PubMed

Theriogenology. 2023 Apr 1;204:8-17. doi: 10.1016/j.theriogenology.2023.03.023. Online ahead of print.ABSTRACTIn ram sperm, metabolites are important components of the plasma membrane, energy metabolism cycle, and precursors for other membrane lipids, and they may have important roles in maintaining plasma membrane integrity, energy metabolism, and regulation of cryotolerance. In this study, the ejaculates from 6 Dorper rams were pooled and sperm were systematically investigated by metabolomics at various steps of cryopreservation (37 °C, fresh [F]; from 37 to 4 °C, cooling [C]; and from 4 to -196 to 37 °C, frozen-thawed [FT]) to identify differential metabolites (DM). There were 310 metabolites identified, of which 86 were considered DMs. Regarding the DMs, there were 23 (0 up and 23 down), 25 (12 up and 13 down), and 38 (7 up and 31 down) identified during cooling (C vs F), freezing (FT vs C), and cryopreservation (FT vs F), respectively. Furthermore, some key polyunsaturated fatty acids (FAs), particularly, linoleic acid (LA), docosahexaenoic acid (DHA), and arachidonic acid (AA) were down-regulated during cooling and cryopreservation. Significant DMs were enriched in several metabolic pathways including biosynthesis of unsaturated FAs, LA metabolism, mammalian target of rapamycin (mTOR), forkhead box transcription factors (FoxO), adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathways, regulation of lipolysis in adipocytes, and FA biosynthesis. This was apparently the first report to compare metabolomics profiles of ram sperm during cryopreservation and provided new knowledge to improve this process.PMID:37030173 | DOI:10.1016/j.theriogenology.2023.03.023

Microbiol Res. 2023 Apr 6;272:127382. doi: 10.1016/j.micres.2023.127382. Online ahead of print.ABSTRACTIndoleamine 2,3-dioxygenase (Ido) is a tryptophan-degrading enzyme that is widely distributed across species. Ido catalyzes the first step of tryptophan (TRP) degradation and drives the de novo synthesis of nicotinamide adenine dinucleotide (NAD+) coenzymes via the kynurenine (KYN) pathway. The budding yeast Saccharomyces cerevisiae possesses a single IDO gene (BNA2) that is responsible for NAD+ synthesis, whereas a number of fungal species contain multiple IDO genes. However, the biological roles of IDO paralogs in plant pathogens remain unclear. In the current study, we identified three FgIDOs from the wheat head blight fungus Fusarium graminearum. FgIDOA/B/C expression was significantly induced upon TRP treatment. Targeted disruption of FgIDOA and/or FgIDOB caused different levels of NAD+ auxotrophy, thus resulting in pleotropic phenotypic defects. Loss of FgIDOA resulted in abnormal conidial morphology, reduced mycelial growth, decreased virulence in wheat heads and reduced deoxynivalenol accumulation. Exogenous addition of KYN or various intermediates involved in the KYN pathway rescued auxotrophy of the mutants. Metabolomics analysis revealed shifts toward alternative TRP degradation pathways to melatonin and indole derivatives in mutants lacking FgIDOB. Upregulation of partner genes in auxotrophic mutants and the capacity to rescue the auxotroph by overexpressing a partner gene indicated functional complementation among FgIDOA/B/C. Taken together, the results of this study provide insights into differential roles in paralogous FgIDOs and how fungal TRP catabolism modulates fungal development and virulence.PMID:37030080 | DOI:10.1016/j.micres.2023.127382

Ecotoxicol Environ Saf. 2023 Apr 6;256:114871. doi: 10.1016/j.ecoenv.2023.114871. Online ahead of print.ABSTRACTMicroplastics (MPs) pose one of the major environmental threats to marine organisms and ecosystems on a global scale. Although many marine crustaceans are highly susceptible to MPs pollution, the toxicological effects and mechanisms of MPs on crustaceans are poorly understood. The current study focused on the impacts of MPs accumulation in shrimp Litopenaeus vannamei at the behavioral, histological and biochemical levels. The results demonstrated the accumulation of polystyrene MPs in various organs of L. vannamei, with highest MPs abundance in the hepatopancreas. The MPs accumulated in shrimp caused growth inhibition, abnormal swimming behavior and reduced swimming performance of L. vannamei. Following MPs exposure, oxidative stress and lipid peroxidation were also observed, which were strongly linked to attenuated swimming activity of L. vannamei. The above MPs-induced disruption in balance of antioxidant system triggered the hepatopancreatic damage in L. vannamei, which was exacerbated with increasing MPs concentrations (from 0.02 to 1 mg L-1). Furthermore, metabolomics revealed that MPs exposure resulted in alterations of metabolic profiles and disturbed glycolysis, lipolysis and amino acid metabolism pathways in hepatopancreas of L. vannamei. This work confirms and expands the knowledge on the sublethal impacts and toxic modes of action of MPs in L. vannamei.PMID:37030048 | DOI:10.1016/j.ecoenv.2023.114871

J Pharm Biomed Anal. 2023 Mar 29;229:115375. doi: 10.1016/j.jpba.2023.115375. Online ahead of print.ABSTRACTTetrastigma hemsleyanum Diels et Gilg (TH) is one of the new eight Genuine Medicinal Materials of Zhejiang. It has extensive biological activities, such as anti-inflammatory, anti-tumor and analgesic activities, etc. In this study, the chemical components of TH were systematically investigated by ultra high-performance liquid chromatography-tandem quadrupole time of flight mass spectrometry (UPLC/Q-TOF-MS). Based on the MS spectrum, 39 compounds in TH extracts including 14 flavonoids, 10 fatty acids, 5 polyphenols and phenolic acids, 4 terpenes and other compounds were detected and tentatively identified. TH samples were treated under different drying methods (vacuum freeze drying, hot air drying, natural drying, light drying and vacuum drying). Besides, the effect of different drying methods on the content of 10 main chemical constituents in TH extracts including catechin, rutin, kaempferol-3-O-rutinoside and so on was also investigated by targeting metabolomics method with ultra high-performance liquid chromatography-tandem triple quadrupole mass spectrometry (UPLC-MS/MS) assisted by multivariate statistical analysis. Large differences were observed between vacuum drying and vacuum freeze drying with remarkable content changes. The contents of rutin, proanthocyanidin B1 and catechin were the most different among the various drying methods. The systematic identification of chemical constituents is helpful for the further medicinal development and application of TH. The effects of drying methods on the content of TH components were studied, which provided experimental data for the processing, storage and quality control of TH.PMID:37030030 | DOI:10.1016/j.jpba.2023.115375

Transfusion. 2023 Apr 8. doi: 10.1111/trf.17345. Online ahead of print.ABSTRACTBACKGROUND: The risk of military and civilian radiation exposure is increasing, and determining the effects of exposure is a high priority. Irradiation of the nearby blood supply after a nuclear event may impede mobilization of blood products for resuscitation at a time of great need. RBCs are administered to patients with trauma and hemorrhage to transport and deliver oxygen and avoid tissue hypoxia. Here we determine the effects of ionizing radiation on the energy metabolome of RBCs isolated from cold stored whole blood to determine if their stability is compromised by radiation exposure.STUDY DESIGN AND METHODS: Whole blood from healthy volunteers was subjected to 0, 25, or 75 Gy of X-irradiation, and stored at 4°C. RBCs were isolated from stored WB at 0, 1, 7, 14, and 21 days of storage. The levels of extracted Krebs cycle intermediates, nicotinamide adenine dinucleotides, and phosphorylated derivatives of adenosine and guanosine were determined by tandem mass spectroscopy.RESULTS: Irradiation at either 25Gy or 75Gy had no significant effect on any parameter measured compared to control (0Gy). However, there was a significant change over time in storage for ATP, GDP, and guanosine.DISCUSSION: Irradiation at doses up to 75Gy had no effect on the energy metabolome of RBCs prepared from blood stored at 4°C for up to 21 days, suggesting that the RBC energy metabolome is not affected by radiation exposure and the blood can still be used for resuscitation in trauma patients.PMID:37029665 | DOI:10.1111/trf.17345

J Vis Exp. 2023 Apr 7;(194). doi: 10.3791/65071.ABSTRACTHyperlipidemia has become a leading risk factor for cardiovascular diseases and liver injury worldwide. Fructus Phyllanthi (FP) is an effective drug against hyperlipidemia in Traditional Chinese Medicine (TCM) and Indian Medicine theories, however the potential mechanism requires further exploration. The present research aims to reveal the mechanism of FP against hyperlipidemia based on an integrated strategy combining network pharmacology prediction with metabolomics validation. A high-fat diet (HFD)-induced mice model was established by evaluating the plasma lipid levels, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Network pharmacology was applied to find out the active ingredients of FP and potential targets against hyperlipidemia. Metabolomics of plasma and liver were performed to identify differential metabolites and their corresponding pathways among the normal group, model group, and intervention group. The relationship between network pharmacology and metabolomics was further constructed to obtain a comprehensive view of the process of FP against hyperlipidemia. The obtained key target proteins were verified by molecular docking. These results reflected that FP improved the plasma lipid levels and liver injury of hyperlipidemia induced by a HFD. Gallic acid, quercetin, and beta-sitosterol in FP were demonstrated as the key active compounds. A total of 16 and six potential differential metabolites in plasma and liver, respectively, were found to be involved in the therapeutic effects of FP against hyperlipidemia by metabolomics. Further, integration analysis indicated that the intervention effects were associated with CYP1A1, AChE, and MGAM, as well as the adjustment of L-kynurenine, corticosterone, acetylcholine, and raffinose, mainly involving tryptophan metabolism pathway. Molecular docking ensured that the above ingredients acting on hyperlipidemia-related protein targets played a key role in lowering lipids. In summary, this research provided a new possibility for preventing and treating hyperlipidemia.PMID:37092814 | DOI:10.3791/65071

Cardiovasc Diabetol. 2023 Apr 7;22(1):82. doi: 10.1186/s12933-023-01815-6.ABSTRACTBACKGROUND: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern.METHODS: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events.RESULTS: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91).CONCLUSIONS: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.PMID:37029406 | DOI:10.1186/s12933-023-01815-6

World J Microbiol Biotechnol. 2023 Apr 8;39(6):151. doi: 10.1007/s11274-023-03603-6.ABSTRACTPesticide pollution in recent times has emerged as a grave environmental problem contaminating both aquatic and terrestrial ecosystems owing to their widespread use. Bioremediation using gene editing and system biology could be developed as an eco-friendly and proficient tool to remediate pesticide-contaminated sites due to its advantages and greater public acceptance over the physical and chemical methods. However, it is indispensable to understand the different aspects associated with microbial metabolism and their physiology for efficient pesticide remediation. Therefore, this review paper analyses the different gene editing tools and multi-omics methods in microbes to produce relevant evidence regarding genes, proteins and metabolites associated with pesticide remediation and the approaches to contend against pesticide-induced stress. We systematically discussed and analyzed the recent reports (2015-2022) on multi-omics methods for pesticide degradation to elucidate the mechanisms and the recent advances associated with the behaviour of microbes under diverse environmental conditions. This study envisages that CRISPR-Cas, ZFN and TALEN as gene editing tools utilizing Pseudomonas, Escherichia coli and Achromobacter sp. can be employed for remediation of chlorpyrifos, parathion-methyl, carbaryl, triphenyltin and triazophos by creating gRNA for expressing specific genes for the bioremediation. Similarly, systems biology accompanying multi-omics tactics revealed that microbial strains from Paenibacillus, Pseudomonas putida, Burkholderia cenocepacia, Rhodococcus sp. and Pencillium oxalicum are capable of degrading deltamethrin, p-nitrophenol, chlorimuron-ethyl and nicosulfuron. This review lends notable insights into the research gaps and provides potential solutions for pesticide remediation by using different microbe-assisted technologies. The inferences drawn from the current study will help researchers, ecologists, and decision-makers gain comprehensive knowledge of value and application of systems biology and gene editing in bioremediation assessments.PMID:37029313 | DOI:10.1007/s11274-023-03603-6

Oncogene. 2023 Apr 7. doi: 10.1038/s41388-023-02688-5. Online ahead of print.ABSTRACTRecurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but preclinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin -dependent SREBP2 expression.PMID:37029299 | DOI:10.1038/s41388-023-02688-5

Sci Rep. 2023 Apr 7;13(1):5747. doi: 10.1038/s41598-023-32797-w.ABSTRACTThis study aimed to investigate the metabolite profile and inflammatory state of follicular fluid (FF) in women with stage III-IV ovarian endometriosis (OE) who underwent in vitro fertilization (IVF). A cohort of 20 consecutive patients with OE were recruited and received progestin-primed ovary stimulation (PPOS) protocol (study group), while another 20 OE patients received one-month ultra-long term protocol (control group) for IVF in this prospective, nonrandomized study. FF samples were obtained from dominant follicles during oocyte retrieval, and liquid chromatography-mass spectrometry (LC-MS) was used to investigate the metabolites profile of FF. Results showed that significant increases in the levels of proline, arginine, threonine, and glycine in patients who received PPOS protocol compared to the control group (P < 0.05). A panel of three metabolites (proline, arginine, and threonine) was identified as specific biomarkers of OE patients using PPOS protocol. Additionally, levels of interleukin-1β, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor-α markedly decreased in women who received PPOS protocol compared to the control group (P < 0.05). In conclusion, PPOS protocol regulates the metabolism of several amino acids in the FF, which may play critical roles in the oocyte development and blastocyst formation, and their specific mechanism should be further elucidated.PMID:37029234 | DOI:10.1038/s41598-023-32797-w

Commun Biol. 2023 Apr 7;6(1):374. doi: 10.1038/s42003-023-04730-4.ABSTRACTCellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose metabolism, resulting in enhanced generation of SARS-CoV-2- specific CD8+Tc, increased cytokine secretion, and augmented memory cell proliferation. Taken together, our study provides critical insight regarding the cellular mechanisms underlying the effect of SARS-CoV-2 infection on host immune cell metabolism, and highlights immunometabolism as a promising therapeutic target for COVID-19 treatment.PMID:37029220 | DOI:10.1038/s42003-023-04730-4

Int J Obes (Lond). 2023 Apr 7. doi: 10.1038/s41366-023-01295-4. Online ahead of print.ABSTRACTBACKGROUND/OBJECTIVES: Obesity in pregnancy associates with changes in the glucose-insulin axis. We hypothesized that these changes affect the maternal metabolome already in the first trimester of human pregnancy and, thus, aimed to identify these metabolites.PATIENTS/METHODS: We performed untargeted metabolomics (HPLC-MS/MS) on maternal serum (n = 181, gestational weeks 4+0-11+6). For further analysis, we included only non-smoking women as assessed by serum cotinine levels (ELISA) (n = 111). In addition to body mass index (BMI) and leptin as measures of obesity and adiposity, we metabolically phenotyped women by their fasting glucose, C-peptide and insulin sensitivity (ISHOMA index). To identify metabolites (outcome) associated with BMI, leptin, glucose, C-peptide and/or ISHOMA (exposures), we used a combination of univariable and multivariable regression analyses with multiple confounders and machine learning methods (Partial Least Squares Discriminant Analysis, Random Forest and Support Vector Machine). Additional statistical tests confirmed robustness of results. Furthermore, we performed network analyses (MoDentify package) to identify sets of correlating metabolites that are coordinately regulated by the exposures.RESULTS: We detected 2449 serum features of which 277 were annotated. After stringent analysis, 15 metabolites associated with at least one exposure (BMI, leptin, glucose, C-peptide, ISHOMA). Among these, palmitoleoyl ethanolamine (POEA), an endocannabinoid-like lipid endogenously synthesized from palmitoleic acid, and N-acetyl-L-alanine were consistently associated with C-peptide in all the analyses (95% CI: 0.10-0.34; effect size: 21%; p < 0.001; 95% CI: 0.04-0.10; effect size: 7%; p < 0.001). In network analysis, most features correlating with palmitoleoyl ethanolamide and N-acetyl-L-alanine and associated with C-peptide, were amino acids or dipeptides (n = 9, 35%), followed by lipids (n = 7, 27%).CONCLUSIONS: We conclude that the metabolome of pregnant women with overweight/obesity is already altered early in pregnancy because of associated changes of C-peptide. Changes of palmitoleoyl ethanolamide concentration in pregnant women with obesity-associated hyperinsulinemia may reflect dysfunctional endocannabinoid-like signalling.PMID:37029207 | DOI:10.1038/s41366-023-01295-4

NPJ Syst Biol Appl. 2023 Apr 7;9(1):11. doi: 10.1038/s41540-023-00274-9.ABSTRACTSaccharomyces cerevisiae is a very well studied organism, yet ∼20% of its proteins remain poorly characterized. Moreover, recent studies seem to indicate that the pace of functional discovery is slow. Previous work has implied that the most probable path forward is via not only automation but fully autonomous systems in which active learning is applied to guide high-throughput experimentation. Development of tools and methods for these types of systems is of paramount importance. In this study we use constrained dynamical flux balance analysis (dFBA) to select ten regulatory deletant strains that are likely to have previously unexplored connections to the diauxic shift. We then analyzed these deletant strains using untargeted metabolomics, generating profiles which were then subsequently investigated to better understand the consequences of the gene deletions in the metabolic reconfiguration of the diauxic shift. We show that metabolic profiles can be utilised to not only gaining insight into cellular transformations such as the diauxic shift, but also on regulatory roles and biological consequences of regulatory gene deletion. We also conclude that untargeted metabolomics is a useful tool for guidance in high-throughput model improvement, and is a fast, sensitive and informative approach appropriate for future large-scale functional analyses of genes. Moreover, it is well-suited for automated approaches due to relative simplicity of processing and the potential to make massively high-throughput.PMID:37029131 | DOI:10.1038/s41540-023-00274-9

J Dairy Sci. 2023 Apr 5:S0022-0302(23)00164-9. doi: 10.3168/jds.2022-22812. Online ahead of print.ABSTRACTSubclinical hyperketonemia (SCHK) is the major metabolic disease observed during the transition period in dairy goats, and is characterized by high plasma levels of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB). However, no prior study has comprehensively assessed metabolomic profiles of dairy goats with SCHK. Plasma samples were collected within 1 h after kidding from SCHK goats (BHB concentration >0.8 mM, n = 7) and clinically healthy goats (BHB concentration <0.8 mM, n = 7) with similar body condition score (2.75 ± 0.15, mean ± standard error of the mean) and parity (primiparous). A combination of targeted and untargeted mass spectrometric approaches was employed for analyzing the various changes in the plasma lipidome and metabolome. Statistical analyses were performed using the GraphPad Prism 8.0, SIMCA-P software (version 14.1), and R packages (version 4.1.3). Plasma aminotransferase, nonesterified fatty acids, and BHB concentrations were greater in the SCHK group, but plasma glucose concentrations were lower. A total of 156 metabolites and 466 lipids were identified. The analysis of untargeted metabolomics data by principal component analysis and orthogonal partial least squares discriminant analysis revealed a separation between SCHK and clinically healthy goats. According to the screening criteria (unpaired t-test, P < 0.05), 30 differentially altered metabolites and 115 differentially altered lipids were detected. Pathway enrichment analysis identified citrate cycle, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine metabolism as significantly altered pathways. A greater concentration of plasma isocitric acid and cis-aconitic acid levels was observed in SCHK goats. In addition, AA such as lysine and isoleucine were greater, whereas alanine and phenylacetylglycine were lower in SCHK dairy goats. Dairy goats with SCHK also exhibited greater oleic acid, acylcarnitine, and phosphatidylcholine and lower choline and sphingomyelins. Acylcarnitines, oleic acid, and tridecanoic acid displayed positive correlations with several lipid species. Alanine, hippuric acid, and histidinyl-phenylalanine were negatively correlated with several lipids. Overall, altered metabolites in SCHK dairy goats indicated a more severe degree of negative energy balance. Data also indicated an imbalance in the tricarboxylic acid (TCA) cycle, lipid metabolism, and AA metabolism. The findings provide a more comprehensive understanding of the pathogenesis of SCHK in dairy goats.PMID:37028962 | DOI:10.3168/jds.2022-22812

J Ethnopharmacol. 2023 Apr 5:116392. doi: 10.1016/j.jep.2023.116392. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis Franch. (CCF), as an extensively used traditional Chinese medicine, has therapeutic effects on Alzheimer's disease (AD), but its mechanism of action has not yet been elucidated.AIM OF THE STUDY: This study aims to reveal the mechanism of action of CCF via the gut-brain axis, and provide a new strategy for the clinical treatment of AD.MATERIALS AND METHODS: APPswe/PS1ΔE9 mice were used as AD models, and were given CCF extract by intragastric administration. Barnes maze was used to test the therapeutic effect of CCF on the treatment of AD. To reveal the mechanism of action of CCF in the treatment of AD, Vanquish Flex UHPLC-orbitrap fusion lumos mass was chosen to detect endogenous differential metabolite; MetaboAnalyst 5.0 was applied to derive relevant metabolic pathways; similarly, to explore the effects of CCF on the gut-brain axis, Vanquish Flex UPLC-Orbitrap fusion lumos mass was utilized to detect the changes in the content of SCFAs in AD mice after CCF administration; the prototype components and metabolites in CCF were identified by UPLC/ESI/qTOF-MS, then their effects on Bifidobacterium breve were explored.RESULTS: CCF shortened the latency time of AD mice, improved the target quadrant ratio of AD mice, and made the maze roadmap simpler of AD mice; CCF regulated fifteen potential metabolites of AD mice, interestingly, ILA (indole-3-lactic acid) in SCFAs (short-chain fatty acids) was also included; CCF acted on histidine and phenylalanine metabolic pathways of AD mice; CCF increased the contents of acetic acid and ILA in AD mice; magnoflorine, jatrorrhizine, coptisine, groenlandicine, thalifendine, palmatine, berberine, epiberberine, hydroxylated jatrorrhizine, and 3-methoxydemethyleneberberine in CCF were detected in fecal samples of AD mice; magnoflorine, palmatrubine, 13-methylberberine, berberine, coptisine, and palmatine promoted the growth of Bifidobacterium breve.CONCLUSIONS: we have demonstrated that CCF acts on the gut-brain axis by regulating SCFAs to treat AD.PMID:37028611 | DOI:10.1016/j.jep.2023.116392

Food Chem. 2023 Mar 31;419:136043. doi: 10.1016/j.foodchem.2023.136043. Online ahead of print.ABSTRACTScutellaria baicalensis is a functional food that has the potential to treat various diseases. Scutellaria baicalensis can be divided into two types: Ziqin (strip types) and (rotten xylem). Ziqin is used to clear lower energizer large intestine heat syndrome, while Kuqin is used for the treatment of upper energizer lung heat syndrome. At present, the substance basis of the differences between Ziqin and Kuqin is not clear. The changes in metabolite accumulation and protein expression between them were analyzed by the non-targeted metabolomic technique in combination with the label-free proteomics approach. The results showed that the differentially accumulated metabolites and abundant proteins were mainly enriched in the pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylpropanoid biosynthesis, flavonoid biosynthesis, flavone and flavonol biosynthesis, isoflavonoid biosynthesis, and anthocyanin biosynthesis. Collectively, these results reveal the changes of Scutellaria baicalensis in different growth years and provide a reference for selecting the appropriate harvest period.PMID:37027979 | DOI:10.1016/j.foodchem.2023.136043

Food Chem. 2023 Mar 29;419:136035. doi: 10.1016/j.foodchem.2023.136035. Online ahead of print.ABSTRACTLepidium latifolium L. is an established phytofood of the Ladakh Himalayas that contains differential content of important glucosinolates (GLS) in specific stages of sprouts. Therefore, in order to harness its nutraceutical potential, a comprehensive mass spectrometry-based stage-specific untargeted metabolomic analysis was performed. A total of 318 metabolites were detected, out of which 229 were significantly (p ≤ 0.05) changed during different stages. The Principal Component Analysis plot clearly differentiated different growth stages into three clusters. The nutritionally important metabolites, including amino acids, sugars, organic acids, and fatty acids, were found significantly (p ≤ 0.05) higher in the first cluster consisting of 1st, 2nd and 3rd week sprouts. The higher energy requirements during the early growth stages were observed with the higher metabolites of glycolysis and the TCA cycle. Further, the trade-off between primary and secondary sulfur-containing metabolites was observed, which may explain the differential GLS content in different growth stages.PMID:37027970 | DOI:10.1016/j.foodchem.2023.136035

EBioMedicine. 2023 Apr 5;91:104533. doi: 10.1016/j.ebiom.2023.104533. Online ahead of print.ABSTRACTBACKGROUND: Probiotics have been increasingly proposed for enhancing immune checkpoint blockade (ICB) treatments against cancer. However, its causal relationship with immunotherapeutic efficacy remains unclear, which promoted us to explore if and how probiotic Lacticaseibacillus rhamnosus Probio-M9 manipulates gut microbiome for expected outcomes.METHODS: We evaluated the effects of Probio-M9 on the anti-PD-1 treatment against colorectal cancer in mice via a multi-omics approach. We defined the mechanisms of Probio-M9-mediated antitumor immunity by comprehensive analyses of metagenome and metabolites of commensal gut microbes as well as the immunologic factors and serum metabolome of the host.FINDINGS: The results indicated that Probio-M9 intervention strengthened the anti-PD-1-based tumor inhibition. Both prophylactic and therapeutic administration of Probio-M9 showed conspicuous performance in controlling tumor growth with ICB treatment. The supplement of Probio-M9 modulated enhanced immunotherapy response through promoting beneficial microbes (e.g., Lactobacillus and Bifidobacterium animalis), producing beneficial metabolites including butyric acids in the gut, and accumulating blood-derived α-ketoglutaric acid, N-acetyl-l-glutamic acid and pyridoxine in particular, which promoted the infiltration and activation of cytotoxic T lymphocytes (CTLs) and suppressing the function of regulatory T cells (Tregs) in the tumor microenvironment (TME). Subsequently, we found that enhanced immunotherapeutic response was transmissible by transplanting either post-probiotic-treatment gut microbes or intestinal metabolites to new tumor-bearing mice.INTERPRETATION: This study offered valuable insight into the causal role of Probio-M9 in correcting the defects in gut microbiota that compromised anti-PD-1 therapeutic efficacy, which can be used as an alternative synergetic agent with ICB for clinical cancer treatment.FUNDING: This research was supported by Research Fund for the National Key R&D Program of China (2022YFD2100702), Inner Mongolia Science and Technology Major Projects (2021ZD0014), and China Agriculture Research System of MOF and MARA.PMID:37027929 | DOI:10.1016/j.ebiom.2023.104533

J Hazard Mater. 2023 Apr 3;452:131358. doi: 10.1016/j.jhazmat.2023.131358. Online ahead of print.ABSTRACTHuman activities have led to elevated levels of selenium (Se) in the environment, which poses a threat to ecosystems and human health. Stenotrophomonas sp. EGS12 (EGS12) has been identified as a potential candidate for the bioremediation of repair selenium-contaminated environment because of its ability to efficiently reduce Se(IV) to form selenium nanospheres (SeNPs). To better understand the molecular mechanism of EGS12 in response to Se(IV) stress, a combination of transmission electron microscopy (TEM), genome sequencing techniques, metabolomics and transcriptomics were employed. The results indicated that under 2 mM Se(IV) stress, 132 differential metabolites (DEMs) were identified, and they were significantly enriched in metabolic pathways such as glutathione metabolism and amino acid metabolism. Under the Se(IV) stress of 2 mM, 662 differential genes (DEGs) involved in heavy metal transport, stress response, and toxin synthesis were identified in EGS12. These findings suggest that EGS12 may respond to Se(IV) stress by engaging various mechanisms such as forming biofilms, repairing damaged cell walls/cell membranes, reducing Se(IV) translocation into cells, increasing Se(IV) efflux, multiplying Se(IV) reduction pathways and expelling SeNPs through cell lysis and vesicular transport. The study also discusses the potential of EGS12 to repair Se contamination alone and co-repair with Se-tolerant plants (e.g. Cardamine enshiensis). Our work provides new insights into microbial tolerance to heavy metals and offers valuable information for bio-remediation techniques on Se(IV) contamination.PMID:37027916 | DOI:10.1016/j.jhazmat.2023.131358

Sci Adv. 2023 Apr 7;9(14):eadd4791. doi: 10.1126/sciadv.add4791. Epub 2023 Apr 7.ABSTRACTCells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase FERONIA (FER), which is a proposed cell wall sensor, modulates phosphatidylserine plasma membrane accumulation and nano-organization, a key regulator of Rho GTPase signaling in Arabidopsis. We demonstrate that FER is required for both Rho-of-Plant 6 (ROP6) nano-partitioning at the membrane and downstream production of reactive oxygen species upon hyperosmotic stimulus. Genetic and pharmacological rescue experiments indicate that phosphatidylserine is required for a subset of, but not all, FER functions. Furthermore, application of FER ligand shows that its signaling controls both phosphatidylserine membrane localization and nanodomains formation, which, in turn, tunes ROP6 signaling. Together, we propose that a cell wall-sensing pathway controls via the regulation of membrane phospholipid content, the nano-organization of the plasma membrane, which is an essential cell acclimation to environmental perturbations.PMID:37027473 | DOI:10.1126/sciadv.add4791