PubMed

bioRxiv. 2023 Feb 24:2023.02.23.529575. doi: 10.1101/2023.02.23.529575. Preprint.ABSTRACTWhile the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, hydrogen peroxide specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo . Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.PMID:36865128 | PMC:PMC9980149 | DOI:10.1101/2023.02.23.529575

bioRxiv. 2023 Feb 22:2023.02.22.529577. doi: 10.1101/2023.02.22.529577. Preprint.ABSTRACTMutations in CHCHD10, a mitochondrial protein with still undefined function, are associated with dominant multi-system mitochondrial diseases. CHCHD10 knock-in mice harboring a heterozygous S55L mutation (equivalent to the human pathogenic S59L mutation) develop a fatal mitochondrial cardiomyopathy. The heart of S55L knock-in mice shows extensive metabolic rewiring triggered by proteotoxic mitochondrial integrated stress response (mtISR). In the mutant heart, mtISR initiates well before the onset of mild bioenergetic impairments and is associated with a shift from fatty acid oxidation to glycolytic metabolism and widespread metabolic imbalance. We tested therapeutic interventions to counteract the metabolic rewiring and ameliorate the metabolic imbalance. Heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. Metabolomics and gene expression profiles demonstrated that HFD achieved an increase of fatty acid utilization in the heart accompanied by a decrease in cardiomyopathy markers. Surprisingly, HFD also decreased the accumulation of aggregated CHCHD10 in the S55L heart. Importantly, HFD increased the survival of mutant female mice exposed to acceleration of the mitochondrial cardiomyopathy associated with pregnancy. Our findings indicate that metabolic alterations can be effectively targeted for therapeutic intervention in mitochondrial cardiomyopathies associated with proteotoxic stress.PMID:36865125 | PMC:PMC9980108 | DOI:10.1101/2023.02.22.529577

Cardiovasc Diagn Ther. 2023 Feb 28;13(1):83-99. doi: 10.21037/cdt-22-386. Epub 2023 Jan 9.ABSTRACTBACKGROUND AND OBJECTIVE: Heart failure (HF) in the pediatric population is a multi-factorial process with a wide spectrum of etiologies and clinical manifestations, that are distinct from the adult HF population, with congenital heart disease (CHD) as the most common cause. CHD has high morbidity/mortality with nearly 60% developing HF during the first 12 months of life. Hence, early discovery and diagnosis of CHD in neonates is pivotal. Plasma B-type natriuretic peptide (BNP) is an increasingly popular clinical marker in pediatric HF, however, in contrast to adult HF, it is not yet included in pediatric HF guidelines and there is no standardized reference cut-off value. We explore the current trends and prospects of biomarkers in pediatric HF, including CHD that can aid in diagnosis and management.METHODS: As a narrative review, we will analyze biomarkers with respect to diagnosis and monitoring in specific anatomical types of CHD in the pediatric population considering all English PubMed publications till June 2022.KEY CONTENT AND FINDINGS: We present a concise description of our own experience in applying plasma BNP as a clinical biomarker in pediatric HF and CHD (tetralogy of fallot vs. ventricular septal defect) in the context of surgical correction, as well as untargeted metabolomics analyses. In the current age of Information Technology and large data sets we also explored new biomarker discovery using Text Mining of 33M manuscripts currently on PubMed.CONCLUSIONS: (Multi) Omics studies from patient samples as well as Data Mining can be considered for the discovery of potential pediatric HF biomarkers useful in clinical care. Future research should focus on validation and defining evidence-based value limits and reference ranges for specific indications using the most up-to-date assays in parallel to commonly used studies.PMID:36864972 | PMC:PMC9971290 | DOI:10.21037/cdt-22-386

Front Cell Infect Microbiol. 2023 Feb 14;13:1129791. doi: 10.3389/fcimb.2023.1129791. eCollection 2023.ABSTRACTPreviously, we reported the development of novel small molecules that are potent inhibitors of the glycolytic enzyme phosphofructokinase (PFK) of Trypanosoma brucei and related protists responsible for serious diseases in humans and domestic animals. Cultured bloodstream-form trypanosomes, which are fully reliant on glycolysis for their ATP production, are rapidly killed at submicromolar concentrations of these compounds, which have no effect on the activity of human PFKs and human cells. Single-day oral dosing cures stage 1 human trypanosomiasis in an animal model. Here we analyze changes in the metabolome of cultured trypanosomes during the first hour after addition of a selected PFK inhibitor, CTCB405. The ATP level of T. brucei drops quickly followed by a partial increase. Already within the first five minutes after dosing, an increase is observed in the amount of fructose 6-phosphate, the metabolite just upstream of the PFK reaction, while intracellular levels of the downstream glycolytic metabolites phosphoenolpyruvate and pyruvate show an increase and decrease, respectively. Intriguingly, a decrease in the level of O-acetylcarnitine and an increase in the amount of L-carnitine were observed. Likely explanations for these metabolomic changes are provided based on existing knowledge of the trypanosome's compartmentalized metabolic network and kinetic properties of its enzymes. Other major changes in the metabolome concerned glycerophospholipids, however, there was no consistent pattern of increase or decrease upon treatment. CTCB405 treatment caused less prominent changes in the metabolome of bloodstream-form Trypanosoma congolense, a ruminant parasite. This agrees with the fact that it has a more elaborate glucose catabolic network with a considerably lower glucose consumption rate than bloodstream-form T. brucei.PMID:36864883 | PMC:PMC9971811 | DOI:10.3389/fcimb.2023.1129791

Front Endocrinol (Lausanne). 2023 Feb 14;14:1009888. doi: 10.3389/fendo.2023.1009888. eCollection 2023.ABSTRACTGestational diabetes mellitus (GDM) is a metabolic disease with an increasing annual incidence. Our previous observational study found that pregnant women with gestational diabetes had mild cognitive decline, which may be related to methylglyoxal (MGO). This study aimed to investigate whether labor pain aggravates the increase in MGO and explored the protective effect of epidural analgesia on metabolism in pregnant women with GDM based on solid-phase microextraction gas chromatography/mass spectrometry (SPME/GC-MS). Pregnant women with GDM were divided into a natural birth group (ND group, n = 30) and epidural analgesia group (PD group, n = 30). After fasting for ≥ 10 h overnight, venous blood samples were collected pre- and post-delivery to detect MGO, interleukin-6 (IL-6), and 8-epi-prostaglandin F2 alpha (8-iso-PGF2α) by ELISA. Serum samples were analyzed for volatile organic compounds (VOCs) using SPME-GC-MS. MGO, IL-6, and 8-iso-PGF2α levels in the ND group increased significantly post-delivery (P < 0.05) and were significantly higher in this group than the levels in the PD group (P < 0.05). Compared to the PD group, VOCs in the ND group increased significantly post-delivery. Further results indicated that propionic acid may be associated with metabolic disorders in pregnant women with GDM. Epidural analgesia can effectively improve the metabolism and immune function in pregnant women with GDM.PMID:36864845 | PMC:PMC9970997 | DOI:10.3389/fendo.2023.1009888

Phytomedicine. 2023 Mar 2;115:154724. doi: 10.1016/j.phymed.2023.154724. Online ahead of print.ABSTRACTBACKGROUND: Danggui Jianzhong Decoction (DGJZD) has been proven as an effective classical prescription for clinically treating primary dysmenorrhoea (PD). However, the industrialisation development and drug innovation of DGJZD remain limited due to its undefined effective constituents and quality markers (Q-markers).PURPOSE: Elucidating the Q-markers of DGJZD, which is related to clinical efficacy.METHODS: In accordance with chinmedomics strategy, we evaluated the therapeutic efficacy of DGJZD on the basis of the metabolomic profile and biomarker of a PD rat model to further identify the constituents of DGJZD in vivo that originated from the formula under the acting condition of DGJZD. The potential effective constituents and Q-markers were identified by mining the dynamic relation between the constituents in vivo and the biomarkers.RESULTS: Subsequently, 29 serum metabolites were characterized as biomarkers for PD, and DGJZD adjusted the levels of the primary biomarkers involved in arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism as well as the synthesis of steroid hormones. Under the active condition of DGJZD, 20 prototype ingredients and 4 metabolites of DGJZD were found in vivo, five of which were mostly related with the efficacy of PD, namely, ferulic acid, zizyphusin, cinnamic acid, protocatechuic acid-3-glucoside, and azelaic acid. They were the potential pharmacodynamic constituents for treating PD, and they could be regarded as the Q-markers of DGJZD.CONCLUSION: Taken together, the Q-markers of DGJZD identified in this research are credible and assist in solving problems related to quality control and drug innovation, accelerating industrialisation development. Besides, the efficacy, mechanism and active ingredients of DGJZD for the treatment of PD were innovatively elucidated for the first time on the basis of the chinmedomics strategy for uncovering the Q-markers of drugs from the system perspective.PMID:37087788 | DOI:10.1016/j.phymed.2023.154724

Lab Med. 2023 Mar 2:lmad004. doi: 10.1093/labmed/lmad004. Online ahead of print.ABSTRACTOBJECTIVE: A nontargeted metabolomics approach was established to characterize serum metabolic profile in type 3c diabetes mellitus (T3cDM) secondary to chronic pancreatitis and compare with T2DM.METHODS: Forty patients were recruited for metabolite analysis based on liquid chromatography-mass spectrometry. Cluster heatmap and KEGG metabolic pathway enrichment analysis were used to analyze the specific and differential metabolites. The receiver operating characteristics (ROCs) were generated and correlation analysis with clinical data was conducted.RESULTS: Metabolites including sphingosine, lipids, carnitine, bile acid, and hippuric acid were found to be different between T2DM and T3cDM, mainly enriched in bile acid biosynthesis, fatty acid biosynthesis, and sphingolipid metabolic pathways. The ROCs were generated with an area under the curve of 0.907 (95% confidence interval, 0.726-1) for the model with 15 metabolites.CONCLUSION: T3cDM is characterized by increased sphingosine, carnitine, bile acid, and most lipids, providing novel biomarkers for clinical diagnosis and a future direction in research on pathophysiological mechanisms.PMID:36864551 | DOI:10.1093/labmed/lmad004

J Transl Med. 2023 Mar 2;21(1):162. doi: 10.1186/s12967-023-04017-6.ABSTRACTMammalian cells responding to specific perturbations of homeostasis can undergo a regulated variant of cell death that elicits adaptive immune responses. As immunogenic cell death (ICD) can only occur in a precise cellular and organismal context, it should be conceptually differentiated from instances of immunostimulation or inflammatory responses that do not mechanistically depend on cellular demise. Here, we critically discuss key conceptual and mechanistic aspects of ICD and its implications for cancer (immuno)therapy.PMID:36864446 | DOI:10.1186/s12967-023-04017-6

Planta. 2023 Mar 2;257(4):73. doi: 10.1007/s00425-023-04105-3.ABSTRACTStemphylium botryosum alters lentil secondary metabolism and differentially affects resistant and susceptible genotypes. Untargeted metabolomics identifies metabolites and their potential biosynthetic pathways that play a crucial role in resistance to S. botryosum. The molecular and metabolic processes that mediate resistance to stemphylium blight caused by Stemphylium botryosum Wallr. in lentil are largely unknown. Identifying metabolites and pathways associated with Stemphylium infection may provide valuable insights and novel targets to breed for enhanced resistance. The metabolic changes following infection of four lentil genotypes by S. botryosum were investigated by comprehensive untargeted metabolic profiling employing reversed-phase or hydrophilic interaction liquid chromatography (HILIC) coupled to a Q-Exactive mass spectrometer. At the pre-flowering stage, plants were inoculated with S. botryosum isolate SB19 spore suspension and leaf samples were collected at 24, 96 and 144 h post-inoculation (hpi). Mock-inoculated plants were used as negative controls. After analyte separation, high-resolution mass spectrometry data was acquired in positive and negative ionization modes. Multivariate modeling revealed significant treatment, genotype and hpi effects on metabolic profile changes that reflect lentil response to Stemphylium infection. In addition, univariate analyses highlighted numerous differentially accumulated metabolites. By contrasting the metabolic profiles of SB19-inoculated and mock-inoculated plants and among lentil genotypes, 840 pathogenesis-related metabolites were detected including seven S. botryosum phytotoxins. These metabolites included amino acids, sugars, fatty acids and flavonoids in primary and secondary metabolism. Metabolic pathway analysis revealed 11 significant pathways including flavonoid and phenylpropanoid biosynthesis, which were affected upon S. botryosum infection. This research contributes to ongoing efforts toward a comprehensive understanding of the regulation and reprogramming of lentil metabolism under biotic stress, which will provide targets for potential applications in breeding for enhanced disease resistance.PMID:36864322 | DOI:10.1007/s00425-023-04105-3

Nat Rev Genet. 2023 Mar 2. doi: 10.1038/s41576-023-00580-2. Online ahead of print.ABSTRACTThe joint analysis of the genome, epigenome, transcriptome, proteome and/or metabolome from single cells is transforming our understanding of cell biology in health and disease. In less than a decade, the field has seen tremendous technological revolutions that enable crucial new insights into the interplay between intracellular and intercellular molecular mechanisms that govern development, physiology and pathogenesis. In this Review, we highlight advances in the fast-developing field of single-cell and spatial multi-omics technologies (also known as multimodal omics approaches), and the computational strategies needed to integrate information across these molecular layers. We demonstrate their impact on fundamental cell biology and translational research, discuss current challenges and provide an outlook to the future.PMID:36864178 | DOI:10.1038/s41576-023-00580-2

Nat Commun. 2023 Mar 2;14(1):1187. doi: 10.1038/s41467-023-36630-w.ABSTRACTFerroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.PMID:36864031 | DOI:10.1038/s41467-023-36630-w

J Pain. 2023 Feb 28:S1526-5900(23)00056-1. doi: 10.1016/j.jpain.2023.02.023. Online ahead of print.ABSTRACTOsteoarthritis (OA) is the most common arthritis affecting synovial joints such as knees and hips of millions of people globally. Usage-related joint pain and reduced function are the most common symptoms experienced by people with OA. To improve pain management, there is a need to identify validated biomarkers predicting therapeutic responses in targeted clinical trials. Our study aimed to identify the metabolic biomarkers for pain and pressure pain detection thresholds (PPTs) in participants with knee pain and symptomatic OA using metabolic phenotyping. Metabolite and cytokine measurements were done on serum samples using LC-MS/MS (liquid gas chromatography integrated magnetic resonance mass spectrometry) and Human Proinflammatory panel 1 kit respectively. Regression analysis was done in a test (n = 75) and replication study (n = 79) to investigate the metabolites associated with current knee pain scores and pressure pain detection thresholds (PPTs). Meta-analysis and correlation were done estimating precision of associated metabolites and identifying relationship between significant metabolites and cytokines respectively. Acyl ornithine, carnosine, cortisol, cortisone, cystine, DOPA, glycolithocholic acid sulphate (GLCAS), phenylethylamine (PEA) and succinic acid were found to be significantly (FDR < 0.1) associated with pain scores in meta-analysis of both studies. IL-10, IL-13, IL-1β, IL2, IL8 and TNF-α were also found to be associated with the significant metabolites. Significant associations of these metabolites and inflammatory markers with knee pain suggests that targeting relevant pathways of amino acid and cholesterol metabolism may modulate cytokines and these could be targeted as novel therapeutics development to improve knee pain and OA management. PERSPECTIVE: Foreseeing the global burden of knee pain in Osteoarthritis (OA) and adverse effects of current pharmacological therapies, this study is envisaged to investigate serum metabolites and molecular pathways involved in knee pain. The replicated metabolites in this study suggests targeting amino-acid pathways for better management of OA knee pain.PMID:36863678 | DOI:10.1016/j.jpain.2023.02.023

Sci Total Environ. 2023 Feb 28:162496. doi: 10.1016/j.scitotenv.2023.162496. Online ahead of print.ABSTRACTDespite the increasing research on the fate of nanoplastics (NPs, <100 nm) in freshwater systems, little is known about the joint toxic effects of metal(loid)s and NPs modified with different functional groups on microalgae. Here, we explored the joint toxic effects of two types of polystyrene NPs [one modified with a sulfonic acid group (PSNPs-SO3H), and one without this functional group (PSNPs)] and arsenic (As) on the microalgae Microcystis aeruginosa. The results highlighted that PSNPs-SO3H showed a smaller hydrodynamic diameter and greater potential to adsorb positively charged ions than PSNPs, contributing to the more severe growth inhibition, while both of them produced oxidative stress. Metabolomics further revealed that the fatty acid metabolism of the microalgae was significantly up-regulated under both NPs exposure, while PSNPs-SO3H down-regulated the tricarboxylic acid cycle (TCA cycle) of the microalgae. As uptake by algae was significantly reduced by 82.58 % and 59.65 % in the presence of 100 mg/L PSNPs and PSNPs-SO3H, respectively. The independent action model showed that the joint toxicity of both NPs with As was assessed as antagonistic. In addition, PSNPs and PSNPs-SO3H had dissimilar effects on the composition of the microalgae extracellular polymeric substances (EPS), resulting in different uptake and adsorption of As, thereby affecting the physiology and biochemistry of algae. Overall, our findings propose that the specific properties of NPs should be considered in future environmental risk assessments.PMID:36863597 | DOI:10.1016/j.scitotenv.2023.162496

Bioresour Technol. 2023 Feb 28:128811. doi: 10.1016/j.biortech.2023.128811. Online ahead of print.ABSTRACTThe utilization of gibberellic acid-3, high carbon/nitrogen ratio and salinity concentration can effectively enhance astaxanthin biosynthesis in Chromochloris zofingiensis under the heterotrophic conditions, but the underlying mechanisms remained yet to be investigated. The metabolomics analysis revealed that enhancement of the glycolysis, pentose phosphate pathways (PPP), and tricarboxylic acid (TCA) cycle led to astaxanthin accumulation under the induction conditions. The increased fatty acids can significantly increase astaxanthin esterification. The addition of appropriate concentrations of glycine (Gly) and γ-aminobutyric acid (GABA) promoted astaxanthin biosynthesis in C. zofingiensis, as well as benefiting for biomass yield. With the addition of 0.5 mM GABA, the astaxanthin yield increased to 0.35 g·L-1, which was 1.97-fold higher than that of the control. This study advanced understanding about astaxanthin biosynthesis in heterotrophic microalga, and provided novel strategies for enhanced astaxanthin production in C. zofingiensis.PMID:36863528 | DOI:10.1016/j.biortech.2023.128811

Antiviral Res. 2023 Feb 28:105570. doi: 10.1016/j.antiviral.2023.105570. Online ahead of print.ABSTRACTCoronaviruses, as enveloped positive-strand RNA viruses, manipulate host lipid compositions to enable robust viral replication. Temporal modulation of the host lipid metabolism is a potential novel strategy against coronaviruses. Here, the dihydroxyflavone pinostrobin (PSB) was identified through bioassay that inhibited the increment of human coronavirus OC43 (HCoV-OC43) in human ileocecal colorectal adenocarcinoma cells. Lipid metabolomic studies showed that PSB interfered with linoleic acid and arachidonic acid metabolism pathways. PSB significantly decreased the level of 12, 13- epoxyoctadecenoic (12, 13-EpOME) and increased the level of prostaglandin E2. Interestingly, exogenous supplement of 12, 13-EpOME in HCoV-OC43-infected cells significantly stimulated HCoV-OC43 virus replication. Transcriptomic analyses showed that PSB is a negative modulator of aryl hydrocarbon receptor (AHR)/cytochrome P450 (CYP) 1A1signaling pathway and its antiviral effects can be counteracted by supplement of FICZ, a well-known AHR agonist. Integrative analyses of metabolomic and transcriptomic indicated that PSB could affect linoleic acid and arachidonic acid metabolism axis through AHR/CYP1A1 pathway. These results high light the importance of the AHR/CYP1A1 pathway and lipid metabolism in the anti-coronavirus activity of the bioflavonoid PSB.PMID:36863496 | DOI:10.1016/j.antiviral.2023.105570

EBioMedicine. 2023 Feb 28;90:104496. doi: 10.1016/j.ebiom.2023.104496. Online ahead of print.ABSTRACTBACKGROUND: More than ten randomized clinical trials are being tested to evaluate the efficacy, effectiveness and safety of a fasting-mimicking diet (FMD) combined with different antitumor agents.METHODS: UMI-mRNA sequencing, Cell-cycle analysis, Label retention, metabolomics, Multilabeling et al. were used to explore mechanisms. A tandem mRFP-GFP-tagged LC3B, Annexin-V-FITC Apoptosis, TUNEL, H&E, Ki-67 and animal model was used to search for synergistic drugs.FINDINGS: Here we showed that fasting or FMD retards tumor growth more effectively but does not increase 5-fluorouracil/oxaliplatin (5-FU/OXA) sensitivity to apoptosis in vitro and in vivo. Mechanistically, we demonstrated that CRC cells would switch from an active proliferative to a slow-cycling state during fasting. Furthermore, metabolomics shows cell proliferation was decreased to survive nutrient stress in vivo, as evidenced by a low level of adenosine and deoxyadenosine monophosphate. CRC cells would decrease proliferation to achieve increased survival and relapse after chemotherapy. In addition, these fasting-induced quiescent cells were more prone to develop drug-tolerant persister (DTP) tumor cells postulated to be responsible for cancer relapse and metastasis. Then, UMI-mRNA sequencing uncovered the ferroptosis pathway as the pathway most influenced by fasting. Combining fasting with ferroptosis inducer treatment leads to tumor inhibition and eradication of quiescent cells by boosting autophagy.INTERPRETATION: Our results suggest that ferroptosis could improve the antitumor activity of FMD + chemotherapy and highlight a potential therapeutic opportunity to avoid DTP cells-driven tumor relapse and therapy failure.FUNDING: A full list of funding bodies can be found in the Acknowledgements section.PMID:36863257 | DOI:10.1016/j.ebiom.2023.104496

Food Chem. 2023 Feb 24;415:135746. doi: 10.1016/j.foodchem.2023.135746. Online ahead of print.ABSTRACTConsumers demand higher levels of food quality and safety, so food legislative organizations need full knowledge of food composition to develop regulations that guarantee quality and safety criteria. This is the context for green natural food colorants and the new category green "coloring foodstuffs". We have exploited the capabilities of targeted metabolomics assisted by powerful software and algorithms to unravel the comprehensive chlorophyll composition in commercial samples of both colorant categories. With the aid of an in-house library, at first, seven new chlorophylls have been identified, among all the samples analyzed, providing data on their structural configuration. Next, taking advantage of an expert-curated database, eight more chlorophylls non-described previously have been found, which will be significant for the chemistry of chlorophylls. Finally, we have deciphered the sequence of chemical reactions that take place during the manufacturing of green food colorants and propose the whole pathway that explains the occurrence of the chlorophylls they contain.PMID:36863233 | DOI:10.1016/j.foodchem.2023.135746

Plant Physiol Biochem. 2023 Feb 18;196:807-820. doi: 10.1016/j.plaphy.2023.02.031. Online ahead of print.ABSTRACTSeed germination is crucial for plant productivity, and the biochemical changes during germination affect seedling survival, plant health and yield. While the general metabolism of germination is extensively studied, the role of specialized metabolism is less investigated. We therefore analyzed the metabolism of the defense compound dhurrin during sorghum (Sorghum bicolor) grain germination and early seedling development. Dhurrin is a cyanogenic glucoside, which is catabolized into different bioactive compounds at other stages of plant development, but its fate and role during germination is unknown. We dissected sorghum grain into three different tissues and investigated dhurrin biosynthesis and catabolism at the transcriptomic, metabolomic and biochemical level. We further analyzed transcriptional signature differences of cyanogenic glucoside metabolism between sorghum and barley (Hordeum vulgare), which produces similar specialized metabolites. We found that dhurrin is de novo biosynthesized and catabolized in the growing embryonic axis as well as the scutellum and aleurone layer, two tissues otherwise mainly acknowledged for their involvement in release and transport of general metabolites from the endosperm to the embryonic axis. In contrast, genes encoding cyanogenic glucoside biosynthesis in barley are exclusively expressed in the embryonic axis. Glutathione transferase enzymes (GSTs) are involved in dhurrin catabolism and the tissue-resolved analysis of GST expression identified new pathway candidate genes and conserved GSTs as potentially important in cereal germination. Our study demonstrates a highly dynamic tissue- and species-specific specialized metabolism during cereal grain germination, highlighting the importance of tissue-resolved analyses and identification of specific roles of specialized metabolites in fundamental plant processes.PMID:36863218 | DOI:10.1016/j.plaphy.2023.02.031

Environ Int. 2023 Feb 26;173:107851. doi: 10.1016/j.envint.2023.107851. Online ahead of print.ABSTRACTEmerging epidemiological evidence has linked per- and polyfluoroalkyl substances (PFAS) exposure could be linked to the disturbance of gestational glucolipid metabolism, but the toxicological mechanism is unclear, especially when the exposure is at a low level. This study examined the glucolipid metabolic changes in pregnant rats treated with relatively low dose perfluorooctanesulfonic acid (PFOS) through oral gavage during pregnancy [gestational day (GD): 1-18]. We explored the molecular mechanisms underlying the metabolic perturbation. Oral glucose tolerance test (OGTT) and biochemical tests were performed to assess the glucose homeostasis and serum lipid profiles in pregnant Sprague-Dawley (SD) rats randomly assigned to starch, 0.03 and 0.3 mg/kg·bw·d groups. Transcriptome sequencing combined with non-targeted metabolomic assays were further performed to identify differentially altered genes and metabolites in the liver of maternal rats, and to determine their correlation with the maternal metabolic phenotypes. Results of transcriptome showed that differentially expressed genes at 0.03 and 0.3 mg/kg·bw·d PFOS exposure were related to several metabolic pathways, such as peroxisome proliferator-activated receptors (PPARs) signaling, ovarian steroid synthesis, arachidonic acid metabolism, insulin resistance, cholesterol metabolism, unsaturated fatty acid synthesis, bile acid secretion. The untargeted metabolomics identified 164 and 158 differential metabolites in 0.03 and 0.3 mg/kg·bw·d exposure groups, respectively under negative ion mode of Electrospray Ionization (ESI-), which could be enriched in metabolic pathways such as α-linolenic acid metabolism, glycolysis/gluconeogenesis, glycerolipid metabolism, glucagon signaling pathway, glycine, serine and threonine metabolism. Co-enrichment analysis indicated that PFOS exposure may disturb the metabolism pathways of glycerolipid, glycolysis/gluconeogenesis, linoleic acid, steroid biosynthesis, glycine, serine and threonine. The key involved genes included down-regulated Ppp1r3c and Abcd2, and up-regulated Ogdhland Ppp1r3g, and the key metabolites such as increased glycerol 3-phosphate and lactosylceramide were further identified. Both of them were significantly associated with maternal fasting blood glucose (FBG) level. Our findings may provide mechanistic clues for clarifying metabolic toxicity of PFOS in human, especially for susceptible population such as pregnant women.PMID:36863164 | DOI:10.1016/j.envint.2023.107851

PLoS One. 2023 Mar 2;18(3):e0282316. doi: 10.1371/journal.pone.0282316. eCollection 2023.ABSTRACTMedicinal plants contain valuable compounds that have attracted worldwide interest for their use in the production of natural drugs. The presence of compounds such as rosmarinic acid, carnosic acid, and carnosol in Rosmarinus officinalis has made it a plant with unique therapeutic effects. The identification and regulation of the biosynthetic pathways and genes will enable the large-scale production of these compounds. Hence, we studied the correlation between the genes involved in biosynthesis of the secondary metabolites in R. officinalis using proteomics and metabolomics data by WGCNA. We identified three modules as having the highest potential for the metabolite engineering. Moreover, the hub genes highly connected to particular modules, TFs, PKs, and transporters were identified. The TFs of MYB, C3H, HB, and C2H2 were the most likely candidates associated with the target metabolic pathways. The results indicated that the hub genes including Copalyl diphosphate synthase (CDS), Phenylalanine ammonia lyase (PAL), Cineole synthase (CIN), Rosmarinic acid synthase (RAS), Tyrosine aminotransferase (TAT), Cinnamate 4-hydroxylase (C4H), and MYB58 are responsible for biosynthesis of important secondary metabolites. Thus, we confirmed these results using qRT-PCR after treating R. officinalis seedlings with methyl jasmonate. These candidate genes may be employed for genetic and metabolic engineering research to increase R. officinalis metabolite production.PMID:36862714 | DOI:10.1371/journal.pone.0282316