PubMed

Anal Bioanal Chem. 2023 Feb 18. doi: 10.1007/s00216-023-04572-3. Online ahead of print.NO ABSTRACTPMID:36808274 | DOI:10.1007/s00216-023-04572-3

Thorax. 2023 Feb 20:thorax-2022-219557. doi: 10.1136/thorax-2022-219557. Online ahead of print.ABSTRACTBACKGROUND: Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses.METHODS: Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome.RESULTS: Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter.CONCLUSIONS: Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.PMID:36808087 | DOI:10.1136/thorax-2022-219557

AMB Express. 2023 Feb 20;13(1):20. doi: 10.1186/s13568-023-01523-0.ABSTRACTThe prevalence of antibiotic resistance in Pseudomonas aeruginosa places a heavy burden on the health care sectors urging the need to find alternative, non-antibiotic strategies. The interference with the P. aeruginosa quorum sensing (QS) system represents a promising alternative strategy to attenuate the bacterial virulency and its ability to form biofilms. Micafungin has been reported to impede the pseudomonal biofilm formation. However, the influences of micafungin on the biochemical composition and metabolites levels of P. aeruginosa have not been explored. In this study, the effect of micafungin (100 µg/mL) on the virulence factors, QS signal molecules and the metabolome of P. aeruginosa was studied using exofactor assay and mass spectrometry-based metabolomics approaches. Furthermore, confocal laser scanning microscopy (CLSM) using the fluorescent dyes ConA-FITC and SYPRO® Ruby was used to visualize micafungin disturbing effects on the pseudomonal glycocalyx and protein biofilm-constituents, respectively. Our findings showed that micafungin significantly decreased the production of various QS-controlled virulence factors (pyocyanin, pyoverdine, pyochelin and rhamnolipid), along with a dysregulation in the level of various metabolites involved in QS system, lysine degradation, tryptophan biosynthesis, TCA cycle, and biotin metabolism. In addition, the CLSM examination showed an altered matrix distribution. The presented findings highlight the promising role of micafungin as a potential quorum sensing inhibitor (QSI) and anti-biofilm agent to attenuate P. aeruginosa pathogenicity. In addition, they point to the promising role of metabolomics study in investigating the altered biochemical pathways in P. aeruginosa.PMID:36807839 | DOI:10.1186/s13568-023-01523-0

J Integr Plant Biol. 2023 Feb 21. doi: 10.1111/jipb.13469. Online ahead of print.ABSTRACTPlants accumulate a vast array of secondary metabolites, which constitute a natural resource for pharmaceuticals. Oldenlandia corymbosa belongs to the Rubiaceae family, and has been used in traditional medicine to treat different diseases, including cancer. However, the active metabolites of the plant, their biosynthetic pathway and mode of action in cancer are unknown. To fill these gaps, we exposed this plant to eight different stress conditions and combined different omics data capturing gene expression, metabolic profiles and anti-cancer activity. Our results show that O. corymbosa extracts are active against breast cancer cell lines and that ursolic acid is responsible for this activity. Moreover, we assembled a high-quality genome and uncovered two genes involved in the biosynthesis of ursolic acid. Finally, we also revealed that ursolic acid causes mitotic catastrophe in cancer cells and identified three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking. Altogether, these results constitute a valuable resource to further characterize the biosynthesis of active metabolites in the Oldenlandia group, while the mode of action of ursolic acid will allow us to further develop this valuable compound. This article is protected by copyright. All rights reserved.PMID:36807520 | DOI:10.1111/jipb.13469

Chemosphere. 2023 Feb 18:138173. doi: 10.1016/j.chemosphere.2023.138173. Online ahead of print.ABSTRACTTo alleviate the arsenic (As) toxicity in aromatic rice, a hydroponic experiment of two As concentrations (0 and 100 μM sodium arsenite: A0, A1), three glutamic acid (Glu) concentrations (0, 100, and 500 μM l-glutamic acid: G0, G1, and G2) with Xiangyaxiangzhan and Meixiangzhan 2 was conducted. Results showed that the root As content were increased under A1G2 but reduced under A1G1 for Xiangyaxiangzhan as compared with A1G0. A decrement of As was transported from root to shoot caused by up-regulated OsABCC1 relative expression in Meixiangzhan 2. Likewise, As stress enhanced the H2O2 and malondialdehyde content, resulting in the impaired cell wall observed by transmission electron microscopy. However, compared with A1G0, the superoxide dismutase activity, ascorbic acid, glutathione, proline, and soluble sugar content were increased under A1G1. Additionally, arsenate reductase, monodehydroascorbate reductase activity, Glu, proline, and soluble sugar content were found positively associated with the As accumulation. Further, the metabolome analysis indicated that the pathway of amino acid and arginine biosynthesis were notably enriched after Glu application. Generally, 100 μM Glu application was the better treatment to enhance As tolerance in aromatic rice through up-regulating amino acid biosynthesis with increasing antioxidants and osmolytes to scavenge excessive reactive oxygen species.PMID:36806810 | DOI:10.1016/j.chemosphere.2023.138173

J Lipid Res. 2023 Feb 18:100349. doi: 10.1016/j.jlr.2023.100349. Online ahead of print.ABSTRACTWe previously demonstrated that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7, the gene encoding Membrane Bound O-Acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated floxed Mboat7 mice and created hepatocyte- and adipocyte-specific knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. After chow and high fat diet feeding (60% kCal fat), mice were subjected to metabolic phenotyping and tissues to molecular workup and analysis. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.PMID:36806709 | DOI:10.1016/j.jlr.2023.100349

Plant Sci. 2023 Feb 17:111644. doi: 10.1016/j.plantsci.2023.111644. Online ahead of print.ABSTRACTAdenylosuccinate synthetase (AdSS, EC.6.3.4.4) is a key enzyme in the de novo synthesis of purine nucleotides in organisms. Its downstream product AMP plays a critical role in the process of energy metabolism, which can affect the content of ADP and ATP. However, impacts of its loss-of-function on plant metabolism and development has been relatively poorly reported. Here, we report the identification and analysis of a maize yu18 mutant obtained by mutagenesis with ethylmethane sulfonate (EMS). The yu18 is a lethal-seed mutant. Map-based cloning and allelic testing confirmed that yu18 encodes adenylosuccinate synthetase and was named ZmAdSS1. ZmAdSS1 is constitutively expressed. In the yu18 mutant, the activity of the ZmAdSS1 enzyme was decreased, which caused AMP content reduced 33.62%. The yu18 mutation significantly suppressed endoreduplication and disrupted nutrient accumulation, resulting in lower starch and protein contents that are responsible for seed filling. Further transcriptome and metabolome analysis revealed dramatic alterations in the carbohydrate metabolic pathway and amino acid metabolic pathway in yu18 kernels. Our findings demonstrate that ZmAdSS1 participates in the synthesis of AMP and affects endosperm development and nutrient accumulation in maize seeds.PMID:36806609 | DOI:10.1016/j.plantsci.2023.111644

Cell Mol Gastroenterol Hepatol. 2023 Feb 16:S2352-345X(23)00023-1. doi: 10.1016/j.jcmgh.2023.02.004. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Metabolic reprogramming is recognized as a cancer hallmark intimately linked to tumor hypoxia, which supports rapid tumor growth and mitigates the consequential oxidative stress. Phosphofructokinase-fructose bisphosphatase (PFKFB) is a family of bidirectional glycolytic enzymes possessing both kinase and phosphatase functions and has emerged as important oncogenes in multiple types of cancer. However, its clinical relevance, functional significance, and underlying mechanistic insights in hepatocellular carcinoma (HCC), the primary malignancy that develops in the most important metabolic organ, has never been addressed.METHODS: PFKFB4 expression was examined by RNA sequencing in TCGA and our in-house HCC cohort. The upregulation of PFKFB4 expression was further confirmed by qPCR in an expanded HBV-associated HCC cohort followed by clinicopathological correlation analysis. CRISPR/Cas9-mediated PFKFB4 knockout cells were generated for functional characterization in vivo, targeted metabolomic profiling as well as RNA-seq analysis to comprehensively examine the impact of PFKFB4 loss in HCC.RESULTS: PFKFB4 expression was significantly upregulated in HCC and positively correlated with TP53 and TSC2 loss-of-function mutations. In silico transcriptome-based analysis further revealed PFKFB4 functions as a critical hypoxia-inducible gene. Clinically, PFKFB4 upregulation was associated with more aggressive tumor behavior. Functionally, CRISPR/Cas9-mediated PFKFB4 knockout significantly impaired in vivo HCC development. Targeted-metabolomic profiling revealed that PFKFB4 functions as a phosphatase in HCC and its ablation caused an accumulation of metabolites in downstream glycolysis and the pentose phosphate pathway. Besides, PFKFB4 loss induced hypoxia-responsive genes in glycolysis and reactive oxygen species detoxification. Conversely, ectopic PFKFB4 expression conferred Sorafenib resistance.CONCLUSIONS: PFKFB4 upregulation supported HCC development and posed therapeutic implications.PMID:36806581 | DOI:10.1016/j.jcmgh.2023.02.004

J Ethnopharmacol. 2023 Feb 17:116270. doi: 10.1016/j.jep.2023.116270. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Qizhi capsule (QZC), a Chinese patent drug, has been utilized to treat hyperlipidemia.AIM OF STUDY: The present study aims to investigate the lipid-lowering effect of QZC, as well as the mechanism of action for treating hyperlipidemia.MATERIALS AND METHODS: High-fat diet (HFD) induced hyperlipidemia rats were administrated with different doses of QZC for 28 days, and atorvastatin calcium tablets was used as the positive control. Serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were used to evaluate the effectiveness of QZC treatment. The metabolic profiles of feces were analyzed by UPLC-MS-based metabolomics approach coupled with multivariate data analysis.RESULTS: The levels of serum TC, TG, LDL-C, and HDL-C were significantly reversed in QZC treatment groups, showing a similar or even better treatment effect compared with the atorvastatin calcium group. Thirty-two potential fecal biomarkers related to hyperlipidemia were identified. QZC could partially recover the disturbed metabolic pathways of alpha-linolenic acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Meanwhile, the signal pathways of regulation of lipid metabolism by peroxisome proliferator-activated receptor α (PPARα), PPARα activates gene expression, and transcriptional regulation of white adipocyte differentiation can be also regulated by QZC.CONCLUSION: The lipid-lowering effect of QZC was confirmed by both serum biochemistry and metabolomics analysis. The beneficial effects of QZC were mainly attributed to the correction of metabolic disorders and the maintenance of the dynamic balance of metabolites.PMID:36806341 | DOI:10.1016/j.jep.2023.116270

Probiotics Antimicrob Proteins. 2023 Feb 20. doi: 10.1007/s12602-023-10049-7. Online ahead of print.ABSTRACTThe use of Bacillus circulans as the sole starter provides better process control compared to natural fermentation. However, the chemical composition of fermented Tibetan tea by B. circulans and its regulatory effects on the intestine-liver axis has not been reported. For this purpose, a high-resolution liquid chromatography tandem mass spectrometry metabolomics approach was performed. The effects of fermented Tibetan tea on the intestine-liver axis of mice were also evaluated. Untargeted metabolomics analysis showed that the contents of catechin derivatives, flavonoids, phenolic acids, and terpenoids increased by 0.3, 2.38, 2.65, and 3.36%, respectively, compared with those before fermentation. Furthermore, 16S ribosomal RNA sequence analysis revealed that the relative abundance of Lactobacillus spp. in the intestine increased after consumption of fermented tea. Additionally, based on histological and quantitative PCR analyses, fermented Tibetan tea also improved intestinal development and intestinal barrier function in mouse, while increasing the antioxidant capacity of mouse liver. Thus, fermented Tibetan tea could provide beneficial health effects through the intestine-liver axis. These findings have facilitated the study of the chemical composition of Tibetan tea and provided theoretical support for its use as a natural beverage with intestinal probiotic functions.PMID:36806153 | DOI:10.1007/s12602-023-10049-7

Mol Biol Evol. 2023 Feb 20:msad040. doi: 10.1093/molbev/msad040. Online ahead of print.ABSTRACTFreeze tolerance, the ability of an organism to survive internal ice formation, is a striking survival strategy employed by some ectotherms living in cold environments. However, the genetic bases of this remarkable adaptation are largely unknown. The Amur sleeper (Perccottus glenii), the only known freeze-tolerant fish species, can overwinter with its entire body frozen in ice. Here, we sequenced the chromosome-level genome of the Amur sleeper and performed comparative genomic, transcriptomic, and metabolomic analyses to investigate its strategies for surviving freezing. Evolutionary analysis suggested that the Amur sleeper diverged from its closest non-cold-hardy relative about 15.07 million years ago and has experienced a high rate of protein evolution. Transcriptomic and metabolomic data identified a coordinated and tissue-specific regulation of genes and metabolites involved in hypometabolism, cellular stress response, and cryoprotectant accumulation involved in freezing and thawing. Several genes show evidence of accelerated protein sequence evolution or family size expansion were found as adaptive responses to freezing induced stresses. Specifically, genetic changes associated with cytoskeleton stability, cryoprotectant synthesis, transmembrane transport and neuroprotective adaptations were identified as potentially key innovations that aid in freezing survival. Our work provides valuable resources and opportunities to unveil the molecular adaptations supporting freeze tolerance in ectothermic vertebrates.PMID:36805964 | DOI:10.1093/molbev/msad040

Nat Chem Biol. 2023 Feb 20. doi: 10.1038/s41589-023-01267-9. Online ahead of print.ABSTRACTTyrosine sulfation is a common posttranslational modification in mammals. To date, it has been thought to be limited to secreted and transmembrane proteins, but little is known about tyrosine sulfation on nuclear proteins. Here we report that SULT1B1 is a histone sulfotransferase that can sulfate the tyrosine 99 residue of nascent histone H3 in cytosol. The sulfated histone H3 can be transported into the nucleus and majorly deposited in the promoter regions of genes in chromatin. While the H3Y99 residue is buried inside octameric nucleosome, dynamically regulated subnucleosomal structures provide chromatin-H3Y99sulf the opportunity of being recognized and bound by PRMT1, which deposits H4R3me2a in chromatin. Disruption of H3Y99sulf reduces PRMT1 binding to chromatin, H4R3me2a level and gene transcription. These findings reveal the mechanisms underlying H3Y99 sulfation and its cross-talk with H4R3me2a to regulate gene transcription. This study extends the spectrum of tyrosine sulfation on nuclear proteins and the repertoire of histone modifications regulating chromatin functions.PMID:36805701 | DOI:10.1038/s41589-023-01267-9

J Bone Miner Res. 2023 Feb 20. doi: 10.1002/jbmr.4790. Online ahead of print.ABSTRACTWhile the maternal intrauterine metabolic environment has been recognized to have a profound impact on fetal growth and development with lifelong health implications, to our knowledge, there have been few large-scale birth cohort studies linking the cord metabolome (reflecting both the maternal and fetal metabolic state) with postnatal height measurements across the pediatric age range. Using data from the Boston Birth Cohort, an ongoing prospective birth cohort, this study investigated the association of cord plasma metabolites with children's height from birth to adolescence. Height was analyzed as attained height and longitudinal trajectories. Distinctive cord metabolite types were associated with attained height at different developmental windows: TAGs, DAGs, CEs, phospholipids, AAs, ACs, and nucleotides in early (age 0-4 years) and middle (age 6-12 years) childhood; various metabolite types other than TAGs in later childhood (after age 14 years). Functional principal component analysis on children's repeated height measurements summarized two typical height trajectory components: loadings on first eigenfunction (FPC1) representing overall height by age, and loadings on second eigenfunction (FPC2) representing speed of pubertal height growth. While only one cord metabolite was correlated with FPC1 after accounting for multiple testing, the study found 27 metabolites with significant overall effect on FPC2 among females, and 18 among males. These metabolites were mostly phospholipids (including PEs, PE_Ps, PCs, LPEs, and LPCs), AAs and nucleotides. Their associations with height differed between overweight/obesity (OWO) and non-OWO children, especially among females. In this prospective study of US understudied urban, low-income, racially diverse children, we demonstrated that cord plasma metabolites were significantly associated with postnatal attained height at different age windows as well as height trajectories from birth to adolescence. We also revealed how these associations differed by children's sex and OWO status. Our findings help elucidate metabolic pathways underlying fetal origins of height growth across developmental stages. This article is protected by copyright. All rights reserved.PMID:36805685 | DOI:10.1002/jbmr.4790

Environ Geochem Health. 2023 Feb 20. doi: 10.1007/s10653-023-01510-1. Online ahead of print.ABSTRACTThis study aimed to determine the common latent patterns of geographical distribution of health-related minerals across the USA and to evaluate the real-world cumulative effects of these patterns on overall population health. It was an ecological study using county-level data (3080 contiguous counties) on the concentrations of 14 minerals (i.e., aluminum, arsenic, calcium, copper, iron, lead, magnesium, manganese, mercury, phosphorus, selenium, sodium, titanium, zinc) in stream sediments (or surface soils), and the measurements of overall health including life expectancy at birth, age-specific mortality risks and cause-specific (summarized by 21 mutually exclusive groups) mortality rates. Latent class analysis (LCA) was employed to identify the common clusters of life expectancy-related minerals based on their concentration characteristics. Multivariate linear regression analyses were then conducted to examine the relationship between the LCA-derived clusters and the health measurements, with adjustment for potential confounding factors. Five minerals (i.e., arsenic, calcium, selenium, sodium and zinc) were associated with life expectancy and were analyzed in LCA. Three clusters were determined across the USA, the 'common' (n = 2056, 66.8%), 'infertile' (n = 739, 24.0%) and 'plentiful' (n = 285, 9.3%) clusters. Residents in counties with the 'infertile' profile were associated with the shortest life expectancy, highest mortality risks at all ages, and highest mortality rates for many reasons including the top five leading causes of death: cardiovascular diseases, neoplasms, neurological disorders, chronic respiratory conditions, and diabetes, urogenital, blood and endocrine diseases. Results remained statistically significant after confounding adjustment. Our study brings novel perspectives regarding environmental geochemistry to explain health disparities in the USA.PMID:36805365 | DOI:10.1007/s10653-023-01510-1

J Biol Chem. 2023 Feb 15:103027. doi: 10.1016/j.jbc.2023.103027. Online ahead of print.ABSTRACTImbalances in the amounts of amyloid-β peptides (Aβ) generated by the membrane proteases β- and γ-secretase are considered as a trigger of Alzheimer´s disease (AD). Cell-free studies of γ-secretase have shown that increasing membrane thickness modulates Aβ generation, but it has remained unclear if these effects are translatable to cells. Here we show that the very long chain fatty acid erucic acid (EA) triggers acyl chain remodeling in AD cell models, resulting in substantial lipidome alterations which included increased esterification of EA in membrane lipids. Membrane remodeling enhanced γ-secretase processivity, resulting in the increased production of the potentially beneficial Aβ37 and/or Aβ38 species in multiple cell lines. Unexpectedly, we found that the membrane remodeling stimulated total Aβ secretion by cells expressing WT γ-secretase, but lowered it for cells expressing an aggressive familial AD mutant γ-secretase. We conclude that EA-mediated modulation of membrane composition is accompanied by complex lipid homeostatic changes that can impact amyloidogenic processing in different ways and elicit distinct γ-secretase responses, providing critical implications for lipid-based AD treatment strategies.PMID:36805335 | DOI:10.1016/j.jbc.2023.103027

Biosens Bioelectron. 2023 Feb 15;227:115152. doi: 10.1016/j.bios.2023.115152. Online ahead of print.ABSTRACTMultiple studies showed that metabolic disorders play a critical role in respiratory infectious diseases, including COVID-19. Metabolites contained in small extracellular vesicles (sEVs) are different from those in plasma at the acute stage, while the metabolic features of plasma sEVs of COVID-19 survivors remain unknown. Here, we used a nanopore membrane-based microfluidic chip for plasma sEVs separation, termed ExoSEC, and compared the sEVs obtained by UC, REG, and ExoSEC in terms the time, cost, purity, and metabolic features. The results indicated the ExoSEC was much less costly, provided higher purity by particles/proteins ratio, and achieved 205-fold and 2-fold higher sEVs yield, than UC and REG, respectively. Moreover, more metabolites were identified and several signaling pathways were significantly enriched in ExoSEC-sEVs compared to UC-sEVs and REG-sEVs. Furthermore, we detected 306 metabolites in plasma sEVs using ExoSEC from recovered asymptomatic (RA), moderate (RM), and severe/critical COVID-19 (RS) patients without underlying diseases 3 months after discharge. Our study demonstrated that COVID-19 survivors, especially RS, experienced significant metabolic alteration and the dysregulated pathways mainly involved fatty acid biosynthesis, phenylalanine metabolism, etc. Metabolites of the fatty acid biosynthesis pathway bore a significantly negative association with red blood cell counts and hemoglobin, which might be ascribed to hypoxia or respiratory failure in RM and RS but not in RA at the acute stage. Our study confirmed that ExoSEC could provide a practical and economical alternative for high throughput sEVs metabolomic study.PMID:36805272 | DOI:10.1016/j.bios.2023.115152

N Biotechnol. 2023 Feb 17:S1871-6784(23)00004-3. doi: 10.1016/j.nbt.2023.02.002. Online ahead of print.ABSTRACTSophorolipids are biobased and biodegradable glycolipid surface-active agents contributing to the shift from petroleum to biobased surfactants, associated with clear environmental benefits. However, their production cost is currently too high to allow commercialisation. Therefore, a continuous sophorolipid production process was evaluated, i.e., a retentostat with an external filtration unit. Despite an initial increase in volumetric productivity, productivity eventually declined to almost 0gL-1 h-1. Following comprehensive metabolomics on supernatant obtained from a standardised retentostat, we hypothesised exhaustion of the N-starvation-induced autophagy as the main mechanism responsible for the decline in bolaform sophorolipid productivity. Thirty-six metabolites that correlate with RNA/protein autophagy and high sophorolipid productivity were putatively identified. In conclusion, our results unveil a plausible cause of this bola sophorolipid productivity decline in an industrially relevant bioreactor set-up, which may thus impact majorly on future yeast biosurfactant regulation studies and the finetuning of bola sophorolipid production processes.PMID:36805132 | DOI:10.1016/j.nbt.2023.02.002

Hepatology. 2023 Feb 21. doi: 10.1097/HEP.0000000000000314. Online ahead of print.ABSTRACTBACKGROUND AIMS: SLC25A47 was initially identified as mitochondrial hepatocellular carcinoma (HCC)-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism.APPROACH RESULTS: Treatment of hepatocytes with metformin found that metformin can transcriptionally activate the expression of Slc25a47, which is required for AMPKα phosphorylation. Slc25a47-deficient mice had increased hepatic lipid content, triglycerides and cholesterol levels, and we found that Slc25a47-deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in inhibition of lipogenesis. Moreover, using a diethylnitrosamine (DEN)-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mTOR cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD+ was an endogenous substrate for SLC25A47 and the activity of NAD+-dependent SIRT3 declined in Slc25a47-deficient mice, followed by inactivation of AMPKα.CONCLUSIONS: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD+ transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating non-alcoholic fatty liver disease (NAFLD) and HCC.PMID:36804859 | DOI:10.1097/HEP.0000000000000314

Chem Commun (Camb). 2023 Feb 21. doi: 10.1039/d2cc06950d. Online ahead of print.ABSTRACTGinsenoside Rg1, a tetracyclic triterpenoid derivative extracted from the roots of Panax ginseng C. A. Meyer, can enhance learning and memory and improve cognitive impairment. However, whether or how it affects vesicular dopamine storage and its release during exocytosis remains unknown. By using single-vesicle electrochemistry, we for the first time find out that Rg1 not only upregulates vesicular dopamine content but also increases exocytosis frequency and modulates dopamine release during exocytosis in PC12 cells, which may relate to the activation of protein kinases, causing a series of biological cascades. This finding offers the possible link between Rg1 and vesicular chemical storage and exocytotic release, which is of significance for understanding the nootropic role of Rg1 from the perspective of neurotransmission.PMID:36804575 | DOI:10.1039/d2cc06950d

Phytochemistry. 2023 Feb 17:113611. doi: 10.1016/j.phytochem.2023.113611. Online ahead of print.ABSTRACTSalvia hispanica L., commonly named Chia, is a food plant from Central America and Australia, producing seeds whose consumption has been increasing in the last decade. Several articles analysed the seeds metabolite content. However, few is known about Chia leaves. This work is the first report on the whole metabolite profile of chia leaves, determined by spectroscopic methods including NMR, GC-MS and LC-MS coupled with chemometrics analysis. Additionally, molecular networking has been applied to the LC-MS data to determine the flavonoid composition. Different chia sources were compared: one commercial (black) and three early flowering (G3, G8 and G17) mutant genotypes cultivated at two irrigation regimes (50 and 100%). Organic extracts were mainly composed by saturated and mono- and polyunsaturated fatty acids with palmitic being the most abundant followed by oleic and linolenic acids. Aqueous extracts contained glucose, galactose, and fructose as main sugars. Flavonoids were based on vitexin and orientin and their analogues. Chemical composition of early flowering genotypes was quite similar to commercial black chia with the exception of G8 showing significant differences in the polar phase. A generally highest content of omega-9 fatty acids has been found in the early flowering genotypes along with high content of nutraceuticals suggesting them as a potential source of raw materials for the food/feed industry.PMID:36804479 | DOI:10.1016/j.phytochem.2023.113611