PubMed

Biomed Pharmacother. 2023 Oct 9;168:115678. doi: 10.1016/j.biopha.2023.115678. Online ahead of print.ABSTRACTAcute lung injury (ALI) is a serious illness with a high mortality rate of 40-60%. It is characterised by systemic inflammatory processes and oxidative stress. Gram-negative bacterial infections are the major cause of ALI, and lipopolysaccharide (LPS) is the major stimulus for the release of inflammatory mediators. Hence, there is an urgent need to develop new therapies which ameliorate ALI and prevent its serious consequences. The Middle Eastern native plant Tamarix nilotica (Ehrenb) Bunge belongs to the family Tamaricaceae, which exhibits strong anti-inflammatory and antioxidant effects. Thus, the current work aimed to ensure the plausible beneficial effects of T. nilotica different fractions on LPS-induced acute lung injury after elucidating their phytochemical constituents using LC/MS analysis. Mice were randomly allocated into six groups: Control saline, LPS group, and four groups treated with total extract, DCM, EtOAc and n-butanol fractions, respectively, intraperitoneal at 100 mg/kg doses 30 min before LPS injection. The lung expression of iNOS, TGF-β1, NOX-1, NOX-4 and GPX-1 levels were evaluated. Also, oxidative stress was assessed via measurements of MDA, SOD and Catalase activity, and histopathological and immunohistochemical investigation of TNF-α in lung tissues were performed. T. nilotica n-butanol fraction caused a significant downregulation in iNOS, TGF-β1, TNF-α, NOX-1, NOX-4, and MDA levels (p ˂ 0.05), and significantly elevated GPX-1 expression levels, SOD, and catalase activity (p ˂ 0.05), and alleviated all histopathological abnormalities confirming its advantageous role in ALI. The antibacterial activities of T. nilotica and its different fractions were investigated by agar well diffusion method and broth microdilution method. Interestingly, the n-butanol fraction exhibited the best antibacterial activity against Klebsiella pneumoniae clinical isolates. It also significantly reduced exopolysaccharide quantity, cell surface hydrophobicity, and biofilm formation.PMID:37820564 | DOI:10.1016/j.biopha.2023.115678

J Pharm Biomed Anal. 2023 Oct 4;237:115766. doi: 10.1016/j.jpba.2023.115766. Online ahead of print.ABSTRACTBaicalin has various neuroprotective effects in models of nervous system disease. Our study has shown baicalin could alleviate depressive-like behaviors in a neuroendocrine mouse model. But the systematic metabolic characteristic and particular targets of baicalin in regulating depressive behaviors have never been investigated. Therefore, this study aims to reveal the hippocampal metabolic profiling of chronic unpredictable mild stress (CUMS) induced depressive rats and the potential metabolic variations after baicalin treatment. We first used the sucrose preference test and open field test to access the antidepressant effects of baicalin. Then, metabolites of the hippocampus after baicalin therapy were monitored by widely-targeted metabolomics based on ultra-performance liquid chromatography-tandem mass spectrometry technology. Finally, the potential mechanism associated with neurogenesis obtained from metabolomics was verified by immunohistochemistry. The results showed that baicalin(40,80 mg/kg) could significantly alleviate depressive behaviors induced by CUMS as demonstrated by an increase in sucrose preference and movement distance and stand-up times in open field test. In the metabolomic analysis, a total of 733 metabolites were identified after baicalin treatment including 15 differential metabolites such as organic acid and its derivatives, heterocyclic compounds, fatty acid, bile acids, amino acid and its metabolites, and so on. Enrichment for differential metabolites showed that the differential metabolites might be involved in the process of folate and cofactor biosynthesis, cholesterol metabolism, primary bile acid biosynthesis, tyrosine metabolism and dopaminergic synapse. Moreover, immunohistochemical analysis confirmed baicalin could facilitate hippocampal neurogenesis of depressive rats in CUMS model. These results suggested baicalin might exert antidepressant effects through regulating the differential metabolites which might play a crucial role in inhibiting oxidative stress and improving neurogenesis. Our findings wish to discover the potential mechanism of baicalin on depression from the metabolomics perspective and promote its clinical application.PMID:37820491 | DOI:10.1016/j.jpba.2023.115766

Ecotoxicol Environ Saf. 2023 Oct 9;266:115558. doi: 10.1016/j.ecoenv.2023.115558. Online ahead of print.ABSTRACTThe persistent organic pollutant 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), a prevalent congener among polybrominated diphenyl ethers (PBDEs), exhibits potent bioaccumulation and toxicity. Despite extensive research into the adverse effects of BDE-47, its neurotoxicity in sea cucumbers remains unexplored. Given the crucial role of the sea cucumber's nervous system in survival and adaptation, evaluating the impacts of BDE-47 is vital for sustainable aquaculture and consumption. In this study, we employed ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Triple-TOF-MS) to analyze metabolomic changes in neuro-related tissues of Apostichopus japonicus exposed to low (0.1 µg/L), medium (1.0 µg/L), and high (10.0 µg/L) BDE-47 concentrations. We identified significantly changed metabolites in each exposure group (87 in low, 79 in medium, and 102 in high), affecting a variety of physiological processes such as steroid hormone balance, nucleotide metabolism, energy metabolism, neurotransmitter levels, and neuroprotection. In addition, we identified concentration-dependent, common, and some other metabolic responses in the neuro-related tissues. Our findings reveal critical insights into the neurotoxic effects of BDE-47 in sea cucumbers and contribute to risk assessment related to BDE-47 exposure in the sea cucumber industry, paving the way for future neurotoxicological research in invertebrates.PMID:37820477 | DOI:10.1016/j.ecoenv.2023.115558

Ecotoxicol Environ Saf. 2023 Oct 9;266:115557. doi: 10.1016/j.ecoenv.2023.115557. Online ahead of print.ABSTRACTPesticide stress on plants is receiving increased scrutiny due to its effect on plant secondary metabolism and nutritional quality. Tannic acid (TA) is a natural polyphenolic compound showing excellent antioxidant properties and is involved in alleviating stress. The present study thoroughly investigated the effects and mechanism of exogenous TA on relieving imidacloprid (IMI) stress in tea plants. Our research found that TA(10 mg/L) activated the antioxidant defense system, enhanced the antioxidant ability, reduced the accumulation of ROS and membrane peroxidation, and notably promoted tea plant tolerance to imidacloprid stress. Additionally, TA boosted photosynthetic capacity, strengthened the accumulation of nutrients. regulated detoxification metabolism, and accelerated the digestion and metabolism of imidacloprid in tea plants. Furthermore, TA induced significant changes in 90 important metabolites in tea, targeting 17 metabolic pathways through extensively targeted metabolomics. Specifically, TA activated the flavonoid biosynthetic pathway, resulting in a 1.3- to 3.1-fold increase in the levels of 17 compounds and a 1.5- to 63.8-fold increase in the transcript level of related genes, such as ANR, LAR and CHS in this pathway. As a potential tea health activator, TA alleviates the oxidative damage caused by imidacloprid and improves the yield and quality of tea under pesticide stress.PMID:37820476 | DOI:10.1016/j.ecoenv.2023.115557

Phytomedicine. 2023 Sep 22;121:155117. doi: 10.1016/j.phymed.2023.155117. Online ahead of print.ABSTRACTBACKGROUND: Effective drugs for the treatment of hepatic fibrosis have not yet been identified. Isovitexin (IVT) is a promising hepatoprotective agent owing to its efficacy against acute liver injury. However, the role of IVT in liver fibrosis has not been reported.PURPOSE: To explore the effect of IVT on liver fibrosis both in vitro and in vivo.STUDY DESIGN AND METHODS: A mouse model of liver fibrosis induced by carbon tetrachloride (CCl4) and two types of hepatic stellate cell models induced by platelet-derived growth factor-BB (PDGF-BB) were established to evaluate the effect of IVT on hepatic fibrosis. Transcriptomics and metabolomics were used to predict the underlying targets of IVT and were validated by a combination of in vitro and in vivo experiments. Exploration of miRNA and N6-methyladenosine (m6A) modifications was also carried out to detect the key upstream targets of the above targets.RESULTS: IVT reduced collagen deposition and hepatic stellate cell activation to alleviate liver fibrosis. The transcriptomics and metabolomics analyses showed that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling and the glutathione (GSH) metabolic pathway may be the main regulatory processes of IVT in hepatic fibrosis. Both the in vitro and in vivo experiments confirmed the inhibitory effect of IVT on the PTEN-PI3K-Akt-mTOR axis and activation of the GSH metabolic pathway. A miR-21 mimic inhibited the effects of IVT on these two pathways, suggesting that miR-21 is the hub for IVT regulation of PI3K-Akt signaling and the GSH metabolic pathway. IVT also increased pri-miR-21 level and reduced the m6A enrichment of pri-miR-21, demonstrating that IVT may regulate pri-miR-21 through m6A modification, thereby affecting the maturation of miR-21.CONCLUSION: This study is the first to propose a protective effect of IVT against liver fibrosis. The mechanism of IVT against hepatic fibrosis is based on the regulation of miR-21, targeting PTEN-Akt signaling and the GSH metabolic pathway, which is also a novel discovery.PMID:37820467 | DOI:10.1016/j.phymed.2023.155117

Atherosclerosis. 2023 Sep 27;383:117316. doi: 10.1016/j.atherosclerosis.2023.117316. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: During fat tolerance tests, plasma triglycerides increase while high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein (IDL) cholesterol decrease. However, it is unknown whether triglyceride content increases and cholesterol content decreases in HDL and LDL + IDL fractions following normal meals in the general population. Therefore, we tested the hypothesis that triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions following normal meals.METHODS: In this cross-sectional study, we included 25,656 individuals aged 20-100 years, all without lipid-lowering therapy at examination and selected for metabolomic profiling from the Copenhagen General Population Study. Triglyceride and cholesterol content of 14 lipoprotein fractions weas measured using nuclear magnetic resonance (NMR) spectroscopy. Time since last meal was recorded by the examiner immediately before blood sampling.RESULTS: Following normal meals in age and sex-adjusted analyses and when compared with fasting levels, plasma triglycerides were higher for up to 5-6 h, and triglyceride content was higher for up to 6-7 h in HDL fractions, for up to 6-7 h in LDL + IDL fractions, and for up to 5-6 h in very-low-density lipoprotein (VLDL) fractions. Further, plasma cholesterol was lower for up to 2-3 h, and cholesterol content was lower for up to 0-1 h in HDL fractions and for up to 4-5 h in LDL + IDL fractions, while cholesterol content was higher for up to 4-5 h in VLDL fractions.CONCLUSIONS: Following normal meals, triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions.PMID:37820443 | DOI:10.1016/j.atherosclerosis.2023.117316

Hepatol Commun. 2023 Oct 12;7(11):e0294. doi: 10.1097/HC9.0000000000000294. eCollection 2023 Nov 1.ABSTRACTBACKGROUND: It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape.METHODS: We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance.RESULTS: Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies.CONCLUSIONS: HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.PMID:37820280 | DOI:10.1097/HC9.0000000000000294

Crit Rev Food Sci Nutr. 2023 Oct 11:1-14. doi: 10.1080/10408398.2023.2267133. Online ahead of print.ABSTRACTHigher intakes of cruciferous and allium vegetables are associated with a lower risk of cardiometabolic-related outcomes in observational studies. Whilst acknowledging the many healthy compounds within these vegetables, animal studies indicate that some of these beneficial effects may be partially mediated by S-methyl cysteine sulfoxide (SMCSO), a sulfur-rich, non-protein, amino acid found almost exclusively within cruciferous and alliums. This scoping review explores evidence for SMCSO, its potential roles in human health and possible mechanistic action. After systematically searching several databases (EMBASE, MEDLINE, SCOPUS, CINAHL Plus Full Text, Agricultural Science), we identified 21 original research articles meeting our inclusion criteria. These were limited primarily to animal and in vitro models, with 14/21 (67%) indicating favorable anti-hyperglycemic, anti-hypercholesterolemic, and antioxidant properties. Potential mechanisms included increased bile acid and sterol excretion, altered glucose- and cholesterol-related enzymes, and improved hepatic and pancreatic β-cell function. Raising antioxidant defenses may help mitigate the oxidative damage observed in these pathologies. Anticancer and antibacterial effects were also explored, along with one steroidogenic study. SMCSO is frequently overlooked as a potential mediator to the benefits of sulfur-rich vegetables. More research into the health benefits of SMCSO, especially for cardiometabolic and inflammatory-based pathology, is warranted. Human studies are especially needed.PMID:37819533 | DOI:10.1080/10408398.2023.2267133

Plant Cell Rep. 2023 Oct 11. doi: 10.1007/s00299-023-03080-z. Online ahead of print.ABSTRACTOsSPL10 is a negative regulator of rice defense against BPH, knockout of OsSPL10 enhances BPH resistance through upregulation of defense-related genes and accumulation of secondary metabolites. Rice (Oryza sativa L.), one of the most important staple foods worldwide, is frequently attacked by various herbivores, including brown planthopper (BPH, Nilaparvata lugens). BPH is a typical monophagous, phloem-sucking herbivore that has been a substantial threat to rice production and global food security. Understanding the regulatory mechanism of defense responses to BPH is essential for improving BPH resistance in rice. In this study, a SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE 10 (OsSPL10) transcription factor was found to play a negative role in the defenses of rice against BPH. To gain insights into the molecular and biochemical mechanisms of OsSPL10, we performed combined analyses of transcriptome and metabolome, and revealed that knockout of OsSPL10 gene improved rice resistance against BPH by enhancing the direct and indirect defenses. Genes involved in plant hormone signal transduction, MAPK signaling pathway, phenylpropanoid biosynthesis, and plant-pathogen interaction pathway were significantly upregulated in spl10 mutant. Moreover, spl10 mutant exhibited increased accumulation of defense-related secondary metabolites in the phenylpropanoid and terpenoid pathways. Our findings reveal a novel role for OsSPL10 gene in regulating the rice defense responses, which can be used as a potential target for genetic improvement of BPH resistance in rice.PMID:37819387 | DOI:10.1007/s00299-023-03080-z

Eur J Prev Cardiol. 2023 Oct 11;30(Supplement_2):ii2-ii8. doi: 10.1093/eurjpc/zwad227.ABSTRACTIn this review, we describe the structure and function of the alveolar-capillary membrane and the identification of a novel potential marker of its integrity in the context of heart failure (HF). The alveolar-capillary membrane is indeed a crucial structure for the maintenance of the lung parenchyma gas exchange capacity, and the occurrence of pathological conditions determining lung fluids accumulation, such as HF, might significantly impair lung diffusion capacity altering the alveolar-capillary membrane protective functions. In the years, we found that the presence of immature forms of the surfactant protein-type B (proSP-B) in the circulation reflects alterations in the alveolar-capillary membrane integrity. We discussed our main achievements showing that proSP-B, due to its chemical properties, specifically binds to high-density lipoprotein, impairing their antioxidant activity, and likely contributing to the progression of the disease. Further, we found that immature proSP-B, not the mature protein, is related to lung abnormalities, more precisely than the lung function parameters. Thus, to the list of the potential proposed markers of HF, we add proSP-B, which represents a precise marker of alveolar-capillary membrane dysfunction in HF, correlates with prognosis, and represents a precocious marker of drug therapy.PMID:37819226 | DOI:10.1093/eurjpc/zwad227

Microbiol Spectr. 2023 Oct 11:e0534922. doi: 10.1128/spectrum.05349-22. Online ahead of print.ABSTRACTThe human gut microbiome is engaged in biological homeostasis in the gut-liver axis and across multi-organs. The aim of this study is to investigate the therapeutic effects of human gut-derived microbes, Bacteroides species on liver cirrhosis in a mouse model. The experiment was performed on male mice, which were divided into five groups: normal control (NC), disease control, Bacteroides dorei-, Bacteroides cellulosilyticus-, and ursodeoxycholic acid-supplemented groups after 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. The therapeutic effect was evaluated based on liver physiology and the expression level of hepatic fibrosis. Untargeted and targeted metabolic profiling was conducted on cecal, fecal, liver, and serum samples using ultra-performance liquid-chromatography coupled with high-resolution mass-spectrometry. The gut microbial taxonomic composition was analyzed by 16S rRNA gene amplicon sequencing from the stool of each mice group. The Bacteroides treatment improved the liver/body weight ratio and normalized hepatic fibrosis biomarkers, including COL1A1. The fecal metabolome showed the most distinctive and characteristic profiles according to different treatments, compared to other sample matrices (cecum, liver, and blood). Key metabolites were identified, which indicated the potential therapeutic effect of the B. dorei treatment. Among them, a short-chain fatty acid, propionic acid, showed consistent upregulation in the cecum and liver after the B. dorei treatment. Microbiome analysis showed that Akkermansia muciniphila was retained in the group treated with B. dorei at a similar level as in the NC group. Our current multiomics study of systemic dynamics demonstrated that Bacteroides species, particularly B. dorei, ameliorated liver cirrhosis by modulating the metabolic and microbial environment to the normal state within the gut-liver axis. IMPORTANCE The human gut microbiome mediates bidirectional interaction within the gut-liver axis, while liver diseases, including liver cirrhosis, are very closely related to the state of the gut environment. Thus, improving the health of the gut-liver axis by targeting the intestinal microbiota is a potential therapeutic approach in hepatic diseases. This study examines changes in metabolomics and microbiome composition by treating bacteria derived from the human gut in mice with liver cirrhosis. Interorgan-based multiomics profiling coupled with functional examination demonstrated that the treatment of Bacteroides dorei pertained to protective effects on liver cirrhosis by normalizing the functional, metabolic, and metagenomic environment through the gut-liver axis. The study provides the potential value of a multiomics-based and interorgan-targeted evaluation platform for the comprehensive examination and mechanistic understanding of a wide range of biologics, including gut microbes. Furthermore, the current finding also suggests in-depth future research focusing on the discovery and validation of next-generation probiotics and products (postbiotics).PMID:37819146 | DOI:10.1128/spectrum.05349-22

Nucleic Acids Res. 2023 Oct 11:gkad811. doi: 10.1093/nar/gkad811. Online ahead of print.ABSTRACTThe Plant Metabolome Hub (PMhub), available at https://pmhub.org.cn, is a valuable resource designed to provide scientists with comprehensive information on plant metabolites. It offers extensive details about their reference spectra, genetic foundations, chemical reactions, metabolic pathways and biological functions. The PMhub contains chemical data for 188 837 plant metabolites gathered from various sources, with 1 467 041 standard/in-silico high-resolution tandem mass-spectrometry (HRMS/MS) spectra corresponding to these metabolites. Beyond its extensive literature-derived data, PMhub also boasts a sizable collection of experimental metabolites; it contains 144 366 detected features in 10 typical plant species, with 16 423 successfully annotated by using standard/in-silico HRMS/MS data, this collection is further supplemented with thousands of features gathered from reference metabolites. For each metabolite, the PMhub enables the reconstructed of a simulated network based on structural similarities and existing metabolic pathways. Unlike previous plant-specific metabolome databases, PMhub not only contains a vast amount of metabolic data but also assembles the corresponding genomic and/or transcriptomic information, incorporating multiple methods for the comprehensive genetic analysis of metabolites. To validate the practicality, we verified a synthetic pathway for N-p-coumaroyltyramine by in vitro enzymatic activity experiments. In summary, the robust functionality provided by the PMhub will make it an indispensable tool for studying plant metabolomics.PMID:37819039 | DOI:10.1093/nar/gkad811

Cardiovasc Res. 2023 Oct 11:cvad157. doi: 10.1093/cvr/cvad157. Online ahead of print.ABSTRACTAIM: Empagliflozin (EMPA), a potent inhibitor of the renal sodium-glucose cotransporter 2 (SGLT2) and an effective treatment for type-2 diabetes, has been shown to have cardioprotective effects, independent of improved glycaemic control. Several non-canonical mechanisms have been proposed to explain these cardiac effects, including increasing circulating ketone supply to the heart. This study aims to test whether EMPA directly alters cardiac ketone metabolism independent of supply.METHODS AND RESULTS: The direct effects of EMPA on cardiac function and metabolomics were investigated in Langendorff rat heart perfused in buffer containing 5 mM glucose, 4 mM β-hydroxybutyrate (βHb) and 0.4 mM intralipid, subject to low flow ischaemia/reperfusion. Cardiac energetics were monitored in situ using 31P NMR spectroscopy. Steady-state 13C-labelling was performed by switching 12C substrates for 13C1 glucose or 13C4 βHb, and 13C incorporation into metabolites determined using 2D 1H-13C HSQC NMR spectroscopy. EMPA treatment improved left ventricular developed pressure during ischaemia and reperfusion compared to vehicle-treated hearts. In EMPA-treated hearts, total ATP and PCr levels, and Gibbs free energy for ATP hydrolysis were significantly higher during ischaemia and reperfusion. EMPA treatment did not alter the incorporation of 13C from glucose into glycolytic products lactate or alanine neither during ischaemia nor reperfusion. In ischaemia, EMPA led to a decrease in 13C1 glucose incorporation and a concurrent increase in 13C4 βHb incorporation into TCA intermediates succinate, citrate, and glutamate. During reperfusion, the concentration of metabolites originating from 13C1 glucose was similar to vehicle but those originating from 13C4 βHb remained elevated in EMPA treated hearts.CONCLUSIONS: Our findings indicate that EMPA causes a switch in metabolism away from glucose oxidation towards increased ketone utilisation in the rat heart, thereby improving function and energetics both during ischaemia and recovery during reperfusion. This preference of ketone utilisation over glucose was observed under conditions of constant supply of substrate, suggesting that EMPA acts directly by modulating cardiac substrate preference, independent of substrate availability. The mechanisms underlying our findings are currently unknown, warranting further study.TRANSLATIONAL PERSPECTIVE: Heart failure remains a huge clinical burden. Clinical trials of SGLT2 inhibitors in patients with diabetes and heart failure have reported significant cardio-protection from EMPA treatment that appears independent of improved glycaemic control. The direct cardiac effect of EMPA in modulating ketone metabolism observed in this study raises the potential for EMPA to be used as a therapy for heart failure in both diabetic and non-diabetic patients alike.PMID:37819017 | DOI:10.1093/cvr/cvad157

Plant Cell. 2023 Oct 11:koad251. doi: 10.1093/plcell/koad251. Online ahead of print.ABSTRACTThe epidermal cells of petunia (Petunia × hybrida) flowers are the main site of volatile emission. However, the mechanisms underlying the release of volatiles into the environment are still being explored. Here, using cell-layer-specific transcriptomic analysis, reverse genetics by VIGS and CRISPR, and metabolomics, we identified EPIDERMIS VOLATILE EMISSION REGULATOR (EVER)-a petal adaxial epidermis-specific MYB activator that affects the emission of volatiles. To generate ever knockout lines, we developed a viral-based CRISPR/Cas9 system for efficient gene-editing in plants. These knockout lines, together with transient-suppression assays, revealed EVER's involvement in the repression of low-vapor-pressure volatiles. Internal pools and annotated scent-related genes involved in volatile production and emission were not affected by EVER. RNA-Seq analyses of petals of ever knockout lines and EVER-overexpressing flowers revealed enrichment in wax-related biosynthesis genes. LC/GC-MS analyses of petal epicuticular waxes revealed substantial reductions in wax loads in ever petals, particularly of monomers of fatty acids and wax esters. These results implicate EVER in the emission of volatiles by fine-tuning the composition of petal epicuticular waxes. We reveal a petunia MYB regulator that interlinks epicuticular wax composition and volatile emission, thus unraveling a regulatory layer in the scent-emission machinery in petunia flowers.PMID:37818992 | DOI:10.1093/plcell/koad251

Circ Res. 2023 Oct 11. doi: 10.1161/CIRCRESAHA.123.323517. Online ahead of print.ABSTRACTBACKGROUND: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis.METHODS: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain.RESULTS: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury.CONCLUSIONS: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.PMID:37818671 | DOI:10.1161/CIRCRESAHA.123.323517

Clin Sci (Lond). 2023 Oct 11:CS20230788. doi: 10.1042/CS20230788. Online ahead of print.ABSTRACTDietary fructose is widely used in beverages, processed foods, and Western diets as food additives, and is closely related to the increased prevalence of multiple diseases, including inflammatory bowel disease (IBD). However, the detailed mechanism by which high fructose disrupts intestinal homeostasis remains elusive. This study showed that high fructose corn syrup (HFCS) administration exacerbated intestinal inflammation and deteriorated barrier integrity. Several in vivo experimental models were utilized to verify the importance of gut microbiota and immune cells in HFCS-mediated dextran sulfate sodium (DSS)-induced colitis. In addition, untargeted metabolomics analysis revealed the imbalance between primary bile acids (PBAs) and secondary bile acids (SBAs) in feces. Hence, high fructose was speculated to modulate gut microbiota community and reduced the relative abundance of Clostridium and Clostridium scindens at genus and species level respectively, followed by a decrease in SBAs, especially isoalloLCA, thereby affecting Th17/Treg cells equilibrium and promoting intestinal inflammation. These findings provide novel insights into the crosstalk between gut flora, bile acids, and mucosal immunity, and highlight potential strategies for precise treatment of IBD.PMID:37818653 | DOI:10.1042/CS20230788

J Nematol. 2023 Aug 29;55(1):20230030. doi: 10.2478/jofnem-2023-0030. eCollection 2023 Feb.ABSTRACTWe previously reported soybean fields double-cropped with winter wheat having reduced soybean cyst nematode (SCN) (Heterodera glycines) counts compared to fallow. A follow-up metagenomics study identified several fungal and bacterial taxa enriched in wheat fields, and some were reported to parasitize SCN. Knowing that phytocompounds with potential nematicidal activity are released via wheat roots and stubble, we implemented a dichloromethane-based extraction method and a gas chromatography-mass spectrometry (GCMS) system to investigate soil chemical profiles of samples collected from these fields and review the potential nematicidal activity of compounds with higher concentration in double cropping fields. 51 compounds were detected during the GCMS analysis, eight with unknown identification. Several compounds, including multiple fatty acids, had larger relative peak areas when double-cropped, compared to fallow samples. This study, along with our previously published one, provided a better understanding of the mechanisms that govern the effect of wheat on SCN populations. Rather than driven by a single mechanism, the suppression of SCN in soybean fields double-cropped with winter wheat was potentially linked to enriched microbial communities, increased populations of beneficial organisms, and higher concentrations of chemicals with potential nematicidal activity. To our knowledge, this is the first study using GCMS to characterize soil chemical profiles in soybean fields double-cropped with winter wheat regarding the suppression of SCN populations.PMID:37818528 | PMC:PMC10561077 | DOI:10.2478/jofnem-2023-0030

J Endocr Soc. 2023 Sep 21;7(11):bvad122. doi: 10.1210/jendso/bvad122. eCollection 2023 Oct 9.ABSTRACTCONTEXT: Hyperglucagonemia may develop in type 2 diabetes due to obesity-prone hepatic steatosis (glucagon resistance). Markers of glucagon resistance (including the glucagon-alanine index) improve following diet-induced weight loss, but the partial contribution of lowering hepatic steatosis vs body weight is unknown.OBJECTIVE: This work aimed to investigate the dependency of body weight loss following a reduction in hepatic steatosis on markers of glucagon resistance in type 2 diabetes.METHODS: A post hoc analysis was conducted from 2 previously published randomized controlled trials. We investigated the effect of weight maintenance (study 1: isocaloric feeding) or weight loss (study 2: hypocaloric feeding), both of which induced reductions in hepatic steatosis, on markers of glucagon sensitivity, including the glucagon-alanine index measured using a validated enzyme-linked immunosorbent assay and metabolomics in 94 individuals (n = 28 in study 1; n = 66 in study 2). Individuals with overweight or obesity with type 2 diabetes were randomly assigned to a 6-week conventional diabetes (CD) or carbohydrate-reduced high-protein (CRHP) diet within both isocaloric and hypocaloric feeding-interventions.RESULTS: By design, weight loss was greater after hypocaloric compared to isocaloric feeding, but both diets caused similar reductions in hepatic steatosis, allowing us to investigate the effect of reducing hepatic steatosis with or without a clinically relevant weight loss on markers of glucagon resistance. The glucagon-alanine index improved following hypocaloric, but not isocaloric, feeding, independently of macronutrient composition.CONCLUSION: Improvements in glucagon resistance may depend on body weight loss in patients with type 2 diabetes.PMID:37818402 | PMC:PMC10561012 | DOI:10.1210/jendso/bvad122

Front Immunol. 2023 Sep 25;14:1230772. doi: 10.3389/fimmu.2023.1230772. eCollection 2023.ABSTRACTMacrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. In vitro macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1- and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM- and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for in vitro macrophage studies.PMID:37818352 | PMC:PMC10560851 | DOI:10.3389/fimmu.2023.1230772

Front Plant Sci. 2023 Sep 25;14:1271303. doi: 10.3389/fpls.2023.1271303. eCollection 2023.ABSTRACTINTRODUCTION: Leptochloa chinensis is an annual weed in paddy fields, which can engage in competition with rice, leading to a severe yield reduction. However, theunderlying mechanism governing this interaction remain unknown.METHODS: In this study, we investigated the mutual inhibition between rice and the weed undermono-culture and co-culture conditions. We found that the root exudates of both species played essential roles in mediating the mutual inhibition. Further metabolomic analysis identified a significant number of differential metabolites. These metabolites were predominantly enriched in the phenylpropanoid and flavonoid biosynthesis pathways in weed and rice. Transcriptomic analysis revealed that the differentially expressed genes responding to the interaction were also enriched in these pathways.RESULTS: Phenylpropanoid and flavonoid biosynthesis pathways are associated with allelopathy, indicating their pivotal role in the response of rice-weed mutual inhibition.DISCUSSION: Our findings shed light on the conserved molecular responses of rice and L. chinensis during theirinteraction, provide evidence to dissect the mechanisms underlying the allelopathic interaction and offer potential strategies for weed management in rice paddies.PMID:37818319 | PMC:PMC10560989 | DOI:10.3389/fpls.2023.1271303