PubMed

Free Radic Biol Med. 2023 May 3:S0891-5849(23)00408-2. doi: 10.1016/j.freeradbiomed.2023.05.004. Online ahead of print.ABSTRACTInfluenza A virus can induce nasal inflammation by stimulating the death of nasal mucosa epithelium, however, the mechanism is not clear. In this study, to study the causes and mechanisms of nasal mucosa epithelial cell death caused by Influenza A virus H1N1, we isolated and cultured human nasal epithelial progenitor cells (hNEPCs) and exposed them to H1N1 virus after leading differentiation. Then we performed high-resolution untargeted metabolomics and RNAseq analysis of human nasal epithelial cells (hNECs) infected with H1N1 virus. Surprisingly, H1N1 virus infection caused the differential expression of a large number of ferroptosis related genes and metabolites in hNECs. Furthermore, we have observed a significant reduction in Nrf2/KEAP1 expression, GCLC expression, and abnormal glutaminolysis. By constructing overexpression vector of GCLC and the shRNAs of GCLC and Keap1, we determined the role of NRF2-KEAP1-GCLC signaling pathway in H1N1 virus-induced ferroptosis. In addition, A glutaminase antagonist, JHU-083, also demonstrated that glutaminolysis can regulate the NRF2-KEAP1-GCLC signal pathway and ferroptosis. According to this study, H1N1 virus can induce the ferroptosis of hNECs via the NRF2-KEAP1-GCLC signal pathway and glutaminolysis, leading to nasal mucosal epithelial inflammation. This discovery is expected to provide an attractive therapeutic target for viral-induced nasal inflammation.PMID:37146698 | DOI:10.1016/j.freeradbiomed.2023.05.004

Aquat Toxicol. 2023 Mar 9;259:106479. doi: 10.1016/j.aquatox.2023.106479. Online ahead of print.ABSTRACTMethamphetamine (MEA) is commonly detected in municipal wastewater. It causes imbalances in the system of neurotransmitters as well as several other adverse effects on human health. The aim of this study was to investigate bioconcentration and depuration rates at an environmentally relevant concentration of 1 µg·L-1 in Aeshna cyanea nymphs exposed to MEA for six days followed by three days of depuration. The metabolomes of nymphs sampled during exposure and depuration were compared using non-targeted screening. Concurrently, a behavioural experiment was run to evaluate the effect of MEA on movement. Since most samples were below the limits of quantification (LOQs) - MEA was quantified in only four out of the 87 samples and only during the first 24 h of exposure at concentrations at LOQ level - we estimated maximal possible bioconcentration factor (BCF) on 0.63 using the LOQ. An MEA metabolite - amphetamine - was not detected in any sample at levels above their LOQs. From 247 up to 1458 significant down- and up-regulated metabolite signals (p ≤ 0.05) were detected by non-targeted screening during initial times of exposure and depuration. Numbers of significant down- and/or up-regulated signals in metabolomes (p ≤ 0.05) calculated for particular sampling times possibly correlated with the size of the effect on movement recorded at the same times. In the MEA treatment, movement was not significantly greater during exposure (p > 0.05) but was significantly lower during depuration (p < 0.05). This study shows how MEA acts on dragonfly nymphs, an ecologically important group of aquatic insects with a high trophic level.PMID:37146511 | DOI:10.1016/j.aquatox.2023.106479

J Pharm Biomed Anal. 2023 Apr 25;232:115419. doi: 10.1016/j.jpba.2023.115419. Online ahead of print.ABSTRACTDepression is a psychiatric disorder and confers an enormous burden on society. Mild to moderate forms of depression (MMD) are particularly common. Our previous studies showed that the Shuganjieyu (SGJY) capsule might improve depressive and cognitive symptoms in patients with MMD. However, biomarkers evaluating the efficacy of SGJY and the underlying mechanism remains unclear. The aim of the present study was to discover efficacy biomarkers and explore the underlying mechanisms of SGJY as antidepression treatment. Twenty-three patients with MMD were recruited and administered with SGJY for 8 weeks. Results showed that the content of 19 metabolites changed significantly in the plasma of patients with MMD, among which 8 metabolites improved significantly after SGJY treatment. Network pharmacology analysis showed that 19 active compounds, 102 potential targets, and 73 enzymes were related to the mechanistic action of SGJY. Through a comprehensive analysis, we identified four hub enzymes (GLS2, GLS, GLUL, and ADC), three key differential metabolites (glutamine, glutamate, and arginine), and two shared pathways (alanine, aspartate, and glutamate metabolism; and arginine biosynthesis). Receiver operating characteristic curve (ROC) analysis showed that the three metabolites had a high diagnostic ability. The expression of hub enzymes was validated using RT-qPCR in animal models. Overall, glutamate, glutamine, and arginine may be potential biomarkers for evaluating the efficacy of SGJY. The present study provides a new strategy for pharmacodynamic evaluation and mechanistic study of SGJY, and offers new information for clinical practice and treatment research.PMID:37146496 | DOI:10.1016/j.jpba.2023.115419

Comp Biochem Physiol Part D Genomics Proteomics. 2023 Apr 20;46:101079. doi: 10.1016/j.cbd.2023.101079. Online ahead of print.ABSTRACTThe molecular mechanisms underlying the stress response are poorly described in crustaceans. This includes the snow crab (Chionoecetes opilio), a commercially important stenotherm species distributed throughout the northern hemisphere. A better understanding of the stress response in C. opilio is desperately needed for commercial and conservation purposes. The purpose of this study was to investigate the transcriptional and metabolomic response of C. opilio exposed to stressors. Crabs were randomly assigned to 24 or 72 h treatment groups where they were exposed to conditions simulating live transport (handling and air exposure). A control group was kept in cold (2 °C) and well‑oxygenated saltwater. The hepatopancreas of the crabs was sampled to perform RNA-sequencing and high-performance chemical isotope labeling metabolomics. Differential gene expression analyses showed that classic crustaceans' stress markers, such as crustacean hyperglycemic hormones and heat shock proteins, were overexpressed in response to stressors. Tyrosine decarboxylase was also up-regulated in stressed crabs, suggesting an implication of the catecholamines tyramine and octopamine in the stress response. Deregulated metabolites revealed that low oxygen was an important trigger in the stress response as intermediate metabolites of the tricarboxylic acid cycle (TCA) accumulated. Lactate, which accumulated unevenly between crabs could potentially be used to predict mortality. This study provides new information on how stressors affect crustaceans and provides a basis for the development of stress markers in C. opilio.PMID:37146452 | DOI:10.1016/j.cbd.2023.101079

J Hazard Mater. 2023 Apr 28;454:131537. doi: 10.1016/j.jhazmat.2023.131537. Online ahead of print.ABSTRACTAs a potential bioremediation strain for Pb contamination, Penicillium oxalicum SL2 sometimes has secondary activation of Pb, so it is crucial to clarify its effect on Pb morphology and its intracellular response to Pb stress. We investigated the effect of P. oxalicum SL2 in medium on Pb2+ and Pb availability in eight minerals, and revealed the prioritization of Pb products. (i)Pb was stabilized within 30 days as Pb3(PO4)2 or Pb5(PO4)3Cl with sufficient phosphorus (P); (ii) under P deficiency but sulfur (S) sufficient, Pb was stabilized mainly in the form of PbSO4; (iii) under conditions of P and S deficiency, Pb was stabilized mainly in the form of PbC2O2. With the help of proteomic and metabolomics analysis, a total of 578 different proteins and 194 different metabolites were found to be matched in 52 pathways. Among them, the activation of chitin synthesis, oxalate production, sulfur metabolism and transporters improved the Pb tolerance of P. oxalicum SL2, and promoted the synergistic effect of extracellular adsorption, bio-precipitation and transmembrane transport on Pb stabilization. Our results fill the gap in the intracellular response of P. oxalicum SL2 to Pb and provide new insights into the development of bioremediation agent and technology for Pb contamination.PMID:37146333 | DOI:10.1016/j.jhazmat.2023.131537

Anal Chem. 2023 May 5. doi: 10.1021/acs.analchem.2c03432. Online ahead of print.ABSTRACTHere, we have documented a new protocol to determine d/l-amino acids by derivatizing amino acids via a chiral phosphinate. (RP)-l-Menthyl phenylphosphinate was able to bond both primary and secondary amines, as well as improve the sensitivity of analytes in MS. Eighteen pairs of amino acids were successfully labeled except for Cys which has a thiol group on the side chain, and the chirality of amino acids can be discriminated by 31P NMR. Seventeen pairs of amino acids were separated by a C18 column within 45 min of elution, and resolution values ranged from 2.01 to 10.76. The lowest limit of detection was 10 pM acquired at parallel reaction monitoring, in which two factors collectively contributed that the ability of protonation of phosphine oxide and the sensitivity of parallel reaction monitoring. Chiral phosphine oxides might be a promising tool in future chiral metabolomics.PMID:37145419 | DOI:10.1021/acs.analchem.2c03432

Int Microbiol. 2023 May 5. doi: 10.1007/s10123-023-00363-z. Online ahead of print.ABSTRACTThe gut microbiota is closely related to the development of sepsis. The aim of this study was to explore changes in the gut microbiota and gut metabolism, as well as potential relationships between the gut microbiota and environmental factors in the early stages of sepsis. Fecal samples were collected from 10 septic patients on the first and third days following diagnosis in this study. The results showed that in the early stages of sepsis, the gut microbiota is dominated by microorganisms that are tightly associated with inflammation, such as Escherichia-Shigella, Enterococcus, Enterobacteriaceae, and Streptococcus. On sepsis day 3 compared to day 1, there was a significant decrease in Lactobacillus and Bacteroides and a significant increase in Enterobacteriaceae, Streptococcus, and Parabacteroides. Culturomica_massiliensis, Prevotella_7 spp., Prevotellaceae, and Pediococcus showed significant differences in abundance on sepsis day 1, but not on sepsis day 3. Additionally, 2-keto-isovaleric acid 1 and 4-hydroxy-6-methyl-2-pyrone metabolites significantly increased on sepsis day 3 compared to day 1. Prevotella_7 spp. was positively correlated with phosphate and negatively correlated with 2-keto-isovaleric acid 1 and 3-hydroxypropionic acid 1, while Prevotella_9 spp. was positively correlated with sequential organ failure assessment score, procalcitonin and intensive care unit stay time. In conclusion, the gut microbiota and metabolites are altered during sepsis, with some beneficial microorganisms decreasing and some pathogenic microorganisms increasing. Furthermore, Prevotellaceae members may play different roles in the intestinal tract, with Prevotella_7 spp. potentially possessing beneficial health properties and Prevotella_9 spp. potentially playing a promoting role in sepsis.PMID:37145385 | DOI:10.1007/s10123-023-00363-z

J Sci Food Agric. 2023 May 5. doi: 10.1002/jsfa.12690. Online ahead of print.ABSTRACTBACKGROUND: Mycoplasma hyorhinis is a prevalent respiratory pathogen in swine, causing significant economic loss to pig producers. There is growing evidence that respiratory pathogen infections have a great impact on intestinal microecology. To study the effect of M. hyorhinis infection on gut microbial composition and metabolome profile, we infected pigs with M. hyorhinis and performed metagenomic sequencing analysis of fecal sample and liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of gut digesta.RESULTS: RESULTS: It is discovered that pigs infected with M. hyorhinis can enrich Sutterella and Mailhella, and deplete Dechloromonas, Succinatimonas, Campylobacter, Blastocystis, Treponema and Megasphaera. Moreover, the M. hyorhinis infected pigs had higher abundances of bacterium_0_1xD8_71, Ruminococcus_sp__CAG_353, Firmicutes_bacterium_CAG_194, Firmicutes_bacterium_CAG_534, bacterium_1xD42_87, etc., and lower abundances of Chlamydia_suis, Megasphaera_elsdenii, Treponema_porcinum, Bacteroides_sp__CAG_1060, Faecalibacterium_prausnitzii, etc. Metabolomics analysis revealed that some lipids and lipid-like molecules were increased in small intestine, while most of lipids and lipid-like molecules metabolites were decreased in large intestine. These altered metabolites induce changes in intestinal sphingolipid metabolism, amino acid metabolism and thiamine metabolism.CONCLUSION: These findings demonstrate that the pigs infection with M. hyorhinis can alter the gut microbial composition and metabolites structure, which may further affect amino acid metabolism and lipid metabolism in intestine. This article is protected by copyright. All rights reserved.PMID:37145100 | DOI:10.1002/jsfa.12690

Mol Carcinog. 2023 May 5. doi: 10.1002/mc.23551. Online ahead of print.ABSTRACTKirsten rat sarcoma virus (KRAS) oncogene, found in 20%-25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS-mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant human lung cancer. LC-MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS-mutant H358 non-small cell lung cancer cells. Furthermore, l-methionine (methyl-13 C) isotope tracer was used to explore the effect of belinostat on one-carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α-ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino-succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. 13 C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2-regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.PMID:37144836 | DOI:10.1002/mc.23551

Adv Sci (Weinh). 2023 May 5:e2301661. doi: 10.1002/advs.202301661. Online ahead of print.ABSTRACTIntratumoral CD8+ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.PMID:37144520 | DOI:10.1002/advs.202301661

Infect Drug Resist. 2023 Apr 28;16:2573-2588. doi: 10.2147/IDR.S407335. eCollection 2023.ABSTRACTPURPOSE: To assess the metabolites associated with Pseudomonas aeruginosa infection by analyzing the microbial diversity and metabolomics in lower respiratory tract of bronchiectasis patients and to explore the therapeutic approaches for Pseudomonas aeruginosa infection.METHODS: Bronchoalveolar lavage fluid samples from bronchiectasis patients and controls were analyzed by 16S rRNA and ITS sequencing, and metabolomic analysis was performed by liquid chromatography/mass spectrometry. A co-culture model of air-liquid interface cultured human bronchial epithelial cell with Pseudomonas aeruginosa was constructed to verify the correlation between sphingosine metabolism, acid ceramidase expression, and Pseudomonas aeruginosa infection.RESULTS: After screening, 54 bronchiectasis patients and 12 healthy controls were included. Sphingosine levels in bronchoalveolar lavage fluid were positively correlated with lower respiratory tract microbial diversity and negatively correlated with the abundance of Pseudomonas spp. Moreover, sphingosine levels in bronchoalveolar lavage fluid and acid ceramidase expression levels in lung tissue specimens were significantly lower in bronchiectasis patients than in healthy controls. Sphingosine levels and acid ceramidase expression levels were also significantly lower in bronchiectasis patients with positive Pseudomonas aeruginosa cultures than in bronchiectasis patients without Pseudomonas aeruginosa infection. Acid ceramidase expression in air-liquid interface cultured human bronchial epithelial cell had significantly increased after 6 h of Pseudomonas aeruginosa infection, while it had decreased significantly after 24 h of infection. In vitro experiments showed that sphingosine had a bactericidal effect on Pseudomonas aeruginosa by directly disrupting its cell wall and cell membrane. Furthermore, adherence of Pseudomonas aeruginosa on bronchial epithelial cells was significantly reduced after sphingosine supplementation.CONCLUSION: Down-regulation of acid ceramidase expression in airway epithelial cells of bronchiectasis patients leads to insufficient metabolism of sphingosine, which has a bactericidal effect, and consequently weakens the clearance of Pseudomonas aeruginosa; thus, a vicious circle is formed. Exogenous supplementation with sphingosine aids bronchial epithelial cells in resisting Pseudomonas aeruginosa infection.PMID:37144155 | PMC:PMC10153545 | DOI:10.2147/IDR.S407335

Front Pediatr. 2023 Apr 18;11:1130179. doi: 10.3389/fped.2023.1130179. eCollection 2023.ABSTRACTBACKGROUND: Human milk (HM) is the ideal source of nutrients for infants. Its composition is highly variable according to the infant's needs. When not enough own mother's milk (OMM) is available, the administration of pasteurized donor human milk (DHM) is considered a suitable alternative for preterm infants. This study protocol describes the NUTRISHIELD clinical study. The main objective of this study is to compare the % weight gain/month in preterm and term infants exclusively receiving either OMM or DHM. Other secondary aims comprise the evaluation of the influence of diet, lifestyle habits, psychological stress, and pasteurization on the milk composition, and how it modulates infant's growth, health, and development.METHODS AND DESIGN: NUTRISHIELD is a prospective mother-infant birth cohort in the Spanish-Mediterranean area including three groups: preterm infants <32 weeks of gestation (i) exclusively receiving (i.e., >80% of total intake) OMM, and (ii) exclusively receiving DHM, and (iii) term infants exclusively receiving OMM, as well as their mothers. Biological samples and nutritional, clinical, and anthropometric characteristics are collected at six time points covering the period from birth and until six months of infant's age. The genotype, metabolome, and microbiota as well as the HM composition are characterized. Portable sensor prototypes for the analysis of HM and urine are benchmarked. Additionally, maternal psychosocial status is measured at the beginning of the study and at month six. Mother-infant postpartum bonding and parental stress are also examined. At six months, infant neurodevelopment scales are applied. Mother's concerns and attitudes to breastfeeding are registered through a specific questionnaire.DISCUSSION: NUTRISHIELD provides an in-depth longitudinal study of the mother-infant-microbiota triad combining multiple biological matrices, newly developed analytical methods, and ad-hoc designed sensor prototypes with a wide range of clinical outcome measures. Data obtained from this study will be used to train a machine-learning algorithm for providing dietary advice to lactating mothers and will be implemented in a user-friendly platform based on a combination of user-provided information and biomarker analysis. A better understanding of the factors affecting milk's composition, together with the health implications for infants plays an important role in developing improved strategies of nutraceutical management in infant care.CLINICAL TRIAL REGISTRATION: https://register.clinicaltrials.gov, identifier: NCT05646940.PMID:37144153 | PMC:PMC10151649 | DOI:10.3389/fped.2023.1130179

Front Plant Sci. 2023 Apr 18;14:1181861. doi: 10.3389/fpls.2023.1181861. eCollection 2023.ABSTRACTObesity has become one of the major threats to human health across the globe. The rhizomes of Polygonatum sibiricum have shown promising anti-obesity effect. However, the metabolic and genetic basis mediating this beneficial effect are not fully resolved. It is well known that older rhizomes of P. sibiricum exert stronger pharmacological effects. Here, we performed high-resolution metabolome profiling of P. sibiricum rhizomes at different growth stages, and identified that three candidate anti-obesity metabolites, namely phloretin, linoleic acid and α-linolenic acid, accumulated more in adult rhizomes. To elucidate the genetic basis controlling the accumulation of these metabolites, we performed transcriptome profiling of rhizomes from juvenile and adult P. sibiricum. Through third-generation long-read sequencing, we built a high-quality transcript pool of P. sibiricum, and resolved the genetic pathways involved in the biosynthesis and metabolism of phloretin, linoleic acid and α-linolenic acid. Comparative transcriptome analysis revealed altered expression of the genetic pathways in adult rhizomes, which likely lead to higher accumulation of these candidate metabolites. Overall, we identified several metabolic and genetic signatures related to the anti-obesity effect of P. sibiricum. The metabolic and transcriptional datasets generated in this work could also facilitate future research on other beneficial effects of this medicinal plant.PMID:37143889 | PMC:PMC10151794 | DOI:10.3389/fpls.2023.1181861

Front Plant Sci. 2023 Apr 18;14:1114266. doi: 10.3389/fpls.2023.1114266. eCollection 2023.ABSTRACTINTRODUCTION: Salinization affects more than 25% of the world's arable land, and Tamarix ramosissima Ledeb (T. ramosissima), the representative of Tamarix plants, is widely grown in salinized soil. In contrast, less is known about the mechanism of potassium's antioxidative enzyme activity in preventing NaCl stress damage to plants.METHOD: This study examined changes in root growth for T. ramosissima at 0h, 48h, and 168h, performed antioxidant enzyme activity assays, transcriptome sequencing, and non-targeted metabolite analysis to understand changes in their roots as well as changes in the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). Quantitative real-time PCR (qRT-PCR) was used to identify differentially expressed genes (DEGs) and differential metabolites associated with antioxidant enzyme activities.RESULT: As the time increased, the results showed that compared with the 200 Mm NaCl group, the root growth of the 200 mM NaCl + 10 mM KCl group increased, the activities of SOD, POD and CAT increased the most, but the contents of hydrogen peroxide (H2O2) and Malondialdehyde (MDA) increased less. Meanwhile, 58 DEGs related to SOD, POD and CAT activities were changed during the application of exogenous K+ for 48h and 168h in T. ramosissima. Based on association analysis of transcriptomic and metabolomic data, we found coniferyl alcohol, which can act as a substrate to label catalytic POD. It is worth noting that Unigene0013825 and Unigene0014843, as POD-related genes, have positively regulated the downstream of coniferyl alcohol, and they have a significant correlation with coniferyl alcohol.DISCUSSION: In summary, 48h and 168h of exogenous K+ applied to the roots of T. ramosissima under NaCl stress can resist NaCl stress by scavenging the reactive oxygen species (ROS) generated by high salt stress by enhancing the mechanism of antioxidant enzyme activity, relieving NaCl toxicity and maintaining growth. This study provides genetic resources and a scientific theoretical basis for further breeding of salt-tolerant Tamarix plants and the molecular mechanism of K+ alleviating NaCl toxicity.PMID:37143868 | PMC:PMC10151674 | DOI:10.3389/fpls.2023.1114266

Front Endocrinol (Lausanne). 2023 Apr 18;14:1129162. doi: 10.3389/fendo.2023.1129162. eCollection 2023.ABSTRACTTargeting tumor cell metabolism is a new frontier in cancer management. Thus, metabolic pathway inhibitors could be used as anti-estrogen receptor α (ERα) breast cancer (BC) drugs. Here, the interplay among metabolic enzyme(s), the ERα levels and cell proliferation was studied. siRNA-based screen directed against different metabolic proteins in MCF10a, MCF-7 and MCF-7 cells genetically resistant to endocrine therapy (ET) drugs and metabolomic analyses in numerous BC cell lines unveil that the inhibition of GART, a key enzyme in the purine de novo biosynthetic pathway, induces ERα degradation and prevent BC cell proliferation. We report here that a reduced GART expression correlates with a longer relapse-free-survival (RFS) in women with ERα-positive BCs. ERα-expressing luminal A invasive ductal carcinomas (IDCs) are sensitive to GART inhibition and GART expression is increased in receptor-positive IDCs of high grade and stage and plays a role in the development of ET resistance. Accordingly, GART inhibition reduces ERα stability and cell proliferation in IDC luminal A cells where it deregulates 17β-estradiol (E2):ERα signaling to cell proliferation. Moreover, the GART inhibitor lometrexol (LMX) and drugs approved for clinical treatment of primary and metastatic BC (4OH-tamoxifen and the CDK4/CDK6 inhibitors) exert synergic antiproliferative effects in BC cells. In conclusion, GART inhibition by LMX or other inhibitors of the de novo purine biosynthetic pathway could be a novel effective strategy for the treatment of primary and metastatic BCs.PMID:37143728 | PMC:PMC10151738 | DOI:10.3389/fendo.2023.1129162

Front Microbiol. 2023 Apr 18;14:1180319. doi: 10.3389/fmicb.2023.1180319. eCollection 2023.ABSTRACTMycorrhizal helper bacteria (MHB) can promote mycorrhizal fungal colonization and form mycorrhizal symbiosis structures. To investigate the effect of interactions between mycorrhizal beneficial microorganisms on the growth of blueberry, 45 strains of bacteria isolated from the rhizosphere soil of Vaccinium uliginosum were screened for potential MHB strains using the dry-plate confrontation assay and the bacterial extracellular metabolite promotion method. The results showed that the growth rate of mycelium of Oidiodendron maius 143, an ericoid mycorrhizal fungal strain, was increased by 33.33 and 77.77% for bacterial strains L6 and LM3, respectively, compared with the control in the dry-plate confrontation assay. In addition, the extracellular metabolites of L6 and LM3 significantly promoted the growth of O. maius 143 mycelium with an average growth rate of 40.9 and 57.1%, respectively, the cell wall-degrading enzyme activities and genes of O. maius 143 was significantly increased. Therefore, L6 and LM3 were preliminarily identified as potential MHB strains. In addition, the co-inoculated treatments significantly increased blueberry growth; increased the nitrate reductase, glutamate dehydrogenase, glutamine synthetase, and glutamate synthase activities in the leaves; and promoted nutrient uptake in blueberry. Based on the physiological, and 16S rDNA gene molecular analyses, we initially identified strain L6 as Paenarthrobacter nicotinovorans and LM3 as Bacillus circulans. Metabolomic analysis revealed that mycelial exudates contain large amounts of sugars, organic acids and amino acids, which can be used as substrates to stimulate the growth of MHB. In conclusion, L6 and LM3 and O. maius 143 promote each other's growth, while co-inoculation of L6 and LM3 with O. maius 143 can promote the growth of blueberry seedlings, providing a theoretical basis for further studies on the mechanism of ericoid mycorrhizal fungi-MHB-blueberry interactions. It laid the technical foundation for the exploitation of biocontrol strain resources and the development of biological fertilizer.PMID:37143547 | PMC:PMC10151510 | DOI:10.3389/fmicb.2023.1180319

Front Microbiol. 2023 Apr 18;14:1160702. doi: 10.3389/fmicb.2023.1160702. eCollection 2023.ABSTRACTThe outbreak of Bacterial blight (BB) caused by Xanthomonas oryzae (Xoo) generates substantial economic losses to agricultural production. Antibiotics application is a valuable measure to control this bacterial disease. However, microbial antibiotic resistance dramatically reduced antibiotic effectiveness. Identifying the resistance mechanism of Xoo to antibiotics and restoring antibiotic susceptibility is one of the crucial ways to solve this problem. This study employed a GC-MS-based metabolomic approach to reveal the differential metabolomics between a kasugamycin-susceptible Xoo strain (Z173-S) and a kasugamycin-resistant strain (Z173-RKA). The metabolic mechanism of kasugamycin (KA) resistance in Xoo by GC-MS showed that the downregulation of the pyruvate cycle (P cycle) is a crucial feature of Z173-RKA resistance to KA. This conclusion was confirmed by the decreased enzyme activities and the related gene transcriptional level in the P cycle. Furfural (an inhibitor of pyruvate dehydrogenase) can effectively inhibit the P cycle and increase the resistance of Z173-RKA to KA. Moreover, exogenous alanine can reduce the resistance of Z173-RKA to KA by promoting the P cycle. Our work seems to be the first exploration of the mechanism of KA resistance in Xoo by GC-MS-based metabonomics approach. These results provide a new idea for developing metabolic regulation to address KA resistance in Xoo.PMID:37143533 | PMC:PMC10151481 | DOI:10.3389/fmicb.2023.1160702

Front Vet Sci. 2023 Apr 18;10:1170573. doi: 10.3389/fvets.2023.1170573. eCollection 2023.ABSTRACTFor the purpose to improve meat quality, pigs were fed a normal diet (ND), a low protein diet (LPD) and a LPD supplemented with glycine (LPDG). Chemical and metabolomic analyses showed that LPD increased IMF deposition and the activities of GPa and PK, but decreased glycogen content, the activities of CS and CcO, and the abundance of acetyl-CoA, tyrosine and its metabolites in muscle. LPDG promoted muscle fiber transition from type II to type I, increased the synthesis of multiple nonessential amino acids, and pantothenic acid in muscle, which should contributed to the improved meat quality and growth rate. This study provides some new insight into the mechanism of diet induced alteration of animal growth performance and meat quality. In addition, the study shows that dietary supplementation of glycine to LPD could be used to improved meat quality without impairment of animal growth.PMID:37143503 | PMC:PMC10153625 | DOI:10.3389/fvets.2023.1170573

Front Vet Sci. 2023 Apr 18;10:1153903. doi: 10.3389/fvets.2023.1153903. eCollection 2023.ABSTRACTINTRODUCTION: Allodynia, which can be induced by paclitaxel administration, is the presence of pain as a result of a stimulus that does not usually provoke pain. Many studies have investigated the analgesic efficacy of acupuncture, including laser acupuncture (LA) and electroacupuncture (EA). Although pain-related diseases are relatively common, few studies have analyzed the analgesic effects and mechanisms of LA combined with EA. The purpose of this study was to investigate the therapeutic effect and mechanism of manual acupuncture (MA), EA, LA, and combined therapy (LA + EA) in a paclitaxel-induced allodynia rat model.METHODS: A total of 56 rats were classified into eight groups: a normal (Nor, n = 7), a control (Con, n = 7), an MA (n = 7), an EA (n = 7), a 650-nm LA (650LA, n = 7), an 830-nm LA (830LA, n = 7), a 650-nm LA combined with EA (650LA + EA, n = 7), and an 830-nm LA combined with EA group (830LA + EA, n = 7). Allodynia was induced by intraperitoneal injection of 2 mg/kg of paclitaxel every other day for a total of four times except the Nor group. Acupuncture treatments were conducted at the points of Jungwan (CV12) and Joksamni (ST36) once every other day for 6 min, for a total of nine times. Withdrawal response reaction times and force intensity of the foot were measured before the start of the experiment, after the 4th paclitaxel administration (day 8), and after the 9th and last treatment (day 15). On the 16th day, mRNA and protein expression in the spinal nerves was assessed, and a metabolome analysis of the animals' feces was performed.RESULTS AND DISCUSSION: Our analyses show that 650LA + EA treatment resulted in an upregulation of protein expression related to pain relief and nerve regeneration, whereas 830LA + EA treatment led to significant changes in metabolomes. This study demonstrates that a combination treatment of EA and LA can suppress allodynia and promote upregulation of protein expression related to nerve regeneration and is effective in changing the intestinal microbiome. Further large-scale research is required to assess the exact mechanism underlying the therapeutic effect of this combination treatment in pain-related diseases.PMID:37143500 | PMC:PMC10151682 | DOI:10.3389/fvets.2023.1153903

J Intern Med. 2023 May 4. doi: 10.1111/joim.13648. Online ahead of print.ABSTRACTThe etiology of type 1 diabetes foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of type 1 diabetes. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden and the US) observational study, children were identified at birth for the type 1 diabetes high risk HLA haplogenotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8 and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to type 1 diabetes (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the aetiology of autoimmune type 1 diabetes. This article is protected by copyright. All rights reserved.PMID:37143363 | DOI:10.1111/joim.13648