PubMed

Sci Rep. 2023 Nov 20;13(1):20303. doi: 10.1038/s41598-023-46820-7.ABSTRACTEndothelial dysfunction is a critical initiating factor contributing to cardiovascular diseases, involving the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). This study aims to clarify the time-dependent molecular pathways by which TMAO mediates endothelial dysfunction through transcriptomics and metabolomics analyses in human microvascular endothelial cells (HMEC-1). Cell viability and reactive oxygen species (ROS) generation were also evaluated. TMAO treatment for either 24H or 48H induces reduced cell viability and enhanced oxidative stress. Interestingly, the molecular signatures were distinct between the two time-points. Specifically, few Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were modulated after a short (24H) compared to a long (48H) treatment. However, the KEGG signalling pathways namely "tumour necrosis factor (TNF)" and "cytokine-cytokine receptor interaction" were downregulated at 24H but activated at 48H. In addition, at 48H, BPs linked to inflammatory phenotypes were activated (confirming KEGG results), while BPs linked to extracellular matrix (ECM) structural organisation, endothelial cell proliferation, and collagen metabolism were repressed. Lastly, metabolic profiling showed that arachidonic acid, prostaglandins, and palmitic acid were enriched at 48H. This study demonstrates that TMAO induces distinct time-dependent molecular signatures involving inflammation and remodelling pathways, while pathways such as oxidative stress are also modulated, but in a non-time-dependent manner.PMID:37985702 | DOI:10.1038/s41598-023-46820-7

Sci Rep. 2023 Nov 20;13(1):20305. doi: 10.1038/s41598-023-46317-3.ABSTRACTOpiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with properly designed pharmacological profiles at the opioid receptor subtypes are long needed. Here a series of 17-N-substituted derivatives of normorphine and noroxymorphone analogues with five- and six-membered ring substituents have been synthesized for structure-activity study. Some compounds showed nanomolar affinity to MOR, DOR and KOR in in vitro competition binding experiments with selective agonists [3H]DAMGO, [3H]Ile5,6-deltorphin II and [3H]HS665, respectively. Pharmacological characterization of the compounds in G-protein signaling was determined by [35S]GTPγS binding assays. The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH substituent resulted in a shift in the pharmacological profiles in the agonist > partial agonist > antagonist direction compared to the parent compounds. A molecular docking-based in silico method was also applied to estimate the pharmacological profile of the compounds. Docking energies and the patterns of the interacting receptor atoms, obtained with experimentally determined active and inactive states of MOR, were used to explain the observed pharmacological features of the compounds.PMID:37985681 | DOI:10.1038/s41598-023-46317-3

Alzheimers Dement. 2023 Nov 20. doi: 10.1002/alz.13546. Online ahead of print.ABSTRACTINTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort.RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism.DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD.HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.PMID:37985399 | DOI:10.1002/alz.13546

J Sci Food Agric. 2023 Nov 20. doi: 10.1002/jsfa.13145. Online ahead of print.ABSTRACTBACKGROUND: Large yellow croaker is highly perishable during storage because of high protein and moisture contents, and the degradation of fish is mainly attributed to microbial growth and enzymes activities, so it is vital to find an efficiently storage method to delay the shelf life of large yellow croaker.METHODOLOGY: The effect of low voltage electrostatic field combined with partial freezing treatment on the physicochemical properties of myofibrillar protein (MP) and metabolomic analysis of large yellow croaker during preservation was investigated in this study. The samples in chilled storage (C), partial freezing storage (PF) and 6 KV/m electrostatic field partial freezing storage (LVEF-PF) were analyzed during 18 days.RESULTS: The results were that compared with C and PF groups, LVEF-PF delayed the oxidation of MP by inhibiting the formation of carbonyl groups content (2.25 nmol/mg pro), and maintaining higher sulfhydryl contents (29.73 nmol/mg pro). In addition, the FT-IR and fluorescence spectroscopy analysis manifested that the LVEF-PF treatment maintained the stability of protein structure by increasing the ratio of α-helix (19.88%) and reducing the ratio of random coils (17.83%). Scanning electron microscopy observed that compared with LVEF-PF group, there are more degeneration and aggregation of MP in C and PF group after 18 days storage. The results of untargeted metabolomic showed that 415 kinds of differential metabolites were identified after storage, and the level of differential metabolites were least between the samples treated with LVEF-PF stored at 9th day and the fresh samples. The main differentia metabolic pathways during storage were amino acid metabolism, lipid metabolism and the pathway of ABC transporters.CONCLUSION: Therefore, the LVEF-PF treatment could maintain the stability of myofibrillar protein in large yellow croaker during storage. These results evidenced a potential application of LVEF-PF method for aquatic products preservation. This article is protected by copyright. All rights reserved.PMID:37985177 | DOI:10.1002/jsfa.13145

Carbohydr Polym. 2024 Jan 15;324:121486. doi: 10.1016/j.carbpol.2023.121486. Epub 2023 Oct 14.ABSTRACTExisting prebiotics, such as fructo-oligosaccharides (FOSs), can be modified to enhance their functionality or introduce additional functionalities. This study aimed to investigate the fermentation characteristics and prebiotic potential of enzymatically synthesized butyryl-FOSs. The esters were successfully synthesized through the reaction of butyric acid and FOSs using both chemical and enzymatic methods, denoted as A-FOSs and B-FOSs, respectively, for comparative analysis. The esterification degree of each component in A-FOSs was significantly higher than that of B-FOSs. Subsequently, the obtained esters were characterized for their fermentation properties, degradation mode and potential prebiotic effects using an in vitro simulated colonic fermentation model. Enzymes of human gut microbiota were found to preferentially cleave the glycosidic bond to the unit without butyryl group and release the sugars for utilization. A significant increase in butyric acid levels was observed during fermentation after the supplementation of B-FOSs. The 16S rRNA gene sequencing, absolute quantification of microbiota, and selected probiotic strains culture showed that B-FOSs supplementation promoted the growth of beneficial bacteria while reducing harmful ones. These results suggest that B-FOSs hold promise as novel prebiotics, possessing dual functions of modulating gut microbiota and delivering butyric acid to the colon in a targeted manner, ultimately contributing to improved gut health.PMID:37985044 | DOI:10.1016/j.carbpol.2023.121486

Anal Chem. 2023 Nov 20. doi: 10.1021/acs.analchem.3c02797. Online ahead of print.ABSTRACTSpectral similarity networks, also known as molecular networks, are crucial in non-targeted metabolomics to aid identification of unknowns aiming to establish a potential structural relation between different metabolite features. However, too extensive differences in compound structures can lead to separate clusters, complicating annotation. To address this challenge, we developed an automated Annotation Propagation through multiple EXperimental Networks (APEX) workflow, which integrates spectral similarity networks with mass difference networks and homologous series. The incorporation of multiple network tools improved annotation quality, as evidenced by high matching rates of the molecular formula derived by SIRIUS. The selection of manual annotations as the Seed Nodes Set (SNS) significantly influenced APEX annotations, with a higher number of seed nodes enhancing the annotation process. We applied APEX to different Caenorhabditis elegans metabolomics data sets as a proof-of-principle for the effective and comprehensive annotation of glycerophospho N-acyl ethanolamides (GPNAEs) and their glyco-variants. Furthermore, we demonstrated the workflow's applicability to two other, well-described metabolite classes in C. elegans, specifically ascarosides and modular glycosides (MOGLs), using an additional publicly available data set. In summary, the APEX workflow presents a powerful approach for metabolite annotation and identification by leveraging multiple experimental networks. By refining the SNS selection and integrating diverse networks, APEX holds promise for comprehensive annotation in metabolomics research, enabling a deeper understanding of the metabolome.PMID:37984857 | DOI:10.1021/acs.analchem.3c02797

New Phytol. 2023 Nov 20. doi: 10.1111/nph.19415. Online ahead of print.ABSTRACTPlant-plant positive interactions are key drivers of community structure. Yet, the underlying molecular mechanisms of facilitation processes remain unexplored. We investigated the 'nursing' effect of Maihueniopsis camachoi, a cactus that thrives in the Atacama Desert between c. 2800 and 3800 m above sea level. We hypothesised that an important protective factor is thermal amelioration of less cold-tolerant species with a corresponding impact on molecular phenotypes. To test this hypothesis, we compared plant cover and temperatures within the cactus foliage with open areas and modelled the effect of temperatures on plant distribution. We combined eco-metabolomics and machine learning to test the molecular consequences of this association. Multiple species benefited from the interaction with M. camachoi. A conspicuous example was the extended distribution of Atriplex imbricata to colder elevations in association with M. camachoi (400 m higher as compared to plants in open areas). Metabolomics identified 93 biochemical markers predicting the interaction status of A. imbricata with 79% accuracy, independently of year. These findings place M. camachoi as a key species in Atacama plant communities, driving local biodiversity with an impact on molecular phenotypes of nursed species. Our results support the stress-gradient hypothesis and provide pioneer insights into the metabolic consequences of facilitation.PMID:37984856 | DOI:10.1111/nph.19415

Genomics. 2023 Nov 18:110748. doi: 10.1016/j.ygeno.2023.110748. Online ahead of print.ABSTRACTTo investigate the molecular impact of graft MaS on post-transplant prognosis, based on multi-omics integrative analysis. Rats were fed by methionine-choline deficient diet (MCD) for MaS grafts. Samples were collected from grafts by sequential biopsies. Transcriptomic and metabolomic profilings were assayed. Post-transplant MaS status showed a close association with graft failure. Differentially expressed genes (DEGs) for in-vivo MaS were mainly enriched on pathways of cell cycle and DNA replication. Post-transplant MaS caused arrests of graft regeneration via inhibiting the E2F1 centered network, which was confirmed by an in vitro experiment. Data from metabolomics assays found insufficient serine/creatine which is located on one‑carbon metabolism was responsible for MaS-related GF. Pre-transplant MaS caused severe fibrosis in long-term survivors. DEGs for grafts from long-term survivors with pre-transplant MaS were mainly enriched in pathways of ECM-receptor interaction and focal adhesion. Transcriptional regulatory network analysis confirmed SOX9 as a key transcription factor (TF) for MaS-related fibrosis. Metabolomic assays found elevation of aromatic amino acid (AAA) was a major feature of fibrosis in long-term survivors. Graft MaS in vivo increased post-transplant GF via negative regulations on graft regeneration. Pre-transplant MaS induced severe fibrosis in long-term survivors via activations on ECM-receptor interaction and AAA metabolism.PMID:37984718 | DOI:10.1016/j.ygeno.2023.110748

Sci Total Environ. 2023 Nov 18:168615. doi: 10.1016/j.scitotenv.2023.168615. Online ahead of print.ABSTRACTLead (Pb) soil contamination has caused serious ecological and environmental issues. Hydrangea macrophylla is a potential Pb-contaminated soil remediation plant, however, their Pb stress defense mechanism is largely unknown. Here, the physiology, transcriptomic and metabolome of two H. macrophylla cultivars (ML, Pb-sensitive cultivar; JC, Pb-resistant cultivar) under Pb stress were investigated. The results demonstrated that JC performed superiorly, with activities of the antioxidant enzymes superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were 1.25, 2.84, and 1.67 times higher than those of ML after Pb treatment, respectively, and the amount of soluble sugar in JC increased by 231.34 % compared with that in ML. The electrical conductivity (EC) value of the root exudates of JC was 43.71 % lower than that of ML under Pb stress. The non-targeted metabolomics analysis revealed 193 metabolites grouped into nine categories. Pb stress-induced differential expression of the 37 metabolites, among which the major metabolites up-regulated in ML were organic acids, while in JC, these were carbohydrates, fatty acids, organic acids and lipids. The transcriptomic analysis revealed that Pb exposure induced 1075 and 1314 differentially expressed genes (DEGs) in JC and ML, respectively. According to the functional annotation results, hub genes were primarily enriched in carbohydrate metabolism, root growth, and plant resistance to external stresses. A conjoint analysis of the two omics indicated that the cutin, suberine and wax biosynthesis pathway in JC played an essential role in Pb detoxification. These findings clarify the resistance mechanism of H. macrophylla to Pb stress and open up a new avenue for breeding H. macrophylla Pb-resistant cultivars.PMID:37984650 | DOI:10.1016/j.scitotenv.2023.168615

Clin Chim Acta. 2023 Nov 18:117671. doi: 10.1016/j.cca.2023.117671. Online ahead of print.ABSTRACTBACKGROUND: The 16p11.2 deletion is one of the most common genetic aetiologies of neurodevelopmental disorders (NDDs). The prenatal phenotype of 16p11.2 deletion and the potential mechanism associated with postnatal clinical manifestations were largely unknow. We revealed the developmental trajectories of 16p11.2 deletion from the prenatal to postnatal periods and to identify key signaling pathways and candidate genes contributing to neurodevelopmental abnormalities.METHODS: In this 5-y retrospective cohort study, women with singleton pregnancies who underwent amniocentesis for chromosomal abnormalities were included. Test of copy-number variations (CNVs) involved single nucleotide polymorphism-array and CNV-seq was performed to detected 16p11.2 deletion. For infants born carrying the 16p11.2 deletion, neurological and intellectual evaluations using the Chinese version of the Gesell Development Scale. For patients observed to have vertebral malformations, Sanger sequencing for T-C-A haplotype of TBX6 was performed. For those infants with clinical manifestations, whole-exome sequencing was consecutively performed in trios to rule out single-gene diseases, and transcriptomics combined with untargeted metabolomics were performed.RESULTS: The prevalence of 16p11.2 deletion was 0.063% (55/86,035) in the prenatal period. Up to 80% (20/25) of the 16p11.2 deletions were proven de novo by parental confirmation. Approximately half of 16p11.2 deletions (28/55) were detected with prenatal abnormal ultrasound findings. Vertebral malformations were identified as the most distinctive structural malformations and were enriched in fetuses with 16p11.2 deletions compared with controls (90.9‰ [5/55] vs. 8.4‰ [72/85,980]; P<0.001). All 5 fetuses with vertebral malformations were confirmed to have the TBX6 haplotype of T-C-A. Overall, 47.6% (10/21) infants birthed were diagnosed with NDDs of different degrees. Language impairment was the predominant manifestation (7/10; 70.0%), followed by motor delay (5/10; 50%). Multi-omics analysis indicated that MAPK3 was the central hub of the differentially expressed gene (DEG) network. We firstly reported that histidine-associated metabolism may be the core metabolic pathway related to the 16p11.2 deletion.CONCLUSION: We demonstrated the prenatal presentation, incomplete penetrance and variable expressivity of the 16p11.2 deletion. We identified vertebral malformations were the most distinctive prenatal phenotypes, and language impairment was the predominant postnatal manifestation. Most of the 16p11.2 deletion was de novo. Meanwhile, we suggested that MAPK3 and histidine-associated metabolism may contribute to neurodevelopmental abnormalities of 16p11.2 deletion.PMID:37984529 | DOI:10.1016/j.cca.2023.117671

BJOG. 2023 Nov 20. doi: 10.1111/1471-0528.17723. Online ahead of print.ABSTRACTOBJECTIVES: To identify and internally validate metabolites predictive of spontaneous preterm birth (sPTB) using multiple machine learning methods and sequential maternal serum samples, and to predict spontaneous early term birth (sETB) using these metabolites.DESIGN: Case-cohort design within a prospective cohort study.SETTING: Cambridge, UK.POPULATION OR SAMPLE: A total of 399 Pregnancy Outcome Prediction study participants, including 98 cases of sPTB.METHODS: An untargeted metabolomic analysis of maternal serum samples at 12, 20, 28 and 36 weeks of gestation was performed. We applied six supervised machine learning methods and a weighted Cox model to measurements at 28 weeks of gestation and sPTB, followed by feature selection. We used logistic regression with elastic net penalty, followed by best subset selection, to reduce the number of predictive metabolites further. We applied coefficients from the chosen models to measurements from different gestational ages to predict sPTB and sETB.MAIN OUTCOME MEASURES: sPTB and sETB.RESULTS: We identified 47 metabolites, mostly lipids, as important predictors of sPTB by two or more methods and 22 were identified by three or more methods. The best 4-predictor model had an optimism-corrected area under the receiver operating characteristics curve (AUC) of 0.703 at 28 weeks of gestation. The model also predicted sPTB in 12-week samples (0.606, 95% CI 0.544-0.667) and 20-week samples (0.657, 95% CI 0.597-0.717) and it predicted sETB in 36-week samples (0.727, 95% CI 0.606-0.849). A lysolipid, 1-palmitoleoyl-GPE (16:1)*, was the strongest predictor of sPTB at 12 weeks of gestation (0.609, 95% CI 0.548-0.670), 20 weeks (0.630, 95% CI 0.569-0.690) and 28 weeks (0.660, 95% CI 0.599-0.722), and of sETB at 36 weeks (0.739, 95% CI 0.618-0.860).CONCLUSIONS: We identified and internally validated maternal serum metabolites predictive of sPTB. A lysolipid, 1-palmitoleoyl-GPE (16:1)*, is a novel predictor of sPTB and sETB. Further validation in external populations is required.PMID:37984426 | DOI:10.1111/1471-0528.17723

Biomed Pharmacother. 2023 Nov 18;169:115895. doi: 10.1016/j.biopha.2023.115895. Online ahead of print.ABSTRACTDiabetic retinopathy (DR) is currently recognized as the leading cause of end-stage eye disease. Pipecolic acid, a metabolite, has a significant regulatory effect on several pathological processes. However, the exact mechanism by which it causes damage in diabetic retinopathy is unknown. Between September 2021 and December 2022, 40 patients were retrospectively examined and divided into two groups: the healthy group (n = 20) and the DR group (n = 20). Metabolomic analysis found that pipecolic acid plays an important role in this process. Streptozotocin-induced diabetic mice and high-glucose cultured human retinal capillary endothelial cells (HRCECs) were then treated with pipecolic acid. Several oxidative stress measurements and RNA sequencing of retinal cells were tested. A gene interaction study was conducted using bioinformatics. Comparison of serological metabolites between healthy volunteers and DR patients showed that pipecolic acid was significantly lower in DR patients, and there was a negative correlation between the level of pipecolic acid with blood glucose and glycated hemoglobin. Yes-associated protein (YAP) mRNA, Malondialdehyde (MDA), and reactive oxygen species (ROS) levels were significantly higher in diabetic mice, but glutathione peroxidase (GSH-Px) levels were significantly lower. Pipecolic acid significantly alleviated oxidative stress and YAP expression. The number of vascular tubes was significantly higher in the DR group, and pipecolic acid treatment significantly reduced tube formation. RNA-Sequencing analysis revealed that YAP and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) expression was reduced, and functional enrichment analysis revealed that ferroptosis and Hippo signaling pathways play an important role in this process. Additionally, pipecolic acid's ability to improve DR is diminished after YAP and GPX4 ablation. This study found that pipecolic acid, as a metabolite, may impede the progression of DR by inhibiting the YAP-GPX4 signaling pathway.PMID:37984309 | DOI:10.1016/j.biopha.2023.115895

Arch Med Res. 2023 Nov 18;55(1):102909. doi: 10.1016/j.arcmed.2023.102909. Online ahead of print.ABSTRACTBACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood.OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups.RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and β-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, β-alanine, and histidine) with potential to distinguish GH and HP.CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.PMID:37984232 | DOI:10.1016/j.arcmed.2023.102909

Phytomedicine. 2023 Nov 10;123:155160. doi: 10.1016/j.phymed.2023.155160. Online ahead of print.ABSTRACTBACKGROUND: Hypericum perforatum L. (HPL) is a potential traditional Chinese medicine. It could promotes menopausal 'kidney-yin deficiency syndrome' that characterized by renal function decline. However, its potential pharmacological effect and mechanism remains unknown.OBJECTIVE: The aim of this study was to investigate whether HPL can improve menopausal renal function decline and to explore its mechanism of action.METHODS: The mainly ingredients of HPL were identified using UPLC-Q-TOF-MS/MS approach, and the potential therapeutic targets of HPL for renal function decline were chose via network pharmacology technique. The key therapeutic metabolites were selected through non-targeted metabolomic and chemometric methods. Then, the network were constructed and the key targets and metabolites were screened. At last, the validation experiments and mechanism exploring were adopted by using Immunofluorescence, enzyme-linked immunosorbent assay (ELISA), real-time PCR (RT-PCR), and western blotting assays.RESULTS: mainly ingredients of HPL were identified and determined 17 compounds and 29 targets were chose as mainly active compounds and potential therapeutic targets. Based on OVX induced renal decline rat model, after chemometric analysis, 59 endo-metabolites were selected as key therapeutic metabolites, and AGE-RAGE signal pathway in diabetes complications was enriched as the key pathway. By constructing a "disease-component-target" network, Hyperoside, Quercetrin, and quinic were selected as the key therapeutic compounds, and the AKT1 and NOS3 were selected as the key therapeutic targets. The results of ELISA, RT-PCR and western blot experiments indicated that HPL could rescue the abnormal expressions both of AKT1 and NOS3, as well as their related metabolites distortion.CONCLUSION: Our findings indicated that HPL regulated expression of AKT1 and NOS3 through modulating AGE-RAGE signaling pathway in OVX stimulated rats` renal dysfunction, implicating the potential values of HPL in menopause syndromes therapy.PMID:37984122 | DOI:10.1016/j.phymed.2023.155160

Plant Physiol Biochem. 2023 Nov 11;205:108173. doi: 10.1016/j.plaphy.2023.108173. Online ahead of print.ABSTRACTArbuscular mycorrhizal (AM) symbiosis can strengthen plant defense against abiotic stress, such as drought, through multiple mechanisms; however, the specialized chemical defenses induced by AM symbiosis are largely unknown. In a pot experiment, licorice (Glycyrrhiza uralensis Fisch.) inoculated with and without arbuscular mycorrhizal fungus Rhizophagus irregularis Schenck & Smith were grown under well-watered or water deficit conditions. Transcriptomic and metabolomic analyses were combined to investigate licorice root specialized metabolism induced by AM symbiosis under drought stress. Results showed that mycorrhizal plants had few dead leaves, less biomass reduction, and less differentially expressed genes and metabolite features in response to drought compared with nonmycorrhizal plants. Transcriptomic and metabolomic data revealed that mycorrhizal roots generally accumulated lignin regardless of the water regime; however, the expression of genes involved in lignin biosynthesis was significantly downregulated by drought stress in mycorrhizal plants. By contrast, AM inoculation significantly decreased specialized metabolites accumulation, including phenolics and flavonoids under well-watered conditions, whereas these decreases turned to be nonsignificant under drought stress. Moreover, these specific phenolics and flavonoids showed significant drought-induced accumulation pattern in mycorrhizal roots. These results highlight that accumulation of specific root phenolics and flavonoids may support the drought tolerance of mycorrhizal plants.PMID:37984021 | DOI:10.1016/j.plaphy.2023.108173

Food Chem. 2023 Nov 17;438:138005. doi: 10.1016/j.foodchem.2023.138005. Online ahead of print.ABSTRACTLow temperatures significantly impact on rice (Oryza sativa) yield and quality. Traditional metabolomic techniques, often involving time-consuming chromatography-mass spectrometry procedures, are currently in use. This study investigated metabolomic responses of rice seedlings under low-temperature stress using nanoliter electrospray ionization mass spectrometry (nanoESI-MS) in combination with multivariate analysis. Results revealed distinct metabolic profiles in 'Qiutianxiaoting' (japonica) and '93-11' (indica) rice seedlings. Among the 36 identified compounds in rice, seven key metabolites, comprising l-glutamic acid, asparagine, tryptophan, citric acid, α-linolenic acid, malic acid, and inositol, were identified as responsive to cold stress. Notably, malic acid content reached 1332.40 μg/g dry weight in Qiutianxiaoting and 1444.13 μg/g in 93-11. Both the qualitative and quantitative results of nanoESI-MS were further confirmed through gas chromatography-mass spectrometry validation. The findings highlight the potential of nanoESI-MS for rapidly characterizing crucial metabolites across diverse plant species under exposure to stress.PMID:37983997 | DOI:10.1016/j.foodchem.2023.138005

Gigascience. 2022 Dec 28;12:giad089. doi: 10.1093/gigascience/giad089.ABSTRACTBACKGROUND: Biomedical research often involves contextual integration of multimodal and multiomic data in search of mechanisms for improved diagnosis, treatment, and monitoring. Researchers need to access information from diverse sources, comprising data in various and sometimes incongruent formats. The downstream processing of the data to decipher mechanisms by reconstructing networks and developing quantitative models warrants considerable effort.RESULTS: MetGENE is a knowledge-based, gene-centric data aggregator that hierarchically retrieves information about the gene(s), their related pathway(s), reaction(s), metabolite(s), and metabolomic studies from standard data repositories under one dashboard to enable ease of access through centralization of relevant information. We note that MetGENE focuses only on those genes that encode for proteins directly associated with metabolites. All other gene-metabolite associations are beyond the current scope of MetGENE. Further, the information can be contextualized by filtering by species, anatomy (tissue), and condition (disease or phenotype).CONCLUSIONS: MetGENE is an open-source tool that aggregates metabolite information for a given gene(s) and presents them in different computable formats (e.g., JSON) for further integration with other omics studies. MetGENE is available at https://bdcw.org/MetGENE/index.php.PMID:37983749 | DOI:10.1093/gigascience/giad089

ACS Synth Biol. 2023 Nov 20. doi: 10.1021/acssynbio.3c00403. Online ahead of print.ABSTRACTGlycolyl-CoA carboxylase (GCC) is a new-to-nature enzyme that catalyzes the key reaction in the tartronyl-CoA (TaCo) pathway, a synthetic photorespiration bypass that was recently designed to improve photosynthetic CO2 fixation. GCC was created from propionyl-CoA carboxylase (PCC) through five mutations. However, despite reaching activities of naturally evolved biotin-dependent carboxylases, the quintuple substitution variant GCC M5 still lags behind 4-fold in catalytic efficiency compared to its template PCC and suffers from futile ATP hydrolysis during CO2 fixation. To further improve upon GCC M5, we developed a machine learning-supported workflow that reduces screening efforts for identifying improved enzymes. Using this workflow, we present two novel GCC variants with 2-fold increased carboxylation rate and 60% reduced energy demand, respectively, which are able to address kinetic and thermodynamic limitations of the TaCo pathway. Our work highlights the potential of combining machine learning and directed evolution strategies to reduce screening efforts in enzyme engineering.PMID:37983631 | DOI:10.1021/acssynbio.3c00403

Plant Biol (Stuttg). 2023 Nov 20. doi: 10.1111/plb.13591. Online ahead of print.ABSTRACTThe stearoyl-ACP desaturase (SACPD) is a key enzyme in the regulation of saturated to unsaturated fatty acid ratio, playing a crucial role in regulating membrane stability and fluidity, as well as photosynthesis efficiency, which makes it an important research focus in crop species. This study reports the characterization and molecular cloning of pale dwarf (pad), a new tomato (Solanum lycopersicum L.) T-DNA recessive mutant, which exhibits a dwarf and chlorotic phenotype. Functional studies of the T-DNA tagged gene were conducted, including phylogenetic analysis, expression and metabolomic analyses, and generation of CRISPR/Cas9 knockout lines. The cloning of T-DNA flanking genomic sequences and a co-segregation analysis found the pad phenotype was caused by a T-DNA insertion disrupting the tomato homologue of the Arabidopsis SUPPRESSOR OF SALICYLIC ACID INSENSITIVITY 2 (SlSSI2), encoding a plastid localized isoform of SACPD. The phenotype of CRISPR/Cas9 SlSSI2 knockout lines confirmed that the morphological abnormalities in pad plants were due to SlSSI2 loss of function. Functional, metabolomic and expression analyses proved that SlSSI2 disruption causes deficiencies in 18:1 fatty acid desaturation and leads to diminished jasmonic acid (JA) content and increased salicylic acid (SA) levels. Overall, these results proved that SSI2 plays a crucial role in the regulation of polyunsaturated fatty acid profiles in tomato, and revealed that SlSSI2 loss of function results in an inhibited JA-responsive signalling pathway and a constitutively activated SA-mediated defence signalling response. This study lays the foundation for further research on tomato SACPDs and their role in plant performance and fitness.PMID:37983594 | DOI:10.1111/plb.13591

J Proteome Res. 2023 Nov 20. doi: 10.1021/acs.jproteome.3c00212. Online ahead of print.ABSTRACTMutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRASG12D mutant proteins, which is one of the main drivers of pancreatic cancer. To better understand the mechanism of action of this compound, I performed both proteomics and metabolomics on four KRASG12D mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single-cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1498 single cells were analyzed. From these cells, 3140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.PMID:37983312 | DOI:10.1021/acs.jproteome.3c00212