PubMed

J Ethnopharmacol. 2023 Jun 13:116782. doi: 10.1016/j.jep.2023.116782. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii polyglycosides (TWP), extracted from the traditional Chinese herb Tripterygium wilfordii, has been widely used in the treatment of rheumatoid arthritis (RA). However, the toxicity of TWP to a variety of organs such as liver, kidney and testis greatly limits its clinical application. Salvia miltiorrhiza Bunge is often used in the treatment of RA due to its blood circulation promoting, stasis resolving, and anti-inflammatory effects. Salvia miltiorrhiza Bunge has also been reported to possess multiple organ protective effects.AIM OF THE STUDY: To investigate the influences of two main components of Salviorrhiza miltiorrhiza Bunge, hydrophilic salvianolic acids (SA) and lipophilic tanshinones (Tan), on the efficacy and toxicity of TWP in treating RA and to explore the underlying mechanisms.MATERIALS AND METHODS: SA and Tan were extracted from Salvia miltiorrhiza Bunge and the extracts were quantitated by HPLC and identified by UPLC-Q/TOF-MS. Then, a collagen-induced arthritis (CIA) rat model was established using bovine type II collagen (CII) and incomplete Freund's adjuvant (IFA). CIA rats were treated with TWP and/or SA/Tan. After 21 days of continuous treatment, arthritis symptoms and organs toxicity were evaluated. Meanwhile, serum metabolomics were investigated by the UPLC-Q/TOF-MS to understand the underlying mechanism.RESULTS: SA and Tan extracts could significantly alleviate arthritis symptoms in CIA rats and decrease the serum levels of inflammatory factors TNF-α, IL-1β and IL-6 when combined with TWP. Meanwhile, both extracts alleviated injury of liver, kidney and testis caused by TWP, and the hydrophilic extract SA was superior. Moreover, a total of 38 endogenous differential metabolites were identified between the CIA model group and the TWP group, among which 33 metabolites were significantly recovered after the combination of SA or Tan. Metabolic pathway analysis showed that SA and Tan can affect metabolic pathways including linoleic acid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and steroid biosynthesis metabolism pathway.CONCLUSIONS: Our findings indicated for the first time that two Salviorrhiza miltiorrhiza Bunge extracts could improve the efficacy and reduce the toxicity of TWP in the treatment of RA by adjusting metabolic pathways, and the hydrophilic extract SA was superior.PMID:37321427 | DOI:10.1016/j.jep.2023.116782

Toxicol Appl Pharmacol. 2023 Jun 13:116597. doi: 10.1016/j.taap.2023.116597. Online ahead of print.ABSTRACTTacrolimus (TAC)-based treatment is associated with nephrotoxicity and hepatotoxicity; however, the underlying molecular mechanisms responsible for this toxicity have not been fully explored. This study elucidated the molecular processes underlying the toxic effects of TAC using an integrative omics approach. Rats were sacrificed after 4 weeks of daily oral TAC administration at a dose of 5 mg/kg. The liver and kidney underwent genome-wide gene expression profiling and untargeted metabolomics assays. Molecular alterations were identified using individual data profiling modalities and further characterized by pathway-level transcriptomics-metabolomics integration analysis. Metabolic disturbances were mainly related to an imbalance in oxidant-antioxidant status, as well as in lipid and amino acid metabolism in the liver and kidney. Gene expression profiles also indicated profound molecular alterations, including in genes associated with a dysregulated immune response, proinflammatory signals, and programmed cell death in the liver and kidney. Joint-pathway analysis indicated that the toxicity of TAC was associated with DNA synthesis disruption, oxidative stress, and cell membrane permeabilization, as well as lipid and glucose metabolism. In conclusion, our pathway-level integration of transcriptome and metabolome and conventional analyses of individual omics profiles, provided a more comprehensive picture of the molecular changes resulting from TAC toxicity. This study also serves as a valuable resource for subsequent investigations aiming to understand the mechanism underlying the molecular toxicology of TAC.PMID:37321324 | DOI:10.1016/j.taap.2023.116597

J Proteomics. 2023 Jun 13:104951. doi: 10.1016/j.jprot.2023.104951. Online ahead of print.ABSTRACTSpontaneous milk lipolysis refers to the breakdown of triacylglycerols in milk. Lipolysis impacts the organoleptic value of milk by causing off-flavours and reduces the technological properties of milk. Lipolysis is caused by lipoprotein lipase (LPL), a tightly regulated enzyme in milk. Our objective was to identify robust biomarkers of lipolysis and putative regulators of LPL enzyme in bovine milk. To achieve this goal, we used feed restriction as a lever to generate highly contrasted samples with regard to milk lipolysis. We combined statistical methods on proteomics data, milk lipolysis and LPL activity values. Following this strategy, we identified CD5L and GP2 as robust biomarkers of high lipolysis in cow milk. We also identified HID1, SURF4 and CUL9 as putative inhibitors of the lipolytic process in the milk. We thus proposed 5 putative biomarkers to be considered in future tools to manage milk lipolysis. SIGNIFICANCE: This manuscript is notable in three aspects. First, this is the first evaluation of the milk proteome relative to milk lipolysis or LPL activity. Second, the relationship between the abundance of proteins and milk traits was evaluated by a combination of univariate and multivariate analyses. Third, we provide a short list of five proteins to be tested in a larger population to feed the pipeline of biomarker discovery.PMID:37321301 | DOI:10.1016/j.jprot.2023.104951

Cell. 2023 Jun 8:S0092-8674(23)00543-3. doi: 10.1016/j.cell.2023.05.024. Online ahead of print.ABSTRACTThe human body contains thousands of metabolites derived from mammalian cells, the microbiota, food, and medical drugs. Many bioactive metabolites act through the engagement of G-protein-coupled receptors (GPCRs); however, technological limitations constrain current explorations of metabolite-GPCR interactions. Here, we developed a highly multiplexed screening technology called PRESTO-Salsa that enables simultaneous assessment of nearly all conventional GPCRs (>300 receptors) in a single well of a 96-well plate. Using PRESTO-Salsa, we screened 1,041 human-associated metabolites against the GPCRome and uncovered previously unreported endogenous, exogenous, and microbial GPCR agonists. Next, we leveraged PRESTO-Salsa to generate an atlas of microbiome-GPCR interactions across 435 human microbiome strains from multiple body sites, revealing conserved patterns of cross-tissue GPCR engagement and activation of CD97/ADGRE5 by the Porphyromonas gingivalis protease gingipain K. These studies thus establish a highly multiplexed bioactivity screening technology and expose a diverse landscape of human, diet, drug, and microbiota metabolome-GPCRome interactions.PMID:37321219 | DOI:10.1016/j.cell.2023.05.024

Phytomedicine. 2023 Jun 2;117:154908. doi: 10.1016/j.phymed.2023.154908. Online ahead of print.ABSTRACTBACKGROUND: Abnormal endocrine metabolism caused by polycystic ovary syndrome combined with insulin resistance (PCOS-IR) poses a serious risk to reproductive health in females. Quercitrin is a flavonoid that can efficiently improve both endocrine and metabolic abnormalities. However, it remains unclear if this agent can exert therapeutic effect on PCOS-IR.METHODS: The present study used a combination of metabolomic and bioinformatic methods to screen key molecules and pathways involved in PCOS-IR. A rat model of PCOS-IR and an adipocyte IR model were generated to investigate the role of quercitrin in regulating reproductive endocrine and lipid metabolism processes in PCOS-IR.RESULTS: Peptidase M20 domain containing 1 (PM20D1) was screened using bioinformatics to evaluate its participation in PCOS-IR. PCOS-IR regulation via the PI3K/Akt signaling pathway was also investigated. Experimental analysis showed that PM20D1 levels were reduced in insulin-resistant 3T3-L1 cells and a letrozole PCOS-IR rat model. Reproductive function was inhibited, and endocrine metabolism was abnormal. The loss of adipocyte PM20D1 aggravated IR. In addition, PM20D1 and PI3K interacted with each other in the PCOS-IR model. Furthermore, the PI3K/Akt signaling pathway was shown to participate in lipid metabolism disorders and PCOS-IR regulation. Quercitrin reversed these reproductive and metabolic disorders.CONCLUSION: PM20D1 and PI3K/Akt were required for lipolysis and endocrine regulation in PCOS-IR to restore ovarian function and maintain normal endocrine metabolism. By upregulating the expression of PM20D1, quercitrin activated the PI3K/Akt signaling pathway, improved adipocyte catabolism, corrected reproductive and metabolic abnormalities, and had a therapeutic effect on PCOS-IR.PMID:37321077 | DOI:10.1016/j.phymed.2023.154908

BMC Bioinformatics. 2023 Jun 15;24(1):250. doi: 10.1186/s12859-023-05383-0.ABSTRACTMetabolomics is a dynamic tool for elucidating biochemical changes in human health and disease. Metabolic profiles provide a close insight into physiological states and are highly volatile to genetic and environmental perturbations. Variation in metabolic profiles can inform mechanisms of pathology, providing potential biomarkers for diagnosis and assessment of the risk of contracting a disease. With the advancement of high-throughput technologies, large-scale metabolomics data sources have become abundant. As such, careful statistical analysis of intricate metabolomics data is essential for deriving relevant and robust results that can be deployed in real-life clinical settings. Multiple tools have been developed for both data analysis and interpretations. In this review, we survey statistical approaches and corresponding statistical tools that are available for discovery of biomarkers using metabolomics.PMID:37322419 | DOI:10.1186/s12859-023-05383-0

Nat Immunol. 2023 Jun 15. doi: 10.1038/s41590-023-01513-1. Online ahead of print.ABSTRACTDespite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19.PMID:37322179 | DOI:10.1038/s41590-023-01513-1

Nat Commun. 2023 Jun 15;14(1):3566. doi: 10.1038/s41467-023-39372-x.NO ABSTRACTPMID:37322043 | DOI:10.1038/s41467-023-39372-x

Biochem Biophys Res Commun. 2023 Jun 7;671:292-300. doi: 10.1016/j.bbrc.2023.06.027. Online ahead of print.ABSTRACTAging adipose tissue exhibits elevated inflammation and oxidative stress that are major sources of age-related metabolic dysfunction. However, the exact metabolic changes associated with inflammation and oxidative stress are unclear. To address this topic, we assessed variation in metabolic phenotypes of adipose tissue from 18 months adult sedentary (ASED), 26 months old sedentary (OSED), and 8 months young sedentary (YSED). The results of metabolomic analysis showed that ASED and OSED group had higher palmitic acid, elaidic acid, 1-heptadecanol, and α-tocopherol levels than YSED, but lower sarcosine levels. Furthermore, stearic acid was specifically elevated in ASED compared with YSED. Cholesterol was upregulated specifically in the OSED group compared with YSED, whereas linoleic acid was downregulated. In addition, ASED and OSED had more inflammatory cytokines, lower antioxidant capacity, and higher expression of ferroptosis-related genes than YSED. Moreover, mitochondrial dysfunction associated with abnormal cardiolipin synthesis was more pronounced in the OSED group. In conclusion, both ASED and OSED can affect the FA metabolism and increase oxidative stress in adipose tissue, leading to inflammation. In particular, linoleic acid content specifically decreases in OSED, which associated with abnormal cardiolipin synthesis and mitochondrial dysfunction in adipose tissue.PMID:37320861 | DOI:10.1016/j.bbrc.2023.06.027

PLoS One. 2023 Jun 15;18(6):e0287121. doi: 10.1371/journal.pone.0287121. eCollection 2023.ABSTRACTMedulloblastoma is one of the most frequent malignant brain tumors in infancy and childhood. Early diagnosis and treatment are quite crucial for the prognosis. However, the pathogenesis of medulloblastoma is still not completely clarified. High-resolution mass spectrometry has enabled a comprehensive investigation on the mechanism of disease from the perspective of metabolism. Herein, we compared the difference of metabolic profiles of serum between medulloblastoma (n = 33) and healthy control (HC, n = 16) by using UPLC-Q/E-MS/MS. Principal component analysis and orthogonal projections to latent structures discriminant analysis (OPLS-DA) intuitively revealed the significantly distinct metabolic profiles between medulloblastoma and HC (p < 0.01 for permutation test on OPLS-DA model). Total of 25 significantly changed metabolites were identified. ROC analysis reported that six of them (Phosphatidic acid (8:0/15:0), 3'-Sialyllactose, Isocoproporphyrin, Acetylspermidine, Fructoseglycine and 3-Hydroxydodecanedioate) showed high specificity and precision to be potential diagnosis biomarkers (AUC > 0.98). Functional analysis discovered that there are four pathways notably perturbed for medulloblastoma. These pathways are related with the dysfunction of arachidonic acid metabolism, steroid hormone biosynthesis, and folate-related metabolism. The target intervention on these pathways may reduce the mortality of medulloblastoma.PMID:37319142 | DOI:10.1371/journal.pone.0287121

Proc Natl Acad Sci U S A. 2023 Jun 20;120(25):e2219373120. doi: 10.1073/pnas.2219373120. Epub 2023 Jun 15.ABSTRACTFungus-growing ants depend on a fungal mutualist that can fall prey to fungal pathogens. This mutualist is cultivated by these ants in structures called fungus gardens. Ants exhibit weeding behaviors that keep their fungus gardens healthy by physically removing compromised pieces. However, how ants detect diseases of their fungus gardens is unknown. Here, we applied the logic of Koch's postulates using environmental fungal community gene sequencing, fungal isolation, and laboratory infection experiments to establish that Trichoderma spp. can act as previously unrecognized pathogens of Trachymyrmex septentrionalis fungus gardens. Our environmental data showed that Trichoderma are the most abundant noncultivar fungi in wild T. septentrionalis fungus gardens. We further determined that metabolites produced by Trichoderma induce an ant weeding response that mirrors their response to live Trichoderma. Combining ant behavioral experiments with bioactivity-guided fractionation and statistical prioritization of metabolites in Trichoderma extracts demonstrated that T. septentrionalis ants weed in response to peptaibols, a specific class of secondary metabolites known to be produced by Trichoderma fungi. Similar assays conducted using purified peptaibols, including the two previously undescribed peptaibols trichokindins VIII and IX, suggested that weeding is likely induced by peptaibols as a class rather than by a single peptaibol metabolite. In addition to their presence in laboratory experiments, we detected peptaibols in wild fungus gardens. Our combination of environmental data and laboratory infection experiments strongly support that peptaibols act as chemical cues of Trichoderma pathogenesis in T. septentrionalis fungus gardens.PMID:37319116 | DOI:10.1073/pnas.2219373120

Anal Chem. 2023 Jun 15. doi: 10.1021/acs.analchem.3c00909. Online ahead of print.ABSTRACTAmino metabolites are essential for life activities and can be used clinically as biomarkers for disease diagnosis and treatment. Solid-phase-supported chemoselective probes can simplify sample handling and enhance detection sensitivity. However, the low efficiency and complicated preparation of traditional probes limit their further application. In this work, a novel solid-phase-supported probe Fe3O4-SiO2-polymers-phenyl isothiocyanate (FSP-PITC) was developed by immobilizing phenyl isothiocyanate on magnetic beads with disulfide as an orthogonal cleavage site, which can couple amino metabolites directly regardless of whether proteins and other matrixes were removed. After purification, the targeted metabolites were released by dithiothreitol and detected by high-resolution mass spectrometry. The simplified processing steps shorten the analysis time, and the introduction of polymers results in a 100-1000-fold increase in probe capacity. With high stability and specificity, FSP-PITC pretreatment allows accurate qualitative and quantitative (R2 > 0.99) analysis, facilitating the detection of metabolites in subfemtomole quantities. Using this strategy, 4158 metabolite signals were detected in negative ion mode. Among them, 352 amino metabolites including human cells (226), serum (227), and mouse samples (274) were searched from the Human Metabolome Database. These metabolites participate in metabolic pathways of amino acids, biogenic amine, and the urea cycle. All these results indicate that FSP-PITC is a promising probe for novel metabolite discovery and high-throughput screening.PMID:37318774 | DOI:10.1021/acs.analchem.3c00909

Biotechnol Lett. 2023 Jun 15. doi: 10.1007/s10529-023-03404-9. Online ahead of print.ABSTRACTPURPOSE: The accumulation of carbon dioxide during large-scale culture of animal cells brings adverse effects, appropriate aeration strategies alleviate CO2 accumulation while improper reactor operation may lead to the presence of low CO2 partial pressure (pCO2) condition as occurs in many industrial cases. Thus, this study aims to reveal the in-depth influence of low pCO2 on Chinese Hamster Ovary (CHO) cells for providing a reference for design space determination of CO2 control with regard to the Quality by Design (QbD) guidelines.METHODS AND RESULTS: The headspace air over purging caused the ultra-low pCO2 (ULC) where the monoclonal antibody production as well as the aerobic metabolic activity were reduced. Intracellular metabolomics analysis indicated a less efficient aerobic glucose metabolic state under ULC conditions. Based on the increase of intracellular pH and lactate dehydrogenase activity, the shortage of intracellular pyruvate could be the cause of the deficient aerobic metabolism, which could be partially mitigated by pyruvate addition under ULC conditions. Finally, a semi-empirical mathematical model was used to better understand, predict and control the occurrence of extreme pCO2 conditions during the cultures of CHO cells.CONCLUSION: Low pCO2 steers CHO cells into a defective metabolic state. A predictive relation among pCO2, lactate, and pH control was applied to get new insights into CHO cell culture for better and more robust metabolic behavior and process performance and the determination of QbD design space for CO2 control.PMID:37318718 | DOI:10.1007/s10529-023-03404-9

Appl Environ Microbiol. 2023 Jun 15:e0023823. doi: 10.1128/aem.00238-23. Online ahead of print.ABSTRACTMetabolic degeneracy describes the phenomenon that cells can use one substrate through different metabolic routes, while metabolic plasticity, refers to the ability of an organism to dynamically rewire its metabolism in response to changing physiological needs. A prime example for both phenomena is the dynamic switch between two alternative and seemingly degenerate acetyl-CoA assimilation routes in the alphaproteobacterium Paracoccus denitrificans Pd1222: the ethylmalonyl-CoA pathway (EMCP) and the glyoxylate cycle (GC). The EMCP and the GC each tightly control the balance between catabolism and anabolism by shifting flux away from the oxidation of acetyl-CoA in the tricarboxylic acid (TCA) cycle toward biomass formation. However, the simultaneous presence of both the EMCP and GC in P. denitrificans Pd1222 raises the question of how this apparent functional degeneracy is globally coordinated during growth. Here, we show that RamB, a transcription factor of the ScfR family, controls expression of the GC in P. denitrificans Pd1222. Combining genetic, molecular biological and biochemical approaches, we identify the binding motif of RamB and demonstrate that CoA-thioester intermediates of the EMCP directly bind to the protein. Overall, our study shows that the EMCP and the GC are metabolically and genetically linked with each other, demonstrating a thus far undescribed bacterial strategy to achieve metabolic plasticity, in which one seemingly degenerate metabolic pathway directly drives expression of the other. IMPORTANCE Carbon metabolism provides organisms with energy and building blocks for cellular functions and growth. The tight regulation between degradation and assimilation of carbon substrates is central for optimal growth. Understanding the underlying mechanisms of metabolic control in bacteria is of importance for applications in health (e.g., targeting of metabolic pathways with new antibiotics, development of resistances) and biotechnology (e.g., metabolic engineering, introduction of new-to-nature pathways). In this study, we use the alphaproteobacterium P. denitrificans as model organism to study functional degeneracy, a well-known phenomenon of bacteria to use the same carbon source through two different (competing) metabolic routes. We demonstrate that two seemingly degenerate central carbon metabolic pathways are metabolically and genetically linked with each other, which allows the organism to control the switch between them in a coordinated manner during growth. Our study elucidates the molecular basis of metabolic plasticity in central carbon metabolism, which improves our understanding of how bacterial metabolism is able to partition fluxes between anabolism and catabolism.PMID:37318336 | DOI:10.1128/aem.00238-23

Microbiol Spectr. 2023 Jun 15:e0002223. doi: 10.1128/spectrum.00022-23. Online ahead of print.ABSTRACTAlicyclobacillus acidoterrestris, which has strong acidophilic and heat-resistant properties, can cause spoilage of pasteurized acidic juice. The current study determined the physiological performance of A. acidoterrestris under acidic stress (pH 3.0) for 1 h. Metabolomic analysis was carried out to investigate the metabolic responses of A. acidoterrestris to acid stress, and integrative analysis with transcriptome data was also performed. Acid stress inhibited the growth of A. acidoterrestris and altered its metabolic profiles. In total, 63 differential metabolites, mainly enriched in amino acid metabolism, nucleotide metabolism, and energy metabolism, were identified between acid-stressed cells and the control. Integrated transcriptomic and metabolomic analysis revealed that A. acidoterrestris maintains intracellular pH (pHi) homeostasis by enhancing amino acids decarboxylation, urea hydrolysis, and energy supply, which was verified using real-time quantitative PCR and pHi measurement. Additionally, two-component systems, ABC transporters, and unsaturated fatty acid synthesis also play crucial roles in resisting acid stress. Finally, a model of the responses of A. acidoterrestris to acid stress was proposed. IMPORTANCE Fruit juice spoilage caused by A. acidoterrestris contamination has become a major concern and challenge in the food industry, and this bacterium has been suggested as a target microbe in the design of the pasteurization process. However, the response mechanisms of A. acidoterrestris to acid stress still remain unknown. In this study, integrative transcriptomic, metabolomic, and physiological approaches were used to uncover the global responses of A. acidoterrestris to acid stress for the first time. The obtained results can provide new insights into the acid stress responses of A. acidoterrestris, which will point out future possible directions for the effective control and application of A. acidoterrestris.PMID:37318333 | DOI:10.1128/spectrum.00022-23

J Agric Food Chem. 2023 Jun 15. doi: 10.1021/acs.jafc.3c01377. Online ahead of print.ABSTRACTHerbicide-resistant soybeans are among the most widely planted transgenic crops. The in situ evaluation of spatial lipidomics in transgenic and non-transgenic soybeans is important for directly assessing the unintended effects of exogenous gene introduction. In this study, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)-based non-targeted analytical strategies were used for the first time for in situ detection and imaging of endogenous lipid distributions in transgenic (EPSPS and PAT genes) herbicide-resistant soybean (Glycine max Merrill) (S4003.14) and non-transgenic soybean (JACK) seeds. Statistical analysis revealed significant differences in lipids between S4003.14 and JACK seeds. The variable importance of projection analysis further revealed that 18 identified lipids, including six phosphatidylcholines (PCs), four phosphatidylethanolamines (PEs), five triacylglycerols (TAGs), and three cytidine diphosphate-diacylglycerols (CDP-DAGs), had the strongest differential expression between S4003.14 and JACK seeds. Among those, the upregulated expressions of PC(P-36:1), PC(36:2), PC(P-36:0), PC(37:5), PE(40:2), TAG(52:1), TAG(55:5), and CDP-DAG(37:2) and the downregulated expressions of PC (36:1), TAG(43:0), and three PEs (i.e., PE(P-38:1), PE(P-38:0), and PE(P-40:3)) were successfully found in the S4003.14 seeds, compared to these lipids detected in the JACK seeds. Meanwhile, the lipids of PC (44:8), CDP-DAG(38:0), and CDP-DAG(42:0) were uniquely detected in the S4003.14 soybean seeds, and TAG(45:2) and TAG(57:10) were detected as the unique lipids in the JACK seeds. The heterogeneous distribution of these lipids in the soybean seeds was also clearly visualized using MALDI-MSI. MSI results showed that lipid expression was significantly up/downregulated in S4003.14 seeds, compared to that in JACK seeds. This study improves our understanding of the unintended effects of herbicide-resistant EPSPS and PAT gene transfers on spatial lipidomes in soybean seeds and enables the continued progression of MALDI-MSI as an emerging, reliable, and rapid molecular imaging tool for evaluating unintended effects in transgenic plants.PMID:37318082 | DOI:10.1021/acs.jafc.3c01377

J Exp Bot. 2023 Jun 15:erad230. doi: 10.1093/jxb/erad230. Online ahead of print.ABSTRACTFruit quality traits are determined to a large extent by their metabolome. The metabolite content of climacteric fruit changes drastically during ripening and postharvest storage and has been investigated extensively. However, the spatial distribution of metabolites and how it changes in time has received much less attention as fruit are usually considered as homogenous plant organs. Yet, spatio-temporal changes of starch, which is hydrolysed during ripening, has been used for ages as a ripening index. As vascular transport of water, and, hence, convective transport of metabolites slows down in mature fruit and even stalls after detachment, spatio-temporal changes in their concentration are likely affected by diffusive transport of gaseous molecules that act as substrate (O2), inhibitor (CO2) or regulator (ethylene, NO) of the metabolic pathways that are active during climacteric ripening. In this review we discuss such spatio-temporal changes of the metabolome and how they are affected by transport of metabolic gases and gaseous hormones. As there are currently no measurement techniques available to measure the metabolite distribution repeatedly by nondestructive means, we introduce reaction-diffusion models as an in silico tool to compute it. We show how the different components of such a model can be integrated and used to better understand the role of spatio-temporal changes of the metabolome in ripening and postharvest storage of climacteric fruit that is detached from the plant and discuss future research needs.PMID:37317945 | DOI:10.1093/jxb/erad230

Hosp Pediatr. 2023 Jun 15:e2022007012. doi: 10.1542/hpeds.2022-007012. Online ahead of print.ABSTRACTBiomarkers are commonly used in pediatric medicine to identify disease and guide clinical management for children. Biomarkers can be used to predict risk of disease, provide diagnostic clarification, and offer prognostic expectations. Specimens for biomarker testing might require noninvasive collection (eg, urine, exhaled breath) or invasive procedures (eg, blood, bronchoalveolar lavage) and testing might use various methodologies (eg, genomics, transcriptomics, proteomics, metabolomics). Specimen type and testing methodology depends on the disease of interest, ability to obtain sample, and availability of biomarker testing. To develop a new biomarker, researchers must first identify and validate the target, and then determine the test characteristics of the biomarker. Once it has undergone initial development and testing, a new biomarker is then tested in the clinical setting before being implemented into practice. An ideal biomarker is one that is feasible to obtain, readily quantifiable, and offers meaningful information that impacts care. Learning how to reliably interpret the performance and clinical application of a new biomarker is an important skillset for all pediatricians in the hospital setting. Here we provide a high-level overview of the process from biomarker discovery to application. In addition, we provide an example for the real-world application of biomarkers as an opportunity for clinicians to build on their ability to critically evaluate, interpret, and implement biomarkers in clinical practice.PMID:37317806 | DOI:10.1542/hpeds.2022-007012

Clin Transl Med. 2023 Jun;13(6):e1298. doi: 10.1002/ctm2.1298.ABSTRACTBACKGROUND: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease.AIM: The presented clinical setting highlights the unmet need for a precise molecular diagnosis of DTC and potential metastatic disease, which should dictate appropriate therapy.MATERIALS AND METHODS: In this article, we present a differential multi-omics model approach, including metabolomics, genomics, and bioinformatic models, to distinguish normal glands from thyroid tumours. Additionally, we are proposing biomarkers that could indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC.RESULTS: Normal and tumour thyroid tissue from DTC patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumour cells. The consistency of the DTC metabolic profile allowed us to build a bioinformatic classification model capable of clearly distinguishing normal from tumor thyroid tissues, which might help diagnose thyroid cancer. Moreover, based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intra-tumour heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease.DISCUSSION: Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy.CONCLUSIONS: Well-designed, prospective translational clinical trials will ultimately show the value of this integrated multi-omics approach and early diagnosis of DTC and potential metastatic PTC.PMID:37317665 | DOI:10.1002/ctm2.1298

J Pineal Res. 2023 Jun 15. doi: 10.1111/jpi.12892. Online ahead of print.ABSTRACTThe accelerated pace of life at the present time has resulted in tremendous alterations in living patterns. Changes in diet and eating patterns, in particular, coupled with irregular light-dark cycles (LD) will further induce circadian misalignment and lead to disease. Emerging data has highlighted the regulatory effects of diet and eating patterns on the host microbe interactions with the circadian clock (CC), immunity, and metabolism. Herein, we studied how LD cycles regulate the homeostatic crosstalk among the gut microbiome (GM), hypothalamic and hepatic CC oscillations, and immunity and metabolism using multi-omics approaches. Our data demonstrated that central CC oscillations lost rhythmicity under irregular LD cycles, but LD cycles had minimal effects on diurnal expression of peripheral CC genes in the liver including Bmal1. We further demonstrated that the GM could regulate hepatic circadian rhythms under irregular LD cycles, the candidate bacteria including Limosilactobacillus, Actinomyces, Veillonella, Prevotella, Campylobacter, Faecalibacterium, Kingella, Clostridia vadinBB60, Veillonella. A comparative transcriptomic study of innate immune genes indicated that different LD cycles had varying effects on immune functions, while irregular LD cycles had greater impacts on hepatic innate immune functions than those in the hypothalamus. Extreme LD cycle alterations (LD0/24 and LD24/0) had worse impacts than slight alterations (LD8/16 and LD16/8), and led to gut dysbiosis in mice receiving antibiotics. Metabolome data also demonstrated that hepatic tryptophan metabolism mediated the homeostatic crosstalk among GM-liver-brain axis in response to different LD cycles. These research findings highlighted that GM could regulate immune and metabolic disorders induced by circadian dysregulation. Further, the data provided potential targets for developing probiotics for individuals with circadian disruption such as shift workers. This article is protected by copyright. All rights reserved.PMID:37317652 | DOI:10.1111/jpi.12892