna.2023.01.003

BMJ Open. 2023 Mar 31;13(3):e067016. doi: 10.1136/bmjopen-2022-067016.ABSTRACTINTRODUCTION: The gut microbiota develops from birth and matures significantly during the first 24 months of life, playing a major role in infant health and development. The composition of the gut microbiota is influenced by several factors including mode of delivery, gestational age, feed type and treatment with antibiotics. Alterations in the pattern of gut microbiota development and composition can be associated with illness and compromised health outcomes.Infants diagnosed with 'congenital heart disease' (CHD) often require surgery involving cardiopulmonary bypass (CPB) early in life. The impact of this type of surgery on the integrity of the gut microbiome is poorly understood. In addition, these infants are at significant risk of developing the potentially devastating intestinal condition necrotising enterocolitis.METHODS AND ANALYSIS: This study will employ a prospective cohort study methodology to investigate the gut microbiota and urine metabolome of infants with CHD undergoing surgery involving CPB. Stool and urine samples, demographic and clinical data will be collected from eligible infants based at the National Centre for Paediatric Cardiac Surgery in Ireland. Shotgun metagenome sequencing will be performed on stool samples and urine metabolomic analysis will identify metabolic biomarkers. The impact of the underlying diagnosis, surgery involving CPB, and the influence of environmental factors will be explored. Data from healthy age-matched infants from the INFANTMET study will serve as a control for this study.ETHICS AND DISSEMINATION: This study has received full ethical approval from the Clinical Research Ethics Committee of Children's Health Ireland, GEN/826/20.PMID:37001916 | DOI:10.1136/bmjopen-2022-067016

Sci Total Environ. 2023 Mar 29:163194. doi: 10.1016/j.scitotenv.2023.163194. Online ahead of print.ABSTRACT6-Benzylaminopurine (6-BA) is ubiquitous in agricultural production and is accessible to humans through diets. The modulation of lipid metabolism by 6-BA has been previously demonstrated in plants and oleaginous microorganisms. Therefore, whether it alters lipid homeostasis in other living organisms requires further investigation. In this study, doses ≥10 mg 6-BA/L caused malformation of the yolk sac, steatosis, and other hepatopathies in zebrafish larvae. Exposure to 25 mg 6-BA/L resulted in increased levels of triglyceride and total cholesterol. Results of transcriptomic analysis indicated that 6-BA alters genes associated with fatty acid and glycerophospholipid metabolism. Among them, the expression levels of hmgcra, elovl7b, and apobb.2 were downregulated, whereas those of lpcat3, bco1l, cyp7al, fabp1b.1, elp6, pde6ha, apoa4b.2_2, sgk1, dgkaa, and mogat2 were upregulated. Correspondingly, a study of the metabolome identified lysophosphatidylcholine (LPC) as the major differentially expressed metabolite in response to 6-BA treatment. Therefore, abnormal accumulation of LPCs and dyshomeostasis of glycerophospholipid metabolism were identified as potential mechanisms causing the toxicity of 6-BA, which should be assessed to understand the risks of 6-BA and the products contaminated by it. ENVIRONMENTAL IMPLICATION: 6-Benzylaminopurine (6-BA), an important residue in "toxic bean sprouts," is ubiquitous in agricultural production and is common in typical diets. Its regulation of lipid metabolism has been demonstrated in plants and oleaginous microorganisms. Whether it alters lipid homeostasis in other organisms and the underlying mechanisms remain largely unknown. The worldwide use of 6-BA and the potential exposure of humans have aroused public attention owing to its hazardous effects; thus, its hazardous effects, particularly those on lipid homeostasis, deserve careful clarification.PMID:37001669 | DOI:10.1016/j.scitotenv.2023.163194

Neurobiol Dis. 2023 Mar 29:106110. doi: 10.1016/j.nbd.2023.106110. Online ahead of print.ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. In this study, we aimed to investigate the molecular changes at both metabolic and proteomic levels during disease progression to identify the most critical metabolic pathways and underlying mechanisms involved in ALS pathophysiological changes. Utilizing liquid chromatography-mass spectrometry-based metabolomics, we analyzed the metabolites levels of plasma, lumbar spinal cord, and motor cortex from SOD1G93A mice and wildtype (WT) littermates at different stages. To elucidate the regulatory network underlying metabolic changes, we further analyzed the proteomics profile in the spinal cords of SOD1G93A and WT mice. A group of metabolites implicated in purine metabolism, methionine cycle, and glycolysis were found differentially expressed in ALS mice, and abnormal expressions of enzymes involved in these metabolic pathways were also confirmed. Notably, we first demonstrated that dysregulation of purine metabolism might contribute to the pathogenesis and disease progression of ALS. Furthermore, dysregulated fatty acid metabolism, TCA cycle, arginine and proline metabolism, and folate-mediated one‑carbon metabolism are also important events in ALS pathophysiology. The identified differential metabolites and proteins in our study could complement existing data on metabolic reprogramming in ALS, which might provide new insight into the pathological mechanisms and novel therapeutic targets of ALS.PMID:37001614 | DOI:10.1016/j.nbd.2023.106110