PubMed

Front Plant Sci. 2023 Feb 14;14:1124750. doi: 10.3389/fpls.2023.1124750. eCollection 2023.ABSTRACTIn the face of a growing world population and limited land, there is an urgent demand for higher productivity of food crops, and cultivation systems must be adapted to future needs. Sustainable crop production should aim for not only high yields, but also high nutritional values. In particular, the consumption of bioactive compounds such as carotenoids and flavonoids is associated with a reduced incidence of non-transmissible diseases. Modulating environmental conditions by improving cultivation systems can lead to the adaption of plant metabolisms and the accumulation of bioactive compounds. The present study investigates the regulation of carotenoid and flavonoid metabolisms in lettuce (Lactuca sativa var capitate L.) grown in a protected environment (polytunnels) compared to plants grown without polytunnels. Carotenoid, flavonoid and phytohormone (ABA) contents were determined using HPLC-MS and transcript levels of key metabolic genes were analyzed by RT-qPCR. In this study, we observed inverse contents of flavonoids and carotenoids in lettuce grown without or under polytunnels. Flavonoid contents on a total and individual level were significantly lower, while total carotenoid content was higher in lettuce plants grown under polytunnels compared to without. However, the adaptation was specific to the level of individual carotenoids. For instance, the accumulation of the main carotenoids lutein and neoxanthin was induced while the β-carotene content remained unchanged. In addition, our findings suggest that the flavonoid content of lettuce depends on transcript levels of the key biosynthetic enzyme, which is modulated by UV light. A regulatory influence can be assumed based on the relation between the concentration of the phytohormone ABA and the flavonoid content in lettuce. In contrast, the carotenoid content is not reflected in transcript levels of the key enzyme of either the biosynthetic or the degradation pathway. Nevertheless, the carotenoid metabolic flux determined using norflurazon was higher in lettuce grown under polytunnels, suggesting posttranscriptional regulation of carotenoid accumulation, which should be an integral part of future studies. Therefore, a balance needs to be found between the individual environmental factors, including light and temperature, in order to optimize the carotenoid or flavonoid contents and to obtain nutritionally highly valuable crops in protected cultivation.PMID:36866364 | PMC:PMC9971571 | DOI:10.3389/fpls.2023.1124750

Toxicol Res (Camb). 2022 Dec 25;12(1):49-61. doi: 10.1093/toxres/tfac081. eCollection 2023 Feb.ABSTRACTThe traditional Mongolian medicine Hunqile-7 (HQL-7), which is mainly used to relieve pain in clinic, has certain toxicity. Therefore, toxicological investigation of HQL-7 is of great significance to its safety assessment. In this study, the toxic mechanism of HQL-7 was explored based on a combination of metabolomics and intestinal flora metabolism. UHPLC-MS was used to analyze the serum, liver and kidney samples of rats after intragastric administration of HQL-7. The decision tree and K Nearest Neighbor (KNN) model were established based on the bootstrap aggregation (bagging) algorithm to classify the omics data. After samples were extracted from rat feces, the high-throughput sequencing platform was used to analyze the 16s rRNA V3-V4 region of bacteria. The experimental results confirm that the bagging algorithm improved the classification accuracy. The toxic dose, toxic intensity, and toxic target organ of HQL-7 were determined in toxicity tests. Seventeen biomarkers were identified and the metabolism dysregulation of these biomarkers may be responsible for the toxicity of HQL-7 in vivo. Several kinds of bacteria was demonstrated to be closely related to the physiological indices of renal and liver function, indicating liver and kidney damage induced by HQL-7 may be related to the disturbance of these intestinal bacteria. Overall, the toxic mechanism of HQL-7 was revealed in vivo, which not only provides a scientific basis for the safe and rational clinical use of HQL-7, but also opens up a new field of research on big data for Mongolian medicine.PMID:36866222 | PMC:PMC9972816 | DOI:10.1093/toxres/tfac081

Front Endocrinol (Lausanne). 2023 Feb 14;13:1123962. doi: 10.3389/fendo.2022.1123962. eCollection 2022.NO ABSTRACTPMID:36866167 | PMC:PMC9973375 | DOI:10.3389/fendo.2022.1123962

EPMA J. 2023 Feb 17;14(1):53-71. doi: 10.1007/s13167-023-00313-9. eCollection 2023 Mar.ABSTRACTMetabolomics refers to the high-through untargeted or targeted screening of metabolites in biofluids, cells, and tissues. Metabolome reflects the functional states of cells and organs of an individual, influenced by genes, RNA, proteins, and environment. Metabolomic analyses help to understand the interaction between metabolism and phenotype and reveal biomarkers for diseases. Advanced ocular diseases can lead to vision loss and blindness, reducing patients' quality of life and aggravating socio-economic burden. Contextually, the transition from reactive medicine to the predictive, preventive, and personalized (PPPM / 3P) medicine is needed. Clinicians and researchers dedicate a lot of efforts to explore effective ways for disease prevention, biomarkers for disease prediction, and personalized treatments, by taking advantages of metabolomics. In this way, metabolomics has great clinical utility in the primary and secondary care. In this review, we summarized much progress achieved by applying metabolomics to ocular diseases and pointed out potential biomarkers and metabolic pathways involved to promote 3P medicine approach in healthcare.PMID:36866159 | PMC:PMC9971428 | DOI:10.1007/s13167-023-00313-9

Front Plant Sci. 2023 Feb 14;13:1066088. doi: 10.3389/fpls.2022.1066088. eCollection 2022.ABSTRACTSeedlings of durum wheat and lentil were utilized to investigate the efficiency of magnetic water on growth and metabolic epicotyl profile. Tap water was passed through a magnetic device with a flow rate of max. 12900 - 13200 Gauss (G). Seeds and plantlets were grown on sand-free paper soaked by magnetized water, with unmagnetized tap water used in a control group. The growth parameters were collected at three time points (48, 96, and 144 hours after treatment), the same times at which metabolomic analysis was conducted on seeds, roots, and epicotyls. Although the effects varied with the species, tissues, and time point considered, compared with tap water (TW), the use of magnetized water treatment (MWT) led to higher root elongation in both genotypes. On the contrary, epicotyl length was not affected by treatment both in durum wheat and lentil. The results indicate that the use of magnetized water in agriculture can be considered a sustainable technology to promote plant development and quality with reduced and more efficient water usage, leading to cost-saving and environmental protection.PMID:36865947 | PMC:PMC9971934 | DOI:10.3389/fpls.2022.1066088

Front Plant Sci. 2023 Feb 14;13:1034788. doi: 10.3389/fpls.2022.1034788. eCollection 2022.ABSTRACT"Memory imprint" refers to the process when prior exposure to stress prepares the plant for subsequent stress episodes. Seed priming is a strategy to change the performance of seedlings to cope with stress; however, mechanisms associated with the metabolic response are fragmentary. Salinity is one of the major abiotic stresses that affect crop production in arid and semiarid areas. Chenopodium quinoa Willd. (Amaranthaceae) is a promising crop to sustain food security and possesses a wide genetic diversity of salinity tolerance. To elucidate if the metabolic memory induced by seed halo-priming (HP) differs among contrasting saline tolerance plants, seeds of two ecotypes of Quinoa (Socaire from Atacama Salar, and BO78 from Chilean Coastal/lowlands) were treated with a saline solution and then germinated and grown under different saline conditions. The seed HP showed a more positive impact on the sensitive ecotype during germination and promoted changes in the metabolomic profile in both ecotypes, including a reduction in carbohydrates (starch) and organic acids (citric and succinic acid), and an increase in antioxidants (ascorbic acid and α-tocopherol) and related metabolites. These changes were linked to a further reduced level of oxidative markers (methionine sulfoxide and malondialdehyde), allowing improvements in the energy use in photosystem II under saline conditions in the salt-sensitive ecotype. In view of these results, we conclude that seed HP prompts a "metabolic imprint" related to ROS scavenger at the thylakoid level, improving further the physiological performance of the most sensitive ecotype.PMID:36865946 | PMC:PMC9971973 | DOI:10.3389/fpls.2022.1034788

Front Pharmacol. 2023 Feb 14;14:1080962. doi: 10.3389/fphar.2023.1080962. eCollection 2023.ABSTRACTBackground: Descurainia sophia seeds (DS) is a herbal medicine in traditional Chinese medicine (TCM) for treating lung diseases. We aimed to evaluate the therapeutic effect of DS and five of its fractions upon pulmonary edema (PE) through metabolomics analysis (MA) of urine and serum samples of rats. Methods: A PE model was established by intrathoracic injection of carrageenan. Rats were pretreated with DS extract or its five fractions (polysaccharides (DS-Pol); oligosaccharides (DS-Oli); flavonoid glycosides (DS-FG); flavonoid aglycone (DS-FA); fat oil fraction (DS-FO)) for seven consecutive days. Forty-eight hours after carrageenan injection, lung tissues were subjected to histopathology. MA of urine and serum was done by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, respectively. Principal component analysis and orthogonal partial least squares-discriminant analysis were operated for the MA of rats and potential biomarkers related to treatment. Heatmaps and metabolic networks were constructed to explore how DS and its five fractions act against PE. Results: DS and its five fractions could all attenuate pathologic lung injury to different degrees, and DS-Oli, DS-FG, and DS-FO had a more potent effect compared with DS-Pol and DS-FA. DS-Oli, DS-FG, DS-FA, and DS-FO could regulate the metabolic profiles of PE rats, but DS-Pol was less potent. According to MA, the five fractions could improve PE to some degree due to their anti-inflammatory, immunoregulatory, and renoprotective activities by mediating the metabolism of taurine, tryptophan, and arachidonic acid. However, DS-Oli, DS-FG, and DS-FO had more important roles in edema-fluid reabsorption, and reduction of vascular leakage through regulating the metabolism of phenylalanine, sphingolipid and bile acid. Finally, heatmaps and hierarchical clustering analysis indicated DS-Oli, DS-FG, and DS-FO to be more efficacious than DS-Pol or DS-FA against PE. The five fractions of DS had a synergistic effect on PE from different aspects, thereby constituting the entire efficacy of DS. DS-Oli, DS-FG, or DS-FO could be used as an alternative to DS. Conclusion: MA combined with use of DS and its fractions provided novel insights into the mechanism of action of TCM.PMID:36865914 | PMC:PMC9971919 | DOI:10.3389/fphar.2023.1080962

Contemp Clin Trials Commun. 2023 Feb 1;32:101085. doi: 10.1016/j.conctc.2023.101085. eCollection 2023 Apr.ABSTRACTBACKGROUND: Probiotics may be an ideal choice for these patients, given it can improve the defecation and quality of life of individuals with chronic diarrhoea. However, evidence-based medical research is still limited to support its use as a diarrhoea agent.METHOD: A randomized, double-blind, placebo-controlled clinical trial is designed to pinpoint the efficiency and possible action modes of probiotics for chronic diarrhoea. 200 eligible volunteers with chronic diarrhoea are randomly assigned to a probiotic group (orally taking Lactobacillus plantarum p9 probiotics powder) or a placebo group. Except an independent project administrator who will be responsible for unblinding, the other researchers are blinded. Primary outcome is diarrhoea severity score, and secondary outcomes include weekly mean frequency of defecation, weekly mean stool appearance score, weekly mean stool urgency score, emotional state score, gut microbiome, and faecal metabolome. Each outcome measure will be assessed at the timepoints of pre-administration (day 0), administration (day 14 and/or 28), and post-administration (day 42) to identity inter- and intra-groups differences. Adverse events will be recorded to evaluate the safety of L. plantarum p9.DISCUSSION: The study protocol will provide high-quality evidence for the use of probiotics as a diarrhoea agent when it is strictly conducted out, providing evidence regarding whether and to what extent L. plantarum p9 can improve the defecation and well-being of individuals with chronic diarrhoea.TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) (NO. ChiCTR2000038410). Registered on November 22, 2020, https://www.chictr.org.cn/showproj.aspx?proj=56542.PMID:36865679 | PMC:PMC9970898 | DOI:10.1016/j.conctc.2023.101085

bioRxiv. 2023 Feb 23:2023.02.23.529704. doi: 10.1101/2023.02.23.529704. Preprint.ABSTRACTAs one of the most successful human pathogens, Mycobacterium tuberculosis ( Mtb ) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb -infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.PMID:36865287 | PMC:PMC9980128 | DOI:10.1101/2023.02.23.529704

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