PubMed

Toxicol Appl Pharmacol. 2023 Mar 7:116451. doi: 10.1016/j.taap.2023.116451. Online ahead of print.ABSTRACTThe toxic effects of alcohol consumption on population health are significant worldwide and the synergistic toxic effects of concurrent intake of Acetaminophen and alcohol is of clinical concern. The understanding of molecular mechanisms beneath such synergism and acute toxicity may be enhanced through assessing underlying metabolomics changes. The molecular toxic activities of the model hereby, is assessed though metabolomics profile with a view to identifying metabolomics targets which could aid in the management of drug-alcohol interactions. In vivo exposure of C57/BL6 mice to APAP (70 mg/kg), single dose of ethanol (6 g/kg of 40%) and APAP after alcohol consumption was employed. Plasma samples were prepared and subjected to biphasic extraction for complete LC-MS profiling, and tandem mass MS2 analysis. Among the detected ions, 174 ions had significant (VIP scores >1 and FDR <0.05) changes between groups and were selected as potential biomarkers and significant variables. The presented metabolomics approach highlighted several affected metabolic pathways, including nucleotide and amino acid metabolism; aminoacyl-tRNA biosynthesis as well as bioenergetics of TCA and Krebs cycle. The impact of APAP on the concurrent administration of alcohol showed great biological interactions in the vital ATP and amino acid producing processes. The metabolomics changes show distinct metabolites which are altered to alcohol-APAP consumption while presenting several unneglectable risks on the vitality of metabolites and cellular molecules which shall be concerned.PMID:36894070 | DOI:10.1016/j.taap.2023.116451

Eur J Med Chem. 2023 Mar 3;251:115234. doi: 10.1016/j.ejmech.2023.115234. Online ahead of print.ABSTRACTP2X7R, which is a member of the purinergic P2 receptor family, is widely expressed in many immune cells, such as macrophages, lymphocytes, monocytes, and neutrophils. P2X7R is upregulated in response to proinflammatory stimulation, which is closely related to a variety of inflammatory diseases. The inhibition of P2X7 receptors has resulted in the elimination or reduction of symptoms in animal models of arthritis, depression, neuropathic pain, multiple sclerosis, and Alzheimer's disease. Therefore, the development of P2X7R antagonists is of great significance for the treatment of various inflammatory diseases. This review classifies the reported P2X7R antagonists according to their different cores, focuses on the structure-activity relationship (SAR) of the compounds, and analyzes some common substituents and strategies in the design of lead compounds, with the hope of providing valuable information for the development of new and efficient P2X7R antagonists.PMID:36893624 | DOI:10.1016/j.ejmech.2023.115234

Med Sci Sports Exerc. 2023 Feb 24. doi: 10.1249/MSS.0000000000003151. Online ahead of print.ABSTRACTPURPOSE: A ketone body (β-hydroxybutyrate [β-HB]) is used as an energy source in the peripheral tissues. However, the effects of acute β-HB supplementation on different modalities of exercise performance remain unclear. This study aimed to assess the effects of acute β-HB administration on the exercise performance of rats.METHODS: In Study 1, Sprague Dawley rats were randomly divided into six groups: endurance exercise (EE + PL and EE + KE), resistance exercise (RE + PL and RE + KE), and high-intensity intermittent exercise (HIIE+PL and HIIE+KE) with placebo (PL) or β-HB salt (KE) administration. In Study 2, metabolome analysis using capillary electrophoresis mass spectrometry was performed to profile the effects of β-HB salt administration on HIIE-induced metabolic responses in the skeletal and heart muscles.RESULTS: The maximal carrying capacity (rest for 3 min after each ladder climb, while carrying heavy weights until the rats could not climb) in the RE + KE group was higher than that in the RE + PL group. The maximum number of HIIE sessions (a 20-s swimming session with a 10-s rest between sessions, while bearing a weight equivalent to 16% of body weight) in the HIIE+KE group was higher than that in the HIIE+PL group. However, there was no significant difference in the time to exhaustion at 30 m/min between the EE + PL and EE + KE groups. Metabolome analysis showed that the overall tricarboxylic acid cycle and creatine phosphate levels in the skeletal muscle were higher in the HIIE+KE group than in the HIIE+PL group.CONCLUSIONS: These results indicate that acute β-HB salt administration may accelerate HIIE and RE performance, and the changes in metabolic responses in the skeletal muscle following β-HB salt administration may be involved in the enhancement of HIIE performance.PMID:36893302 | DOI:10.1249/MSS.0000000000003151

PLoS One. 2023 Mar 9;18(3):e0277293. doi: 10.1371/journal.pone.0277293. eCollection 2023.ABSTRACTThe medicinal plant Digitalis purpurea produces cardiac glycosides that are useful in the pharmaceutical industry. These bioactive compounds are in high demand due to ethnobotany's application to therapeutic procedures. Recent studies have investigated the role of integrative analysis of multi-omics data in understanding cellular metabolic status through systems metabolic engineering approach, as well as its application to genetically engineering metabolic pathways. In spite of numerous omics experiments, most molecular mechanisms involved in metabolic pathways biosynthesis in D. purpurea remain unclear. Using R Package Weighted Gene Co-expression Network Analysis, co-expression analysis was performed on the transcriptome and metabolome data. As a result of our study, we identified transcription factors, transcriptional regulators, protein kinases, transporters, non-coding RNAs, and hub genes that are involved in the production of secondary metabolites. Since jasmonates are involved in the biosynthesis of cardiac glycosides, the candidate genes for Scarecrow-Like Protein 14 (SCL14), Delta24-sterol reductase (DWF1), HYDRA1 (HYD1), and Jasmonate-ZIM domain3 (JAZ3) were validated under methyl jasmonate treatment (MeJA, 100 μM). Despite early induction of JAZ3, which affected downstream genes, it was dramatically suppressed after 48 hours. SCL14, which targets DWF1, and HYD1, which induces cholesterol and cardiac glycoside biosynthesis, were both promoted. The correlation between key genes and main metabolites and validation of expression patterns provide a unique insight into the biosynthesis mechanisms of cardiac glycosides in D. purpurea.PMID:36893121 | DOI:10.1371/journal.pone.0277293

J Agric Food Chem. 2023 Mar 9. doi: 10.1021/acs.jafc.3c00311. Online ahead of print.ABSTRACTPlants can recruit beneficial microbes to help improve their fitness under abiotic or biotic stress. Our previous studies found that Panax notoginseng could enrich beneficial Burkholderia sp. B36 in the rhizosphere soil under autotoxic ginsenoside stress. Here, we clarified that ginsenoside stress activated the phenylpropanoid biosynthesis and α-linolenic acid metabolism pathways of roots to increase the secretion of cinnamic acid, 2-dodecenoic acid, and 12-oxo-phytodienoic acid. These metabolites could promote the growth of B36. Importantly, cinnamic acid could simultaneously promote the chemotaxis and growth of B36, enhance the colonization of B36 in the rhizosphere, and eventually increase the survival rate of P. notoginseng. Overall, the plants could promote the growth and colonization of beneficial bacteria through key metabolites in root exudates under autotoxin stress. This finding will facilitate the practical application of beneficial bacteria in agricultural production and lead to successful and reproducible biocontrol efficacy by the exogenous addition of key metabolites.PMID:36893094 | DOI:10.1021/acs.jafc.3c00311

Curr Opin Clin Nutr Metab Care. 2023 Mar 1;26(2):189-194. doi: 10.1097/MCO.0000000000000908. Epub 2022 Dec 30.ABSTRACTPURPOSE OF REVIEW: An increase in the plant-based characteristics of the diet is now recommended for human and planetary health. There is growing evidence that plant protein (PP) intake has beneficial effects on cardiometabolic risk. However, proteins are not consumed isolated and the protein package (lipid species, fiber, vitamins, phytochemicals, etc) may contribute, besides the protein effects per se, to explain the beneficial effects associated with PP-rich diets.RECENT FINDINGS: Recent studies have shown the potential of nutrimetabolomics to apprehend the complexity of both the human metabolism and the dietary habits, by providing signatures associated to the consumption of PP-rich diets. Those signatures comprised an important proportion of metabolites that were representative of the protein package, including specific amino acids (branched-chain amino acids and their derivates, glycine, lysine), but also lipid species (lysophosphatidylcholine, phosphatidylcholine, plasmalogens) and polyphenol metabolites (catechin sulfate, conjugated valerolactones and phenolic acids).SUMMARY: Further studies are needed to go deeper in the identification of all metabolites making part of the specific metabolomic signatures, associated to the large range of protein package constituents and their effects on the endogenous metabolism, rather than to the protein fraction itself. The objective is to determine the bioactive metabolites, as well as the modulated metabolic pathways and the mechanisms responsible for the observed effects on cardiometabolic health.PMID:36892966 | DOI:10.1097/MCO.0000000000000908

J Appl Physiol (1985). 2023 Mar 9. doi: 10.1152/japplphysiol.00508.2022. Online ahead of print.ABSTRACTAngiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the non-canonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction and fibrosis. Pre-clinical evidence suggests that Ang (1-7) is a promising therapeutic target that may ameliorate physical and cognitive function in late life. However, treatment pharmacodynamics limits its clinical applicability. Therefore, this study explored the underlying mechanisms altered by a genetically modified probiotic (GMP) that expresses Ang (1-7) combined with and without exercise training in an aging male rat model as a potential adjunct strategy to exercise training to counteract the decline of physical and cognitive function. We evaluated cross-tissue (prefrontal cortex, hippocampus, colon, liver and skeletal muscle) multi-omics responses. After 12-weeks of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within and between groups. The probiotic treatment enhanced alpha diversity (Inverse Simpson (F[2,56] = 4.44; p = 0.02); Shannon-Wiener (F[2,56] = 4.27; p = 0.02)) and beta-diversity (F[2,56] = 2.66; p = 0.01) amongst rats receiving our GMP. The analysis of microbes' composition revealed 3 genera's altered by our GMP (Enterorhabdus, Muribaculaceae unclassified and Faecalitalea). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuro-remodeling pathways on prefrontal cortex (i.e., 140 genes), inflammation gene expression in the liver (i.e., 63 genes) and circadian rhythm signaling on skeletal muscle. Lastly, the integrative network analysis detected different communities of tightly (|r| > 0.8 and p < 0.05) correlated metabolites, genera's and genes in these tissues.PMID:36892893 | DOI:10.1152/japplphysiol.00508.2022

Metabolomics. 2023 Mar 9;19(3):17. doi: 10.1007/s11306-023-01979-y.ABSTRACTINTRODUCTION: Liverworts are a group of non-vascular plants that possess unique metabolism not found in other plants. Many liverwort metabolites have interesting structural and biochemical characteristics, however the fluctuations of these metabolites in response to stressors is largely unknown.OBJECTIVES: To investigate the metabolic stress-response of the leafy liverwort Radula complanata.METHODS: Five phytohormones were applied exogenously to in vitro cultured R. complanata and an untargeted metabolomic analysis was conducted. Compound classification and identification was performed with CANOPUS and SIRIUS while statistical analyses including PCA, ANOVA, and variable selection using BORUTA were conducted to identify metabolic shifts.RESULTS: It was found that R. complanata was predominantly composed of carboxylic acids and derivatives, followed by benzene and substituted derivatives, fatty acyls, organooxygen compounds, prenol lipids, and flavonoids. The PCA revealed that samples grouped based on the type of hormone applied, and the variable selection using BORUTA (Random Forest) revealed 71 identified and/or classified features that fluctuated with phytohormone application. The stress-response treatments largely reduced the production of the selected primary metabolites while the growth treatments resulted in increased production of these compounds. 4-(3-Methyl-2-butenyl)-5-phenethylbenzene-1,3-diol was identified as a biomarker for the growth treatments while GDP-hexose was identified as a biomarker for the stress-response treatments.CONCLUSION: Exogenous phytohormone application caused clear metabolic shifts in Radula complanata that deviate from the responses of vascular plants. Further identification of the selected metabolite features can reveal metabolic biomarkers unique to liverworts and provide more insight into liverwort stress responses.PMID:36892716 | DOI:10.1007/s11306-023-01979-y

Metabolomics. 2023 Mar 9;19(3):16. doi: 10.1007/s11306-023-01980-5.ABSTRACTINTRODUCTION: Compared to synthetic herbicides, natural products with allelochemical properties can inhibit weed germination, aiding agricultural output with less phytotoxic residue in water and soil.OBJECTIVES: To identify natural product extracts of three Cassia species; C. javanica, C. roxburghii, and C. fistula and to investigate the possible phytotoxic and allelopathic potential.METHODS: Allelopathic activity of three Cassia species extracts was evaluated. To further investigate the active constituents, untergated metabolomics using UPLC-qTOF-MS/MS and ion-identity molecular networking (IIMN) approach was performed to identify and determine the distribution of metabolites in different Cassia species and plant parts.RESULTS: We observed in our study that the plant extracts showed consistent allelopathic activity against seed germination (P < 0.05) and the inhibition of shoot and root development of Chenopodium murale in a dose-dependent manner. Our comprehensive study identified at least 127 compounds comprising flavonoids, coumarins, anthraquinones, phenolic acids, lipids, and fatty acid derivatives. We also report the inhibition of seed germination, shoot growth, and root growth when treated with enriched leaf and flower extracts of C. fistula, and C. javanica, and the leaf extract of C. roxburghii.CONCLUSION: The present study recommends further evaluation of Cassia extracts as a potential source of allelopathic compounds in agricultural systems.PMID:36892715 | DOI:10.1007/s11306-023-01980-5

Invest Ophthalmol Vis Sci. 2023 Mar 1;64(3):18. doi: 10.1167/iovs.64.3.18.ABSTRACTPURPOSE: Visual physiology and various ocular diseases demonstrate sexual dimorphisms; however, how sex influences metabolism in different eye tissues remains undetermined. This study aims to address common and tissue-specific sex differences in metabolism in the retina, RPE, lens, and brain under fed and fasted conditions.METHODS: After ad libitum fed or being deprived of food for 18 hours, mouse eye tissues (retina, RPE/choroid, and lens), brain, and plasma were harvested for targeted metabolomics. The data were analyzed with both partial least squares-discriminant analysis and volcano plot analysis.RESULTS: Among 133 metabolites that cover major metabolic pathways, we found 9 to 45 metabolites that are sex different in different tissues under the fed state and 6 to 18 metabolites under the fasted state. Among these sex-different metabolites, 33 were changed in 2 or more tissues, and 64 were tissue specific. Pantothenic acid, hypotaurine, and 4-hydroxyproline were the top commonly changed metabolites. The lens and the retina had the most tissue-specific, sex-different metabolites enriched in the metabolism of amino acid, nucleotide, lipids, and tricarboxylic acid cycle. The lens and the brain had more similar sex-different metabolites than other ocular tissues. The female RPE and female brain were more sensitive to fasting with more decreased metabolites in amino acid metabolism, tricarboxylic acid cycles, and glycolysis. The plasma had the fewest sex-different metabolites, with very few overlapping changes with tissues.CONCLUSIONS: Sex has a strong influence on eye and brain metabolism in tissue-specific and metabolic state-specific manners. Our findings may implicate the sexual dimorphisms in eye physiology and susceptibility to ocular diseases.PMID:36892534 | DOI:10.1167/iovs.64.3.18

Elife. 2023 Mar 9;12:e78877. doi: 10.7554/eLife.78877. Online ahead of print.ABSTRACTThere are no pharmacological disease-modifying treatments that have an enduring effect to mitigate the seizures and comorbidities associated with established chronic temporal lobe epilepsy (TLE). Sodium selenate has been reported to have anti-epileptogenic effects if given before TLE onset. However, the majority of TLE patients already have established epilepsy when they present to the clinic. This study aimed to evaluate for disease modifying effects of sodium selenate treatment in the chronically epileptic rat post-status epilepticus (SE) model of drug-resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, rats were randomly assigned to receive either sodium selenate, levetiracetam, or vehicle subcutaneous infusions continuously for 4 weeks. To evaluate the effects of the treatments, one week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length has emerged as a potential biomarker of chronic brain conditions, was investigated as a novel surrogate marker of epilepsy disease severity in our current study. The results showed that sodium selenate treatment was associated with mitigation of measures of disease severity at 8 weeks post-treatment cessation; reducing the number of spontaneous seizures (p< 0.05), cognitive dysfunction (p< 0.05 in both novel object placement and recognition tasks), and sensorimotor deficits (p< 0.01). Moreover, in the brain post-mortem selenate treatment was associated with increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening (p< 0.05). Network medicine integration of multi-omics/ pre-clinical outcomes identified protein-metabolite modules positively correlated with the TLE phenotype. Our results provide evidence that treatment with sodium selenate results in a sustained disease-modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.PMID:36892461 | DOI:10.7554/eLife.78877

Cancer Res. 2023 Mar 9:CAN-22-1999. doi: 10.1158/0008-5472.CAN-22-1999. Online ahead of print.ABSTRACTInduction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anti-cancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non-small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative TCA cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1-SREBP1-SCD5 axis to promote de novo monounsaturated fatty acid synthesis by utilizing acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared to either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC.PMID:36892426 | DOI:10.1158/0008-5472.CAN-22-1999

Biotechnol J. 2023 Mar 9:e2200243. doi: 10.1002/biot.202200243. Online ahead of print.ABSTRACTHydrolysates are used as media supplements although their role is not well characterized. In this study, cottonseed hydrolysates, which contained peptides and galactose as supplemental substrates, were added to CHO batch cultures, enhancing cell growth, IgG titers, and productivities. Extracellular metabolomics coupled with TMT proteomics revealed metabolic and proteomic changes in cottonseed-supplemented cultures. Shifts in production and consumption dynamics of glucose, glutamine, lactate, pyruvate, serine, glycine, glutamate and aspartate suggest changes in TCA and glycolysis metabolism following hydrolysate inputs. Quantitative proteomics revealed 5521 proteins and numerous changes in relative abundance of proteins related to growth, metabolism, oxidative stress, protein productivity, and apoptosis/cell death at day 5 and day 6. Differential abundance of amino acid transporter proteins and catabolism enzymes such as BCAT1 and FAH can alter availability and utilization of several amino acids. Also, pathways involved in growth including the polyamine biosynthesis through higher ODC1 abundance and hippo signaling were upregulated and downregulated, respectively. Central metabolism rewiring was indicated by GAPDH downregulation, which corresponded with re-uptake of secreted lactate in the cottonseed-supplemented cultures. Overall, cottonseed hydrolysate supplementation modified culture performance by altering cellular activities critical to growth and protein productivity including metabolism, transport, mitosis, transcription, translation, protein processing, and apoptosis. Cottonseed hydrolysate, as a medium additive, enhances CHO cell culture performance Metabolite profiling and TMT proteomics characterize its impact on CHO cells Rewired nutrient utilization is observed via glycolysis, amino acid and polyamine metabolism Hippo signaling pathway impacts cell growth in the presence of cottonseed hydrolysate This article is protected by copyright. All rights reserved.PMID:36892270 | DOI:10.1002/biot.202200243

J Am Heart Assoc. 2023 Mar 9:e027725. doi: 10.1161/JAHA.122.027725. Online ahead of print.NO ABSTRACTPMID:36892040 | DOI:10.1161/JAHA.122.027725

Int J Urol. 2023 Mar 9. doi: 10.1111/iju.15158. Online ahead of print.ABSTRACTOBJECTIVE: Post-transplantation diabetes mellitus (PTDM) is a common complication in renal transplant recipients (RTRs). Gut microbiome plays important roles in a variety of chronic metabolic diseases, but its association with the occurrence and development of PTDM is still unknown. The present study integrates the analysis of gut microbiome and metabolites to further identify the characteristics of PTDM.METHODS: A total of 100 RTRs fecal samples were collected in our study. Among them, 55 samples were submitted to Hiseq sequencing, and 100 samples were used for non-targeted metabolomics analysis. The gut microbiome and metabolomics of RTRs were comprehensively characterized.RESULTS: The species Dialister invisus was significantly associated with fasting plasma glucose (FPG). The functions of tryptophan and phenylalanine biosynthesis were enhanced in RTRs with PTDM, while the functions of fructose and butyric acid metabolism were reduced. Fecal metabolome analysis indicated that RTRs with PTDM had unique metabolite distribution characteristics, and two differentially expressed specific metabolites were significantly correlated with FPG. The correlation analysis of gut microbiome and metabolites showed that gut microbiome had an obvious effect on the metabolic characteristics of RTRs with PTDM. Moreover, the relative abundance of microbial function is associated with the expression of several specific gut microbiome and metabolites.CONCLUSIONS: Our study identified the characteristics of gut microbiome and fecal metabolites in RTRs with PTDM, and we also found two important metabolites and a bacterium were significantly associated with PTDM, which might be used as novel targets in the research field of PTDM.PMID:36892039 | DOI:10.1111/iju.15158

Chem Biodivers. 2023 Mar 9:e202201082. doi: 10.1002/cbdv.202201082. Online ahead of print.ABSTRACTIn order to investigate the differences in the chemical composition of Dendrobium officinale at different altitudes, we collected Dendrobium officinale from different altitudes in Guizhou Province, China, and firstly determined its polysaccharide content by using a sulphuric acid-phenol colour development method with reference to the Chinese Pharmacopoeia, and further determined its metabolites by using widely targeted metabolomics, and explored the differences in the chemical composition of Dendrobium officinale at different altitudes using multivariate statistical analysis. We found that the polysaccharide content was higher in plants growing at 1122 m, a total of 902 secondary metabolites were detected by wildly targeted metabolomics, and amino acids and their derivatives were more highly expressed at 1122 m, while other metabolites were more highly expressed at 835 m. Furthermore, we found that the phenolic acid compound nerugein was only present in plants at 835 m, and two lipid compounds, namely Lyso PE 20:4 and its isomer, were only present at 1122 m. Taken together, these results may provide a basis for the selection and clinical application of D. officinale cultivated at different altitudes.PMID:36891987 | DOI:10.1002/cbdv.202201082

Elife. 2023 Mar 9;12:e86416. doi: 10.7554/eLife.86416.ABSTRACTExpanding a statistical approach called Mendelian randomization to include multiple variables may help researchers to identify new molecular causes of specific traits.PMID:36891986 | DOI:10.7554/eLife.86416

Elife. 2023 Mar 9;12:e81097. doi: 10.7554/eLife.81097.ABSTRACTDespite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 216 transcript-metabolite-trait causal triplets involving 26 medically relevant phenotypes. Among these associations, 58% were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. This allowed the identification of biologically relevant pathways, such as between ANKH and calcium levels mediated by citrate levels and SLC6A12 and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found, thanks to the increase in power conferred by integrating multiple omics layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes.PMID:36891970 | DOI:10.7554/eLife.81097

Plant Cell Environ. 2023 Mar 9. doi: 10.1111/pce.14578. Online ahead of print.ABSTRACTSalt stress is a major environmental factor limiting crop growth and productivity. Here, we show that Salt-Tolerant Gene 1 (ZmSTG1) contributes to salt tolerance by maintaining photosystem activity in maize. ZmSTG1 encodes an endoplasmic reticulum localized protein and retrotransposon insertion in the promoter region causes differential expression levels in maize inbred lines. Overexpression of ZmSTG1 improved plant growth vigor, and knockout of ZmSTG1 weakened plant growth under normal and salt stress conditions. Transcriptome and metabolome analyses indicated that ZmSTG1 might regulate the expression of lipid trafficking-related genes dependent on the ABA signalling pathway, thereby increasing the galactolipids and phospholipid concentrations in the photosynthetic membrane under salt stress. Chlorophyll fluorescence parameters showed that the knockout of ZmSTG1 led to significant impairment of plant photosystem II (PSII) activity under normal and salt stress conditions, whereas overexpression of ZmSTG1 dramatically improved plant PSII activity under salt stress conditions. We also demonstrated that the application of the salt-tolerant locus could enhance salt tolerance in hybrid maize plants. Taken together, we propose that ZmSTG1 may modulate the lipid composition in the photosynthetic membrane by affecting the expression of lipid trafficking-related genes to maintain the photosynthetic activity of plants under salt stress. This article is protected by copyright. All rights reserved.PMID:36891878 | DOI:10.1111/pce.14578

Plant Physiol. 2023 Mar 9:kiad151. doi: 10.1093/plphys/kiad151. Online ahead of print.ABSTRACTETHYLENE-INSENSITIVE 3/ETHYLENE-INSENSITIVE 3-LIKEs (EIN3/EILs) are important ethylene response factors during fruit ripening. Here, we discovered that EIL2 controls carotenoid metabolism and ascorbic acid (AsA) biosynthesis in tomato (Solanum lycopersicum). In contrast to the red fruits presented in the wild type (WT) 45 days after pollination, the fruits of CRISPR/Cas9 eil2 mutants and SlEIL2 RNAi lines (ERIs) showed yellow or orange fruits. Correlation analysis of transcriptome and metabolome data for the ERI and WT ripe fruits revealed that SlEIL2 is involved in β-carotene and AsA accumulation. ETHYLENE RESPONSE FACTORs (ERFs) are the typical components downstream from EIN3 in the ethylene response pathway. Through a comprehensive screening of ERF family members, we determined that SlEIL2 directly regulates the expression of four SlERFs. Two of these, SlERF.H30 and SlERF.G6, encode proteins that participate in the regulation of LYCOPENE-β-CYCLASE 2 (SlLCYB2), encoding an enzyme that mediates the conversion of lycopene to carotene in fruits. In addition, SlEIL2 transcriptionally repressed L-GALACTOSE 1-PHOSPHATE PHOSPHATASE 3 (SlGPP3) and MYO-INOSITOL OXYGENASE 1 (SlMIOX1) expression, which resulted in 1.62 fold increase of AsA via both the L-galactose and myoinositol pathways. Overall, we demonstrated that SlEIL2 functions in controlling β-carotene and AsA levels, providing a potential strategy for genetic engineering to improve the nutritional value and quality of tomato fruit.PMID:36891812 | DOI:10.1093/plphys/kiad151